Direct palladium-catalyzed aromatic fluorination
11179710 · 2021-11-23
Assignee
- President And Fellows Of Harvard College (Cambridge, MA)
- STUDIENGESELLSCHAFT KOHLE MBH (Mülheim an der Ruhr, DE)
Inventors
Cpc classification
B01J2531/025
PERFORMING OPERATIONS; TRANSPORTING
B01J2231/4277
PERFORMING OPERATIONS; TRANSPORTING
B01J31/183
PERFORMING OPERATIONS; TRANSPORTING
International classification
B01J31/18
PERFORMING OPERATIONS; TRANSPORTING
Abstract
Provided herein are palladium complexes comprising a ligand of Formula (A′) and a ligand of Formula (B), wherein R.sup.1-R.sup.18 are as defined herein. The palladium complexes are useful in methods of fluorinating aryl and heteroaryl substrates. Further provided are compositions and kits comprising the palladium complexes. ##STR00001##
Claims
1. A palladium complex that comprises a moiety, wherein the moiety is represented by: ##STR00110## wherein: R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are independently selected from the group consisting of hydrogen, halogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR, —N(R).sub.2, —SR, —CN, —SCN, —C(═NR)R, —C(═NR)OR, —C(═NR)N(R).sub.2, —C(═O)R, —C(═O)OR, —C(═O)N(R).sub.2, —NO.sub.2, —NRC(═O)R, —NRC(═O)OR, —NRC(═O)N(R).sub.2, —OC(═O)R, —OC(═O)OR, —OC(═O)N(R).sub.2, —SO.sub.3H, and —NR.sub.3.sup.+Y′, wherein Y′ is an anionic counterion; R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 are independently selected from the group consisting of hydrogen, halogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR, —N(R).sub.2, —SR, —CN, —SCN, —C(═NR)R, —C(═NR)OR, —C(═NR)N(R).sub.2, —C(═O)R, —C(═O)OR, —C(═O)N(R).sub.2, —NO.sub.2, —NRC(═O)R, —NRC(═O)OR, —NRC(═O)N(R).sub.2, —OC(═O)R, —OC(═O)OR, —OC(═O)N(R).sub.2, —SO.sub.3H, and —NR.sub.3.sup.+Y′, wherein Y′ is an anionic counterion; and each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R attached to the same nitrogen atom are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
2. The palladium complex of claim 1, wherein the palladium complex is of Formula (C): ##STR00111## wherein Y is an anionic counterion, alkenyl, or alkynyl.
3. The palladium complex of claim 2, wherein Y is an anionic counterion.
4. The palladium complex of claim 2, wherein Y is BF.sub.4.sup.− or OTf.sup.−.
5. The palladium complex of claim 1, wherein each of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 is hydrogen.
6. The palladium complex of claim 1, wherein R.sup.8 is halogen, —COR, —COOR —CN, —SO.sub.3H, —NO.sub.2, haloalkyl, or —NR.sub.3.sup.+Y′.
7. The palladium complex of claim 1, wherein R.sup.8 is halogen.
8. The palladium complex of claim 1, wherein R.sup.8 is chloro.
9. The palladium complex of claim 1, wherein each of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 is hydrogen, and R.sup.8 is halogen.
10. The palladium complex of claim 1, wherein each of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 is hydrogen.
11. The palladium complex of claim 1, wherein each of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 is hydrogen; each of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 is hydrogen; and R.sup.8 is hydrogen, halogen, —COR, —COOR, —CN, —SO.sub.3H, —NO.sub.2, haloalkyl, or —NR.sub.3.sup.+Y′.
12. The palladium complex of claim 1, wherein the palladium complex is of Formula (C-1): ##STR00112## wherein R.sup.8 is halogen, and Y is BF.sub.4.sup.− or OTf.sup.−.
13. The palladium complex of claim 1, wherein the palladium complex is of the formula: ##STR00113##
14. A composition comprising a palladium complex of claim 1.
15. A kit comprising a palladium complex of claim 1.
16. The kit of claim 15 further comprising a compound of Formula (D), (E), or (F): ##STR00114## wherein: each of W.sub.1, W.sub.2, W.sub.3, W.sub.4, and W.sub.5 is independently CH, CR.sup.A, or N, provided that at least one of W.sub.1, W.sub.2, W.sub.3, W.sub.4, and W.sub.5 is N; each of W.sub.6, W.sub.7, W.sub.8, and W.sub.9 is CH, CR.sup.A, N, NH, NR.sup.A, O, or S, provided that at least one of W.sub.6, W.sub.7, W.sub.8, and W.sub.9 is N, NH, NR.sup.A, O, or S; each instance of R.sup.A is independently halogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.A1, —N(R.sup.A1).sub.2, —SR.sup.A1, —CN, —SCN, —C(═NR.sup.A1)R.sup.A1, —C(═NR.sup.A1)OR.sup.A1, —C(═NR.sup.A1)N(R.sup.A1).sub.2, —C(═O)R.sup.A1, —C(═O)OR.sup.A1, —C(═O)N(R.sup.A1).sub.2, —NO.sub.2, —NR.sup.A1C(═O)R.sup.A1, —NR.sup.A1C(═O)OR.sup.A1, —NR.sup.A1C(═O)N(R.sup.A1).sub.2, —OC(═O)R.sup.A1, —OC(═O)OR.sup.A1, or —OC(═O)N(R.sup.A1).sub.2, or two vicinal R.sup.A groups are joined to form a substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ring; each instance of R.sup.A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.A1 attached to the same nitrogen atom are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and k is 0, 1, 2, 3, 4, or 5.
17. The kit of claim 15 further comprising a fluorinating agent.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)
(12)
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
(13) Described herein is a palladium-catalyzed process for the preparation of aryl and heteroaryl fluorides, such as compounds of Formula (I), (II), and (III), from aryl and heteroaryl substrates, such as compounds of Formula (D), (E), and (F):
(14) ##STR00002##
wherein:
(15) W.sub.1, W.sub.2, W.sub.3, W.sub.4, and W.sub.5 is CH, CR.sup.A, or N, provided at least one of W.sub.1, W.sub.2, W.sub.3, W.sub.4, and W.sub.5 is N;
(16) W.sub.6, W.sub.7, W.sub.8, and W.sub.9 is CH, CR.sup.A, N, NH, NR.sup.A, O, or S, provided at least one of W.sub.6, W.sub.7, W.sub.8, and W.sub.9 is N, NH, NR.sup.A, O, or S;
(17) each instance of R.sup.A is independently halogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.A1, —N(R.sup.A1).sub.2, —SR.sup.A1, —CN, —SCN, —C(═NR.sup.A1)R.sup.A1, —C(═NR.sup.A1)OR.sup.A1, —C(═NR.sup.A1)N(R.sup.A1).sub.2, —C(═O)R.sup.A1, —C(═O)OR.sup.A1, —C(═O)N(R.sup.A1).sub.2, —NO.sub.2, —NR.sup.A1C(═O)R.sup.A1, —NR.sup.A1C(═O)OR.sup.A1, —NR.sup.A1C(═O)N(R.sup.A1).sub.2, —OC(═O)R.sup.A1, —OC(═O)OR.sup.A1, or —OC(═O)N(R.sup.A1).sub.2, or two vicinal R.sup.A groups (groups attached to two adjacent carbon atoms) are joined to form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ring;
(18) each instance of R.sup.A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.A1 attached the same nitrogen atom are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; and
(19) k is 0, 1, 2, 3, 4, or 5.
(20) In one aspect, provided herein is a method of preparing a compound of Formula (I), (II), or (III), comprising contacting an aryl substrate of Formula (D), or a heteroaryl substrate of Formula (E) or (F), with a palladium complex, wherein the palladium complex comprises a bidentate ligand of Formula (B) and a tridentate ligand of Formula (A′):
(21) ##STR00003##
wherein R.sup.1 to R.sup.18 are described herein.
(22) In certain embodiments, the method further comprises a fluorinating agent as described herein. Also provided herein is a palladium complex comprising a ligand of Formula (B) and a ligand of Formula (A′) and compositions thereof. In certain embodiments, the palladium of the complex is palladium (II). In certain embodiments, the palladium of the complex is palladium (III). In certain embodiments, the palladium complex further comprises a fluoro (F) ligand. In certain embodiments, the palladium complex comprises palladium (III) and a fluoro (F) ligand.
(23) In one aspect, provided herein is a method of preparing a compound of Formula (I) comprising:
(24) contacting a palladium(II) complex of formula (A) with a phenanthroline ligand of formula (B) to form a palladium(II) catalyst of formula (C); and
(25) contacting an aryl substrate of Formula (D), or a heteroaryl substrate of formula (E) or (F), with a fluorinating agent in the presence of the palladium (II) catalyst of Formula (C) to provide the compound of Formula (I), (II), or (III).
(26) Formula A, B, and C are as follows:
(27) ##STR00004##
wherein:
(28) each instance of R.sup.A is independently halogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.A1, —N(R.sup.A1).sub.2, —SR.sup.A1, —CN, —SCN, —C(═NR.sup.A1)R.sup.A1, —C(═NR A)OR.sup.A1, —C(═NR.sup.A1)N(R.sup.A1).sub.2, —C(═O)R.sup.A1, —C(═O)OR.sup.A1, —C(═O)N(R.sup.A1).sub.2, —NO.sub.2, —NR.sup.A1C(═O)R.sup.A1, —NR.sup.A1C(═O)OR.sup.A1, —NR.sup.A1C(═O)N(R.sup.A1).sub.2, —OC(═O)R.sup.A1, —OC(═O)OR.sup.A1, or —OC(═O)N(R.sup.A1).sub.2, or two vicinal R.sup.A groups (groups attached to two adjacent carbon atoms) are joined to form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ring;
(29) each instance of R.sup.A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.A1 attached the same nitrogen atom are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
(30) k is 0, 1, 2, 3, 4, or 5;
(31) Y is an anionic counterion or Y is an alkenyl or alkynyl moiety;
(32) L is an uncharged, monodentate ligand selected from the group consisting of carbon monoxide, an isonitrile (e.g., tert-butylisonitrile, cyclohexylisonitrile, adamantylisonitrile), an acetonitrile (e.g., —NCMe), an amine (e.g., trimethylamine, trirnethylamine), morpholine, phosphines (e.g., trifluorophosphine), aliphatic, aromatic or heteroaromatic phosphines (e.g, trimethylphoshine, tricyclohexylphosphine, dicyclohexylphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine, tri-phenylphosphine, tris(pentafluorophenyl)phosphine), phosphites (e.g., trimethyl phosphite, triethyl phosphite), arsines (e.g., trifluoroarsine, trimethylarsine, tricyclohexylarsine, tri-tert-butylarsine, triphenylarsine, tris(pentafluorophenyl)-arsine), stibines (e.g., trifluorostibine, trimethylstibine, tricyclohexylstibine, tri-tert-butylstibine, triphenylstibine, tris(pentafluoro-phenyl)stibine, or a nitrogen-containing heterocycle (e.g., pyridine, pyridazine, pyrazine, triazine);
(33) R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are independently selected from the group consisting of hydrogen, halogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR, —N(R).sub.2, —SR, —CN, —SCN, —C(═NR)R, —C(═NR)OR, —C(═NR)N(R).sub.2, —C(═O)R, —C(═O)OR, —C(═O)N(R).sub.2, —NO.sub.2, —NRC(═O)R, —NRC(═O)OR, —NRC(═O)N(R).sub.2, —OC(═O)R, —OC(═O)OR, —OC(═O)N(R).sub.2, —SO.sub.3H, and —NR.sub.3.sup.+Y′ wherein Y′ is an anionic counterion;
(34) each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R attached the same nitrogen atom are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
(35) R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 are independently selected from the group consisting of hydrogen, halogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR, —N(R).sub.2, —SR, —CN, —SCN, —C(═NR)R, —C(═NR)OR, —C(═NR)N(R).sub.2, —C(═O)R, —C(═O)OR, —C(═O)N(R).sub.2, —NO.sub.2, —NRC(═O)R, —NRC(═O)OR, —NRC(═O)N(R).sub.2, —OC(═O)R, —OC(═O)OR, —OC(═O)N(R).sub.2, —SO.sub.3H, and —NR.sub.3.sup.+Y′ wherein Y′ is an anionic counterion.
(36) In another aspect, the method of preparing a compound of Formula (I), (II), or (II), comprises contacting an aryl substrate of Formula (D), or a heteroaryl substrate of Formula (E) or (F), with a fluorinating agent in the presence of a palladium (II) catalyst of Formula (C) to provide the compound of Formula (I), (II), or (III).
(37) In certain embodiments, the fluorination method is performed at a temperature ranging from about 0-10° C., 10-20° C., 20-30° C., 30-40° C., or 40-50° C., 60-70° C., or 70-80° C.
(38) Provided herein is a palladium catalyst of Formula (C) and compositions thereof.
(39) As shown below by the black arrows (structures herein are not drawn to scale), the three nitrogens of the terpyridine derived ligand and one nitrogen of the phenanthroline derived ligand form a Pd complex of square planar geometry. The other nitrogen of the phenanthroline derived ligand has an antibonding interaction with the dz2-based orbital on palladium. This interaction likely facilitates oxidation to a high valent palladium complex such as a palladium(III) complex of Formula (G) with an octahedral geometry (or distorted octahedral due to Jahn Teller distortion) because in the high valent state of Pd, the interaction from Pd to the nitrogen becomes bonding.
(40) ##STR00005##
(41) In certain embodiments of Formula (C), R.sup.9 to R.sup.18 are hydrogen; R.sup.1 to R.sup.7 are hydrogen; and R.sup.8 is hydrogen, halogen, —COR, —COOR —CN, —SO.sub.3H, —NO.sub.2, haloalkyl, or —NR.sub.3.sup.+Y′ In certain embodiments, R.sup.9 to R.sup.18 are hydrogen; R.sup.1 to R.sup.7 are hydrogen; and R.sup.8 is halogen. In certain embodiments of Formula (C), R.sup.8 is halogen. In certain embodiments, R.sup.8 is Br or Cl. In certain embodiments, R.sup.8 is Cl.
(42) In certain embodiments, the compound of formula (C) is a compound of formula (C-1):
(43) ##STR00006##
wherein R.sup.8 is halogen and Y is BF.sub.4.sup.− or OTf.sup.−. In certain embodiments of C-1, R.sup.8 is Cl and Y is BF.sub.4.sup.−.
(44) In certain embodiments, the palladium catalyst of Formula (C) is formed in situ. For example, Pd(OAc).sub.2 is reacted with terpyridine or a derivative thereof in an appropriate solvent, such as acetonitrile (MeCN), in the presence of a reagent, such as HBF.sub.4.OEt.sub.2. Other solvents are known in the art and include, but not limited to, MeCN, acetone, acetic anhydride (Ac.sub.2O), propylene carbonate, chloroform, diglyme, dimethoxyethane (DME), tetrahydrofuan (THF), butanone, and tert-butyl methyl ether (TBME). In certain embodiments, the palladium catalyst is prepared prior to the fluorination reaction. For example, a commercially available palladium source such as Pd(MeCN).sub.4(BF.sub.4).sub.2 and ligands (e.g., terpyrdine or derivatives thereof, such as those of Formula A′, and/or phenanthroline or derivatives thereof, such as those of Formula B) can be used to prepare the palladium catalyst of Formula (C).
(45) Without wishing to be bound by theory, the catalytic cycle for direct C—H fluorination using the palladium complexes described herein is thought to involve a Pd(III)-F complex of Formula (G). Therefore, provided herein is a palladium catalyst of Formula (G):
(46) ##STR00007##
wherein R.sup.1 to R.sup.18 and Y are as described herein. The various general and specific embodiments described for Formula C are applicable to Formula E.
(47) In certain embodiments, the compound of Formula E is a compound of Formula G-1:
(48) ##STR00008##
wherein R.sup.8 is halogen and Y is BF.sub.4.sup.− or OTf.sup.−. In certain embodiments of Formula E-1, R.sup.8 is Cl and Y is BF.sub.4.sup.−.
(49) The proposed mechanism of aryl or heteroaryl fluorination is exemplified by the mechanism depicted in
(50) Variables R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8
(51) As generally defined herein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are independently selected from the group consisting of hydrogen, halogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR, —N(R).sub.2, —SR, —CN, —SCN, —C(═NR)R, —C(═NR)OR, —C(═NR)N(R).sub.2, —C(═O)R, —C(═O)OR, —C(═O)N(R).sub.2, —NO.sub.2, —NRC(═O)R, —NRC(═O)OR, —NRC(═O)N(R).sub.2, —OC(═O)R, —OC(═O)OR, —OC(═O)N(R).sub.2, —SO.sub.3H, and —NR.sub.3.sup.+Y′ wherein Y′ is an anionic counterion, and wherein each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R attached the same nitrogen atom are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
(52) In certain embodiments, the phenanthroline ligand of Formula B is electron deficient. For example, in certain embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are independently selected from the group consisting of hydrogen, halogen, —COR, —COOR —CN, —SO.sub.3H, —NO.sub.2, haloalkyl, or —NR.sub.3.sup.+Y′, wherein each instance of R is independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are hydrogen. In certain embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 are hydrogen and R.sup.8 is halogen, —COR, —COOR —CN, —SO.sub.3H, —NO.sub.2, haloalkyl, or —NR.sub.3.sup.+Y′, wherein each instance of R is independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R.sup.8 is halogen. In certain embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.8 are hydrogen and R.sup.7 is halogen, —COR, —COOR —CN, —SO.sub.3H, —NO.sub.2, haloalkyl, or —NR.sub.3+Y′, wherein each instance of R is independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R.sup.7 is halogen. In certain embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.7, and R.sup.8 are hydrogen and R.sup.6 is halogen, —COR, —COOR —CN, —SO.sub.3H, —NO.sub.2, haloalkyl, or —NR.sub.3.sup.+Y′, wherein each instance of R is independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R.sup.6 is halogen. In certain embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, and R.sup.8 are hydrogen and R.sup.5 is halogen, —COR, —COOR —CN, —SO.sub.3H, —NO.sub.2, haloalkyl, or —NR.sub.3.sup.+Y′, wherein each instance of R is independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R.sup.5 is halogen. In certain embodiments, R.sup.1, R.sup.2, R.sup.3, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are hydrogen and R.sup.4 is halogen, —COR, —COOR —CN, —SO.sub.3H, —NO.sub.2, haloalkyl, or —NR.sub.3.sup.+Y′, wherein each instance of R is independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R.sup.4 is halogen. In certain embodiments, R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are hydrogen and R.sup.3 is halogen, —COR, —COOR —CN, —SO.sub.3H, —NO.sub.2, haloalkyl, or —NR.sub.3.sup.+Y′, wherein each instance of R is independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R.sup.3 is halogen. In certain embodiments, R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are hydrogen and R.sup.2 is halogen, —COR, —COOR —CN, —SO.sub.3H, —NO.sub.2, haloalkyl, or —NR.sub.3.sup.+Y′, wherein each instance of R is independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R.sup.2 is halogen. In certain embodiments, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are hydrogen and R.sup.1 is halogen, —COR, —COOR —CN, —SO.sub.3H, —NO.sub.2, haloalkyl, or —NR.sub.3.sup.+Y′, wherein each instance of R is independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R.sup.1 is halogen.
(53) In certain embodiments, two of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are each independently halogen, —COR, —COOR —CN, —SO.sub.3H, —NO.sub.2, haloalkyl, or —NR.sub.3.sup.+Y′, wherein each instance of R is independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, three of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are each independently halogen, —COR, —COOR —CN, —SO.sub.3H, —NO.sub.2, haloalkyl, or —NR.sub.3.sup.+Y′, wherein each instance of R is independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, four of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are each independently halogen, —COR, —COOR —CN, —SO.sub.3H, —NO.sub.2, haloalkyl, or —NR.sub.3.sup.+Y′, wherein each instance of R is independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, five of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are each independently halogen, —COR, —COOR —CN, —SO.sub.3H, —NO.sub.2, haloalkyl, or —NR.sub.3.sup.+Y′, wherein each instance of R is independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, six of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are each independently halogen, —COR, —COOR —CN, —SO.sub.3H, —NO.sub.2, haloalkyl, or —NR.sub.3.sup.+Y′, wherein each instance of R is independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, seven of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are each independently halogen, —COR, —COOR —CN, —SO.sub.3H, —NO.sub.2, haloalkyl, or —NR.sub.3.sup.+Y′, wherein each instance of R is independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, all of R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 are each independently halogen, —COR, —COOR —CN, —SO.sub.3H, —NO.sub.2, haloalkyl, or —NR.sub.3.sup.+Y′, wherein each instance of R is independently hydrogen or substituted or unsubstituted alkyl.
(54) Variables R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, R.sup.18
(55) As generally defined herein, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 are independently selected from the group consisting of hydrogen, halogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR, —N(R).sub.2, —SR, —CN, —SCN, —C(═NR)R, —C(═NR)OR, —C(═NR)N(R).sub.2, —C(═O)R, —C(═O)OR, —C(═O)N(R).sub.2, —NO.sub.2, —NRC(═O)R, —NRC(═O)OR, —NRC(═O)N(R).sub.2, —OC(═O)R, —OC(═O)OR, —OC(═O)N(R).sub.2, —SO.sub.3H, and —NR.sub.3.sup.+Y′ wherein Y′ is an anionic counterion, wherein each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R attached the same nitrogen atom are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
(56) In certain embodiments, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 are hydrogen and R.sup.9 is selected from the foregoing non-hydrogen groups. In certain embodiments, R.sup.9, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 are hydrogen and R.sup.10 is selected from the foregoing non-hydrogen groups. In certain embodiments, R.sup.9, R.sup.10, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 are hydrogen and R.sup.11 is selected from the foregoing non-hydrogen groups. In certain embodiments, R.sup.9, R.sup.10, R.sup.11, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 are hydrogen and R.sup.12 is selected from the foregoing non-hydrogen groups. In certain embodiments, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 are hydrogen and R.sup.13 is selected from the foregoing non-hydrogen groups. In certain embodiments, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 are hydrogen and R.sup.14 is selected from the foregoing non-hydrogen groups. In certain embodiments, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.16, R.sup.17, and R.sup.18 are hydrogen and R.sup.15 is selected from the foregoing non-hydrogen groups. In certain embodiments, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.17, and R.sup.18 are hydrogen and R.sup.16 is selected from the foregoing non-hydrogen groups. In certain embodiments, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, and R.sup.18 are hydrogen and R.sup.17 is selected from the foregoing non-hydrogen groups. In certain embodiments, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, and R.sup.17 are hydrogen and R.sup.18 is selected from the foregoing non-hydrogen groups.
(57) In certain embodiments, two of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 are independently selected from the foregoing non-hydrogen groups. In certain embodiments, three of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 are independently selected from the foregoing non-hydrogen groups. In certain embodiments, four of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 are independently selected from the foregoing non-hydrogen groups. In certain embodiments, five of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 are independently selected from the foregoing non-hydrogen groups.
(58) In certain embodiments, R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 are hydrogen. In certain embodiments, one of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.8 is halogen. In certain embodiments, one of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 is acyl. In certain embodiments, one of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 is substituted or unsubstituted alkyl. In certain embodiments, one of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 is substituted or unsubstituted alkenyl. In certain embodiments, one of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 is substituted or unsubstituted alkynyl. In certain embodiments, one of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 is substituted or unsubstituted carbocyclyl. In certain embodiments, one of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 is substituted or unsubstituted heterocyclyl. In certain embodiments, one of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 is substituted or unsubstituted aryl. In certain embodiments, one of R.sup.9, R.sup.10, R.sup.11, R.sup.12, R.sup.13, R.sup.14, R.sup.15, R.sup.16, R.sup.17, and R.sup.18 is substituted or unsubstituted heteroaryl.
(59) Variable Y
(60) Palladium complexes of Formula (C) and (E) are typically electrically neutral compounds and include two anionic counterions Y to counterbalance the positive charge on the palladium compounds. In certain embodiments, Y is a non-coordinating anionic counterion or Y is a non-coordinating alkenyl or alkynyl moiety. In certain embodiments, Y is a monovalent anionic counterion. In certain embodiments, Y is ClO.sub.4.sup.−, OTf.sup.−, BF.sub.4.sup.−, PF.sub.4.sup.−, PF.sub.6.sup.−, or SbF.sub.6.sup.−. In certain embodiments, Y is BF.sub.4.sup.− or OTf.sup.−. In certain embodiments, Y is BF.sub.4.sup.−. In certain embodiments, Y is OTf.sup.−. In certain embodiments. Y is B[3,5-(CF.sub.3).sub.2C.sub.6H.sub.3].sub.4].sup.−, BPh.sub.4.sup.−, Al(OC(CF.sub.3).sub.3).sub.4.sup.−, or a carborane anion (e.g., CB.sub.11H.sub.12.sup.− or (HCB.sub.11Me.sub.5Br.sub.6).sup.−). In certain embodiments, Y is a non-coordinating alkenyl or alkynyl moiety. In certain embodiments, Y is substituted or unsubstituted acetylene. In certain embodiments, Y is substituted or unsubstituted ethylene.
(61) Fluorinating Agents
(62) A variety of fluorinating agents can be used in the methods described herein. In certain embodiments, the fluorinating agent is an N-fluorinated amine or N-fluorinated quaternary amine salt. In certain embodiments, the fluorinating agent is 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (F-TEDA-BF.sub.4/Selectfluor®). In certain embodiments, the fluorinating agent is N-fluorobenzenesulfonimide (NFBS). In certain embodiments, the fluorinating agent is 1-fluoro-4-methyl-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), N-fluoro-N′-methyl-triethylenediamine bis(tetrafluoroborate), N-fluoro-o-benzenedisulfonimide (NFOBS), N-fluorobenzenesulfonimide (NFSI or NFBS), 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2,2,2]octane bis(tetrafluoroborate) (NFTh), N-fluoropyridinium pyridine heptafluorodiborate (NFPy), N-fluoropyridinium trifluoromethanesulfonate, N-fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate, N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, or 2,6-dichloro-1-fluoropyridinium trifluoromethanesulfonate. In certain embodiments, the fluorinating agent is F-TEDA-BF4 or NFBS.
