PHOTOCATALYSTS, PREPARATION AND USE THEREOF
20250367649 ยท 2025-12-04
Inventors
Cpc classification
C07C2531/28
CHEMISTRY; METALLURGY
B01J2231/44
PERFORMING OPERATIONS; TRANSPORTING
C07C2531/18
CHEMISTRY; METALLURGY
B01J31/1815
PERFORMING OPERATIONS; TRANSPORTING
C07C2531/12
CHEMISTRY; METALLURGY
International classification
B01J31/18
PERFORMING OPERATIONS; TRANSPORTING
Abstract
There is provided a process for alkylating a substrate with a photocatalytic system. The process comprises providing a mixture containing an acid, and a substrate (an organic compound). Then, an organophotoredox catalyst of formula Ia is contact with the mixture. Finally, the organophotoredox catalyst is activated with a light irradiation to alkylate the substrate and form a carbon covalent bond.
##STR00001##
Claims
1. A process for alkylating a substrate with a photocatalytic system, the process comprising: a) providing mixture comprising an acid, and the substrate, the substrate being an organic compound; b) contacting an organophotoredox catalyst of formula Ia with the mixture of step a) ##STR00284## wherein R.sub.1, R.sub.1, R.sub.1 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted X-alkyl, chemical linker, or X-chemical linker with X being one of an oxygen, an amine or a sulfur, X.sub.1, and X.sub.2 are independently selected from CH or N, when X.sub.1 is N, X.sub.2 is CH, R.sub.1 and R.sub.1 are hydrogen, when X.sub.2 is N, X.sub.1 is CH, R.sub.1 and R.sub.1 are hydrogen, when X.sub.1, and X.sub.2 are both CH, R.sub.1 and R.sub.1 are hydrogen, wherein R.sub.2, R.sub.2, R.sub.2 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted X-alkyl, chemical linker, or X-chemical linker with X being one of an oxygen, an amine or a sulfur, X.sub.3, and X.sub.4 are independently selected from CH or N, when X.sub.3 is N, X.sub.4 is CH, R.sub.2 and R.sub.2 are hydrogen, when X.sub.4 is N, X.sub.3 is CH, R.sub.2 and R.sub.2 are hydrogen, when X.sub.3, and X.sub.4 are both CH, R.sub.2 and R.sub.2 are hydrogen, wherein R.sub.1, R.sub.1, R.sub.1, R.sub.2, R.sub.2, R.sub.2 are not all hydrogen, wherein R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl; and c) activating the organophotoredox catalyst of step b) with a light irradiation to alkylate the substrate and form a carbon covalent bond.
2. The process according to claim 1, wherein the process is performed in an inert atmosphere.
3. The process according to claim 1, wherein the light irradiation has a wavelength of from 380 nm to 780 nm.
4. The process according to claim 1, wherein the organophotoredox catalyst is present in a concentration of at least 0.025 mol %.
5. The process of claim 1, further comprising after the step of contacting and before the step of activating, protonating the quinoline nitrogen of the organophotoredox catalyst.
6. The process according to claim 1, further comprising providing an alkylation precursor in the mixture.
7. The process according to claim , wherein the alkylation precursor is an alkyltrifluoroborate salt, ##STR00285## Boc.sub.2(NH)SO.sub.2-alkyl, NH.sub.3COO-alkyl, ##STR00286##
8. The process according to claim , wherein the alkylation precursor comprises an alkyl moiety functionalized with one or more of an ester, a ketone, an ethereal, a carbamoyl, a benzyloxy, an allyloxy, and propargyloxy.
9. The process according to claim 1, wherein step b) further comprises contacting the organophotoredox catalyst with a co-catalyst comprising Ni, Co, Fe or Cu.
10. The process according to claim 1, wherein the acid is trifluoroacetic acid or HCl.
11. The process according to claim 1, wherein the organophotoredox catalyst is of formula Ib, Ic or Id ##STR00287## wherein X.sub.3 is N or CH, R.sub.1 and R.sub.2 are not both H, and R.sub.1, R.sub.2 R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are as defined in claim 1.
12. (canceled)
13. (canceled)
14. The process according to claim 1, wherein the organophotoredox catalyst is selected from the group consisting of: ##STR00288## ##STR00289##
15. The process according to claim 1, wherein the organophotoredox catalyst is ##STR00290##
16. (canceled)
17. (canceled)
18. The process according to claim 1, wherein activating the organophotoredox catalyst further comprises obtaining an activated catalyst of formula IIa ##STR00291## and wherein R.sub.1, R.sub.2, R.sub.3 R.sub.4, R.sub.5, R.sub.6, X.sub.1, X.sub.2, X.sub.3, and X.sub.4, are as defined in claim 1.
19. The process according to claim 1, wherein the mixture further comprises a co-catalyst selected from Ni, Cu, Co or Fe and X.sub.3 is N.
20. The process according to claim 19, further comprising obtaining a metallophotoredox catalyst after the step of contacting the organophotoredox catalyst with the mixture.