(63) In certain embodiments, the fluorinating agent comprises a fluorine isotope. A compound of Formula (I), (II), or (III) may be enriched with a particular isotope of fluorine, such as .sup.18F. e.g. e.g. .sup.18F-fluorinated organic compounds are particularly useful for imaging technology, such as positron-emission tomography (PET) imaging. PET is a noninvasive imaging technology that is currently used in the clinic to image cancers and neurological disorders at an early stage of illness. PET tracers are molecules which incorporate a PET-active nucleus and can therefore be visualized by their positron emission in the body. The fluorine isotope .sup.18F is the most common nucleus for PET imaging because of its superior properties to other nuclei. The .sup.18F isotope is radioactive and has a half-life of about 109.77 minutes. The short half-life dictates restrictions on chemical synthesis of PET tracers, because introduction of the fluorine atom has to take place at a very late stage of the synthesis to avoid the unproductive decay of .sup.18F before it is injected into the body. Fluoride ion is the most common reagent to introduce .sup.18F but the specific chemical properties of the fluoride ion currently limit the available pool of PET tracers. Due to the narrow functional group compatibility of the strongly basic fluoride ion, only a limited set of chemical reactions can be employed for fluorination, and hence the synthesis of PET tracers is limited to fairly simple molecules. The field of PET imaging would benefit from the availability of a new method that is capable of introducing radiolabeled fluoride into structurally more complex organic molecules. An easy access to drug-based PET tracers would simplify determining the fate of such drugs in the body and thereby help to identify and understand their mode of action, bioavailability, and time-dependent biodistribution.
(64) The described methods are useful in preparing aryl and heteroaryl compounds labeled with .sup.18F. In certain embodiments, one or more fluorine atoms of a compound of Formula (I), (II), or (III) are enriched with .sup.18F, e.g., for example, the compound of Formula (I), (II), or (III) encompass compounds of Formula (I*), (II*), or (III*):
(65) ##STR00009##
wherein the fluorine atom marked with an asterix (*) is enriched with .sup.18F.
(66) In certain embodiments, the compound of Formula (I*), (II*), or (III*) is at least 0.01%, at least 0.03%, at least 0.1%, at least 0.3%, or at least 1% mole:mole enriched with .sup.18F, or the specific activity of the fluorine in a compound of Formula (I*), (II*), or (III*) is at least 0.01, at least 0.03, at least 0.1, at least 0.3, at least 1, at least 3, or at least 10 Ci/μmol. An aryl substrate (e.g., a compound of Formula (D)) or heteroaryl substrated (e.g., a compound of Formula (E) or (F)) may be labeled with .sup.18F using a fluorinating agent that is enriched with .sup.18F. In certain embodiments, the fluorinating agent is enriched with .sup.18F, e.g., at least 0.01%, at least 0.03%, at least 0.1%, at least 0.3%, or at least 1% mole:mole of the fluorine in a fluorinating agent is .sup.18F, or the specific activity of the fluorine in a compound of Formula (I*), (II*), or (III*) is at least 0.01, at least 0.03, at least 0.1, at least 0.3, at least 1, at least 3, or at least 10 Ci/μmol. In certain embodiments, the fluorinating agent is an N-*fluorinated amine or N-*fluorinated quaternary amine salt, wherein the fluorine atom marked with an asterix (*) is enriched with .sup.18F. In certain embodiments, the fluorinating agent is 1-(chloromethyl)-4-*fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), wherein the fluorine atom marked with * is enriched with .sup.18F. In certain embodiments, the fluorinating agent is 1-*fluoro-4-methyl-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), N-*fluoro-N′-methyl-triethylenediamine bis(tetrafluoroborate), N-*fluoro-o-benzenedisulfonimide, N-*fluorobenzenesulfonimide, 1-*fluoro-4-hydroxy-1,4-diazoniabicyclo[2,2,2]octane bis(tetrafluoroborate), N-*fluoropyridinium pyridine heptafluorodiborate, N-*fluoropyridinium trifluoromethanesulfonate, N-*fluoro-2,4,6-trimethylpyridinium trifluoromethanesulfonate, N-*fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, or 2,6-dichloro-1-*fluoropyridinium trifluoromethanesulfonate, wherein each one of the fluorine atom marked with an asterix (*) is enriched with .sup.18F.
(67) Aromatic Substrates and Variables R.sup.A, k, and W.sub.1 to W.sub.9
(68) A variety of aryl and heteroaryl substrates, e.g., (D), (E), and (F), can be fluorinated using the methods and palladium complexes described herein, to provide fluorinated compounds (I), (II), and (III).
(69) The methods provided herein do not require directing groups on the substrate for C—H fluorination. In certain embodiments, the aryl and heteroaryl substrate is electron rich. Non-limiting examples of an electron rich aryl substrate is the substrate for compounds 3aa and 3ab in the Examples. In certain embodiments, the aryl and heteroaryl substrate is electron neutral. Non-limiting examples of an electron neutral aryl substrate is the substrate for compound 3fa and 3fb in the Examples. In certain embodiments, the aryl and heteroaryl substrate is electron deficient. Non-limiting examples of an electron deficient aryl substrate is the substrate for compounds 3ba, 3bb, 3ca, 3cb, 3da, 3db, 3ea, 3eb in the Examples. In certain embodiments, the aryl or heteroaryl substrate comprises one aryl ring such as the substrate for compounds 3b and 3c. In certain embodiments, the aryl or heteroaryl substrate comprise an aryl ring (e.g., phenyl) substituted with one or more aryl groups (e.g., phenyl), heteroaryl groups (e.g., pyrimidine, pyridinyl), cyclic groups (e.g., cyclohexyl, cyclohexanone), or alkyl substituted with heterocyclic groups (e.g., the substrate for compounds 3na and 3nb).
(70) In certain embodiments, heteroaryl substituents on the aryl substrate are tolerated as stable spectators for the fluorination of more activated aryl C—H bonds on the aryl substrate (e.g., see substrates for compounds 3g, 3i, 3j, 3n).
(71) In certain embodiments, for substrates with multiple aryl or heteroaryl rings, the more electron rich aryl or heteroaryl ring is preferentially fluorinated, albeit with low regioselectivity between electronically similar positions (e.g., see substrates for compounds 3d, 3e, 3g, 3i, 3j).
(72) In certain embodiments, many types of functional groups are compatible with the reactions conditions, including esters (e.g., see substrate for compounds 3h, 3k, 3o), amides (e.g., see substrates for compounds 3k, 3n, 3o), fully-substituted sulfonamides (e.g., see substrate for compound 3g), carbamates (s e.g., ee substrate for compound 3n), aryl bromides (e.g., see substrate for compound 3b) and chlorides (e.g., see substrate for compound 3c), alkyl bromides (e.g., see substrate for compound 3f), alcohols (e.g., see substrate for compound 3l), ketones (e.g., see substrates for compounds 3g, 3n) and nitriles (e.g., see substrates for compound 3d).
(73) In certain embodiments, the aryl or heteroaryl substrate does not comprise fluorine atoms, and only a single fluorine is inserted from the reaction, to provide a fluorinated product with one fluorine atom. In certain embodiments, the aryl or heteroaryl substrate comprises 1, 2, 3, or 4 fluorine atoms, and only a single fluorine is inserted from the reaction to provide the fluorinated product comprising 2, 3, 4, or 5 fluorine atoms, respectively.
(74) In certain embodiments, the fluorine is added to a monosubstituted aryl or heteroaryl ring ortho to the point of substitution. In certain embodiments, the fluorine is added to a monosubstituted aryl or heteroaryl ring para to the point of substitution. In certain embodiments, the fluorine is added to a monosubstituted aryl or heteroaryl meta to the point of substitution.
(75) In certain embodiments, the fluorine is added to a di or tri substituted aryl or heteroaryl ring at a more sterically hindered position on the substrate, e.g., at a position on the substrate which is adjacent to (on either side of) two non-hydrogen groups. In certain embodiments, the fluorine is added to a di or tri substituted aryl or heteroaryl ring at a less sterically hindered position on the substrate, e.g., at a position on the substrate which is not adjacent to (on either side of) non-hydrogen groups.
(76) As generally defined herein, W.sub.1, W.sub.2, W.sub.3, W.sub.4, and W.sub.5 (of compounds of Formula (E) and (II)) is CH, CR.sup.A, or N, provided at least one of W.sub.1, W.sub.2, W.sub.3, W.sub.4, and W.sub.5 is N. In certain embodiments, W.sub.1 is N and the remainder of the W groups are CH or CR.sup.A. In certain embodiments, W.sub.2 is N and the remainder of the W groups are CH or CR.sup.A. In certain embodiments, W.sub.3 is N and the remainder of the W groups are CH or CR.sup.A. In certain embodiments, W.sub.1 and W.sub.2 are each N and the remainder of the W groups are CH or CR.sup.A. In certain embodiments, W.sub.2 and W.sub.3 are each N and the remainder of the W groups are CH or CR.sup.A. In certain embodiments, W.sub.2 and W.sub.4 are each N and the remainder of the W groups are CH or CR.sup.A. In certain embodiments, W, and W.sub.3 are each N and the remainder of the W groups are CH or CR.sup.A. In certain embodiments, W.sub.1 and W.sub.4 are each N and the remainder of the W groups are CH or CR.sup.A. In certain embodiments, W.sub.1 and W.sub.5 are each N and the remainder of the W groups are CH or CR.sup.A. In certain embodiments, W.sub.1, W.sub.3, and W.sub.5 are each N and the remainder of the W groups are CH or CR.sup.A. In certain embodiments, W.sub.1, W.sub.2, and W.sub.4 are each N and the remainder of the W groups are CH or CR.sup.A. In certain embodiments, W.sub.1, W.sub.2, and W.sub.5 are each N and the remainder of the W groups are CH or CR.sup.A. In certain embodiments, W.sub.1, W.sub.2, W.sub.4, and W.sub.5 are each N and W.sub.3 is CH or CR.sup.A.
(77) As generally defined herein, W.sub.6, W.sub.7, W.sub.8, and W.sub.9 (of compounds of Formula (F) and (III)) is CH, CR.sup.A, N, NH, NR.sup.A, O, or S, provided at least one of W.sub.6, W.sub.7, W.sub.8, and W.sub.9 is N, NH, NR.sup.A, O, or S. In certain embodiments, W.sub.6 is NR.sup.A, O, or S, and the remainder of the W groups are CH or CR.sup.A. In certain embodiments, W.sub.7 is NR.sup.A, O, or S, and the remainder of the W groups are CH or CR.sup.A. In certain embodiments, W.sub.6 is N, W.sub.7 is NR.sup.A, O, or S, and the remainder of the W groups are CH or CR.sup.A. In certain embodiments, W.sub.7 is N, W.sub.6 is NR.sup.A, O, or S, and the remainder of the W groups are CH or CR.sup.A. In certain embodiments, W.sub.6 is N, W.sub.8 is NR.sup.A, O, or S, and the remainder of the W groups are CH or CR.sup.A. In certain embodiments, W.sub.8 is N, W.sub.6 is NR.sup.A, O, or S, and the remainder of the W groups are CH or CR.sup.A.
(78) As generally defined herein, each instance of R.sup.A is independently halogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR.sup.A1, —N(R.sup.A1).sub.2, —SR.sup.A1, —CN, —SCN, —C(═NR.sup.A1)R.sup.A1, —C(═NR.sup.A1)OR.sup.A1, —C(═NR.sup.A1)N(R.sup.A1).sub.2, —C(═O)R.sup.A1, —C(═O)OR.sup.A1, —C(═O)N(R.sup.A1).sub.2, —NO.sub.2, —NR.sup.A1C(═O)R.sup.A1, —NR.sup.A1C(═O)OR.sup.A1, —NR.sup.A1C(═O)N(R.sup.A1).sub.2, —OC(═O)R.sup.A1, —OC(═O)OR.sup.A1, or —OC(═O)N(R.sup.A1).sub.2, or two vicinal R.sup.A groups (groups attached to two adjacent carbon atoms) are joined to form a substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ring; and each instance of R.sup.A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R.sup.A1 attached the same nitrogen atom are joined to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring.
(79) In certain embodiments, the aryl or heteroaryl substrate is not electron deficient (e.g., such as methyl benzoate
(80) ##STR00010##
In certain embodiments, R.sup.A is not a reactive functional group, such as tertiary amines or carboxylic acids. For example, R.sup.A is not —C(═O)OH or —N(R.sup.Z).sub.3.sup.+, wherein each instance of R.sup.Z is independently acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In certain embodiments, R.sup.A is not a benzylic heteroatom (e.g., a benzylic amide). For example, the aryl or heteroaryl substrate is not ArCH.sub.2N(R.sup.Z1).sub.2, ArCH.sub.2OR.sup.Z2, or ArCH.sub.2SR.sup.Z2, wherein Ar is aryl or heteroaryl, and each instance of R.sup.Z1 is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and wherein each instance of R.sup.Z2 is independently hydrogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
(81) In certain embodiments, compounds of Formula (I), (II), (III), (D), (E), or (F) are unsubstituted, wherein k is 0 or wherein the non-hydrogen group R.sup.A is not present. For example, In certain embodiments, compounds of Formula (I), (II), (III), (D), (E), or (F) include one to five substituents R.sup.A, as valency permits.
(82) In certain embodiments, at least one instance of R.sup.A is halogen. In certain embodiments, at least one instance of R.sup.A is F. In certain embodiments, at least one instance of R.sup.A is Cl. In certain embodiments, at least one instance of R.sup.A is Br. In certain embodiments, at least one instance of R.sup.A is I (iodine).
(83) In certain embodiments, at least one instance of R.sup.A is acyl.
(84) In certain embodiments, at least one instance of R.sup.A is substituted alkyl. In certain embodiments, at least one instance of R.sup.A is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.A is C.sub.1-12 alkyl. In certain embodiments, at least one instance of R.sup.A is substituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.A is unsubstituted C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.A is substituted methyl. In certain embodiments, at least one instance of R.sup.A is —CH.sub.2F. In certain embodiments, at least one instance of R.sup.A is —CHF.sub.2. In certain embodiments, at least one instance of R.sup.A is —CF.sub.3. In certain embodiments, at least one instance of R.sup.A is Bn. In certain embodiments, at least one instance of R.sup.A is —(CH.sub.2).sub.3OH, —CH.sub.2CO.sub.2H, —CH.sub.2CO.sub.2Me, or
(85) ##STR00011##
In certain embodiments, at least one instance of R.sup.A is unsubstituted methyl. In certain embodiments, at least one instance of R.sup.A is ethyl. In certain embodiments, at least one instance of R.sup.A is propyl. In certain embodiments, at least one instance of R.sup.A is i-propyl. In certain embodiments, at least one instance of R.sup.A is butyl. In certain embodiments, at least one instance of R.sup.A is t-butyl. In certain embodiments, at least one instance of R.sup.A is pentyl. In certain embodiments, at least one instance of R.sup.A is hexyl.
(86) In certain embodiments, at least one instance of R.sup.A is substituted alkenyl. In certain embodiments, at least one instance of R.sup.A is unsubstituted alkenyl. In certain embodiments, at least one instance of R.sup.A is substituted or unsubstituted C.sub.1-6 alkenyl. In certain embodiments, at least one instance of R.sup.A is vinyl. In certain embodiments, at least one instance of R.sup.A is of the formula:
(87) ##STR00012##
(88) In certain embodiments, at least one instance of R.sup.A is substituted alkynyl. In certain embodiments, at least one instance of R.sup.A is unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.A is ethynyl.
(89) In certain embodiments, at least one instance of R.sup.A is substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.A is unsubstituted carbocyclyl. In certain embodiments, at least one instance of R.sup.A is saturated carbocyclyl. In certain embodiments, at least one instance of R.sup.A is unsaturated carbocyclyl. In certain embodiments, at least one instance of R.sup.A is carbocyclyl including zero, one, two, or three double bonds in the carbocyclic ring system. In certain embodiments, at least one instance of R.sup.A is monocyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.A is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.A is cyclopropyl. In certain embodiments, at least one instance of R.sup.A is cyclobutyl. In certain embodiments, at least one instance of R.sup.A is cyclopentyl. In certain embodiments, at least one instance of R.sup.A is cyclohexyl. In certain embodiments, at least one instance of R.sup.A is cycloheptyl. In certain embodiments, at least one instance of R.sup.A is bicyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.A is 5- to 13-membered, bicyclic carbocyclyl.
(90) In certain embodiments, at least one instance of R.sup.A is substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.A is unsubstituted heterocyclyl. In certain embodiments, at least one instance of R.sup.A is saturated heterocyclyl. In certain embodiments, at least one instance of R.sup.A is unsaturated heterocyclyl. In certain embodiments, at least one instance of R.sup.A is heterocyclyl including zero, one, two, or three double bonds in the heterocyclic ring system. In certain embodiments, at least one instance of R.sup.A is heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.A is monocyclic heterocyclyl. In certain embodiments, at least one instance of R.sup.A is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, at least one instance of R.sup.A is bicyclic heterocyclyl. In certain embodiments, at least one instance of R.sup.A is 5- to 13-membered, bicyclic heterocyclyl.
(91) In certain embodiments, at least one instance of R.sup.A is substituted aryl. In certain embodiments, at least one instance of R.sup.A is unsubstituted aryl. In certain embodiments, at least one instance of R.sup.A is 6- to 14-membered aryl. In certain embodiments, at least one instance of R.sup.A is 6- to 10-membered aryl. In certain embodiments, at least one instance of R.sup.A is substituted phenyl. In certain embodiments, at least one instance of R.sup.A is unsubstituted phenyl. In certain embodiments, at least one instance of R.sup.A is substituted naphthyl. In certain embodiments, at least one instance of R.sup.A is unsubstituted naphthyl.
(92) In certain embodiments, at least one instance of R.sup.A is substituted heteroaryl. In certain embodiments, at least one instance of R.sup.A is unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.A is heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.A is monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.A is 5-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.A is 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.A is substituted pyridyl. In certain embodiments, at least one instance of R.sup.A is unsubstituted 2-pyridyl, unsubstituted 3-pyridyl, or unsubstituted 4-pyridyl. In certain embodiments, at least one instance of R.sup.A is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, at least one instance of R.sup.A is 9-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of R.sup.A is 10-membered, bicyclic heteroaryl.
(93) In certain embodiments, at least one instance of R.sup.A is —OR.sup.A1. In certain embodiments, at least one instance of R.sup.A is —OMe. In certain embodiments, at least one instance of R.sup.A is —OEt. In certain embodiments, at least one instance of R.sup.A is —OPr. In certain embodiments, at least one instance of R.sup.A is —OBu. In certain embodiments, at least one instance of R.sup.A is —O(pentyl). In certain embodiments, at least one instance of R.sup.A is —O(hexyl). In certain embodiments, at least one instance of R.sup.A is —OBn. In certain embodiments, at least one instance of R.sup.A is —OR.sup.A1, wherein R.sup.A1 is acyl or substituted or unsubstituted aryl. In certain embodiments, at least one instance of R.sup.A is —O(Boc). In certain embodiments, at least one instance of R.sup.A is —OPh. In certain embodiments, at least one instance of R.sup.A is —OH.
(94) In certain embodiments, at least one instance of R.sup.A is —SR.sup.A1. In certain embodiments, at least one instance of R.sup.A is —SMe. In certain embodiments, at least one instance of R.sup.A is —SH. In certain embodiments, no instance of R.sup.A is —SR.sup.A1.
(95) In certain embodiments, at least one instance of R.sup.A is —N(R.sup.A1).sub.2. In certain embodiments, at least one instance of R.sup.A is —NMe.sub.2. In certain embodiments, at least one instance of R.sup.A is —NH.sub.2.
(96) In certain embodiments, at least one instance of R.sup.A is —CN. In certain embodiments, at least one instance of R.sup.A is —SCN.
(97) In certain embodiments, at least one instance of R.sup.A is —C(═NR.sup.A1)R.sup.A1, —C(═NR.sup.A1)OR.sup.A1, or —C(═NR.sup.A1)N(R.sup.A1).sub.2.
(98) In certain embodiments, at least one instance of R.sup.A is —C(═O)R.sup.A1 or —C(═O)OR.sup.A1. In certain embodiments, at least one instance of R.sup.A is —C(═O)N(R.sup.A1).sub.2. In certain embodiments, at least one instance of R.sup.A is —C(═O)N(R.sup.A1).sub.2, wherein each instance of R.sup.A1 is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, or a nitrogen protecting group. In certain embodiments, at least one instance of R.sup.A is —C(═O)N(R.sup.A1).sub.2, wherein each instance of R.sup.A1 is independently selected from the group consisting of hydrogen, unsubstituted C.sub.1-6 alkyl, Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts. In certain embodiments, at least one instance of R.sup.A is —C(═O)NH.sub.2.
(99) In certain embodiments, at least one instance of R.sup.A is —NO.sub.2.
(100) In certain embodiments, at least one instance of R.sup.A is —NR.sup.A1C(═O)R.sup.A1, —NR.sup.A1C(═O)OR.sup.A1, or —NR.sup.A1C(═O)N(R.sup.A1).sub.2.
(101) In certain embodiments, at least one instance of R.sup.A is —OC(═O)R.sup.A1, —OC(═O)OR.sup.A1, or —OC(═O)N(R.sup.A1).sub.2.
(102) In certain embodiments, at least one instance of R.sup.A is halogen or substituted or unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.A is halogen or unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.A is halogen or unsubstituted C.sub.1-6 alkyl.
(103) In certain embodiments, two vicinal R.sup.A groups (groups attached to two adjacent carbon atoms) are joined to form a substituted or unsubstituted carbocyclyl.
(104) In certain embodiments, two vicinal R.sup.A groups (groups attached to two adjacent carbon atoms) are joined to form a substituted or unsubstituted heterocyclyl.
(105) In certain embodiments, two vicinal R.sup.A groups (groups attached to two adjacent carbon atoms) are joined to form a substituted or unsubstituted aryl.
(106) In certain embodiments, two vicinal R.sup.A groups (groups attached to two adjacent carbon atoms) are joined to form a substituted or unsubstituted heteroaryl.
(107) In certain embodiments, at least one instance of R.sup.A1 is hydrogen.
(108) In certain embodiments, at least one instance of R.sup.A1 is acyl (e.g., acetyl, —C(═O)CH.sub.3).
(109) In certain embodiments, at least one instance of R.sup.A1 is substituted alkyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted alkyl. In certain embodiments, at least one instance of R.sup.A1 is C.sub.1-12 alkyl. In certain embodiments, at least one instance of R.sup.A1 is C.sub.1-6 alkyl. In certain embodiments, at least one instance of R.sup.A1 is methyl. In certain embodiments, at least one instance of R.sup.A1 is ethyl. In certain embodiments, at least one instance of R.sup.A1 is propyl. In certain embodiments, at least one instance of R.sup.A1 is butyl. In certain embodiments, at least one instance of R.sup.A1 is pentyl. In certain embodiments, at least one instance of R.sup.A1 is hexyl.
(110) In certain embodiments, at least one instance of R.sup.A1 is substituted alkenyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted alkenyl. In certain embodiments, at least one instance of R.sup.A1 is vinyl.
(111) In certain embodiments, at least one instance of R.sup.A1 is substituted alkynyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted alkynyl. In certain embodiments, at least one instance of R.sup.A1 is ethynyl.
(112) In certain embodiments, at least one instance of R.sup.A1 is substituted carbocyclyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted carbocyclyl. In certain embodiments, at least one instance of R.sup.A1 is saturated carbocyclyl. In certain embodiments, at least one instance of R.sup.A1 is unsaturated carbocyclyl. In certain embodiments, at least one instance of R.sup.A1 is carbocyclyl including zero, one, two, or three double bonds in the carbocyclic ring system. In certain embodiments, at least one instance of R.sup.A1 is 3- to 7-membered, monocyclic carbocyclyl. In certain embodiments, at least one instance of R.sup.A1 is cyclopropyl. In certain embodiments, at least one instance of R.sup.A1 is cyclobutyl. In certain embodiments, at least one instance of R.sup.A1 is cyclopentyl. In certain embodiments, at least one instance of R.sup.A1 is cyclohexyl. In certain embodiments, at least one instance of R.sup.A1 is cycloheptyl. In certain embodiments, at least one instance of R.sup.A1 is 5- to 13-membered, bicyclic carbocyclyl.
(113) In certain embodiments, at least one instance of R.sup.A1 is substituted heterocyclyl. In certain embodiments, at least one instance of R.sup.A1 is unsubstituted heterocyclyl. In certain embodiments, at least one instance of R.sup.A1 is saturated heterocyclyl. In certain embodiments, at least one instance of R.sup.A1 is unsaturated heterocyclyl. In certain embodiments, at least one instance of R.sup.A1 is heterocyclyl including zero, one, two, or three double bonds in the heterocyclic ring system. In certain embodiments, at least one instance of R.sup.A1 is heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.A1 is 3- to 7-membered, monocyclic heterocyclyl. In certain embodiments, at least one instance of R.sup.A1 is 5- to 13-membered, bicyclic heterocyclyl.
(114) In certain embodiments, at least one instance of R.sup.A1 is substituted or unsubstituted aryl. In certain embodiments, at least one instance of R.sup.A1 is 6- to 14-membered aryl. In certain embodiments, at least one instance of R.sup.A1 is 6- to 10-membered aryl. In certain embodiments, at least one instance of R.sup.A1 is monocyclic aryl. In certain embodiments, at least one instance of R.sup.A1 is phenyl. In certain embodiments, at least one instance of R.sup.A1 is bicyclic aryl. In certain embodiments, at least one instance of R.sup.A1 is naphthyl.
(115) In certain embodiments, at least one instance of R.sup.A1 is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R.sup.A1 is heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, at least one instance of R.sup.A1 is monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.A1 is 5-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.A1 is 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R.sup.A1 is pyridyl. In certain embodiments, at least one instance of R.sup.A1 is bicyclic heteroaryl, wherein the point of attachment may be on any atom of the bicyclic heteroaryl ring system, as valency permits. In certain embodiments, at least one instance of R.sup.A1 is 9-membered, bicyclic heteroaryl. In certain embodiments, at least one instance of R.sup.A1 is 10-membered, bicyclic heteroaryl.
(116) In certain embodiments, at least one instance of R.sup.A1 is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one instance of R.sup.A1 is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts when attached to a nitrogen atom.
(117) In certain embodiments, R.sup.A1 is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R.sup.A1 is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom.
(118) In certain embodiments, R.sup.A1 is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R.sup.A1 is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom.
(119) In certain embodiments, two instances of R.sup.A1 on the same nitrogen atom are joined to form a substituted or unsubstituted heterocyclic ring. In certain embodiments, two instances of R.sup.A1 on the same nitrogen atom are joined to form a saturated or unsaturated heterocyclic ring. In certain embodiments, two instances of R.sup.A1 on the same nitrogen atom are joined to form a heterocyclic ring including zero, one, two, or three double bonds in the heterocyclic ring system. In certain embodiments, two instances of R.sup.A1 on the same nitrogen atom are joined to form a heterocyclic ring, wherein one, two, or three atoms in the heterocyclic ring system are independently selected from the group consisting of nitrogen, oxygen, and sulfur. In certain embodiments, two instances of R.sup.A1 on the same nitrogen atom are joined to form a 3- to 7-membered, monocyclic heterocyclic ring. In certain embodiments, two instances of R.sup.A1 on the same nitrogen atom are joined to form a 5- to 13-membered, bicyclic heterocyclic ring.
(120) As generally defined herein, k is 0, 1, 2, 3, 4, or 5. In certain embodiments, k is 0. In certain embodiments, k is 1. In certain embodiments, k is 2. In certain embodiments, k is 3. In certain embodiments, k is 4. In certain embodiments, k is 5.
(121) In certain embodiments, k is land/or one R.sup.A non-hydrogen substituent is present on the aryl or heteroaryl ring selected from the group consisting of halogen, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted carbocyclyl. In certain embodiments, k is land/or one R.sup.A non-hydrogen substituent is present on the aryl or heteroaryl ring selected from the group consisting of halogen, substituted or unsubstituted C.sub.1-6 alkyl, substituted or unsubstituted C.sub.1-6 alkenyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidinyl, and substituted or unsubstituted C.sub.1-6 carbocyclyl. In certain embodiments, k is 2 and/or two R.sup.A non-hydrogen substituents are present on the aryl or heteroaryl ring selected from the group consisting of substituted or unsubstituted alkyl. In certain embodiments, k is 3 and/or three R.sup.A non-hydrogen substituents are present on the aryl or heteroaryl ring selected from the group consisting of substituted or unsubstituted alkyl. In certain embodiments, k is 3 and/or three R.sup.A non-hydrogen substituents are present on the aryl or heteroaryl ring selected from the group consisting of substituted or unsubstituted C.sub.1-6 alkyl.
(122) In certain embodiments, k is 1 and/or one R.sup.A non-hydrogen substituent is present on the aryl or heteroaryl ring selected from the group consisting of substituted or unsubstituted C.sub.1-3 alkyl. In certain embodiments, the alkyl is substituted with —COOR, wherein R is a C.sub.1-6 alkyl; with —NHR, wherein R is acetyl; with —NHCOR, wherein R is a C.sub.1-6 alkyl or substituted or unsubstituted carbocyclyl; or with substituted or unsubstituted heterocyclyl. In certain embodiments, the C.sub.1-3 alkyl is substituted with a halogen. In certain embodiments, k is 1 and/or one R.sup.A non-hydrogen substituent is present on the aryl or heteroaryl ring selected from the group consisting of halogen. In certain embodiments, R.sup.A is Br or Cl. In certain embodiments, k is 1 and/or one R.sup.A non-hydrogen substituent is present on the aryl or heteroaryl ring selected from the group consisting of substituted or unsubstituted phenyl. In certain embodiments, the phenyl is substituted with one or more —CN, —CF.sub.3, —SO.sub.2NR.sub.2, wherein R is joined to form a substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl ring. In certain embodiments, k is 1 and/or one R.sup.A non-hydrogen substituent is present on the aryl or heteroaryl ring selected from the group consisting substituted or unsubstituted pyridyl. In certain embodiments, k is 1 and/or one R.sup.A non-hydrogen substituent is present on the aryl or heteroaryl ring selected from the group consisting of substituted or unsubstituted pyrimidinyl. In certain embodiments, k is 1 and/or one R.sup.A non-hydrogen substituent is present on the aryl or heteroaryl ring selected from the group consisting of substituted or unsubstituted cyclohexanone. In certain embodiments, k is 1 and/or one R.sup.A non-hydrogen substituent is present on the aryl or heteroaryl ring selected from the group consisting of substituted or unsubstituted C.sub.3-6 carbocyclyl. In certain embodiments, the carbocyclyl is substituted with —OR or —COOR, wherein R is a H or C.sub.1-6 alkyl. In certain embodiments, k is 1 and/or one R.sup.A non-hydrogen substituent is present on the aryl or heteroaryl ring selected from the group consisting of substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted bicyclic heterocyclyl, such as nortropinone).
(123) In certain embodiments, a substrate of formula:
(124) ##STR00013##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(125) ##STR00014##
(126) In certain embodiments, a substrate of formula:
(127) ##STR00015##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(128) ##STR00016##
(129) In certain embodiments, a substrate of formula:
(130) ##STR00017##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(131) ##STR00018##
(132) In certain embodiments, a substrate of formula:
(133) ##STR00019##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(134) ##STR00020##
(135) In certain embodiments, a substrate of formula:
(136) ##STR00021##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(137) ##STR00022##
(138) In certain embodiments, a substrate of formula:
(139) ##STR00023##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(140) ##STR00024##
(141) In certain embodiments, a substrate of formula:
(142) ##STR00025##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(143) ##STR00026##
(144) In certain embodiments, a substrate of formula:
(145) ##STR00027##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(146) ##STR00028##
(147) In certain embodiments, a substrate of formula:
(148) ##STR00029##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(149) ##STR00030##
(150) In certain embodiments, a substrate of formula:
(151) ##STR00031##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(152) ##STR00032##
(153) In certain embodiments, a substrate of formula:
(154) ##STR00033##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(155) ##STR00034##
(156) In certain embodiments, a substrate of formula:
(157) ##STR00035##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(158) ##STR00036##
(159) In certain embodiments, a substrate of formula:
(160) ##STR00037##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(161) ##STR00038##
(162) In certain embodiments, a substrate of formula:
(163) ##STR00039##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(164) ##STR00040##
(165) In certain embodiments, a substrate of formula:
(166) ##STR00041##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(167) ##STR00042##
(168) In certain embodiments, a substrate of formula:
(169) ##STR00043##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(170) ##STR00044##
(171) In certain embodiments, a substrate of formula:
(172) ##STR00045##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(173) ##STR00046##
(174) In certain embodiments, a substrate of formula:
(175) ##STR00047##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(176) ##STR00048##
(177) In certain embodiments, a substrate of formula:
(178) ##STR00049##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(179) ##STR00050##
(180) In certain embodiments, a substrate of formula:
(181) ##STR00051##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(182) ##STR00052##
(183) In certain embodiments, a substrate of formula:
(184) ##STR00053##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(185) ##STR00054##
(186) In certain embodiments, a substrate of formula:
(187) ##STR00055##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(188) ##STR00056##
(189) In certain embodiments, a substrate of formula:
(190) ##STR00057##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(191) ##STR00058##
(192) In certain embodiments, a substrate of formula:
(193) ##STR00059##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(194) ##STR00060##
(195) In certain embodiments, a substrate of formula:
(196) ##STR00061##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(197) ##STR00062##
(198) In certain embodiments, a substrate of formula:
(199) ##STR00063##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(200) ##STR00064##
(201) In certain embodiments, a substrate of formula:
(202) ##STR00065##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(203) ##STR00066##
(204) In certain embodiments, a substrate of formula:
(205) ##STR00067##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(206) ##STR00068##
(207) In certain embodiments, a substrate of formula:
(208) ##STR00069##
is fluorinated following the procedures and methods described herein to provide a compound of formula:
(209) ##STR00070##
Kits
(210) Provided herein are kits (e.g., packs). In certain embodiments, the kits are useful for preparing the fluorinated compounds described herein (e.g., aryl fluorides fluorides). In certain embodiments, the kits are useful for preparing compounds of Formula (I), (II), or (III).
(211) In certain embodiments, a kit of the invention includes a palladium(II) complex of Formula (C); and optionally a fluorinating agent described herein. In certain embodiments, a kit of the invention includes a palladium(II) complex of Formula (C-1); and optionally a fluorinating agent described herein. In certain embodiments, a kit of the invention includes a palladium(III) complex of Formula (G); and a fluorinating agent described herein. In certain embodiments, a kit of the invention includes a palladium(III) complex of Formula (G-1); and a fluorinating agent described herein. In certain embodiments, the fluorinating agent is an N-fluorinated amine or N-fluorinated quaternary amine salt. In certain embodiments, the fluorinating agent is 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (F-TEDA-BF.sub.4/Selectfluor®). In certain embodiments, the fluorinating agent is enriched with .sup.18F.
(212) In certain embodiments, a kit of the invention further includes an aryl or heteroaryl substrate of Formula (D), (E), or (F).
(213) The kits provided may further include a container (e.g., a vial, ampule, bottle, syringe, flask, tube, beaker, dish, microtiter plate, and/or dispenser package, or other suitable container), a solvent (e.g., a suitable solvent described herein), or an organic or inorganic agent (e.g., a phase-transfer agent, a solubilizing agent, a stabilizing agent, an anti-oxidative agent, protecting agent, deprotecting agent, and/or a preservative agent). In some embodiments, the kits further include instructions for using the kits of the invention. In certain embodiments, the kits and instructions provide for preparing the compounds described herein (e.g., aryl or heteroaryl fluorides). In certain embodiments, the kits and instructions provide for preparing the compounds of Formula (I), (II), or (III). In certain embodiments, the kits and instructions provide for preparing the compounds of Formula (I), (II), or (III) and isotopically labeled derivatives (e.g., .sup.18F-labeled derivatives) thereof.
EXAMPLES
(214) In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.
(215) Materials and Methods
(216) Reactions were carried out under ambient atmosphere unless otherwise noted. Purified compounds were further dried under high vacuum (0.01-0.05 Torr). Yields refer to purified and spectroscopically pure compounds. Thin layer chromatography (TLC) was performed using EMD TLC plates pre-coated with 250 μm thickness silica gel 60 F.sub.254 plates and visualized by fluorescence quenching under UV light and KMnO.sub.4 stain. Flash chromatography was performed using silica gel (230-400 mesh) purchased from Silicycle Inc. Melting points were measured on a Thomas Scientific Uni-Melt capillary melting point apparatus. All melting points were measured in open capillaries and are uncorrected. NMR spectra were recorded on either a Varian Unity/Inova 600 spectrometer operating at 600 MHz for .sup.1H acquisitions, a Varian Unity/Inova 500 spectrometer operating at 500 MHz and 125 MHz for .sup.1H and .sup.13C acquisitions, respectively, or a Varian Mercury 400 spectrometer operating at 400 HMz and 375 MHz for .sup.1H and .sup.19F acquisitions, respectively. Chemical shifts are reported in ppm with the solvent resonance as the internal standard (.sup.1H: CDCl.sub.3, δ 7.26; (CD.sub.3).sub.2SO, δ2.50; CD.sub.3CN, δ1.94; (CD.sub.3).sub.2CO, δ2.05), (.sup.13C: CDCl.sub.3, δ77.16; CD.sub.3CN, δδ1.32, (CD.sub.3).sub.2SO, δ39.52; (CD.sub.3).sub.2CO, δ29.84, 206.26) (Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H. E.; Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldberg, K. I. Organometallics 2010, 29, 2176-2179). Data is reported as follows: s=singlet, br=broad, d=doublet, t=triplet, q=quartet, quin=quintet, m=multiplet; coupling constants in Hz; integration. All deuterated solvents were purchased from Cambridge Isotope Laboratories. Solution-state magnetic susceptibility measurements were obtained using the Evans method (Evans, D. F. J. Chem. Soc. 1959, 2003-2005) and are reported as follows: (field strength, solvent, temperature): μeff (concentration in mg/mL). EPR spectra were recorded on a Bruker ElexSys E500 EPR spectrometer operating at X-band frequency (9 GHz). UV-vis/NIR spectra were measured on a PerkinElmer Lambda 750 spectrophotometer. Electrochemical measurements were made using a CH Instruments Model 600E Series Electrochemical Analyzer/Workstation. High-resolution mass spectra were obtained using an Agilent ESI-TOF (6210) mass spectrometer or a Bruker q-TOF Maxis Impact mass spectrometer. LC/MS data were obtained using a Shimadzu LCMS-2020. Pd(OAc).sub.2 was purchased from Strem. HBF.sub.4.OEt.sub.2 was purchased from Alfa Aesar. 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor®) and 2,2′:6′,2″-terpyridine (terpy) were purchased from Strem or SigmaAldrich. All chemicals were used as received. DMF was ACS Reagent grade, purchased from SigmaAldrich; MeCN was ACS grade, purchased from BDH. These solvents were used as received without further purification.
(217) Representative Procedure for Evaluation of C—H Fluorination Reaction Using Selectfluor and Catalyst 1
(218) Under N.sub.2 atmosphere, an oven-dried 4 mL vial was charged 3,5-bis(trifluoromethyl)biphenyl (29.0 mg, 100 μmol, 1.0 equiv.), Selectfluor (71 mg, 200 μmol, 2.0 equiv.) and acetonitrile (0.5 mL). To a separate 4 mL vial, a solution of the given Pd(II) complex was formed from the appropriate Pd(II) source and ligands (5 mol % Pd(II) per 0.5 mL). The catalyst solution was then added to the reaction mixture (final c=0.1 M) and the resulting reaction mixture was stirred at 25, 50 or 80° C. for 24 h. After cooling to room temperature, 1,4-bistrifluoromethylbenzene (3.6 mg, 2.6 μl, 17 μmol, 0.17 equiv.) was added to the reaction mixture, stirred and a sample (approx. 0.1 mL) was diluted with CD.sub.3CN (0.5 mL) and a yield was determined by .sup.19F NMR using 1,4-bis(trifluoromethyl)benzene as an internal standard (standard: δ −63.4 ppm, 6 F; compared with product peaks at δ −113.8 and −118.2 ppm; first relaxation time of 10 s to ensure accurate integration.
Experimental Procedures and Compound Characterization
I. Preparation of Substrates for Fluorination
Nortropinone (4-biphenyl))sulfonamide (2q)
(219) ##STR00071##
(220) A 50 mL round bottom flask was charged with nortropinone hydrochloride (0.808 g, 5.00 mmol, 1.00 equiv.), dichloromethane (25 mL, c=0.2 M), 4-biphenyl sulfonyl chloride (1.27 g, 5.00 mmol, 1.00 equiv.), triethylamine (2.0 g, 2.8 mL, 20 mmol, 4.0 equiv.) and 4-dimethylamino pyridine (61 mg, 0.50 mmol, 0.10 equiv.) were added. After 24 h the reaction mixture was diluted with dichloromethane (100 mL) and washed with 0.5 M HCl (150 mL). The aqueous layer was extracted with dichloromethane (3×50 mL) and the combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography, eluting with dichloromethane and ethyl acetate (90:10 (v/v)) to afford nortropinone (4-biphenyl))sulfonamide 2q (1.12 g, 3.27 mmol, 65%) as a colorless solid. R.sub.f=0.40 (ethyl acetate/dichloromethane, 10:90 (v/v)).
(221) NMR Spectroscopy: .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 7.97 (d, J=8.8 Hz, 2H), 7.74 (d, J=8.8 Hz, 2H), 7.63-7.59 (m, 2H), 7.52-7.46 (m, 2H), 7.45-7.41 (m, 1H), 4.55 (tt, J=3.9, 2.1 Hz, 2H), 2.83 (dd, J=16.4, 4.6 Hz, 2H), 2.48-2.27 (m, 2H), 1.84-1.74 (m, 2H), 1.66-1.59 (m, 2H) ppm. .sup.13C NMR (126 MHz, CDCl.sub.3, 23° C., δ): δ 206.9, 146.2, 139.1, 138.4, 129.2, 128.8, 127.9 (d, J=1.6 Hz), 127.4, 56.2, 50.4, 29.5 ppm. HRMS-ESI (m/z) calculated for C.sub.19H.sub.19S.sub.1NO.sub.3Na [M+Na].sup.+, 364.0978; found, 364.0981.
II. Preparation of Palladium Precursor [(Terpy)Pd(MeCN)][BF.SUB.4.].SUB.2 .(S1)
(222) ##STR00072##
(223) To Pd(OAc).sub.2 (4.49 g, 20.0 mmol, 1.00 equiv) in MeCN (300 mL) at 23° C. was added 2,2′:6′,2″-terpyridine (4.67 g, 20.0 mmol, 1.00 equiv). The reaction mixture was stirred for 20 minutes, affording a pink/orange slurry. To this slurry was added HBF.sub.4.OEt.sub.2 (5.63 mL, 6.64 g, 41.0 mmol, 2.05 equiv.) via syringe. The reaction mixture was stirred vigorously for 30 min, at which point a suspension of tan solids was observed and Et.sub.2O (250 mL) was added. The solids were collected by filtration and washed with Et.sub.2O (200 mL). The combined solids were then dried under vacuum to afford 9.07 g of the title compound as a pale tan solid (97% yield). Spectra matched that previously reported. This procedure was adapted from the previously published procedure from Mazzotti et al., J. Am. Chem. Soc., 2013, 135, 14012-14015.
III. Palladium Catalyzed Fluorination of Arenes
(224) (i) Representative Procedure A: C—H Fluorination Reaction Using NFSI or
(225) ##STR00073##
(226) Under N.sub.2 atmosphere, an oven-dried 20 mL vial was charged with arene (1.00 mmol, 1.00 equiv.), either NFBS or NFSI (631 mg, 2.00 mmol, 2.00 equiv.) or Selectfluor (709 mg, 2.00 mmol, 2.00 equiv.), and acetonitrile (5.0 mL). To a separate 20 mL vial, Pd(II) terpyridine acetonitrile tetrafluoroborate complex (Pd(terpy)(MeCN)(BF.sub.4).sub.2, [Si]) (27.7 mg, 50.0 μmol, 5.00 mol %) and 2-chloro-phenanthroline (10.7 mg, 50.0 μmol, 5.00 mol %) were added and dissolved in acetonitrile (5.0 mL). The catalyst-containing solution was added to the mixture of (hetero)arene and oxidant (final c=0.10 M). The resulting reaction mixture was stirred at 25° C. for 24 h and was then transferred to a separatory funnel. Chloroform (75 mL) was added and the organic layer was washed water (50 mL) with added brine (10 mL). The aqueous layer was extracted with chloroform (4×75 mL) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in dichloromethane (2 mL), loaded onto a short plug of silica (20 g) and eluted with an appropriate solvent (50 mL). A mixture of the fluorinated product isomers, remaining starting material, and minor inseparable impurities was obtained and a yield was determined by .sup.19F NMR using 1,4-bis(trifluoromethyl)benzene (δδ−63.4 ppm, 6 F) as an internal standard with a first relaxation time of 10 s to ensure accurate integration.
(227) (ii) Representative Procedure B: C—H Fluorination Reaction without Palladium Catalyst
(228) Under N.sub.2 atmosphere, an oven-dried 4 mL vial was charged with arene (100.0 μmol, 1.00 equiv.), Selectfluor (70.8 mg, 200.0 μmol, 2.00 equiv.) and acetonitrile (1.0 mL, c=0.10 M). The resulting reaction mixture was stirred at 80° C. for 24 h. After cooling to room temperature, 1,4-bistrifluoromethylbenzene (3.6 mg, 2.6 μl, 17 μmol, 0.17 equiv.) was added to the reaction mixture, stirred and a sample (approx. 0.1 mL) was diluted with CD.sub.3CN (0.5 mL) and a yield was determined by .sup.19F NMR using 1,4-bis(trifluoromethyl)benzene (δ −63.4 ppm, 6 F) as an internal standard with a first relaxation time of 10 s to ensure accurate integration.
Example 1. 1-tert-Butyl-2-fluoro-3,5-dimethylbenzene (3aa) and 1-tert-butyl-2-fluoro-3,5-dimethylbenzene (3ab)
(229) ##STR00074##
(230) A mixture of palladium complex S1 (27.7 mg, 50.0 μmol, 5.00 mol %) and 2-chloro-phenanthroline (10.7 mg, 50.0 μmol, 5.00 mol %.) was dissolved in acetonitrile (5.0 mL). This mixture was added to a 20 mL vial containing a solution of NFBS (315 mg, 1.00 mmol, 2.00 equiv.) and 1-tert-butyl-3,5-dimethylbenzene (162 mg, 188 μl, 1.00 mmol, 1.00 equiv.) in acetonitrile (5.0 mL, final c=0.10 M). The reaction mixture was stirred for 24 hours at 25° C. and then transferred to a separatory funnel. Pentane (50 mL) was added and the organic layer was washed with saturated aqueous NaHCO.sub.3 solution (1×25 mL). The aqueous layer was extracted with pentane (4×50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo at 40° C. to afford a yellow oil. The residue was dissolved in hexane (2 mL), loaded onto a short plug of silica (20 g) and eluted with hexane. A colorless oil (136 mg) containing the title compounds 3aa and 3ab (118 mg, 0.65 mmol, 65% yield, 3aa:3ab (83:17)), 1-tert-butyl-3,5-dimethylbenzene and residual solvent was obtained. The solvent and starting material content of the residue was established by .sup.1H NMR spectrum of the mixture. The yield and selectivity were determined by .sup.19F using 1,4-bis(trifluoromethyl)benzene as an internal standard (standard: δ −63.4 ppm, 6 F; compared with product peaks at δ −119.7 and −126.9 ppm; first relaxation time of 10 s to ensure accurate integration). The spectra matched the reported spectra for the title compound 3ab, reported in Yamato et al., J. Chem. Soc., Perkin Trans. 1, 1987, 1-7. R.sub.f=0.70 (hexane).
(231) NMR Spectroscopy: .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): δ 7.04 (s, 1H), 6.93 (dd, J=7.6, 2.2 Hz, 1H), 6.89-6.83 (m, 1H), 2.35 (d, J=0.7 Hz, 3H), 2.30 (d, J=1.0 Hz, 2H), 2.28 (d, J=2.1 Hz, 1H), 2.25 (d, J=2.6 Hz, 2H), 1.39 (d, J=1.1 Hz, 6H), 1.34 (s, 4H), 1.32 (s, 1H). ppm. .sup.13C NMR (126 MHz, CDCl.sub.3, 23° C., δ): 158.7 (d, J=244.1 Hz), 151.3, 137.5, 136.3 (d, J=12.3 Hz), 132.2 (d, J=4.2 Hz), 129.7 (d, J=5.2 Hz), 127.2, 125.9 (d, J=4.4 Hz), 125.3 (d, J=5.7 Hz), 125.1 (d, J=20.1 Hz), 123.3, 34.6, 34.3, 34.3, 31.7, 31.6, 30.2 (d, J=3.7 Hz), 21.7, 21.0, 15.0 (d, J=4.4 Hz), 14.9 (d, J=6.6 Hz) ppm. 1-tert-butyl-2-fluoro-3,5-dimethylbenzene (3aa): .sup.19F NMR (471 MHz, CDCl.sub.3, 23° C., δ) −119.7 ppm. 1-tert-butyl-2-fluoro-3,5-dimethylbenzene (3ab): .sup.19F NMR (471 MHz, CDCl.sub.3, 23° C., δ) −126.9 ppm. HRMS-FIA(m/z) calculated for C.sub.12H.sub.18F [M+H].sup.+, 181.1393; found, 181.1387.
(232) Reaction without Catalyst.
(233) Under N.sub.2 atmosphere, an oven-dried 4 mL vial was charged with Selectfluor (71 mg, 200 μmol, 2.0 equiv.) and 1-tert-butyl-3,5-dimethylbenzene (81 mg, 9.4 μl, 100 μmol, 1.0 equiv.) in acetonitrile (1.0 mL, c=0.10 M). The resulting reaction mixture was stirred at 80° C. for 24 h. After cooling to room temperature, 1,4-bistrifluoromethylbenzene (3.6 mg, 2.6 μl, 17 μmol, 0.17 equiv.) was added to the reaction mixture, stirred and a sample (approx. 0.1 mL) was diluted with CD.sub.3CN (0.5 mL) and the yield of the title products was determined by .sup.19F NMR using 1,4-bis(trifluoromethyl)benzene as an internal standard to be 23% (3aa:3ab 52:48) and 69% of 11 new, unidentified fluorine peaks (based on .sup.19F NMR integration relative to the standard between δ −110 and −130 ppm; the percentage does not necessarily correlate to a yield of product because it does not correct for difluoro- or poly-fluoroarenes).