21. The process of claim 20, wherein the metallophotoredox catalyst is of formula Ie: ##STR00292## wherein R.sub.1, R.sub.1, R.sub.1, R.sub.2, R.sub.2, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, X.sub.1, and X.sub.2 are as defined in claim 1.
22. The process of claim 20, wherein the metallophotoredox catalyst is of formula If: ##STR00293## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6, are as defined in claim 1.
23. The process of claim 20, wherein the metallophotoredox catalyst is of formula Ig: ##STR00294## wherein R.sub.1 and R.sub.2 are as defined in claim 1.
24. A compound of formula Ia ##STR00295## wherein R.sub.1, R.sub.1, R.sub.1 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted X-alkyl, chemical linker, or X-chemical linker with X being one of an oxygen, an amine or a sulfur, X.sub.1, and X.sub.2 are independently selected from CH or N, when X.sub.1 is N, X.sub.2 is CH, R.sub.1 and R.sub.1 are hydrogen, when X.sub.2 is N, X.sub.1 is CH, R.sub.1 and R.sub.1 are hydrogen, when X.sub.1, and X.sub.2 are both CH, R.sub.1 and R.sub.1 are hydrogen, wherein R.sub.2, R.sub.2, R.sub.2 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted X-alkyl, chemical linker, or X-chemical linker with X being one of an oxygen, an amine or a sulfur, X.sub.3, and X.sub.4 are independently selected from CH or N, when X.sub.3 is N, X.sub.4 is CH, R.sub.2 and R.sub.2 are hydrogen, when X.sub.4 is N, X.sub.3 is CH, R.sub.2 and R.sub.2 are hydrogen, when X.sub.3, and X.sub.4 are both CH, R.sub.2 and R.sub.2 are hydrogen, wherein R.sub.1, R.sub.1, R.sub.1, R.sub.2, R.sub.2, R.sub.2 are not all hydrogen, wherein at least one of X.sub.1, X.sub.2 X.sub.3, and X.sub.4 is N, and wherein R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl.
25. A compound selected from the group consisting of ##STR00296##
Description
DESCRIPTION OF THE DRAWINGS
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DETAILED DESCRIPTION
[0038] There is provided a cost-effective organophotoredox catalyst that is an efficient, low-cost, homogeneous co-catalyst to perform chemical reactions such as an alkylation, for example a Minisci alkylation. The organophotoredox catalyst of the present disclosure has a simple photoactivation mechanism, and has reduced sensitive functionalities and byproduct formation. The organophotoredox catalyst of the present disclosure does not require laborious and expensive electrochemical systems or semiconductors to perform an alkylation such as a Minisci alkylation.
[0039] The terms alkylating, alkylation and the like, as used herein refer to a chemical reaction that forms a covalent carbon bond or that grafts a chemical structure to a substrate using a carbon covalent bond. The carbon covalent bond may be a CC bond, a CO bond, a CN bond or a CS bond. In some embodiments, the carbon covalent bond is a single bond. The alkylation can also occur within a compound, for example a cyclisation of a compound that would result in the formation of a carbon covalent bond within the same molecule, such as a CC bond. Many different types of alkylations are contemplated by the present disclosure including but not limited to alkyne additions, group transfers, alkyl addition (e.g. to a nitrogen or sulfur of a substrate) and Minisci alkylations. A Minisci alkylation is type of alkylation in which a radical reaction that introduces an alkyl group to an electron deficient aromatic heterocycle occurs. In some embodiments, the heterocycle is a heterocycle containing a nitrogen. In further embodiments, the heterocycle is a quinoline group, a pyridine group, an indole group or an acridine group.
[0040] Unlike the prior art photocatalysts, which impart their photoreactivities as covalently linked entities, the present organophotoredox catalyst has a distinct activation that is a proton activation mode or a Lewis acid coordination activation mode. Simply upon protonation, the organophotoredox catalyst reaches an oxidizing excited state. The protonation may be activated by a suitable acid and following protonation light irradiation, for example a visible light irradiation catalyzes the alkylation. In some embodiments, the light irradiation has a wave length of from 380 to 780 nm, of from 380 to 680 nm, or of from 380 to 580 nm. The organophotoredox catalyst can be employed alone or in combination with one or more co-catalysts such as metal organocatalysts. In some embodiments, the alkylation is a Minisci alkylation and the organophotoredox catalyst is combined with a cobalt organocatalyst such as a cobaloxime (e.g. chloro(pyridine)cobaloxime) to formulate an oxidative cross-coupling platform, enabling alkylation reactions such as Minisci alkylations and various CC bond-forming reactions. In some embodiments, the present disclosure does not contemplate the addition of any other chemical oxidants.
[0041] The organophotoredox catalyst of the present disclosure has a chemical structure according to formula Ia.
##STR00003## [0042] R.sub.1, R.sub.1, R.sub.1 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted X-alkyl, chemical linker, or X-chemical linker with X being one of an oxygen, an amine or a sulfur. X.sub.1, and X.sub.2 are independently selected from CH or N. When X.sub.1 is N, X.sub.2 is CH, R.sub.1 and R.sub.1 are hydrogen. When X.sub.2 is N, X, is CH, R.sub.1 and R.sub.1 are hydrogen. When X.sub.1, and X.sub.2 are both CH, R.sub.1 and R.sub.1 are hydrogen.