Example 2. 4-Fluoro-bromobenzene (3ba) and 2-fluoro-bromobenzene (3bb)
(234) ##STR00075##
(235) A mixture of palladium complex S1 (27.7 mg, 50.0 μmol, 5.00 mol %) and 2-chloro-phenanthroline (10.7 mg, 50.0 μmol, 5.00 mol %.) was dissolved in acetonitrile (5.0 mL). This mixture was added to a 20 mL vial containing a solution of Selectfluor (709 mg, 2.00 mmol, 2.00 equiv.) and bromobenzene (157 mg, 106 μl, 1.0 mmol, 1.0 equiv.) in acetonitrile (5.0 mL, final c=0.10 M). The reaction mixture was stirred for 12 hours at 50° C. and then transferred to a separatory funnel. Pentane (25 mL) was added and the organic layer was washed with saturated aqueous NaHCO.sub.3 solution (1×25 mL). The aqueous layer was extracted with pentane (3×25 mL). The combined organic layers were filtered through a short plug of silica and and concentrated in vacuo at 20° C. to afford a colorless oil (178 mg) containing the title compound (101 mg, 0.58 mmol, 58% yield, 3ba:3bb (62:38)), bromobenzene, pentane and minor fluorinated impurities. The remaining solvent was not removed from the sample due to volatility of the product. The solvent and bromobenzene content of the residue was established by .sup.1H NMR spectrum of the mixture (diagnostic signal for bromobenzene: δ 7.52-7.48 ppm (m, 1H)). The yield and selectivity were determined by .sup.19F using 1,4-bis(trifluoromethyl)benzene as an internal standard (standard: δ −63.4 ppm, 6 F; compared with product peaks at δ −110.2 and −118.4 ppm; first relaxation time of 10 s to ensure accurate integration). A sample with of higher purity was obtained for characterization by further purification using column chromatography with spherical silica gel (Biotage ZIP Sphere 30 g, pentane). The spectra matched the reported spectra for the title compounds. (See Mazzotti et al., J Am. Chem. Soc., 2013, 135, 14012-14015; Seo et al., Chem. Commun., 2012, 48, 8270-8272). R.sub.f=0.70 (hexane).
(236) NMR Spectroscopy: 1-Bromo-4-fluorobenzene (3ba): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 7.47-7.41 (m, 2H), 6.99-6.92 (m, 2H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): 162.0 (d, J=246.6 Hz), 133.1 (d, J=7.8 Hz), 117.4 (d, J=22.3 Hz), 116.7 (d, J=3.2 Hz) ppm. .sup.19F NMR (470 MHz, CDCl.sub.3, 23° C., δ): −118.4 ppm. 1-Bromo-2-fluorobenzene (3bb): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 7.59-7.52 (m, 1H), 7.28 (m, 1H), 7.12 (td, J=8.5, 1.5 Hz, 1H), 7.03 (td, J=7.7, 1.5 Hz, 1H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): 159.3 (d, J=247.6 Hz), 133.7 (s), 129.1 (d, J=7.2 Hz), 125.4 (d, J=3.9 Hz), 116.7 (d, J=22.5 Hz), 109.2 (d, J=20.9 Hz) ppm. .sup.19F NMR (470 MHz, CDCl.sub.3, 23° C., δ): −110.2 ppm. HRMS-FIA(m/z) calculated for C.sub.6H.sub.4BrF [M]+, 173.9475; found, 173.9475.
(237) Reaction without Catalyst:
(238) Under N.sub.2 atmosphere, an oven-dried 4 mL vial was charged with Selectfluor (71 mg, 200 μmol, 2.0 equiv.) and bromobenzene (81 mg, 9.4 μl, 100 μmol, 1.0 equiv.) in acetonitrile (1.0 mL, c=0.10 M). The resulting reaction mixture was stirred at 80° C. for 24 h. After cooling to room temperature, 1,4-bistrifluoromethylbenzene (3.6 mg, 2.6 μl, 17 μmol, 0.17 equiv.) was added to the reaction mixture, stirred and a sample (approx. 0.1 mL) was diluted with CD.sub.3CN (0.5 mL) and the yield of the title products was determined by .sup.19F NMR using 1,4-bis(trifluoromethyl)benzene as an internal standard to be <.sup.1%.
Example 3. 4-Fluoro-chlorobenzene (3ca) and 2-fluoro-chlorobenzene (3cb)
(239) ##STR00076##
(240) A mixture of palladium complex S1 (27.7 mg, 50.0 μmol, 5.00 mol %) and 2-chloro-phenanthroline (10.7 mg, 50.0 μmol, 5.00 mol %.) was dissolved in acetonitrile (5.0 mL). This mixture was added to a 20 mL vial containing a solution of Selectfluor (709 mg, 2.00 mmol, 2.00 equiv.) and chlorobenzene (113 mg, 102 μl, 1.0 mmol, 1.0 equiv.) in acetonitrile (5.0 mL, final c=0.10 M). The reaction mixture was stirred for 12 hours at 50° C. and then transferred to a separatory funnel. Pentane (25 mL) was added and the organic layer was washed with saturated aqueous NaHCO.sub.3 solution (1×25 mL). The aqueous layer was extracted with pentane (3×25 mL). The combined organic layers were filtered through a short plug of silica and and concentrated in vacuo at 0° C. to afford a colorless oil (153 mg) containing the title compound (76 mg, 0.58 mmol, 58% yield, 3ca:3cb (62:38)), chlorobenzene pentane and other minor impurities. The remaining solvent was not removed from the sample due to volatility of the product. The solvent and chlorobenzene content of the residue was established by .sup.1H NMR spectrum of the mixture (signals for chlorobenzene overlap with product: δ 7.20-7.36 ppm (m, 5H)). The yield and selectivity were determined by .sup.19F using 1,4-bis(trifluoromethyl)benzene as an internal standard (standard: δ −63.4 ppm, 6 F; compared with product peaks at δ −115.5 and −116.0 ppm; first relaxation time of 10 s to ensure accurate integration). The yield was also confirmed by a GC assay with 1,4-bis(trifluoromethyl)benzene as an internal standard. The spectra matched the reported spectra for the title compounds and authentic samples. See Dubbaka, et al., Tetrahedron, 2014, 70, 9676-9681; Dmowski et al., J. Fluor. Chem., 1998, 88, 143-151. R.sub.f=0.70 (hexane). HRMS-APPI (m/z) calculated for C.sub.6H.sub.4ClF [M].sup.+, 129.9980; found, 129.9980.
(241) NMR Spectroscopy: 1-Chloro-4-fluorobenzene (3ca): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 7.36-7.27 (m, 2H), 7.00 (dd, J=9.0, 8.2 Hz, 2H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): 161.48 (d, J=246.1 Hz), 130.1 (d, J=8.1 Hz), 129.32 (d, J=3.2 Hz), 116.9 (d, J=23.2 Hz) ppm. .sup.19F NMR (470 MHz, CDCl.sub.3, 23° C., δ): −116.0 ppm. 1-Chloro-2-fluorobenzene (3cb):
(242) .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 7.40 (td, J=7.7, 1.7 Hz, 1H), 7.32-7.21 (m, 1H), 7.14 (ddd, J=9.6, 8.2, 1.5 Hz, 1H), 7.12-7.05 (m, 1H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): 158.37 (d, J=248.6 Hz), 130.8, 128.3 (d, J=7.2 Hz), 125.0 (d, J=4.1 Hz), 121.1, 116.8 (d, J=20.8 Hz) ppm. .sup.19F NMR (470 MHz, CDCl.sub.3, 23° C., δ): −115.5 ppm.
(243) Reaction without Catalyst:
(244) Under N.sub.2 atmosphere, an oven-dried 4 mL vial was charged with Selectfluor (71 mg, 200 μmol, 2.0 equiv.) and chlorobenzene (81 mg, 9.4 μl, 100 μmol, 1.0 equiv.) in acetonitrile (1.0 mL, c=0.10 M). The resulting reaction mixture was stirred at 80° C. for 24 h. After cooling to room temperature, 1,4-bistrifluoromethylbenzene (3.6 mg, 2.6 μl, 17 μmol, 0.17 equiv.) was added to the reaction mixture, stirred and a sample (approx. 0.1 mL) was diluted with CD.sub.3CN (0.5 mL) and the yield of the title products was determined by .sup.19F NMR using 1,4-bis(trifluoromethyl)benzene as an internal standard to be <.sup.1%.
Example 4. 4′-Cyano-2-fluorobiphenyl (3da) and 4′-cyano-4-fluorobiphenyl (3db)
(245) ##STR00077##
(246) A mixture of palladium complex S1 (27.7 mg, 50.0 μmol, 5.00 mol %) and 2-chloro-phenanthroline (10.7 mg, 50.0 μmol, 5.00 mol %.) was dissolved in acetonitrile (5.0 mL). This mixture was added to a 20 mL vial containing a solution of NFBS (615 mg, 2.00 mmol, 2.00 equiv.) and 4-cyanobiphenyl (179 mg, 1.0 mmol, 1.0 equiv.) in acetonitrile (5.0 mL, final c=0.10 M). The reaction mixture was stirred for 20 hours at 25° C. The remaining oxidant was quenched by adding a solution of Na.sub.2S.sub.2O.sub.3(H.sub.2O).sub.5 (1.22 g, 5.00 mmol, 5.00 equiv.) in water (20 mL) and stirring for 30 min. The mixture was added to a separatory funnel with 50 mL dichloromethane. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo at 40° C. to afford a pale yellow solid. The residue was dissolved in dichloromethane (2 mL), loaded onto a short plug of silica (20 g) and eluted with dichloromethane. and concentrated in vacuo to afford a pale yellow solid (191 mg) containing the title compounds (144 mg, 0.73 mmol, 73% yield, 3da:3db (73:27)), 4-cyano-biphenyl and minor inseparable impurities. The 4-cyano-biphenyl content of the residue was established by 1H NMR spectrum of the mixture (diagnostic signal at δ 7.48 ppm (m, 2H)). The yield and selectivity were determined by .sup.19F using 1,4-bis(trifluoromethyl)benzene as an internal standard (standard: δ −63.4 ppm, 6 F; compared with product peaks at δ −113.8 and −118.2 ppm; first relaxation time of 10 s to ensure accurate integration). The spectra matched the reported spectra for the title compounds and authentic samples. See Zhou et al., J. Org. Chem., 2012, 77, 10468-10472; Bernhardt et al., Angew. Chem., Int. Ed., 2011, 50, 9205-9209.
Example 5. Larger Scale Fluorination Under Ambient Atmosphere
(247) A mixture of palladium complex S1 (416 mg, 750 μmol, 5.00 mol %) and 2-chloro-phenanthroline (161 mg, 750 μmol, 5.00 mol %.) was dissolved in acetonitrile (75 mL). This mixture was added to a 20 mL vial containing a solution of NFBS (9.46 g, 30.0 mmol, 2.00 equiv.) and 4-cyanobiphenyl (2.69 g, 15.0 mmol, 1.0 equiv.) in acetonitrile (75 mL, final c=0.10 M). The reaction mixture was stirred for 20 hours at 25° C. The remaining oxidant was quenched by adding a solution of Na.sub.2S.sub.2O.sub.3.(H.sub.2O).sub.5 (14.9 g, 60.0 mmol, 4.00 equiv.) in water (200 mL) and stirring for 1 hour. The mixture was added to a separatory funnel with 200 mL dichloromethane. The aqueous layer was extracted with dichloromethane (3×200 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo at 40° C. to afford a pale yellow solid. The residue was dissolved in dichloromethane (15 mL), loaded onto a short plug of silica (150 g) and eluted with dichloromethane and concentrated in vacuo to afford a pale yellow solid (2.86 g) containing the title compounds (2.2 g, 11 mmol, 73% yield, 3da:3db (73:27)), 4-cyano-biphenyl (710 mg, 26%) and minor inseparable impurities. The yield and selectivity were as determined by .sup.1H and .sup.19F NMR using the relative integrations of the cyanophenyl moiety protons (δ 7.60-7.75 ppm, 4H combined for all components), cyanobiphenyl diagnostic protons (δ 7.48 ppm (m, 2H)) and product protons (δ 7.25-7.13 ppm (m, 2H)) combined with the relative ratio of the .sup.19F NMR signals (δ −113.8 and −118.2 ppm). R.sub.f=0.75 (dichloromethane).
(248) NMR Spectroscopy: 4′-cyano-2-fluorobiphenyl (3da): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 7.75-7.60 (m, 4H), 7.45-7.36 (m, 2H), 7.25-7.16 (m, 2H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): 159.8 (d, J=249.3 Hz), 140.6, 135.4, 132.4, 130.6 (d, J=3.0 Hz), 130.5 (d, J=8.6 Hz), 129.8 (d, J=3.0 Hz), 127.8 (d, J=19.1 Hz), 127.3 (d, J=13.1 Hz), 124.9 (d, J=3.6 Hz), 119.0, 116.6 (d, J=22.6 Hz), 111.1 ppm. .sup.19F NMR (470 MHz, CDCl.sub.3, 23° C., δ): −118.2 ppm. 4′-cyano-4-fluorobiphenyl (3db): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 7.75-7.60 (m, 4H), 7.60-7.53 (m, 2H), 7.21-7.13 (m, 2H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): 163.3 (d, J=248.9 Hz), 144.6, 135.4, 132.8, 129.1 (d, J=8.3 Hz), 127.4, 118.9, 116.3 (d, J=21.5 Hz), 111.5 ppm. .sup.19F NMR (470 MHz, CDCl.sub.3, 23° C., δ): −113.8 ppm. HRMS-EI (m/z) calculated for C.sub.13H.sub.8FN [M].sup.+, 197.0641; found, 197.0640.
(249) Reactions without Catalyst
(250) Under N.sub.2 atmosphere, an oven-dried 4 mL vial was charged with Selectfluor (71 mg, 200 μmol, 2.0 equiv.), 4-cyanobiphenyl (19.7 mg, 100 μmol, 1.0 equiv.), and acetonitrile (1.0 mL, c=0.10 M). The resulting reaction mixture was stirred at 80° C. for 24 h. After cooling to room temperature, 1,4-bistrifluoromethylbenzene (3.6 mg, 2.6 μl, 17 μmol, 0.17 equiv.) was added to the reaction mixture, stirred and a sample (approx. 0.1 mL) was diluted with CD.sub.3CN (0.5 mL) and the yield of the title products was determined by .sup.19F NMR using 1,4-bis(trifluoromethyl)benzene as an internal standard to be 19% (5da:5db 79:21).
(251) Under N.sub.2 atmosphere, an oven-dried 4 mL vial was charged with NFBS (63.0 mg, 200.0 μmol, 2.00 equiv.), cyanobiphenyl (19.7 mg, 100 μmol, 1.0 equiv.), and acetonitrile (1.0 mL, c=0.10 M). The resulting reaction mixture was stirred at 80° C. for 24 h. After cooling to room temperature, 1,4-bistrifluoromethylbenzene (3.6 mg, 2.6 μl, 17 μmol, 0.17 equiv.) was added to the reaction mixture, stirred and a sample (approx. 0.1 mL) was diluted with CD.sub.3CN (0.5 mL) and the yield of the title products was determined by .sup.19F NMR using 1,4-bis(trifluoromethyl)benzene as an internal standard to be <1%.
Example 6. 2-Fluoro-3′,5′-bis(trifluoromethyl)biphenyl (3ea) and 4-fluoro-3′,5′-bis(trifluoromethyl)biphenyl (3eb)
(252) ##STR00078##
(253) A mixture of palladium complex S1 (27.7 mg, 50.0 μmol, 5.00 mol %) and 2-chloro-phenanthroline (10.7 mg, 50.0 μmol, 5.00 mol %.) was dissolved in acetonitrile (5.0 mL). This mixture was added to a 20 mL vial containing a solution of Selectfluor (709 mg, 2.00 mmol, 2.00 equiv.) and 3,5-bis(trifluoromethyl)biphenyl (290 mg, 1.0 mmol, 1.0 equiv.) in acetonitrile (5.0 mL, final c=0.10 M). The reaction mixture was stirred for 16 hours at 50° C. and then transferred to a separatory funnel. Pentane (25 mL) was added and the organic layer was washed with saturated aqueous NaHCO.sub.3 solution (25 mL). The aqueous layer was extracted with pentane (3×25 mL). The combined organic layers were filtered through a short plug of silica (20 g), eluted with pentane and concentrated in vacuo at 25° C. to afford a colorless oil (312 mg) containing the title compounds (230 mg, 0.75 mmol, 75% yield, 3ea: 3eb (72:28)), 3,5-bis(trifluoromethyl)biphenyl and pentane. The remaining solvent was not removed from the sample due to volatility of the product. The yield and selectivity were determined by .sup.19F using 1,4-bis(trifluoromethyl)benzene as an internal standard (standard: δ −63.4 ppm, 6 F; compared with product peaks at δ −113.8 and −118.2 ppm; first relaxation time of 10 s to ensure accurate integration). The solvent content of the residue and selectivity was determined by integration of the .sup.1H NMR spectrum of the mixture and the yield was .sup.19F and .sup.1H NMR using 1,4-bis(trifluoromethyl)benzene as an internal standard. The spectra matched the reported spectra for the title compound 3eb. See Minami et al., Angew. Chem., Int. Ed., 2015, 54, 4665-4668. R.sub.f=0.75 (pentane). HRMS-FIA(m/z) calculated for C.sub.14H.sub.7F.sub.7 [M]+, 308.0432; found, 308.0436.
(254) NMR Spectroscopy: 2-fluoro-3′,5′-bis(trifluoromethyl)biphenyl (3ea): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 8.01 (s, 2H), 7.89 (s, 1H), 7.47 (td, J=7.7, 1.8 Hz, 1H), 7.45-7.40 (m, 1H), 7.29 (td, J=7.6, 1.2 Hz, 1H), 7.20 (t, J=8.7 Hz, 1H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): 159.75 (d, J=249.2 Hz), 138.0, 132.0 (q, J=33.3 Hz), 130.9 (d, J=8.4 Hz), 130.6 (d, J=2.8 Hz), 129.3 (m), 126.3 (d, J=13.1 Hz), 125.0 (d, J=3.7 Hz), 123.5 (q, J=272.8 Hz), 121.6 (hept, J=3.3 Hz), 116.7 (d, J=22.5 Hz) ppm. .sup.19F NMR (470 MHz, CDCl.sub.3, 23° C., δ): −62.9 (3F), −118.0 (1F) ppm. 4-fluoro-3′,5′-bis(trifluoromethyl)biphenyl (3eb): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 7.97 (s, 2H), 7.86 (s, 1H), 7.59 (dd, J=8.8, 5.1 Hz, 2H), 7.23 (dd, J=8.3, 1.2 Hz, 2H), 132.4 (q, J=33.4 Hz). .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): 163.5 (d, J=249.6 Hz), 142.5, 134.5, 134.5, 129.3 (m), 127.2, 123.5 (q, J=272.8 Hz), 121.1 (hept, J=3.8 Hz), 116.5 (d, J=21.7 Hz) ppm. .sup.19F NMR (470 MHz, CDCl.sub.3, 23° C., δ): −62.9 (3F), −112.8 (1F) ppm.
(255) Reactions without Catalyst
(256) Under N.sub.2 atmosphere, an oven-dried 4 mL vial was charged with Selectfluor (71 mg, 200 μmol, 2.0 equiv.) and 3,5-bis(trifluoromethyl)biphenyl (29.0 mg, 100 μmol, 1.0 equiv.) in acetonitrile (1.0 mL, c=0.10 M). The resulting reaction mixture was stirred at 80° C. for 24 h. After cooling to room temperature, 1,4-bistrifluoromethylbenzene (3.6 mg, 2.6 μl, 17 μmol, 0.17 equiv.) was added to the reaction mixture, stirred and a sample (approx. 0.1 mL) was diluted with CD3CN (0.5 mL) and the yield of the title products was determined by .sup.19F NMR using 1,4-bis(trifluoromethyl)benzene as an internal standard to be 7% (5ea:5eb 75:25).
Example 7. 1-(3-Bromopropyl)-2-fluorobenzene (3fa) and 1-(3-bromopropyl)-4-fluorobenzene (3fb)
(257) ##STR00079##
(258) A mixture of palladium complex S1 (27.7 mg, 50.0 μmol, 5.00 mol %) and 2-chloro-phenanthroline (10.7 mg, 25 μmol, 5.0 mol %) was dissolved in acetonitrile (5.0 mL). This mixture was added to a 20 mL vial containing a solution of NFBS (315 mg, 1.00 mmol, 2.00 equiv.) and 3-bromopropylbenzene (199 mg, 152 μl, 1.00 mmol, 1.0 equiv.) in acetonitrile (5.0 mL, final c=0.10 M). The reaction mixture was stirred for 24 hours at 25° C. and then transferred to a separatory funnel. Pentane (50 mL) was added and the organic layer was washed with 5% sodium chloride solution (75 mL). The aqueous layer was extracted with pentane (4×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo at 40° C. to afford a yellow oil. The residue was dissolved in pentane (2 mL), loaded onto a short plug of silica (20 g) and eluted with pentane. A colorless oil (137 mg) containing the title compounds (112 mg, 0.52 mmol, 52% yield, 3fa:3fb (64:36)), 3-bromopropylbenzene and residual solvent was obtained. Residual solvent was not removed due to volatility of the product. The yield and selectivity were determined by .sup.19F NMR using 1,4-bis(trifluoromethyl)benzene as an internal standard (standard: δ −63.4 ppm, 6 F; compared with product peaks at δ −115.5 and −116.0 ppm; first relaxation time of 10 s to ensure accurate integration). Purification using column chromatography with spherical silica gel (Biotage ZIP Sphere 30 g, dichloromethane:pentane 0:100 to 2:98 (v:v)), provided samples of 3fa (>95% pure by .sup.19F NMR) and 3fb (contaminated with 3-bromopropylbenzene). The spectra matched the reported spectra for the title compounds. See European Patent, EP2168944. R.sub.f=0.55 (pentane).
(259) NMR Spectroscopy: 1-(3-bromopropyl)-2-fluorobenzene (3fa): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 7.25-7.15 (m, 2H), 7.07 (td, J=7.5, 1.2 Hz, 1H), 7.02 (ddd, J=9.6, 8.1, 1.2 Hz, 1H), 3.41 (t, J=6.6 Hz, 2H), 2.82 (t, J=7.4 Hz, 2H), 2.18 (dq, J=8.5, 6.7 Hz, 2H) ppm. .sup.13C NMR (126 MHz, CDCl.sub.3, 23° C., δ): 161.2 (d, J=245.3 Hz), 130.9 (d, J=5.0 Hz), 128.0 (d, J=7.8 Hz), 127.4 (d, J=15.7 Hz), 124.1 (d, J=3.6 Hz), 115.4 (d, J=22.0 Hz), 33.0, 32.8, 27.6 (d, J=2.7 Hz) ppm. .sup.19F NMR (471 MHz, CDCl.sub.3, 23° C., δ) −118.6 ppm. 1-(3-bromopropyl)-2-fluorobenzene (3fb): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 7.25-7.18 (m, 1H), 6.98 (t, J=8.7 Hz, 0H), 3.47-3.27 (m, 1H), 2.77 (dt, J=12.5, 7.4 Hz, 1H), 2.27-2.06 (m, 1H) ppm. .sup.13C NMR (126 MHz, CDCl.sub.3, 23° C., δ): 161.6 (d, J=244.3 Hz), 136.3 (d, J=3.4 Hz), 128.7 (d, J=7.1 Hz), 115.4 (d, J=20.9 Hz), 34.3, 33.3 ppm. .sup.19F NMR (471 MHz, CDCl.sub.3, 23° C., δ) −117.2 ppm. HRMS-APPI (m/z) calculated for C.sub.12H.sub.18F [M].sup.+, 215.9945; found, 215.9947.
(260) Reaction without Catalyst.
(261) Under N.sub.2 atmosphere, an oven-dried 4 mL vial was charged with Selectfluor (71 mg, 200 μmol, 2.0 equiv.) and 3-bromopropylbenzene (8.1 mg, 9.4 μl, 100 μmol, 1.0 equiv.) in acetonitrile (1.0 mL, c=0.10 M). The resulting reaction mixture was stirred at 80° C. for 24 h. After cooling to room temperature, 1,4-bistrifluoromethylbenzene (3.6 mg, 2.6 17 μmol, 0.17 equiv.) was added to the reaction mixture, stirred and a sample (approx. 0.1 mL) was diluted with CD.sub.3CN (0.5 mL) and the yield of the title products was determined by .sup.19F NMR using 1,4-bis(trifluoromethyl)benzene as an internal standard to be 24% (3fa:3fb 71:29).
Example 8. Nortropinone (4-(2′-fluoro-biphenyl))sulfonamide (3ga) and nortropinone (4-(4′-fluoro-biphenyl))sulfonamide (3gb)
(262) ##STR00080##
(263) A mixture of palladium complex S1 (27.7 mg, 50.0 μmol, 5.00 mol %) and 2-chloro-phenanthroline (10.7 mg, 50.0 μmol, 5.00 mol %.) was dissolved in acetonitrile (5.0 mL). This mixture was added to a 20 mL vial containing a solution of NFBS (615 mg, 2.00 mmol, 2.00 equiv.) and 8-(biphenyl-4-ylsulfonyl)-8-azabicyclo[3.2.1]octan-3-one (341 mg, 1.0 mmol, 1.0 equiv.) in dichloroethane (5.0 mL, final c=0.10 M). The reaction mixture was stirred for 25 hours at 25° C. The remaining oxidant was quenched by adding a solution of Na.sub.2S.sub.2O.sub.3(H.sub.2O).sub.5 (1.22 g, 5.00 mmol, 5.00 equiv.) in water (20 mL) and stirring for 30 min. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo at 40° C. to afford a pale yellow solid. The residue was dissolved in dichloromethane (2 mL), loaded onto a short plug of silica (20 g) and eluted with ethyl acetate. and concentrated in vacuo to afford a colorless solid (312 mg) containing the title compounds (262 mg, 0.729 mmol 73% yield, 3ga: 3gb (74:26)), 8-(biphenyl-4-ylsulfonyl)-8-azabicyclo[3.2.1]octan-3-one and minor inseparable impurities. The yield and selectivity were determined by .sup.19F using 1,4-bis(trifluoromethyl)benzene as an internal standard (standard: δ −63.4 ppm, 6 F; compared with product peaks at δ −113.2 and −117.5 ppm; first relaxation time of 10 s to ensure accurate integration). Purification by HPLC (MultoKrom Si, 3 μm, 20 mm×250 mm, isohexane:isopropanol 95:5, 20 mL/min, 8.9 MPa, 308 K, 220 nm UV) provided purified product isomers, yielding the title compound 3ga (83% pure by HPLC, retention time 12.9 min.) and a second fraction enriched with 3gb relative to the unpurified material (43% 3gb by HPLC, 65:35 ratio with 3ga by .sup.19F NMR, retention time 15.5 min.). The relevant signals of the spectra matched the corresponding signals of spectra reported for a 4′-fluoro-4-sulfonamide biphenyl and a 2′-fluoro-4-sulfonamide biphenyl motifs. See 2′-fluoro-4-sulfonamide biphenyl, similar to 5ka3ga: De Brabander, J; Shay, J. W.; Wang, W. Therapeutics Targeting Truncated Adenomatous Polypsis Coli (APC) Proteins. US Patent US2015232444, Aug. 20, 2015; 4′-fluoro-4-sulfonamide biphenyl, similar to 5 kb3gb: Urlam, M. K.; Pireddu, R.; Ge, Y; Zhang, X.; Sun, Y; Lawrence, H. R.; Guida, W. C.; Sebti, S. M.; Lawrence, N. J. Med Chem Comm 2013, 4, 932-941. R.sub.f=0.40 (ethyl acetate/dichloromethane, 10:90 (v/v)). HRMS-FIA(m/z) calculated for C.sub.19H.sub.18FNO.sub.3 SNa [M+Na].sup.+, 382.0884; found, 382.0887.
(264) NMR Spectroscopy: 8-((2′-fluoro-biphenyl-4-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-one (3ga): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 7.98 (d, J=8.5 Hz, 2H), 7.70 (d, J=8.5 Hz, 2H), 7.51-7.36 (m, 2H), 7.30-7.22 (m, 1H), 7.19 (dd, J=10.9, 8.2 Hz, 1H), 4.60-4.50 (m, 1H), 2.83 (dd, J=16.5, 4.5 Hz, 2H), 2.47-2.31 (m, 2H), 1.87-1.70 (m, 2H), 1.63 (d, J=7.8 Hz, 2H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): 206.9, 159.8 (d, J=249.2 Hz), 141.0, 138.9, 130.7 (d, J=2.9 Hz), 130.5 (d, J=8.4 Hz), 130.0 (d, J=3.4 Hz), 129.3, 128.8, 128.0, 127.5, 124.9 (d, J=3.6 Hz), 116.6 (d, J=22.6 Hz), 56.3, 50.4, 29.6. ppm. .sup.19F NMR (470 MHz, CDCl.sub.3, 23° C., δ): −117.5 ppm. 8-((4′-fluoro-biphenyl-4-yl)sulfonyl)-8-azabicyclo[3.2.1]octan-3-one (3gb): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 7.97 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.5 Hz, 2H), 7.58 (dd, J=8.8, 5.2 Hz, 2H), 7.18 (t, J=8.6 Hz, 2H), 4.63-4.45 (m, 2H), 2.83 (d, J=16.4 Hz, 2H), 2.54-2.14 (m, 2H), 1.91-1.70 (m, 2H), 1.63 (d, J=7.8 Hz, 2H). .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): 206.8, 163.4 (d, J=248.6 Hz), 145.2, 138.6, 129.2 (d, J=8.2 Hz), 128.0, 127.8, 127.6, 116.3 (d, J=21.5 Hz), 56.2, 50.4, 29.6. ppm. .sup.19F NMR (470 MHz, CDCl.sub.3, 23° C., δ): −113.2 ppm.
(265) Reaction without Catalyst:
(266) Under N.sub.2 atmosphere, an oven-dried 4 mL vial was charged with Selectfluor (71 mg, 200 μmol, 2.0 equiv.) and 8-(biphenyl-4-ylsulfonyl)-8-azabicyclo[3.2.1]octan-3-one (34.1 mg, 100 μmol, 1.0 equiv.) in acetonitrile (1.0 mL, c=0.10 M). The resulting reaction mixture was stirred at 80° C. for 24 h. After cooling to room temperature, 1,4-bistrifluoromethylbenzene (3.6 mg, 2.6 μl, 17 μmol, 0.17 equiv.) was added to the reaction mixture, stirred and a sample (approx. 0.1 mL) was diluted with CD.sub.3CN (0.5 mL) and the yield of the title products was determined by .sup.19F NMR using 1,4-bis(trifluoromethyl)benzene as an internal standard to be 27% (standard: δ −63.4 ppm, 6 F; compared with product peaks at δ −113.2 and −117.5 ppm; first relaxation time of 10 s to ensure accurate integration) to be 18% (3ga:3gb (84:16)) and 109% of 2 new, unidentified fluorine peaks at δ −175.9 ppm (23%) and −178.8 ppm (86%) most likely derived from α-fluorination of the ketone (based on fluoride integration relative to the standard; the percentage does not necessarily correlate to a yield of product because it does not correct for difluoro- or poly-fluoro products).
Example 9. Ethyl trans-2-(2-fluorophenyl)cyclopropane-1-carboxylate (3ha) and ethyl trans-2-(4-fluorophenyl)cyclopropane-1-carboxylate (3hb)
(267) ##STR00081##
(268) A mixture of palladium complex S1 (27.7 mg, 50.0 μmol, 5.00 mol %) and 2-chloro-phenanthroline (10.7 mg, 50.0 μmol, 5.00 mol %.) was dissolved in acetonitrile (5.0 mL). This mixture was added to a 20 mL vial containing a solution of NFBS (615 mg, 2.00 mmol, 2.00 equiv.) and racemic ethyl trans-2-phenylcyclopropane-1-carboxylate (190 mg, 1.0 mmol, 1.0 equiv.) in acetonitrile (5.0 mL, final c=0.10 M). The reaction mixture was stirred for 20 hours at 25° C. The remaining oxidant was quenched by adding a solution of Na.sub.2S.sub.2O.sub.3(H.sub.2O).sub.5 (1.22 g, 5.00 mmol, 5.00 equiv.) in water (20 mL) and stirring for 30 min. The mixture was added to a separatory funnel with 50 mL dichloromethane. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo at 40° C. to afford a pale yellow solid. The residue was dissolved in dichloromethane (2 mL), loaded onto a short plug of silica (20 g) and eluted with dichloromethane/pentane 30:70 (v/v). and concentrated in vacuo to afford a colorless solid (147 mg) containing the title compounds (110 mg, 0.53 mmol, 53% yield, 3ha:3hb (70:30)), ethyl trans-2-phenylcyclopropane-1-carboxylate and minor inseparable impurities The yield and selectivity were determined by .sup.19F using 1,4-bis(trifluoromethyl)benzene as an internal standard (standard: δ −63.4 ppm, 6 F; compared with product peaks at δ −116.4 and −118.8 ppm; first relaxation time of 10 s to ensure accurate integration). The spectra matched the reported spectra for the title compounds. See WIPO patent, WO2007025144; Pryde et al., Bioorg. Med. Chem. 2007, 15, 142-159. R.sub.f=0.70 (dichloromethane). HRMS-FIA(m/z) calculated for C.sub.12H.sub.13FO.sub.2Na [M+Na].sup.+, 231.0792; found, 231.0792.
(269) NMR Spectroscopy: Ethyl trans-2-(2-fluorophenyl)cyclopropane-1-carboxylate (3ha): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 7.31-6.99 (m, 4H), 4.17 (q, J=7.0 Hz, 2H), 2.55-2.44 (m, 1H), 1.84 (ddd, J=8.4, 5.2, 4.2 Hz, 1H), 1.62-1.55 (m, 1H), 1.28 (t, J=7.2 Hz, 3H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): 173.4, 161.7 (d, J=244.9 Hz), 127.9 (d, J=8.1 Hz), 127.2 (d, J=14.0 Hz), 127.1 (d, J=4.0 Hz) 124.1 (d, J=3.5 Hz), 115.4 (d, J=21.4 Hz), 60.9, 25.6, 20.0 (d, J=4.8 Hz), 15.8 (d, J=1.0 Hz), 14.4 ppm. .sup.19F NMR (470 MHz, CDCl.sub.3, 23° C., δ): −116.4 ppm. Ethyl trans-2-(4-fluorophenyl)cyclopropane-1-carboxylate (3hb): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 7.30-6.99 (m, 1H), 4.23-4.13 (m, 1H), 2.66 (ddd, J=9.4, 6.6, 4.3 Hz, 1H), 1.96-1.91 (m, 1H), 1.65-1.53 (m, 1H), 1.28 (t, J=7.2 Hz, 3H). .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): 173.6, 161.8 (d, J=246.3 Hz), 135.9 (d, J=3.2 Hz), 128.0 (d, J=8.3 Hz), 115.5 (d, J=22.0 Hz), 60.8, 26.3, 24.3, 24.1, 22.9, 17.2, 17.0. ppm. .sup.19F NMR (470 MHz, CDCl.sub.3, 23° C., δ): −118.8 ppm.
(270) Reactions without Catalyst
(271) Under N.sub.2 atmosphere, an oven-dried 4 mL vial was charged with Selectfluor (71 mg, 200 μmol, 2.0 equiv.) and ethyl trans-2-phenylcyclopropane-1-carboxylate (19.0 mg, 100 μmol, 1.0 equiv.) in acetonitrile (1.0 mL, c=0.10 M). The resulting reaction mixture was stirred at 80° C. for 24 h. After cooling to room temperature, 1,4-bistrifluoromethylbenzene (3.6 mg, 2.6 μl, 17 μmol, 0.17 equiv.) was added to the reaction mixture, stirred and a sample (approx. 0.1 mL) was diluted with CD.sub.3CN (0.5 mL) and the yield of the title products was determined by .sup.19F NMR using 1,4-bis(trifluoromethyl)benzene as an internal standard to be <.sup.1%.
Example 10. 5-(2-Fluorophenyl)pyrimidine (3ia) and 5-(4-fluorophenyl)pyrimidine (3ib)
(272) ##STR00082##
(273) A mixture of palladium complex S1 (27.7 mg, 50.0 μmol, 5.00 mol %) and 2-chloro-phenanthroline (10.7 mg, 50.0 μmol, 5.00 mol %.) was dissolved in acetonitrile (5.0 mL). This mixture was added to a 20 mL vial containing a solution of Selectfluor (709 mg, 2.00 mmol, 2.00 equiv.) and 5-phenylpyrimidine (156 mg, 1.0 mmol, 1.0 equiv.) in acetonitrile (5.0 mL, final c=0.10 M). The reaction mixture was stirred for 14 hours at 50° C. and then transferred to a separatory funnel. Ethyl acetate (50 mL) was added and the organic layer was washed with water (50 mL) with brine added (10 mL). The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo at 40° C. to afford a pale yellow solid. The residue was dissolved in dichloromethane (2 mL), loaded onto a short plug of silica (20 g) and eluted with ethyl acetate/dichloromethane 20:80 (v/v) and concentrated in vacuo to afford a yellow-orange solid (123 mg) containing the title compounds (111 mg, 0.580, 58% yield, 3ia:3ib (52:48)), 5-phenylpyrimidine and minor inseparable impurities. The yield and selectivity were determined by .sup.19F using 1,4-bis(trifluoromethyl)benzene as an internal standard (standard: δ −63.4 ppm, 6 F; compared with product peaks at δ −112.4 and −117.5 ppm; first relaxation time of 10 s to ensure accurate integration). The spectra matched the reported spectra for the title compound 5ib. See Liu et al., Chem. Commun., 2009, 6267-6269. R.sub.f=0.45 (ethyl acetate/dichloromethane 20:80 (v/v)). HRMS-FIA(m/z) calculated for C.sub.10H.sub.8FN.sub.2 [M+H]+, 175.0666; found, 175.0667.
(274) NMR Spectroscopy: .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): 163.5 (d, J=249.7 Hz), 159.9 (d, J=249.7 Hz), 157.7, 157.6, 157.6, 156.4 (d, J=4.1 Hz), 155.0, 154.8, 134.4 (d, J=8.3 Hz), 131.1 (d, J=8.3 Hz), 130.2 (d, J=2.9 Hz), 129.8 (d, J=1.8 Hz), 129.5, 129.1, 128.9 (d, J=8.4 Hz), 127.1, 125.2, 125.1, 116.7 (d, J=21.8 Hz), 116.6 (d, J=22.0 Hz). 5-(2-fluorophenyl)pyrimidine (3ia): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 9.15 (s, 1H), 8.91-8.84 (m, 3H), 7.55-7.33 (m, 4H), 7.27-7.10 (m, 3H). .sup.19F NMR (470 MHz, CDCl.sub.3, 23° C., δ): −117.5 ppm. 5-(4-fluorophenyl)pyrimidine (3ib): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 9.21 (d, J=1.2 Hz, 1H), 8.96 (s, 1H), 8.92 (s, 1H), 7.62-7.51 (m, 3H), 7.50-7.44 (m, 1H), 7.22 (t, J=8.6 Hz, 1H). .sup.19F NMR (500 MHz, CDCl.sub.3, 23° C., δ): −112.4 ppm.
(275) Reactions without Catalyst
(276) Under N.sub.2 atmosphere, an oven-dried 4 mL vial was charged with Selectfluor (71 mg, 200 μmol, 2.0 equiv.) and 5-phenylpyrimidine (15.6 mg, 100 μmol, 1.0 equiv.) in acetonitrile (1.0 mL, c=0.10 M). The resulting reaction mixture was stirred at 80° C. for 24 h. After cooling to room temperature, 1,4-bistrifluoromethylbenzene (3.6 mg, 2.6 μl, 17 μmol, 0.17 equiv.) was added to the reaction mixture, stirred and a sample (approx. 0.1 mL) was diluted with CD.sub.3CN (0.5 mL) and the yield of the title products was determined by .sup.19F NMR using 1,4-bis(trifluoromethyl)benzene as an internal standard to be 2%.
Example 11. 5-(2-Fluorophenyl)pyridine (3ja) and 5-(4-fluorophenyl)pyrimidine (3jb)
(277) ##STR00083##
(278) A mixture of palladium complex S1 (27.7 mg, 50.0 μmol, 5.00 mol %) and 2-chloro-phenanthroline (10.7 mg, 50.0 μmol, 5.00 mol %.) was dissolved in acetonitrile (5.0 mL). This mixture was added to a 20 mL vial containing a solution of Selectfluor (709 mg, 2.00 mmol, 2.00 equiv.) and 2-phenylpyridine (155 mg, 143 μl, 1.0 mmol, 1.0 equiv.) in acetonitrile (5.0 mL, final c=0.10 M). The reaction mixture was stirred for 14 hours at 50° C. and then transferred to a separatory funnel. Dichloromethane (50 mL) was added and the organic layer was washed with water (50 mL) with brine added (10 mL). The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo at 40° C. to afford a pale yellow solid. The residue was dissolved in dichloromethane (2 mL), loaded onto a short plug of silica (20 g) and eluted with 0.35 ethyl acetate/dichloromethane 30/70 (v/v), and concentrated in vacuo to afford a yellow oil (110 mg) containing the title compounds (85 mg, 0.49 mmol, 49% yield, 3ja:3jb (70:30)), 2-phenylpyridine, minor inseparable impurities and dichloromethane. The yield and selectivity were determined by .sup.19F using 1,4-bis(trifluoromethyl)benzene as an internal standard (standard: δ −63.4 ppm, 6 F; compared with product peaks at δ −113.4 and −117.7 ppm for the neutral pyridine; first relaxation time of 10 s to ensure accurate integration). Purification by HPLC (Kromasil-5 C18, 5 μm, 30 mm×150 mm, MeCN:H.sub.2O 35:65, 42.5 mL/min, 11.4 MPa, 293 K, 254 nm UV) provided purified product isomers 3ja (>99% pure by HPLC, retention time 15.3 min.) and 3jb (>99% pure by HPLC, retention time 18.3 min.). To decrease the volatility of the products, before concentrating the HPLC fractions were treated with excess trifluoroacetic acid, yielding the trifluoroacetic acid salt of the title compounds 3ja TFA and 3jb TFA as colorless solids. The spectra of the unpurified mixture matched the reported spectra for the title compounds. See Yu et al., Org. Lett., 2013, 15, 940-943. Wu et al., Chem. Commun., 2015, 51, 2286-2289. R.sub.f=0.35 (ethyl acetate/dichloromethane 30/70 (v/v)). HRMS-ESI (m/z) calculated for C.sub.11H.sub.9FN [M+H].sup.+, 174.0714; found 174.0714.
(279) NMR Spectroscopy: 2-(2-fluorophenyl)pyridine (3ja TFA): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 14.46 (br s), 9.07 (d, J=5.4 Hz, 1H), 8.42 (t, J=7.9 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.87 (t, J=6.3 Hz, 1H), 7.79 (t, J=7.9 Hz, 1H), 7.62 (td, J=7.9, 5.5 Hz, 1H), 7.41 (t, J=7.5 Hz, 1H), 7.31 (dd, J=10.8, 8.4 Hz, 1H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): 159.9 (d, J=253.8 Hz), 149.4, 144.7, 143.6, 134.6 (d, J=8.9 Hz), 130.9, 127.9 (d, J=6.5 Hz), 125.8 (d, J=3.7 Hz), 125.2, 119.6 (d, J=11.7 Hz), 117.1 (d, J=21.5 Hz) ppm. .sup.19F NMR (470 MHz, CDCl.sub.3, 23° C., δ): −75.8, −116.4 ppm. 2-(4-fluorophenyl)pyridine (3jb TFA): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): δ 15.56 (s, 1H), 9.02 (dd, J=5.7, 1.7 Hz, 1H), 8.31 (td, J=7.9, 1.4 Hz, 1H), 7.96 (dd, J=8.2, 1.1 Hz, 1H), 7.94-7.89 (m, 1H), 7.74 (ddd, J=7.2, 5.7, 1.2 Hz, 1H), 7.29 (t, J=8.5 Hz, 1H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): δ 165.2 (d, J=254.8 Hz), 161.7, 153.7, 144.2, 144.0, 130.6 (d, J=9.3 Hz), 128.5 (d, J=3.5 Hz), 124.6, 124.3, 117.2 (d, J=22.4 Hz). ppm. .sup.19F NMR (470 MHz, CDCl.sub.3, 23° C., δ): −75.8, −106.8 ppm.
(280) Reactions without Catalyst
(281) Under N.sub.2 atmosphere, an oven-dried 4 mL vial was charged with Selectfluor (71 mg, 200 μmol, 2.0 equiv.) and 2-phenylpyridine (15.6 mg, 100 μmol, 1.0 equiv.) in acetonitrile (1.0 mL, c=0.10 M). The resulting reaction mixture was stirred at 80° C. for 24 h. After cooling to room temperature, 1,4-bistrifluoromethylbenzene (3.6 mg, 2.6 μl, 17 μmol, 0.17 equiv.) was added to the reaction mixture, stirred and a sample (approx. 0.1 mL) was diluted with CD.sub.3CN (0.5 mL) and the yield of the title products was determined by .sup.19F NMR using 1,4-bis(trifluoromethyl)benzene as an internal standard to be <.sup.1%.
Example 12. Ethyl (2-fluorophenyl) nateglinide derivative (3ka) and ethyl (4-fluorophenyl) nateglinide Derivative (3kb)
(282) ##STR00084##
(283) A mixture of palladium complex S1 (27.7 mg, 50.0 μmol, 5.00 mol %) and 2-chloro-phenanthroline (10.7 mg, 50.0 μmol, 5.00 mol %.) was dissolved in acetonitrile (5.0 mL). This mixture was added to a 20 mL vial containing a solution of Selectfluor (709 mg, 2.00 mmol, 2.00 equiv.) and ethyl nateglinide (2k, ethyl (trans-4-isopropylcyclohexane-1-carbonyl)-D-phenylalaninate) (233 mg, 1.0 mmol, 1.0 equiv.) in acetonitrile (5.0 mL, final c=0.10 M). The reaction mixture was stirred for 24 hours at 0° C. and then transferred to a separatory funnel. Dichloromethane (50 mL) was added and the organic layer was washed with water (50 mL) with brine added (10 mL). The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo at 40° C. to afford a pale yellow solid. The residue was dissolved in dichloromethane (2 mL), loaded onto a short plug of silica (20 g) and eluted with ethyl acetate/dichloromethane 50:50 (v/v). and concentrated in vacuo to afford a colorless solid (265 mg) containing the title compounds (207 mg, 0.572 mmol, 57% yield, 3ka:3kb (60:40)), ethyl nateglinide and minor inseparable impurities. The yield and selectivity were determined by .sup.19F using 1,4-bis(trifluoromethyl)benzene as an internal standard (standard: δ −63.4 ppm, 6 F; compared with product peaks at δ −115.8 and −117.3 ppm; first relaxation time of 10 s to ensure accurate integration). Purification by HPLC (MultoKrom Si, 3 μm, 20 mm×250 mm, isohexane:isopropanol 99:1, 15 mL/min, 7.9 MPa, 308 K, 220 nm UV) provided purified product isomers, yielding the title compound 2ka (92% pure by HPLC, retention time 15.3 min.) and 2kb (97% pure by HPLC, retention time 18.1 min.). The spectra were comparable to the reported spectra for the corresponding acids of the title compounds. See US Patent: US2015045435. R.sub.f=0.55 (ethyl acetate/dichloromethane 50:50 (v/v)). HRMS-ESI (m/z) calculated for C.sub.21H.sub.30FNO.sub.3Na [M+Na].sup.+, 386.2102; found, 386.2106.
(284) NMR Spectroscopy: Ethyl (R)-3-(2-fluorophenyl)-2-((trans-4-isopropylcyclohexane-1-carboxamido)propanoate (3pa): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 7.25-7.19 (m, 1H), 7.13 (td, J=7.5, 1.9 Hz, 1H), 7.06 (td, J=7.5, 1.2 Hz, 1H), 7.01 (ddd, J=9.6, 8.2, 1.2 Hz, 1H), 5.96 (d, J=7.8 Hz, 1H), 4.84 (dt, J=7.8, 6.1 Hz, 1H), 4.18 (qd, J=7.2, 4.3 Hz, 2H), 3.26-3.09 (m, 2H), 1.99 (tt, J=12.2, 3.6 Hz, 1H), 1.93-1.81 (m, 2H), 1.81-1.72 (m, 2H), 1.44-1.30 (m, 3H), 1.25 (t, J=7.2 Hz, 3H), 1.13-0.90 (m, 3H), 0.85 (d, J=6.8 Hz, 6H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): 175.7, 171.8, 161.5 (d, J=245.0 Hz), 132.0 (d, J=4.7 Hz), 129.0 (d, J=8.3 Hz), 124.2 (d, J=3.5 Hz), 123.3 (d, J=16.0 Hz), 115.4 (d, J=22.1 Hz), 61.8, 52.3, 45.6, 43.4, 32.9, 31.6, 29.8, 29.6, 29.1, 29.1, 19.9, 14.2 ppm. .sup.19F NMR (470 MHz, CDCl.sub.3, 23° C., δ): −117.3 ppm. Ethyl (R)-3-(2-fluorophenyl)-2-((trans-4-isopropylcyclohexane-1-carboxamido)propanoate (5pb): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 7.05 (dd, J=8.6, 5.5 Hz, 2H), 6.97 (t, J=8.6 Hz, 2H), 5.89 (d, J=7.6 Hz, 1H), 4.83 (dt, J=7.7, 5.7 Hz, 1H), 4.18 (qd, J=7.1, 1.5 Hz, 2H), 3.22-2.98 (m, 2H), 2.01 (tt, J=12.2, 3.5 Hz, 1H), 1.93-1.82 (m, 2H), 1.78 (dtd, J=11.2, 3.7, 1.9 Hz, 3H), 1.48-1.32 (m, 4H), 1.26 (t, J=7.2 Hz, 3H), 1.10-0.91 (m, 2H), 0.85 (d, J=6.8 Hz, 6H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): 175.7, 171.8, 162.1 (d, J=245.1 Hz), 131.9 (d, J=3.1 Hz), 131.0 (d, J=7.9 Hz), 115.4 (d, J=21.4 Hz), 61.7, 52.9, 45.7, 43.4, 37.3, 32.9, 30.0, 29.7, 29.1, 29.1, 19.9, 14.3 ppm. .sup.19F NMR (470 MHz, CDCl.sub.3, 23° C., δ):): −115.8 ppm.
(285) Reactions without Catalyst
(286) Under N.sub.2 atmosphere, an oven-dried 4 mL vial was charged with Selectfluor (71 mg, 200 μmol, 2.0 equiv.) and ethyl nateglinide (4p, ethyl (trans-4-isopropylcyclohexane-1-carbonyl)-D-phenylalaninate) (34.5 mg, 100 μmol, 1.0 equiv.) in acetonitrile (1.0 mL, c=0.10 M). The resulting reaction mixture was stirred at 80° C. for 24 h. After cooling to room temperature, 1,4-bistrifluoromethylbenzene (3.6 mg, 2.6 μl, 17 μmol, 0.17 equiv.) was added to the reaction mixture, stirred and a sample (approx. 0.1 mL) was diluted with CD.sub.3CN (0.5 mL) and the yield of the title products was determined by .sup.19F NMR using 1,4-bis(trifluoromethyl)benzene as an internal standard (standard: δ −63.4 ppm, 6 F; compared with product peaks at δ −115.8 and −117.3 ppm; first relaxation time of 10 s to ensure accurate integration) to be 11% (3pa:3pb (80:20)).
Example 13. Trans-2-(4-fluorophenyl)cyclohexanol (3la) and trans-2-(4-fluorophenyl)cyclohexanol (3lb)
(287) ##STR00085##
(288) A mixture of palladium complex S1 (27.7 mg, 50.0 μmol, 5.00 mol %) and 2-chloro-phenanthroline (10.7 mg, 50.0 μmol, 5.00 mol %.) was dissolved in acetonitrile (5.0 mL). This mixture was added to a 20 mL vial containing a solution of NFBS (615 mg, 2.00 mmol, 2.00 equiv.) and trans-2-phenylcyclohexanol (176 mg, 1.0 mmol, 1.0 equiv.) in acetonitrile (5.0 mL, final c=0.10 M). The reaction mixture was stirred for 24 hours at 25° C. The remaining oxidant was quenched by adding a solution of Na.sub.2S.sub.2O.sub.3.(H.sub.2O).sub.5 (1.22 g, 5.00 mmol, 5.00 equiv.) in water (20 mL) and stirring for 30 min. The mixture was added to a separatory funnel with 50 mL dichloromethane. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo at 40° C. to afford a pale yellow solid. The residue was dissolved in dichloromethane (2 mL), loaded onto a short plug of silica (20 g) and eluted with dichloromethane/pentane 50:50 (v/v). and concentrated in vacuo to afford a colorless solid (98 mg) containing the title compounds (81.5 mg, 0.421 mmol, 42% yield, 3la:3lb (59:41)), trans-2-phenylcyclohexanol and minor inseparable impurities. The yield and selectivity were determined by .sup.19F using 1,4-bis(trifluoromethyl)benzene as an internal standard ((standard: δ −63.4 ppm, 6 F; compared with product peaks at δ −116.8 and −118.8 ppm; first relaxation time of 10 s to ensure accurate integration). Purification by HPLC (MultoKrom Si, 3 μm, 20 mm×250 mm, isohexane:isopropanol 99:1, 15 mL/min, 8.3 MPa, 308 K, 220 nm UV) provided purified product isomers, yielding the title compound 3la (82% pure by HPLC, retention time 15.8 min.) and 3lb (87% pure by HPLC, retention time 16.5 min.). The spectra matched the reported spectra for the title compound 3la. See Powell et al., J Am. Chem. Soc., 2005, 127, 510. R.sub.f=0.40 (dichloromethane/pentane, 50:50 (v/v)). HRMS-FIA(m/z) calculated for C.sub.12H.sub.15FONa [M+Na].sup.+, 217.0999; found, 217.0998,
(289) NMR Spectroscopy: Trans-2-(4-fluorophenyl)cyclohexanol (3la): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 7.22 (dd, J=8.6, 5.5 Hz, 1H), 7.02 (t, J=8.7 Hz, 1H), 3.61 (td, J=10.1, 4.3 Hz, 1H), 2.42 (ddd, J=12.3, 9.9, 3.6 Hz, 1H), 2.19-2.08 (m, 1H), 2.00-1.80 (m, 1H), 1.81-1.72 (m, 1H), 1.58-1.18 (m, 3H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): 161.9 (d, J=244.8 Hz), 139.1 (d, J=3.0 Hz), 129.4 (d, J=7.7 Hz), 115.7 (d, J=20.9 Hz), 74.7, 52.6, 34.7, 33.6, 26.2, 25.2. ppm. .sup.19F NMR (470 MHz, CDCl.sub.3, 23° C., δ): −116.8 ppm. Trans-2-(2-fluorophenyl)cyclohexanol (3lb): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 7.28 (td, J=7.5, 1.9 Hz, 1H), 7.20 (tdd, J=7.2, 4.9, 1.9 Hz, 1H), 7.12 (td, J=7.5, 1.3 Hz, 1H), 7.04 (ddd, J=9.7, 8.1, 1.3 Hz, 1H), 3.79 (td, J=10.1, 4.4 Hz, 1H), 2.83 (ddd, J=12.4, 10.1, 3.6 Hz, 1H), 2.17-2.10 (m, 1H), 1.94-1.81 (m, 2H), 1.81-1.69 (m, 1H), 1.66-1.18 (m, 4H), 0.93-0.79 (m, 1H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): 161.5 (d, J=245.0 Hz), 130.3 (d, J=14.4 Hz), 128.7 (d, J=5.1 Hz), 128.1 (d, J=8.4 Hz), 124.5 (d, J=3.4 Hz), 115.9 (d, J=23.2 Hz), 73.5, 46.2, 35.3, 32.5, 26.1, 25.2 ppm. .sup.19F NMR (470 MHz, CDCl.sub.3, 23° C., δ): −118.8 ppm.
(290) Reactions without Catalyst
(291) Under N.sub.2 atmosphere, an oven-dried 4 mL vial was charged with Selectfluor (71 mg, 200 μmol, 2.0 equiv.) and trans-2-phenylcyclohexanol (17.6 mg, 100 μmol, 1.0 equiv.) in acetonitrile (1.0 mL, c=0.10 M). The resulting reaction mixture was stirred at 80° C. for 24 h. After cooling to room temperature, 1,4-bistrifluoromethylbenzene (3.6 mg, 2.6 μl, 17 μmol, 0.17 equiv.) was added to the reaction mixture, stirred and a sample (approx. 0.1 mL) was diluted with CD.sub.3CN (0.5 mL) and the yield of the title products was determined by .sup.19F NMR using 1,4-bis(trifluoromethyl)benzene as an internal standard to be <3%.
Example 14. 4-(4-Fluorophenyl)cyclohexanone (3ma) and 4-(2-fluorophenyl)cyclohexanone (3mb)
(292) ##STR00086##
(293) A mixture of palladium complex S1 (27.7 mg, 50.0 μmol, 5.00 mol %) and 2-chloro-phenanthroline (10.7 mg, 50.0 μmol, 5.00 mol %.) was dissolved in acetonitrile (5.0 mL). This mixture was added to a 20 mL vial containing a solution of Selectfluor (709 mg, 2.00 mmol, 2.00 equiv.) and 4-phenylcyclohexanone (174 mg, 1.0 mmol, 1.0 equiv.) in acetonitrile (5.0 mL, final c=0.10 M). The reaction mixture was stirred for 24 hours at 0° C. and then transferred to a separatory funnel. Dichloromethane (50 mL) was added and the organic layer was washed with water (50 mL) with brine added (10 mL). The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo at 40° C. to afford a pale yellow solid. The residue was dissolved in dichloromethane (2 mL), loaded onto a short plug of silica (20 g) and eluted with ethyl acetate. and concentrated in vacuo to afford a colorless solid (132 mg) containing the title compounds (109 mg, 0.57 mmol, 57% yield, 3ma:3mb (60:40)), 4-phenylcyclohexanone and minor inseparable impurities. The yield and selectivity were determined by and .sup.19F using 1,4-bis(trifluoromethyl)benzene as an internal standard (standard: δ −63.4 ppm, 6 F; compared with product peaks at δ −116.5 and −119.0 ppm; first relaxation time of 10 s to ensure accurate integration). The spectra matched the reported spectra for the title compounds. See Müller et al, J. Am. Chem. Soc. 2011, 133, 18534-18537. U.S. Pat. No. 6,037,354. R.sub.f=0.40 (dichloromethane:pentane, 40:60 (v/v)). HRMS-ESI (m/z) calculated for C.sub.12H.sub.13FONa [M+Na].sup.+, 215.0843; found, 215.0844.
(294) NMR Spectroscopy: 4-(4-fluorophenyl)cyclohexanone (3ma): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 7.25-7.17 (m, 2H), 7.01 (t, J=8.7 Hz, 2H), 3.02 (tt, J=12.1, 3.4 Hz, 1H), 2.60-2.44 (m, 4H), 2.28-2.11 (m, 3H), 2.06-1.80 (m, 2H). ppm. .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): 211.0, 161.7 (d, J=244.4 Hz), 140.6 (d, J=3.1 Hz), 128.2 (d, J=7.8 Hz), 115.5 (d, J=21.1 Hz), 42.2, 41.5, 34.3 ppm. .sup.19F NMR (470 MHz, CDCl.sub.3, 23° C., δ): −116.5 ppm. 4-(2-fluorophenyl)cyclohexanone (3mb): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 7.25-7.17 (m, 2H), 7.11 (td, J=7.5, 1.3 Hz, 1H), 7.08-7.02 (m, 1H), 3.37 (tt, J=12.2, 3.3 Hz, 1H), 2.60-2.44 (m, 4H), 2.28-2.11 (m, 2H), 2.06-1.80 (m, 2H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): 211.0, 160.7 (d, J=245.2 Hz), 131.6 (d, J=14.5 Hz), 128.1 (d, J=8.5 Hz), 127.4 (d, J=4.8 Hz), 124.4 (d, J=3.5 Hz), 115.7 (d, J=22.7 Hz) 41.4, 35.8 (d, J=2.4 Hz) 32.7 ppm. .sup.19F NMR (470 MHz, CDCl.sub.3, 23° C., δ): −119.0 ppm.
(295) Reactions without Catalyst
(296) Under N.sub.2 atmosphere, an oven-dried 4 mL vial was charged with Selectfluor (71 mg, 200 μmol, 2.0 equiv.) and 4-phenylcyclohexanone (17.4 mg, 100 μmol, 1.0 equiv.) in acetonitrile (1.0 mL, c=0.10 M). The resulting reaction mixture was stirred at 80° C. for 24 h. After cooling to room temperature, 1,4-bistrifluoromethylbenzene (3.6 mg, 2.6 μl, 17 μmol, 0.17 equiv.) was added to the reaction mixture, stirred and a sample (approx. 0.1 mL) was diluted with CD.sub.3CN (0.5 mL) and the yield of the title products was determined by .sup.19F NMR using 1,4-bis(trifluoromethyl)benzene as an internal standard to be <1%.
Example 15. (R)-4-(2-Fluorobenzyl)-3-propionyloxazolidin-2-one (3na) and (R)-4-(4-fluorobenzyl)-3-propionyloxazolidin-2-one (3nb)
(297) ##STR00087##
(298) A mixture of palladium complex S1 (27.7 mg, 50.0 μmol, 5.00 mol %) and 2-chloro-phenanthroline (10.7 mg, 50.0 μmol, 5.00 mol %.) was dissolved in acetonitrile (5.0 mL). This mixture was added to a 20 mL vial containing a solution of Selectfluor (709 mg, 2.00 mmol, 2.00 equiv.) and (R)-4-benzyl-3-propionyloxazolidin-2-one (233 mg, 1.0 mmol, 1.0 equiv.) in acetonitrile (5.0 mL, final c=0.10 M). The reaction mixture was stirred for 36 hours at 0° C. and then transferred to a separatory funnel. Dichloromethane (50 mL) was added and the organic layer was washed with water (50 mL) with brine added (10 mL). The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo at 40° C. to afford a pale yellow solid. The residue was dissolved in dichloromethane (2 mL), loaded onto a short plug of silica (20 g) and eluted with ethyl acetate/dichloromethane 20:90 (v/v) and concentrated in vacuo to afford a colorless solid (225 mg) containing the title compounds (171 mg, 0.68 mmol, 68% yield, 3na:3nb (69:31)), (R)-4-benzyl-3-propionyloxazolidin-2-one and minor inseparable impurities. The yield and selectivity were determined by .sup.19F using 1,4-bis(trifluoromethyl)benzene as an internal standard (standard: δ −63.4 ppm, 6 F; compared with product peaks at δ −116.8 and −118.8 ppm; first relaxation time of 10 s to ensure accurate integration). The yield and selectivity were determined by .sup.19F using 1,4-bis(trifluoromethyl)benzene as an internal standard (standard: δ −63.4 ppm, 6 F; compared with product peaks at δ −115.1 and −117.1 ppm; first relaxation time of 10 s to ensure accurate integration). Purification by HPLC (MultoKrom Si, 3 μm, 20 mm×250 mm, isohexane:isopropanol 99:1, 20 mL/min, 8.3 MPa, 308 K, 220 nm UV) provided purified product isomers, yielding the title compound 3na (98% pure by HPLC, retention time 7.1 min.) and 3nb (99% pure by HPLC, retention time 8.8 min). R.sub.f=0.35 (ethyl acetate/dichloromethane 10:90 (v/v)). HRMS-FIA(m/z) calculated for C.sub.13H.sub.14FNO.sub.3Na [M+Na].sup.+, 274.0850; found, 274.0849.
(299) NMR Spectroscopy: (R)-4-(2-fluorobenzyl)-3-propionyloxazolidin-2-one (3na): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 7.31-7.22 (m, 1H), 7.19 (td, J=7.5, 1.9 Hz, 1H), 7.11 (td, J=7.5, 1.2 Hz, 1H), 7.07 (ddd, J=9.7, 8.3, 1.1 Hz, 1H), 4.75 (tt, J=8.1, 3.1 Hz, 1H), 4.30-4.22 (m, 1H), 4.20 (dd, J=9.1, 2.7 Hz, 1H), 3.22 (dd, J=13.7, 3.5 Hz, 1H), 3.11-2.84 (m, 3H), 1.20 (t, J=7.2 Hz, 3H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): 174.2, 161.5 (d, J=245.1 Hz), 153.6, 131.9 (d, J=4.7 Hz), 129.5 (d, J=8.3 Hz), 124.7 (d, J=3.5 Hz), 122.4 (d, J=16.0 Hz), 115.9 (d, J=22.2 Hz), 66.6 (d, J=2.5 Hz), 54.4, 31.4, 29.3, 8.4 ppm. .sup.19F NMR (470 MHz, CDCl.sub.3, 23° C., δ): −117.1 ppm. (R)-4-(4-fluorobenzyl)-3-propionyloxazolidin-2-one (3nb): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ): 7.17 (dd, J=8.5, 5.4 Hz, 2H), 7.02 (t, J=8.6 Hz, 2H), 4.64 (ddt, J=9.3, 7.7, 3.0 Hz, 1H), 4.22 (ddd, J=8.8, 7.9, 0.7 Hz, 1H), 4.14 (dd, J=9.1, 2.7 Hz, 1H), 3.25 (dd, J=13.5, 3.3 Hz, 1H), 3.07-2.84 (m, 2H), 2.77 (dd, J=13.6, 9.4 Hz, 1H), 1.20 (td, J=7.3, 1.3 Hz, 3H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): 174.2, 162.3 (d, J=246.2 Hz), 153.5, 131.1 (d, J=3.4 Hz), 131.0 (d, J=7.9 Hz), 116.0 (d, J=21.4 Hz), 66.3, 55.2 (d, J=1.5 Hz), 37.3, 29.3, 8.4 ppm. .sup.19F NMR (470 MHz, CDCl.sub.3, 23° C., δ): −115.1 ppm.
(300) Reactions without Catalyst
(301) Under N.sub.2 atmosphere, an oven-dried 4 mL vial was charged with Selectfluor (71 mg, 200 μmol, 2.0 equiv.) and (R)-4-benzyl-3-propionyloxazolidin-2-one (23.3 mg, 100 μmol, 1.0 equiv.) in acetonitrile (1.0 mL, c=0.10 M). The resulting reaction mixture was stirred at 80° C. for 24 h. After cooling to room temperature, 1,4-bistrifluoromethylbenzene (3.6 mg, 2.6 μl, 17 μmol, 0.17 equiv.) was added to the reaction mixture, stirred and a sample (approx. 0.1 mL) was diluted with CD.sub.3CN (0.5 mL) and the yield of the title products was determined by .sup.19F NMR using 1,4-bis(trifluoromethyl)benzene as an internal standard to be 17% (3na:3nb (65:35)).
Example 16. N-Acetyl-L-(2-fluoro)phenylalanine methyl ester (3oa) and N-Acetyl-L-(4-fluoro)phenylalanine methyl ester (3ob)
(302) ##STR00088##
(303) A mixture of palladium complex S1 (27.7 mg, 50.0 μmol, 5.00 mol %) and 2-chloro-phenanthroline (10.7 mg, 50.0 μmol, 5.00 mol %.) was dissolved in acetonitrile (8.0 mL). This mixture was added to a 20 mL vial containing a solution of Selectfluor (709 mg, 2.00 mmol, 2.00 equiv.) and N-Acetyl-L-phenylalanine methyl ester (221 mg, 1.00 mmol, 1.00 equiv.) in acetonitrile (2.0 mL, final c=0.10 M). The reaction mixture was stirred for 36 hours at 23° C. and then transferred to a separatory funnel. Chloroform (100 mL) was added and the organic layer was washed with saturated aqueous NaHCO.sub.3 solution (1×50 mL). The aqueous layer was extracted with chloroform (4×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo at 40° C. to afford a pale yellow solid. The residue was dissolved in ethyl acetate (2 mL), loaded onto a short plug of silica (20 g) and eluted with ethyl acetate. A colorless solid (172 mg) containing the title compounds (158 mg, 0.659 mmol, 66% yield, 3oa:3ob (62:38)) and N-Acetyl-L-(4-fluoro)phenylalanine methyl ester was obtained. The yield and selectivity were determined by .sup.19F using 1,4-bis(trifluoromethyl)benzene as an internal standard (standard: δ −63.4 ppm, 6 F; compared with product peaks at δ −116.0 and −118.1 ppm; first relaxation time of 10 s to ensure accurate integration). Purification by HPLC (YMC-Triart C18, 5 μm, 4.6 mm×150 mm, MeCN:H.sub.2O 75:25, 20 mL/min, 9.2 MPa, 308 K, 210 nm UV) provided purified product isomers on a preparative scale, yielding the title compounds 3oa (56 mg, 0.234 mmol, 23%, >99% pure by HPLC, retention time 11.2 min.) and 3ob (35 mg, 0.146 mmol, 15%, >99% pure by HPLC, retention time 12.3 min.). The spectra matched the reported spectra for the title compounds. See Burk et al., J. Am. Chem. Soc., 1993, 115, 10125-10138. R.sub.f=0.80 (ethyl acetate).
(304) NMR Spectroscopy: N-Acetyl-L-(2-fluoro)phenylalanine methyl ester (3fa): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ) 7.25-7.20 (m, 1H), 7.12 (td, J=7.4, 1.9 Hz, 1H), 7.08 (td, J=7.4, 1.2 Hz, 1H), 7.03 (ddd, J=9.7, 8.2, 1.2 Hz, 1H), 5.96 (d, J=7.8 Hz, 2H), 4.87 (dt, J=7.9, 5.9 Hz, 1H), 3.74 (s, 3H), 3.18 (dddd, J=40.8, 13.8, 6.0, 1.2 Hz, 2H), 1.98 (s, 3H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ): 172.1, 169.8, 161.5 (d, J=245.0 Hz), 131.8 (d, J=4.3 Hz), 129.2 (d, J=8.0 Hz), 124.4 (d, J=3.5 Hz), 123.1 (d, J=16.0 Hz), 115.5 (d, J=22.2 Hz), 52.6, 52.6, 31.6, 23.5 ppm. .sup.19F NMR (471 MHz, CDCl.sub.3, 23° C., δ) −118.1 ppm. N-Acetyl-L-(4-fluoro)phenylalanine methyl ester (3fb): .sup.1H NMR (500 MHz, CDCl.sub.3, 23° C., δ) δ 7.05 (dd, J=8.6, 5.5 Hz, 2H), 6.98 (t, J=8.7 Hz, 2H), 5.91 (d, J=7.7 Hz, 1H), 4.86 (dt, J=7.7, 5.7 Hz, 1H), 3.73 (s, 3H), 3.22-3.01 (m, 2H), 1.99 (s, 3H) ppm. .sup.13C NMR (125 MHz, CDCl.sub.3, 23° C., δ):172.1, 169.7, 162.2 (d, J=245.6 Hz), 131.7 (d, J=3.1 Hz), 130.9 (d, J=8.0 Hz), 115.6 (d, J=21.3 Hz), 53.3, 52.6, 37.3, 23.3 ppm. .sup.19F NMR (471 MHz, CDCl.sub.3, 23° C., δ) −116.0 ppm. HRMS-FIA(m/z) calculated for C.sub.12H.sub.15FNO.sub.3 [M+H].sup.+, 240.1036; found, 240.1059.
(305) Reaction without Catalyst:
(306) Under N.sub.2 atmosphere, an oven-dried 4 mL vial was charged with Selectfluor (71 mg, 200 μmol, 2.0 equiv.), N-Acetyl-L-phenylalanine methyl ester (22.1 mg, 1.00 mmol, 1.00 equiv.) and acetonitrile (1.0 mL, c=0.10 M). The resulting reaction mixture was stirred at 80° C. for 24 h. After cooling to room temperature, 1,4-bistrifluoromethylbenzene (3.6 mg, 2.6 μl, 17 μmol, 0.17 equiv.) was added to the reaction mixture, stirred and a sample (approx. 0.1 mL) was diluted with CD.sub.3CN (0.5 mL) and the yield of the title products was determined by .sup.19F NMR using 1,4-bis(trifluoromethyl)benzene as an internal standard to be 7% (6% 3oa, 1% 3ob).
Example 17. NMR Evaluation of Oxidation of Complex 1
(307) ##STR00089##
(308) To solution of catalyst 1 at −40° C., prepared from a mixture of palladium complex S1 (13.9 mg, 25 μmol, 1.0 equiv.) and 2-chloro-phenanthroline (5.4 mg, 25 μmol, 1.0 equiv.) in CD.sub.3CN (2 mL), a solution of 2,6-dichloro-1-fluoropyridinium tetrafluoroborate (4) (6.4 mg, 25 μmol, 1.0 equiv. in 0.25 mL CD.sub.3CN) at −40° C. was added in a 4 mL vial in the cold well of glovebox. The solution was stirred for 5 min and a dark purple color formed. The solution was carefully transferred to a cooled J-Young NMR tube then frozen at −60° C., sealed and removed from the glovebox. Vacuum was applied to the frozen solid and then the sample was transferred to the NMR instrument set to −40° C. After allowing 5 min in the NMR for the sample to thaw and the temperature to stabilize, the .sup.19F NMR spectra were measured. After −40° C., the sample was warmed at 10° C. intervals up to −10° C., allowing the sample to equilibrate for 5 min before the .sup.19F NMR were measured. The tetrafluoroborate was taken as an internal standard for .sup.19F NMR (δ −150.1 ppm, 12 F) and used to determine oxidant consumption (δ 30.1 ppm, 1 F). The amount of oxidant remaining was determined to be: 68% at −40° C.; 63% at −30° C.; 48% at −20° C.; and 42% at −10° C. The region between δ −150 and −400 ppm contained no signals that could be attributed to formation of a Pd(IV)-F.
Example 18. Representative Procedure for Fluorination of Heteroaryl Substrates
(309) Under N.sub.2 atmosphere, an oven-dried 4 mL vial was charged with the heteroaryl substrate (50 mmol, 1.0 equiv.), either Selectfluor (35.4 mg, 100 mmol, 2.00 equiv.) or NFBS (30.7 mg, 100 mmol, 2.00 equiv.) and acetonitrile (0.25 mL). In a separate 4 mL vial, a solution of the palladium catalyst 1 was prepared (5 mol % Pd(II) per 0.25 mL). The catalyst solution was then added to the reaction mixture (final c=0.1 M) and the resulting reaction mixture was stirred at 0, 25 or 50° C. for 8 to 36 h. After cooling to room temperature, 1,4-bis(trifluoromethyl)benzene (1.8 mg, 1.3 ml, 17 mmol, 0.17 equiv.) was added to the reaction mixture, stirred and a sample (approx. 0.1 mL) was diluted with CD.sub.3CN (0.5 mL), and a yield was determined by .sup.19F NMR using 1,4-bis(trifluoromethyl)benzene as an internal standard (standard: d −63.4 ppm, 6 F; compared with product peaks).
IV. Electron Paramagnetic Resonance (EPR) Spectroscopy
(310) (i) Synthesis of Complex 5
(311) ##STR00090##
(312) To a solution of catalyst 1 at −40° C., prepared from a mixture of palladium complex S1 (13.9 mg, 25 μmol, 1.0 equiv.) and 2-chloro-phenanthroline (5.4 mg, 25 μmol, 1.0 equiv.) in MeCN (2 mL), a solution of 2,6-dichloro-1-fluoropyridinium tetrafluoroborate (4) (6.4 mg, 25 μmol, 1.0 equiv. in 0.25 mL MeCN) at −40° C. was added in a 4 mL vial in the cold well of glovebox. The resulting solution gradually (30 min) turned red-orange and then dark purple and was then quickly transferred into an EPR tube and frozen at 77K.
(313) The solid- and solution-state EPR data for Pd(III) complex 5 display spectra (
V. X-Ray Crystallographic Analysis
(314) (i) General Procedure for X-Ray Data Collection and Refinement
(315) A crystal was mounted on a nylon loop using Perfluoropolyether, and transferred to a Bruker AXS Enraf-Nonius KappaCCD diffractometer (MoKα radiation, λ=0.71073 Å) equipped with an Oxford Cryosystems nitrogen flow apparatus. The sample was held at 100(2) K during the experiment. The collection method involved 0.4° scans in ω at 30.9980 in 2θ. Data integration down to 0.69 Å resolution was carried out using EVALCCD 1.6 (Bruker diffractometer, 2008) with reflection spot size optimisation. Absorption corrections were made with the program SADABS (Bruker diffractometer, 2012). The structure was solved by the direct methods procedure and refined by least-squares methods against F.sup.2 using SHELXS and SHELXL (Sheldrick, 2014). Non-hydrogen atoms were refined anisotropically, and hydrogen atoms were allowed to ride on the respective atoms. Special refinement details, if applicable, are given for each compound below. Crystal data, details of data collection and refinement, and selected geometric parameters are given in the tables below. Graphics were produced using the DIAMOND software program (© Crystal Impact GbR, 1997-2013)). Computer programs: APEX2 v2009.3.0 (Bruker-AXS, 2009), EVALCCD 1.6 (Bruker-AXS, 2008), SHELXS (Sheldrick, 2014), SHELXL (Sheldrick, 2014), Olex2 (Dolomanov et al., 2009).
(316) (ii) [(terpy)Pd(2-Cl-phen)][BF.sub.4].sub.2 (1). (CCDC <1465063>)
(317) Compound 1 was crystallized from MeCN/Et.sub.2O. The X-ray structure of compound 1 is shown in
(318) The X-ray crystal structure of Pd (II) compound 1 shows a square planar geometry at Pd, with the apical phenanthroline nitrogen in close proximity to the palladium (2.6 Å of the apical Pd—N; the sum of Pd and N van der Waals radii is 3.7 Å) (
(319) TABLE-US-00001 TABLE 1 X-ray crystal data of compound 1. (9764sadabs) Crystal data Chemical formula C.sub.27H.sub.18ClN.sub.5Pd•2(BF.sub.4)•C.sub.2H.sub.3N M.sub.r 768.99 Crystal system, MONOCLINIC, P2.sub.1/c space group Temperature (K) 100 a, b, c (Å) 8.070 (1), 41.823 (5), 9.1701 (6) β (°) 104.662 (7) V (Å.sup.3) 2994.3 (5) Z 4 Radiation type Mo Ka μ (mm.sup.−1) 0.79 Crystal size (mm) 0.15 × 0.10 × 0.06 Data collection Diffractometer Bruker AXS Enraf-Nonius KappaCCD Absorption Gaussian correction SADABS (Bruker AXS, 2012) T.sub.min, T.sub.max 0.891, 0.955 No. of measured, 49913, 9465, 8874 independent and observed [I > 2σ (I)] reflections R.sub.int 0.023 (sin θ/λ).sub.max (Å.sup.−1) 0.725 Refinement R[F.sup.2 > 2σ(F.sup.2)], 0.025, 0.060, 1.11 wR(F.sup.2), S No. of reflections 9465 No. of parameters 425 H-atom treatment H-atom parameters constrained Δρ.sub.max, Δρ.sub.min (e Å.sup.−3) 0.50, −0.89
VI. Density Functional Theory Experiments
(320) (i) Methods for DFT Calculations
(321) Density Functional Theory (DFT) calculations were performed at the Max-Planck-Institut für Kohlenforschung Computer Cluster using the Gaussian09 program package. Structural optimizations and frequency calculations, used to confirm if the structure is a minimum and then to obtain thermal corrections to the Gibbs Free Energy, were performed with B3LYP or ωB97X-D along with the 6−31+G(d) basis set on all atoms except Pd and the effective core potential (ECP) LanL2DZ on Pd, using the atomic coordinates of molecular structures created in GaussView 5.0.8 and using the atomic coordinates of the crystal structure as starting points for Pd(II)(terpy)(2-Cl-phen) (1 without counterions). Single point energy calculations were performed with M06L or M11L functional and 6−311++G(d,p) basis set on all atoms except Pd and the Stuttgart-Dresden (SDD) quasirelativistic pseudopotential (MWB28) with basis set (Pd: (8s7p6d)/[6s5p3d]), with basis set Pd (SDD), extended by polarization function (Pd: f, f-orbital coefficient: 1.472) on Pd. Solvent effects of acetonitrile were taken into account for the single point calculations using the conductor-like polarized continuum solvation model (CPCM). Frequency calculations were performed to confirm whether the structure is a minimum. Images were generated using GaussView 5.0.8.
(322)
(323) (ii) Visualization of LUMO, HOMO, and SOMO
(324) Shown in
(325) (iii) The Optimized Structure of Compound 1 with M06L/B3L YP and Cartesian Coordinates (Å)
(326) The optimized structure of 1 with M06/BS I and Cartesian coordinates (Å) are shown in
(327) TABLE-US-00002 TABLE 2 The Cartesian coordinates (A) of an optimized structure of compound 1. Atom X Y Z Pd −0.43700600 −0.00082700 −0.69650100 Cl −0.62112200 0.00396300 3.35758700 N −0.80264800 2.05776200 −0.66646300 N −2.35851000 0.00051700 −0.23140400 N 1.55888200 −0.00230300 −1.38057700 N −0.80423500 −2.05900500 −0.66329700 C −0.28425100 4.39496500 −0.81885800 H 0.44886600 5.16470400 −1.02462600 C −4.33270100 1.21852600 0.27338600 H −4.86020100 2.15397000 0.40508100 C −2.51072900 3.69106000 −0.20759600 H −3.52925700 3.92970200 0.07095300 C −1.59563100 4.71934400 −0.46306000 H −1.90568000 5.75458900 −0.38455000 C −2.10212500 2.36051400 −0.31386500 N 1.23091100 0.00098700 1.41552200 C 2.65552300 −0.00154300 −0.54342000 C −1.59973400 −4.71950400 −0.45606700 H −1.91074400 −5.75435600 −0.37626300 C −2.10397200 −2.35997300 −0.31034700 C 2.14429100 0.00366600 3.64700500 H 1.95060800 0.00511200 4.71114200 C −5.00356900 0.00198500 0.44883700 H −6.05297000 0.00253300 0.71839300 C 3.64217100 0.00121100 1.72961500 C −2.97830200 −1.19798300 −0.07382500 C 3.97557000 −0.00217500 −1.08891400 C 3.42940500 0.00291200 3.13487000 H 4.28269700 0.00372000 3.80431800 C −2.97740400 1.19959900 −0.07554500 C −4.33359200 −1.21535700 0.27507600 H −4.86196600 −2.15012200 0.40802100 C 2.49301700 0.00013200 0.89060700 C 4.12467200 −0.00362700 −2.49727900 H 5.12091900 −0.00414900 −2.92626500 C −2.51388400 −3.69001800 −0.20218800 H −3.53266400 −3.92723000 0.07663300 C 0.07760400 −3.05149100 −0.90458400 H 1.08108800 −2.75391600 −1.17402400 C 1.73232900 −0.00356000 −2.71947800 H 0.83587100 −0.00413300 −3.32629400 C 5.11168600 −0.00133900 −0.20983000 H 6.10265000 −0.00214200 −0.64990200 C 1.08100600 0.00255400 2.72127100 C 4.95327500 0.00027900 1.14709400 H 5.81673000 0.00114900 1.80316000 C −0.28796600 −4.39686700 −0.81211300 H 0.44445500 −5.16763900 −1.01651200 C 3.00435700 −0.00434000 −3.31234500 H 3.09028300 −0.00550700 −4.39162000 C 0.08004400 3.04908800 −0.90937300 H 1.08329700 2.75032200 −1.17848400
(328) TABLE-US-00003 TABLE 3 Zero-point correction = 0.399440 (Hartree/Particle) Thermal correction to Energy = 0.425043 Thermal correction to Enthalpy = 0.425987 Thermal correction to Gibbs Free Energy = 0.342251 Sum of electronic and zero-point Energies = −1899.290678 Sum of electronic and thermal Energies = −1899.265075 Sum of electronic and thermal Enthalpies = −1899.264131 Sum of electronic and thermal Free Energies = −1899.347867 CPCM (MeCN) M06L/6-311 + + G(d, p) with SDD + f (for Pd) E = −1901.616198
(iv) The Optimized Structure of Compound 1 with M11L/ωB97X-D and Cartesian Coordinates (Å)
(329) The optimized structure of 1 with M11L/ωB97X-D and Cartesian coordinates (Å) are shown in
(330) TABLE-US-00004 TABLE 4 The Cartesian coordinates (Å) of an optimized structure of compound 1. Atom X Y Z Pd −0.40028300 −0.00000700 −0.75245200 Cl −0.88621200 0.00025800 3.15269000 N −0.74536900 2.03998800 −0.70422400 N −2.31124800 −0.00038600 −0.30176500 N 1.60567700 0.00026600 −1.35821100 N −0.74450300 −2.04013100 −0.70400200 C −0.19003400 4.35976400 −0.80580500 H 0.55507000 5.12260500 −0.98727200 C −4.26537100 1.21402900 0.23468400 H −4.79013900 2.14833200 0.38018000 C −2.42840900 3.67807300 −0.23175500 H −3.44547600 3.92670700 0.04112300 C −1.49673500 4.69441500 −0.45953900 H −1.79177500 5.73182100 −0.36443900 C −2.03485100 2.35164000 −0.35777600 N 1.09836500 0.00030500 1.38695500 C 2.64552500 0.00031000 −0.46200100 C −1.49475200 −4.69485200 −0.45907800 H −1.78935700 −5.73237200 −0.36388200 C −2.03387200 −2.35229700 −0.35755600 C 1.83936700 0.00058600 3.66862700 H 1.57086800 0.00068800 4.71587100 C −4.93106500 −0.00090200 0.41489600 H −5.97608900 −0.00109700 0.69817200 C 3.46693700 0.00052500 1.86788100 C −2.92085400 −1.19323200 −0.13108800 C 3.98678200 0.00028300 −0.91532800 C 3.15448500 0.00063700 3.25154600 H 3.95605500 0.00075500 3.98117000 C −2.92135000 1.19223100 −0.13117000 C −4.26488200 −1.21556400 0.23475000 H −4.78925800 −2.15008300 0.38027100 C 2.38826800 0.00039400 0.95799500 C 4.22430400 0.00013600 −2.30858300 H 5.24439800 0.00006900 −2.67600100 C −2.42686500 −3.67888000 −0.23140900 H −3.44382800 −3.92792700 0.04148200 C 0.15518800 −3.01449500 −0.91861000 H 1.15574500 −2.70089800 −1.18143900 C 1.85644900 0.00018300 −2.67713300 H 0.99866200 0.00021300 −3.33722500 C 5.06313400 0.00040400 0.03845200 H 6.08051200 0.00039500 −0.33521700 C 0.84801100 0.00039400 2.67145600 C 4.81585300 0.00053400 1.37515700 H 5.63217800 0.00063200 2.08803400 C −0.18819100 −4.35968400 −0.80535100 H 0.55724100 −5.12222800 −0.98672600 C 3.15995700 0.00008600 −3.18880000 H 3.31314300 −0.00003700 −4.25966700 C 0.15391300 3.01471500 −0.91894100 H 1.15459200 2.70149900 −1.18175700
(331) TABLE-US-00005 TABLE 5 Zero-point correction = 0.405285 (Hartree/Particle) Thermal correction to Energy = 0.430491 Thermal correction to Enthalpy = 0.431435 Thermal correction to Gibbs Free Energy = 0.347953 Sum of electronic and zero-point Energies = −1898.826135 Sum of electronic and thermal Energies = −1898.800930 Sum of electronic and thermal Enthalpies = −1898.799986 Sum of electronic and thermal Free Energies = −1898.883467 CPCM (MeCN) M11L/6-311 + + G(d, p) with SDD + f (for Pd) E = −1901.596284
(v) The Optimized Structure of Complex 5 with M06L/B3L YP and Cartesian Coordinates (Å)
(332) The optimized structure of 5 with M06L/B3LYP and Cartesian coordinates (Å) are shown in
(333) TABLE-US-00006 TABLE 6 The Cartesian coordinates (Å) of an optimized structure of complex 5. Atom X Y Z Pd 0.32263300 −0.00024000 −0.62389800 Cl 0.88825100 0.00183100 3.21056700 N 0.67957100 −2.08074900 −0.51949400 N 2.22876900 −0.00026000 −0.07916000 N −1.63422300 −0.00048300 −1.31713700 N 0.68009100 2.08016500 −0.52106000 C 0.19279200 −4.41341200 −0.74552000 H −0.53050800 −5.18775800 −0.96795900 C 4.22075400 −1.21648300 0.33472200 H 4.75479100 −2.15177000 0.43659600 C 2.41932000 −3.69386500 −0.14730000 H 3.44724800 −3.92611800 0.10005100 C 1.51475800 −4.72698400 −0.42053200 H 1.84259300 −5.75905800 −0.38319600 C 1.98845100 −2.36697300 −0.20435000 N −1.10101100 0.00081200 1.40438400 C −2.67865400 −0.00010700 −0.42358000 C 1.51568100 4.72632100 −0.42392900 H 1.84367800 5.75837000 −0.38731100 C 1.98899700 2.36639500 −0.20606500 C −1.84199100 0.00222500 3.69804300 H −1.56537700 0.00284500 4.74376500 C 4.89617800 −0.00037200 0.48940000 H 5.95489600 −0.00041700 0.71976100 C −3.48840700 0.00119400 1.90819800 C 2.85411300 1.19895100 0.03346900 C −4.02265900 −0.00042100 −0.88777200 C −3.16499000 0.00201500 3.29177200 H −3.96017700 0.00246000 4.02926300 C 2.85381300 −1.19953200 0.03434400 C 4.22105200 1.21579700 0.33381600 H 4.75531400 2.15103400 0.43497300 C −2.40876800 0.00065400 0.98569200 C −4.23962600 −0.00117800 −2.29055900 H −5.25539100 −0.00145300 −2.67137900 C 2.42007300 3.69325800 −0.14992700 H 3.44802500 3.92552100 0.09731500 C −0.19250900 3.07016000 −0.78915200 H −1.20187800 2.77702700 −1.04155100 C −1.85128500 −0.00118600 −2.64536700 H −0.95503000 −0.00147800 −3.25869500 C −5.09326700 0.00009100 0.07083100 H −6.11420000 −0.00015200 −0.29440200 C −0.84638100 0.00158300 2.70016000 C −4.83706200 0.00089400 1.41504100 H −5.65246400 0.00130300 2.12977500 C 0.19368000 4.41273300 −0.74877000 H −0.52947700 5.18704100 −0.97180200 C −3.16075000 −0.00155300 −3.16149400 H −3.30436600 −0.00210400 −4.23463400 F 0.97225800 −0.00116300 −2.63114100 C −0.19318300 −3.07080300 −0.78683200 H −1.20253000 −2.77771200 −1.03937400
(334) TABLE-US-00007 TABLE 7 Zero-point correction = 0.401756 (Hartree/Particle) Thermal correction to Energy = 0.428689 Thermal correction to Enthalpy = 0.429634 Thermal correction to Gibbs Free Energy = 0.343490 Sum of electronic and zero-point Energies = −1999.067450 Sum of electronic and thermal Energies = −1999.040516 Sum of electronic and theimal Enthalpies = −1999.039572 Sum of electronic and theimal Free Energies = −1999.125716 CPCM (MeCN) M06L/6-311 + + G(d, p) with SDD + f (for Pd) E = −2001.443197
(vi) The Optimized Structure of Complex 5 with M11L/ωB97X-D and Cartesian Coordinates (Å)
(335) The optimized structure of 5 with M11L/ωB97X-D and Cartesian coordinates (Å) are shown in
(336) TABLE-US-00008 TABLE 8 The Cartesian coordinates (Å) of an optimized structure of complex 5. Atom X Y Z Pd 0.30591200 −0.00002700 −0.65222400 Cl 1.05332300 0.00007100 3.06956700 N 0.63810500 −2.05371100 −0.54191300 N 2.19946300 0.00000000 −0.12970900 N −1.64778200 −0.00008900 −1.29463800 N 0.63814000 2.05368500 −0.54204300 C 0.10616000 −4.36824100 −0.72829300 H −0.63149300 −5.13280400 −0.93130900 C 4.17439200 −1.21437300 0.30224100 H 4.70691700 −2.14893000 0.41262400 C 2.34723800 −3.68142900 −0.16468500 H 3.37295300 −3.92872700 0.07452800 C 1.42220200 −4.69883800 −0.41463900 H 1.73136600 −5.73536200 −0.36647400 C 1.93654100 −2.35616100 −0.23482300 N −1.00769400 0.00003700 1.38248100 C −2.65557700 0.00000100 −0.36922700 C 1.42225500 4.69881100 −0.41501900 H 1.73141900 5.73534000 −0.36696700 C 1.93655600 2.35615300 −0.23489700 C −1.63756100 0.00020000 3.69757500 H −1.31454800 0.00027900 4.72935200 C 4.84599400 −0.00000700 0.45983000 H 5.90237900 −0.00000400 0.69727000 C −3.35737000 0.00019200 1.98811300 C 2.81651700 1.19347900 −0.00680600 C −4.00559300 −0.00002200 −0.77478400 C −2.97354300 0.00025900 3.35316500 H −3.73401800 0.00036800 4.12538700 C 2.81652000 −1.19348400 −0.00683100 C 4.17438200 1.21436600 0.30229500 H 4.70689800 2.14891800 0.41275400 C −2.32703300 0.00007500 1.02755600 C −4.27575000 −0.00021900 −2.16578800 H −5.30437800 −0.00026000 −2.50878900 C 2.34726300 3.68142600 −0.16487100 H 3.37296500 3.92872300 0.07440400 C −0.25488000 3.02401800 −0.78566600 H −1.26015000 2.71168500 −1.03146700 C −1.90919700 −0.00024100 −2.60751700 H −1.03498400 −0.00019800 −3.25204000 C −5.03716200 0.00011600 0.22701900 H −6.07161900 0.00013200 −0.09604200 C −0.69025600 0.00005900 2.65871400 C −4.72688800 0.00023000 1.55287000 H −5.51034800 0.00035200 2.30145100 C 0.10623700 4.36819300 −0.72876200 H −0.63137100 5.13275000 −0.93195900 C −3.23391600 −0.00033500 −3.07362100 H −3.41772100 −0.00052400 −4.13960000 F 0.91670700 −0.00002900 −2.65760800 C −0.25494200 −3.02407400 −0.78534000 H −1.26023600 −2.71177600 −1.03108200
(337) TABLE-US-00009 TABLE 9 Zero-point correction = 0.407683 (Hartree/Particle) Thermal correction to Energy = 0.434154 Thermal correction to Enthalpy = 0.435098 Thermal correction to Gibbs Free Energy = 0.349812 Sum of electronic and zero-point Energies = −1998.574792 Sum of electronic and thermal Energies = −1998.548321 Sum of electronic and thermal Enthalpies = −1998.547377 Sum of electronic and thermal Free Energies = −1998.632662 CPCM (MeCN) M11L/6-311 + + G(d, p) with SDD + f (for Pd) E = −2001.390395
(vii) The Optimized Structure of Complex 5 with M06L/B3L YP and Cartesian Coordinates (Å)
(338) The optimized structure of 5 with M06L/B3LYP and Cartesian coordinates (Å) are shown in
(339) TABLE-US-00010 TABLE 10 The Cartesian coordinates (Å) of an optimized structure of complex 5. Atom X Y Z Pd 0.24938500 0.00039800 0.44724500 Cl 0.54474800 −0.00326000 −3.34093500 N 0.58046600 2.07526500 0.27354300 N 2.03748500 −0.00014900 −0.43961100 N −1.61769800 0.00110000 1.40256600 N 0.58093000 −2.07468200 0.27710900 C 0.09439000 4.40984000 0.49917200 H −0.58885800 5.18250500 0.82966500 C 3.87623900 1.21801600 −1.30388800 H 4.37095300 2.15194300 −1.53729100 C 2.17085200 3.69678200 −0.51196800 H 3.11850000 3.93550800 −0.97852400 C 1.31574500 4.72871900 −0.10072000 H 1.60317600 5.76326400 −0.24885500 C 1.79449800 2.36640900 −0.31915900 N −1.28348600 −0.00138100 −1.34742700 C −2.73035400 0.00039200 0.59023600 C 1.31683400 −4.72859800 −0.09257100 H 1.60451300 −5.76332900 −0.23891500 C 1.79506800 −2.36655800 −0.31502300 C −2.19554000 −0.00360500 −3.57776300 H −1.99715800 −0.00466300 −4.64161600 C 4.50118400 −0.00087100 −1.60039000 H 5.48036100 −0.00116100 −2.06539600 C −3.70385800 −0.00175300 −1.67382900 C 2.61050800 −1.20366900 −0.70390700 C −4.04024600 0.00092500 1.14880600 C −3.48489100 −0.00312200 −3.07705200 H −4.33140200 −0.00381300 −3.75529200 C 2.61019800 1.20303700 −0.70606300 C 3.87656300 −1.21938800 −1.30167900 H 4.37154000 −2.15360100 −1.53337600 C −2.56103400 −0.00092100 −0.82925400 C −4.15911400 0.00221200 2.56252200 H −5.14446400 0.00265500 3.01636900 C 2.17174000 −3.69717400 −0.50551700 H 3.11947200 −3.93648900 −0.97159900 C −0.24516900 −3.06359400 0.67734700 H −1.17947800 −2.77071200 1.13572100 C −1.75288800 0.00228100 2.74310000 H −0.84307600 0.00275200 3.32643400 C −5.17694200 0.00011400 0.27115900 H −6.16965000 0.00052800 0.70711900 C −1.11970400 −0.00267800 −2.66741700 C −5.01469800 −0.00118600 −1.08767900 H −5.87739900 −0.00183600 −1.74452500 C 0.09535500 −4.40897600 0.50667100 H −0.58774600 −5.18123200 0.83842000 C −3.01932500 0.00286700 3.35353100 H −3.08647100 0.00381100 4.43440300 C −0.24581600 3.06467400 0.67217100 H −1.18001400 2.77236800 1.13113800 N 1.49420400 0.00227900 2.54129400 C 2.19577000 0.00310700 3.47776900 C 3.05631700 0.00412100 4.65154600 H 2.86955900 0.89287300 5.26424700 H 2.87068500 −0.88438300 5.26495200 H 4.11113500 0.00466500 4.35631100
(340) TABLE-US-00011 TABLE 11 Zero-point correction = 0.446791 (Hartree/Particle) Thermal correction to Energy = 0.477353 Thermal correction to Enthalpy = 0.478298 Thermal correction to Gibbs Free Energy = 0.383001 Sum of electronic and zero-point Energies = −2031.527339 Sum of electronic and thermal Energies = −2031.496777 Sum of electronic and thermal Enthalpies = −2031.495833 Sum of electronic and thermal Free Energies = −2031.591129 CPCM (MeCN) M06L/6-311 + + G(d, p) with SDD + f (for Pd) E = −2034.181162
(viii) The Optimized Structure of Selectfluor (F-TEDA) with M06L/B3L YP and Cartesian Coordinates (Å)
(341) The optimized structure of Selectfluor (F-TEDA) with M06L/B3LYP and Cartesian coordinates (Å) are shown in
(342) TABLE-US-00012 TABLE 12 The Cartesian coordinates (Å) of an optimized structure of Selectfluor. Atom X Y Z C 0.28758800 1.66408300 0.10897300 H 0.13440700 2.08355200 1.10584800 H −0.05377200 2.38902100 −0.63358200 C −0.26365900 −0.49618200 1.18588900 H −0.77312500 −1.44517600 1.01644200 H −0.67442500 −0.03705400 2.08787300 C 1.27264200 −0.66959600 1.30602400 H 1.72085700 −0.06235300 2.09516200 H 1.55961400 −1.71398100 1.44789800 C 1.77080700 1.28687500 −0.14045100 H 2.43986700 1.73032500 0.60049800 H 2.12306900 1.54125600 −1.14220400 C −0.21692600 −0.31485800 −1.29130600 H −0.28887300 0.41254700 −2.10320900 C 1.20842800 −0.90745700 −1.16443700 H 1.21770700 −1.97726100 −0.94608000 N −0.57827700 0.41223700 0.00002100 N 1.86800100 −0.21120900 −0.00081100 F 3.21964100 −0.55452300 −0.00259300 C −2.06184700 0.84713300 −0.00139600 H −2.21171100 1.44980600 0.89602300 H −2.21126700 1.44626900 −0.90117300 H 1.81629300 −0.71485200 −2.05145600 H −0.95251600 −1.10378700 −1.45761800 Cl −3.16665600 −0.52204600 −0.00031400
(343) TABLE-US-00013 TABLE 13 Zero-point correction = 0.222194 (Hartree/Particle) Thermal correction to Energy = 0.231884 Thermal correction to Enthalpy = 0.232828 Thermal correction to Gibbs Free Energy = 0.187274 Sum of electronic and zero-point Energies = −943.762856 Sum of electronic and thermal Energies = −943.753167 Sum of electronic and thermal Enthalpies = −943.752222 Sum of electronic and thermal Free Energies = −943.797776 CPCM (MeCN) M06L/6-311 + + G(d, p) with SDD + f (for Pd) E = −944.3154877
(ix) The Optimized Structure of Selectfluor (F-TEDA) with M11L/ωB97X-D and Cartesian Coordinates (Å)
(344) The optimized structure of Selectfluor (F-Teda) with M11L/ωB97X-D and Cartesian coordinates (Å) are shown in
(345) TABLE-US-00014 TABLE 14 The Cartesian coordinates (Å) of an optimized structure of Selectfluor. Atom X Y Z C 0.28497900 1.64793600 0.13492100 H 0.14577000 2.03987800 1.14496000 H −0.06162700 2.39568300 −0.58165400 C −0.26727300 −0.51496900 1.16094100 H −0.75231700 −1.47114600 0.96151500 H −0.70027600 −0.08919100 2.06855200 C 1.26328100 −0.66005900 1.29906200 H 1.69274300 −0.03677800 2.08568400 H 1.56182300 −1.69807700 1.45814900 C 1.75672700 1.27691200 −0.14403900 H 2.43825600 1.72662400 0.58086200 H 2.08606000 1.52953800 −1.15369600 C −0.21122200 −0.28914800 −1.29188000 H −0.25900100 0.45609600 −2.08912200 C 1.19643000 −0.90349600 −1.15397600 H 1.18517200 −1.97152400 −0.92843600 N −0.57494100 0.40915400 0.00077700 N 1.85822400 −0.21111400 −0.00086400 F 3.19176600 −0.55099200 −0.00342400 C −2.04220700 0.84341700 −0.00014100 H −2.19457100 1.44652200 0.89668200 H −2.19401200 1.44380000 −0.89879600 H 1.80819000 −0.72859400 −2.04129100 H −0.95354400 −1.06468000 −1.48908500 Cl −3.14093100 −0.51818100 −0.00071900
(346) TABLE-US-00015 TABLE 15 Zero-point correction = 0.225634 (Hartree/Particle) Thermal correction to Energy = 0.234940 Thermal correction to Enthalpy = 0.235885 Thermal correction to Gibbs Free Energy = 0.191134 Sum of electronic and zero-point Energies = −943.618155 Sum of electronic and thermal Energies = −943.608849 Sum of electronic and thermal Enthalpies = −943.607905 Sum of electronic and thermal Free Energies = −943.652655 CPCM (MeCN) M11L/6-311 + + G(d, p) with SDD + f (for Pd) E = −944.2390953
(x) The Optimized Structure of Selectfluor Radical (TEDA) with M06L/B3L YP and Cartesian Coordinates (Å)
(347) The optimized structure of Selectfluor radical (TEDA) with M06L/B2LYP and Cartesian coordinates (Å) are shown in
(348) TABLE-US-00016 TABLE 16 The Cartesian coordinates (Å) of an optimized structure of Selectfluor radical. Atom X Y Z C −0.74946300 1.55850900 −0.08312200 H −0.60888900 2.03771500 −1.05417500 H −0.50305000 2.26621500 0.71157200 C −0.02357100 −0.53813500 −1.20483300 H 0.59731500 −1.42556600 −1.08009500 H 0.28236200 −0.00480100 −2.10755100 C −1.56207600 −0.90707500 −1.26542100 H −2.06960100 −0.40671100 −2.09250100 H −1.69867700 −1.98888100 −1.34446100 C −2.22718100 1.02272900 0.09002700 H −2.87184600 1.39078900 −0.71272000 H −2.64899000 1.29518400 1.05937900 C −0.06904200 −0.40238500 1.28526900 H −0.00740700 0.30271400 2.11689500 C −1.50682700 −1.05253600 1.17830200 H −1.45608200 −2.13314700 1.03259100 N 0.21288300 0.37404400 −0.00064800 N −2.08353300 −0.42231500 0.00174700 C 1.65704100 0.93285800 −0.00135500 H 1.75696700 1.54288700 −0.90054900 H 1.75743500 1.54489300 0.89628200 H −2.10330600 −0.82396200 2.06592300 H 0.69545200 −1.17259300 1.40049900 Cl 2.87409300 −0.33944900 0.00047100
(349) TABLE-US-00017 TABLE 17 Zero-point correction = 0.220071 (Hartree/Particle) Thermal correction to Energy = 0.228657 Thermal correction to Enthalpy = 0.229602 Thermal correction to Gibbs Free Energy = 0.185737 Sum of electronic and zero-point Energies = −843.819959 Sum of electronic and thermal Energies = −843.811373 Sum of electronic and thermal Enthalpies = −843.810428 Sum of electronic and thermal Free Energies = −843.854293 CPCM (MeCN) M06L/6-311 + + G(d, p) with SDD + f (for Pd) E = −844.4656741.
(xi) The Optimized Structure of Selectfluor Radical (TEDA) with M11L/ωB97X-D and Cartesian Coordinates (Å)
(350) The optimized structure of Selectfluor radical (TEDA) with M11L/ωB97X-D and Cartesian coordinates (Å) are shown in
(351) TABLE-US-00018 TABLE 18 The Cartesian coordinates (Å) of an optimized structure of Selectfluor radical. Atom X Y Z C −0.74619400 1.54149600 −0.12115400 H −0.62877500 1.97025500 −1.11857800 H −0.48540100 2.29143200 0.62853900 C −0.01452200 −0.56724900 −1.17314800 H 0.56730100 −1.47247900 −0.99747400 H 0.33997200 −0.08224600 −2.08502100 C −1.55328800 −0.87957600 −1.26998500 H −2.03520500 −0.33492900 −2.08348100 H −1.72260000 −1.95270500 −1.38825000 C −2.20789200 1.01552400 0.11505400 H −2.88758400 1.39488100 −0.65216000 H −2.58434700 1.27433700 1.10590500 C −0.07921800 −0.36791500 1.29124700 H −0.06607900 0.36494200 2.10064600 C −1.48178700 −1.06500900 1.15944900 H −1.39254600 −2.13760100 0.98127500 N 0.21147100 0.37055100 −0.00133200 N −2.06757700 −0.42135000 0.00261700 C 1.63886700 0.92849600 −0.00305500 H 1.73936200 1.53918700 −0.90190400 H 1.74041400 1.54310900 0.89285300 H −2.08948900 −0.88313100 2.04959800 H 0.70371000 −1.11008800 1.45723900 Cl 2.85048300 −0.33435100 0.00066900
(352) TABLE-US-00019 TABLE 19 Zero-point correction = 0.220071 (Hartree/Particle) Thermal correction to Energy = 0.228657 Thermal correction to Enthalpy = 0.229602 Thermal correction to Gibbs Free Energy = 0.185737 Sum of electronic and zero-point Energies = −843.819959 Sum of electronic and thermal Energies = −843.811373 Sum of electronic and thermal Enthalpies = −843.810428 Sum of electronic and thermal Free Energies = −843.854293 CPCM (MeCN) M11L/6-311 + + G(d, p) with SDD + f (for Pd) E = −844.4222131
(xii) The Optimized Structure of Selectfluor Reduced Radical (F-TEDA Reduced Radical) with M06L/B3L YP and Cartesian Coordinates (Å)
(353) The optimized structure of Selectfluor reduced radical (F-Teda reduced radical) with M06L/B3LYP and Cartesian coordinates (Å) are shown in
(354) TABLE-US-00020 TABLE 20 The Cartesian coordinates (Å) of an optimized structure of Selectfluor reduced radical. Atom X Y Z C 0.19148500 1.68302300 0.05964700 H −0.04751200 2.17099100 1.00762400 H −0.13822600 2.32409100 −0.76135100 C −0.29782800 −0.46173200 1.21778300 H −0.86393200 −1.38828800 1.12061500 H −0.65355900 0.07505500 2.10058700 C 1.24403800 −0.69581500 1.23254100 H 1.72104100 −0.19643900 2.07808600 H 1.48194400 −1.75969600 1.29052300 C 1.69960200 1.29686100 −0.05200300 H 2.27877800 1.72210200 0.76990400 H 2.13626800 1.64519000 −0.98993600 C −0.27633100 −0.36037400 −1.27607800 H −0.47214300 0.32022100 −2.10854400 C 1.22142600 −0.78316100 −1.18220000 H 1.32916400 −1.86544500 −1.08859000 N −0.64485000 0.39949600 0.00017600 N 1.79967300 −0.15471200 −0.00115500 F 3.73851900 −0.57429800 −0.00003800 C −2.10499100 0.80776600 0.00151700 H −2.27794600 1.40231900 0.89886900 H −2.27920800 1.40486100 −0.89384900 H 1.77986100 −0.46277300 −2.06400400 H −0.95168100 −1.21307100 −1.35208800 Cl −3.22574600 −0.56725500 −0.00046400
(355) TABLE-US-00021 TABLE 21 Zero-point correction = 0.219732 (Hartree/Particle) Thermal correction to Energy = 0.230460 Thermal correction to Enthalpy = 0.231404 Thermal correction to Gibbs Free Energy = 0.181921 Sum of electronic and zero-point Energies = −944.160882 Sum of electronic and thermal Energies = −944.150153 Sum of electronic and thermal Enthalpies = −944.149209 Sum of electronic and thermal Free Energies = −944.198692 CPCM (MeCN) M06L/6-311 + + G(d, p) with SDD + f (for Pd) E = −944.5287822
(xiii) The Optimized Structure of NFSI (N-Fluorobenzenesulfonimide) with M06L/B3L YP and Cartesian Coordinates (Å)
(356) The optimized structure of NFSI (N-fluorobenzenesulfonimide) with M06L/B3LYP and Cartesian coordinates (Å) are shown in
(357) TABLE-US-00022 TABLE 22 The Cartesian coordinates (Å) of an optimized structure of NFSI. Atom X Y Z C 2.57155400 −0.41783300 0.18882300 C 3.12734800 −1.21632100 −0.81321500 H 2.49916700 −1.89298800 −1.38255500 C 4.50014000 −1.12461700 −1.05126100 H 4.95322100 −1.73867500 −1.82429800 C 5.28629400 −0.24814100 −0.29725100 H 6.35405500 −0.18144800 −0.48804100 C 4.70947400 0.54217800 0.70316000 H 5.32515200 1.21892600 1.28867500 C 3.33974500 0.46406800 0.95454400 H 2.87448200 1.06542600 1.72879600 C −2.53829900 0.23201300 −0.02654400 C −2.85401300 −0.29854300 1.22758600 H −2.40330100 0.11288300 2.12416900 C −3.75743700 −1.36021800 1.28935100 H −4.01944100 −1.78518600 2.25403700 C −4.31948500 −1.87456100 0.11675300 H −5.01993500 −2.70356400 0.17326000 C −3.98949500 −1.32897500 −1.12821300 H −4.43224900 −1.72936700 −2.03576400 C −3.09238700 −0.26377500 −1.21055900 H −2.83341000 0.18184600 −2.16500000 N 0.26854700 0.90957300 −0.42892300 O −1.64398400 2.36219900 −1.33461100 O −1.23402600 2.21439400 1.18963800 O 0.53815300 −0.16657200 1.90143200 O 0.28989300 −1.75046300 −0.09311500 S −1.38933100 1.59657300 −0.12047000 S 0.81887300 −0.53211400 0.51526900 F 0.27209400 0.46063200 −1.77926400
(358) TABLE-US-00023 TABLE 23 Zero-point correction = 0.208407 (Hartree/Particle) Thermal correction to Energy = 0.226484 Thermal correction to Enthalpy = 0.227428 Thermal correction to Gibbs Free Energy = 0.159637 Sum of electronic and zero-point Energies = −1714.765356 Sum of electronic and thermal Energies = −1714.747279 Sum of electronic and thermal Enthalpies = −1714.746334 Sum of electronic and thermal Free Energies = −1714.814125 CPCM (MeCN) M06L/6-311 + + G(d, p) with SDD + f (for Pd) E = −1715.121608
(xiv) The Optimized Structure of NFSI (N-Fluorobenzenesulfonimide) with M11L/ωB97X-D and Cartesian Coordinates (Å)
(359) The optimized structure of NFSI (N-fluorobenzenesulfonimide) with M11L/ωB97X-D and Cartesian coordinates (Å) are shown in
(360) TABLE-US-00024 TABLE 24 The Cartesian coordinates (Å) of an optimized structure of NFSI. Atom X Y Z C 2.49565000 −0.42062800 0.19065700 C 3.04084100 −1.20807000 −0.81925600 H 2.40444400 −1.86365700 −1.40392700 C 4.41122800 −1.13215600 −1.05105200 H 4.85828400 −1.73825300 −1.83267300 C 5.20410900 −0.28300300 −0.28110500 H 6.27274800 −0.22822600 −0.46663800 C 4.63757200 0.49788100 0.72679000 H 5.26100600 1.15469700 1.32504800 C 3.27036600 0.43565200 0.97043500 H 2.80905800 1.03230600 1.75076400 C −2.47975900 0.24293800 −0.02240600 C −2.76862200 −0.29670300 1.22907700 H −2.33560800 0.13716700 2.12382200 C −3.61223900 −1.40048800 1.29264900 H −3.85081700 −1.83809500 2.25674800 C −4.14144300 −1.94494700 0.12367000 H −4.79623400 −2.80958000 0.18118500 C −3.84004600 −1.38903500 −1.11917400 H −4.25859100 −1.81635000 −2.02487500 C −3.00121900 −0.28335700 −1.20236700 H −2.75908200 0.16951400 −2.15783400 N 0.24742900 0.92201900 −0.42239000 O −1.62507100 2.36562800 −1.33117100 O −1.21670400 2.23644800 1.17172500 O 0.46971100 −0.14726900 1.87491600 O 0.20948100 −1.69458200 −0.11645500 S −1.36657300 1.61608100 −0.12353400 S 0.75409100 −0.50327600 0.50034500 F 0.27383500 0.50568500 −1.76038700
(361) TABLE-US-00025 TABLE 25 Zero-point correction= 0.212670 (Hartree/Particle) Thermal correction to Energy= 0.230197 Thermal correction to Enthalpy= 0.231141 Thermal correction to Gibbs Free Energy= 0.165085 Sum of electronic and zero-point Energies= −1714.430838 Sum of electronic and thermal Energies= −1714.413312 Sum of electronic and thermal Enthalpies= −1714.412368 Sum of electronic and thermal Free Energies= −1714.478424 CPCM (MeCN) M11L/6-311++G(d, p) with −1714.981376 SDD+f (for Pd) E=
(xv) The Optimized Structure of NFSI Radical (N-Fluorobenzenesulfonimide) with M06L/B3L YP and Cartesian Coordinates (Å)
(362) The optimized structure of NFSI (N-fluorobenzenesulfonimide) radical with M06L/B3LYP and Cartesian coordinates (Å) are shown in
(363) TABLE-US-00026 TABLE 26 The Cartesian coordinates (Å) of an optimized structure of NFSI radical. Atom X Y Z C −2.55213300 −0.39343500 0.00001900 C −3.22505100 −0.33554200 1.22285600 H −2.67181300 −0.39345700 2.15443100 C −4.61545400 −0.21402700 1.21392900 H −5.15670000 −0.17035900 2.15471400 C −5.30717500 −0.15124900 0.00002000 H −6.38971700 −0.05658700 0.00002100 C −4.61546000 −0.21408100 −1.21388900 H −5.15671100 −0.17045400 −2.15467400 C −3.22505700 −0.33559700 −1.22281800 H −2.67182400 −0.39355300 −2.15439300 C 2.45872300 0.25981200 −0.00001300 C 2.90453800 −0.24735400 −1.22360200 H 2.54265800 0.17412100 −2.15488400 C 3.82378400 −1.29667400 −1.21410000 H 4.18275600 −1.70391600 −2.15491300 C 4.28003000 −1.81953200 0.00005300 H 4.99585500 −2.63727600 0.00007900 C 3.82380200 −1.29658200 1.21417200 H 4.18278700 −1.70375300 2.15501200 C 2.90455600 −0.24726100 1.22360900 H 2.54269000 0.17428500 2.15486500 N −0.33063500 1.10800500 −0.00002700 O 1.41976900 2.33894500 1.28036300 O 1.41975200 2.33884800 −1.28053200 O −0.33588800 −1.12259800 −1.27803400 O −0.33587900 −1.12253000 1.27809700 S 1.31200000 1.63423700 −0.00005700 S −0.77188700 −0.54594200 0.00001700
(364) TABLE-US-00027 TABLE 27 Zero-point correction= 0.204537 (Hartree/Particle) Thermal correction to Energy= 0.221664 Thermal correction to Enthalpy= 0.222608 Thermal correction to Gibbs Free Energy= 0.155783 Sum of electronic and zero-point Energies= −1614.943259 Sum of electronic and thermal Energies= −1614.926131 Sum of electronic and thermal Enthalpies= −1614.925187 Sum of electronic and thermal Free Energies= −1614.992012 CPCM (MeCN) M06L/6-311++G(d, p) with −1615.279275 SDD+f (for Pd) E=
(xvi) The Optimized Structure of NFSI Radical (N-Fluorobenzenesulfonimide) with M11L/ωB97X-D and Cartesian Coordinates (Å)
(365) The optimized structure of NFSI (N-fluorobenzenesulfonimide) radical with M11L/ωB97X-D and Cartesian coordinates (Å) are shown in
(366) TABLE-US-00028 TABLE 28 The Cartesian coordinates (Å) of an optimized structure of NFSI radical. Atom X Y Z C −2.49886500 −0.39867900 0.00001000 C −3.16892200 −0.34289800 1.21923500 H −2.61522300 −0.39661400 2.15080400 C −4.55535500 −0.22683700 1.21074200 H −5.09635900 −0.18378600 2.15070500 C −5.24422600 −0.16666100 0.00004400 H −6.32623800 −0.07363600 0.00005800 C −4.55539500 −0.22696100 −1.21067000 H −5.09643200 −0.18400800 −2.15061900 C −3.16896200 −0.34302100 −1.21919800 H −2.61529500 −0.39683200 −2.15078000 C 2.41615500 0.26882100 −0.00000500 C 2.83974300 −0.25354700 −1.21993800 H 2.48764700 0.17745900 −2.15058500 C 3.71612400 −1.33280900 −1.21104000 H 4.05878600 −1.75485300 −2.15038900 C 4.15112700 −1.86935600 0.00006100 H 4.83638700 −2.71201300 0.00008700 C 3.71609100 −1.33276200 1.21112800 H 4.05872700 −1.75476800 2.15050400 C 2.83971000 −0.25349800 1.21996000 H 2.48759000 0.17754500 2.15058000 N −0.31765400 1.11810300 −0.00004600 O 1.41215300 2.34443300 1.27010400 O 1.41217200 2.34437100 −1.27023200 O −0.28940000 −1.08477200 −1.26788000 O −0.28936700 −1.08471600 1.26787300 S 1.30416800 1.65116800 −0.00004800 S −0.73190800 −0.52682400 −0.00001000
(367) TABLE-US-00029 TABLE 29 Zero-point correction= 0.208315 (Hartree/Particle) Thermal correction to Energy= 0.225021 Thermal correction to Enthalpy= 0.225965 Thermal correction to Gibbs Free Energy= 0.160252 Sum of electronic and zero-point Energies= −1614.632297 Sum of electronic and thermal Energies= −1614.615591 Sum of electronic and thermal Enthalpies= −1614.614647 Sum of electronic and thermal Free Energies= −1614.680360 CPCM (MeCN) M11L/6-311++G(d, p) with −1615.164493 SDD+f (for Pd) E=
(xvii) The Optimized Structure of NFSI (N-Fluorobenzenesulfonimide Reduced Radical with M06L/B3L YP and Cartesian Coordinates (Å)
(368) The optimized structure of NFSI (N-fluorobenzenesulfonimide) reduced radical with M06L/B3LYP and Cartesian coordinates (Å) are shown in
(369) TABLE-US-00030 TABLE 30 The Cartesian coordinates (Å) of an optimized structure of NFSI reduced radical. Atom X Y Z C 2.87850700 −0.32582600 0.06415800 C 3.49508400 −0.53399300 −1.17171400 H 2.88224500 −0.74315600 −2.04240800 C 4.88917800 −0.48062200 −1.26028100 H 5.37475800 −0.64200600 −2.22038200 C 5.65765300 −0.22285800 −0.12063100 H 6.74263000 −0.18417200 −0.19234300 C 5.02937400 −0.01614800 1.11306900 H 5.62472500 0.18146000 2.00197300 C 3.63681800 −0.06191500 1.20817200 H 3.12986700 0.09552200 2.15523200 C −2.90187300 0.00737400 0.05055300 C −2.78972500 −0.85679700 1.14040900 H −2.29882800 −0.52240200 2.04838700 C −3.30614400 −2.15026000 1.03329600 H −3.21950600 −2.83448900 1.87419300 C −3.91559800 −2.56964000 −0.15389300 H −4.30862300 −3.58099000 −0.23481100 C −4.00662300 −1.69562900 −1.24182200 H −4.47323900 −2.02340300 −2.16843500 C −3.48974900 −0.40047700 −1.14680200 H −3.54392100 0.29470200 −1.97864900 N 0.60061100 1.25539800 0.02084700 O −2.78059000 2.45472600 −0.97160900 O −2.47682400 2.14534600 1.57130700 O 0.73494100 −0.66196100 1.58988100 O 0.61485800 −1.24899500 −0.89506900 S −2.17646000 1.68754500 0.17292900 S 1.06648800 −0.34477300 0.18291900 F 0.87163000 1.55717800 −1.39171300
(370) TABLE-US-00031 TABLE 31 Zero-point correction= 0.203584 (Hartree/Particle) Thermal correction to Energy= 0.223259 Thermal correction to Enthalpy= 0.224203 Thermal correction to Gibbs Free Energy= 0.148230 Sum of electronic and zero-point Energies= −1714.850713 Sum of electronic and thermal Energies= −1714.831038 Sum of electronic and thermal Enthalpies= −1714.830094 Sum of electronic and thermal Free Energies= −1714.906067 CPCM (MeCN) M06L/6-311++G(d, p) with −1715.259329 SDD+f (for Pd) E=
(xviii) The Optimized Structure of MeCN Reduced Radical with M06L/B3L YP and Cartesian Coordinates (Å)
(371) The optimized structure of MeCN reduced radical with M06L/B3LYP and Cartesian coordinates (Å) are shown in
(372) TABLE-US-00032 TABLE 32 The Cartesian coordinates (Å) of an optimized structure of MeCN with M06L/B3LYP. Atom X Y Z C 0.00000000 0.00000000 −1.18195100 H 0.00000000 1.02729700 −1.56051500 H 0.88966500 −0.51364900 −1.56051500 H −0.88966500 −0.51364900 −1.56051500 C 0.00000000 0.00000000 0.28041900 N 0.00000000 0.00000000 1.44153400
(373) TABLE-US-00033 TABLE 33 Zero-point correction= 0.045484 (Hartree/Particle) Thermal correction to Energy= 0.049096 Thermal correction to Enthalpy= 0.050040 Thermal correction to Gibbs Free Energy= 0.022491 Sum of electronic and zero-point Energies= −132.716212 Sum of electronic and thermal Energies= −132.712601 Sum of electronic and thermal Enthalpies= −132.711656 Sum of electronic and thermal Free Energies= −132.739206 CPCM (MeCN) M06L/6-311++G(d, p) with −132.7820383 SDD+f (for Pd) E=
VII. Evaluation of Other [Pd] Catalysts in Fluorination
(374) ##STR00091##
(375) TABLE-US-00034 TABLE 34 Pd catalyst (5 mol %) ligand (mol %) temp..sup.a yield.sup.b Pd(OAc).sub.2 none 80° C. 3% Pd(MeCN).sub.4(BF4).sub.2 none 80° C. 4% Pd(terpy)(MeCN)(BF.sub.4).sub.2 terpy (10%) 80° C. 18% Pd(terpy)(MeCN)(BF.sub.4).sub.2 4,7-(OMe).sub.2 phen (5%) 80° C. 5% Pd(terpy)(MeCN)(BF.sub.4).sub.2 phen (5%) 50° C. 34% Pd(terpy)(MeCN)(BF 2-Cl phen (5%) 75% .sup.aTemperature listed is that which provided highest yield among reactions conducted at 23, 50 and 80° C. after 24 h. bYields determined by .sup.19F-NMR of reaction with internal standard.
(376) The proposed mechanism for the Pd-catalyzed fluorination reaction suggests the possibility that the combination of a tridentate terpyridine ligand and a bidentate phenanthroline ligand in a catalyst would be competent in the fluorination reaction. Therefore, an evaluation of other potential catalysts including these ligand combinations was performed, summarized in Table 34 above. The results indicate that electron deficient phenanthroline ligands combined with terpyridine are more effective.
(377) Results
(378) As shown in Table 35, a wide variety of arenes can be fluorinated, including both electron-rich, electron-neutral and electron-poor arenes. A wide range of compounds of Formula (I) have been prepared using the inventive methods, including compounds where one or more R.sup.A is a halogen, alkyl, carbocyclyl, aryl, or heteroaryl.
(379) TABLE-US-00035 TABLE 35 Substrate scope for the Pd-catalyzed fluorination of arenes..sup.a
Discussion of Potential Fluorination Mechanism
(380) DFT calculations for catalyst 1 indicate the HOMO lies largely on the Pd with some N contribution (see DFT Calculations section). Although not bound to this theory, the Pd—N interaction may be important for facile oxidation of the Pd(II) and enables formation of the high-valent palladium species. For an example of decreased oxidation potential of a Pd complex induced by increasing the coordination capacity of linked apical ligands, see Tang, F.; Qu, F.; Khusnutdinova, J. R.; Rath, N. P.; Mirica, L. M. Dalton Trans. 2012, 41, 14046.
(381) A previously developed catalyst capable of a single electron reduction of Selecfluor, in situ generated Pd(terpy).sub.2(BF.sub.4).sub.2, is significantly less effective than the optimized catalyst 1. See Mazzotti, A. R.; Campbell, M. G.; Tang, P.; Murphy, J. M.; Ritter, T. J. Am. Chem. Soc. 2013, 135, 14012. The lower reactivity of a known SET catalyst relative to the optimized catalyst 1 precludes initial single-electron reduction of the N—F reagents as a possible mechanism. Additionally, DFT calculations indicate the reduction of NFSI with catalyst 1 is a highly endothermic (56 kcal mol.sup.−1, see DFT Calculations section), which effectively eliminates single electron reduction of NFSI as a viable pathway. Conversely, DFT calculations indicate oxidation of compound 1 by N—F reagents to a Pd(III)-F species are also endergonic, but significantly less so than a SET pathway (11 kcal mol.sup.−1).
(382) ##STR00109##
(383) As depicted in Scheme 1, after a cold solution of catalyst 1 was treated with N-fluoropyridinium 4 and then frozen, an EPR signal was observed with hyperfine splitting by two nitrogens.
(384) To solution of catalyst 1 at −40° C., prepared from a mixture of palladium complex S1 (13.9 mg, 25 μmol, 1.0 equiv.) and 2-chloro-phenanthroline (5.4 mg, 25 μmol, 1.0 equiv.) in CD.sub.3CN (2 mL), a solution of 2,6-dichloro-1-fluoropyridinium tetrafluoroborate (4) (6.4 mg, 25 μmol, 1.0 equiv. in 0.25 mL CD.sub.3CN) at −40° C. was added in a 4 mL vial in the cold well of glovebox. The solution was stirred for 5 min and a dark purple color formed. The solution was carefully transferred to a cooled J-Young NMR tube then frozen at −60° C., sealed and removed from the glovebox. Vacuum was applied to the frozen solid and then the sample was transferred to the NMR instrument set to −40° C. After allowing 5 min in the NMR for the sample to thaw and the temperature to stabilize, the .sup.19F NMR spectra were measured. After −40° C., the sample was warmed at 10° C. intervals up to −10° C., allowing the sample to equilibrate for 5 min before the .sup.19F NMR were measured. The tetrafluoroborate was taken as an internal standard for .sup.19F NMR (δ −150.1 ppm, 12 F) and used to determine oxidant consumption (δ 30.1 ppm, 1 F). The amount of oxidant remaining was determined to be: 68% at −40° C.; 63% at −30° C.; 48% at −20° C.; and 42% at −10° C. The region between δ −150 and −400 ppm contained no signals that could be attributed to formation of a Pd(IV)-F.
(385) The hyperfine splitting is consistent with coupling from either two trans terpyridine nitrogens in 5, or from an MeCN, in place of a fluoride in 5, and the trans phenanthroline nitrogen. The observed EPR signal of a Pd(III) species in presence of an N—F oxidant may indicate the involvement of an open-shell metal species in catalysis via catalyst 1.
EQUIVALENTS AND SCOPE
(386) In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
(387) All patents, patent applications, and literature references cited herein are incorporated herein by reference.
(388) The foregoing has been a description of certain non-limiting embodiments of the invention. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.
(389) Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.
(390) This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.
(391) Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.