[0043] R.sub.2, R.sub.2, R.sup.2 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted X-alkyl, chemical linker, or X-chemical linker with X being one of an oxygen, an amine or a sulfur. X.sub.3, and X.sub.4 are independently selected from CH or N. When X.sub.3 is N, X.sub.4 is CH, R.sub.2 and R.sup.2 are hydrogen. When X.sub.4 is N, X.sub.3 is CH, R.sub.2 and R.sub.2 are hydrogen. When X.sub.3, and X.sub.4 are both CH, R.sub.2 and R.sup.2 are hydrogen.
[0044] In some embodiments, R.sup.1, R.sub.1, R.sub.1, R.sub.2, R.sub.2, R.sup.2 are not all hydrogen unless X.sub.3 is N. In some embodiments, R.sub.1, R.sub.1, R.sub.1, R.sub.2, R.sub.2, R.sup.2 are not all hydrogen. In some embodiments, at least one of R.sub.1, R.sub.1, R.sub.1, R.sub.2, R.sub.2, R.sup.2 has or is an electron donating group to promote and facilitate the protonation of the nitrogen of the quinoline ring. In some embodiments, an alkyl group is a weak electron donating group that is sufficient to promote the protonation of the nitrogen of the quinoline ring. In some embodiments, at least one of X.sub.1, X.sub.2 X.sub.3, and X.sub.4 is N.
[0045] R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl.
[0046] The term alkyl, as used herein, is understood as referring to a saturated, monovalent unbranched or branched hydrocarbon chain. In some embodiments, the alkyl can be the backbone of a polymer such as polystyrene. In other embodiments, the alkyl group can comprise up to 20 carbon atoms. Examples of alkyl groups include, but are not limited to, C.sub.1-C.sub.10 alkyl groups, provided that branched alkyls comprise at least 3 carbon atoms, such as C.sub.3-C.sub.10. Lower straight alkyl may have 1 to 6 or 1 to 3 carbon atoms; whereas branched lower alkyl comprise C.sub.3-C.sub.6. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl and decyl. In some embodiments, the term alkyl in the context of the present disclosure and particularly for groups R.sub.1 and R.sub.2 is further defined to exclude alkyl groups with one or more hydrogen atom being replaced by a halogen, ie. a haloalkyl.
[0047] The term alkylenyl, as used herein, is understood as referring to bivalent alkyl residue. Examples of alkylenyl groups include, but are not limited to, ethenyl, propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 2-methyl-3-butenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl, 4-methyl-1-pentenyl, 2-methyl-2-pentenyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-ethyl-1-butenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl and decenyl.
[0048] The term cycloalkyl represents a cyclic hydrocarbon moiety having 3 to 10 carbon atoms. Cycloalkyl may be a monocyclic hydrocarbon moiety having 3 to 8 carbon atoms. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and cyclooctyl. The cycloalkyl group can be a polycyclic group for example a polycyclic group having 7 to 10 carbons. For example, the cycloalkyl can be a bicycloalkyl such as bicycloheptane. In a further example, the cycloalkyl can be a tricycloalkyl such as adamantanyl. In an additional example, the cycloalkyl can be a multicyclic alkyl such as cubanyl.
[0049] The term cycloalkenyl is a cycloalkyl group which has one or more double bonds, preferably one double bond. Examples of cycloalkenyl include but are not limited to cyclopentenyl, cyclohexenyl, and cycloheptenyl.
[0050] The term aryl represents a carbocyclic moiety containing at least one benzenoid-type ring (i.e., may be monocyclic or polycyclic). Preferably, the aryl comprises 6 to 10 or more preferably 6 carbon atoms. Examples of aryl include but are not limited to phenyl and naphthyl.
[0051] The term heteroaryl represents an aryl having one or more carbon in the aromatic ring(s) replaced by nitrogen. The heteroaryl can have 3 to 9 carbon atoms (C.sub.3-C.sub.9) with the remainder atoms of the aromatic ring(s) being nitrogen. Examples of heteroaryl include but are not limited to pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, quinolinyl, quinoxalinyl, quinazonyl, cinnolinyl, triazolopyridinyl, trioazolopyrimidinyl, diaazolopyrimidinyl, diazolopyridinyl, and triazynyl.
[0052] The term heterocyclyl represents a 3 to 10 membered saturated (heterocycloalkyl), partially saturated (heterocycloalkylene), and any other heterocyclic ring that can be aromatic or non-aromatic. The heterocyclyl comprises at least one heteroatom selected from oxygen (O), sulfur (S), silicon (Si) or nitrogen (N) replacing a carbon atom in at least one cyclic ring. Heterocyclyl may be monocyclic or polycyclic rings. Heterocyclyl may be 3 to 8 membered monocyclic ring. The heterocyclyl ring, in some examples, can contain only 1 carbon atom (for example tetrazolyl). Therefore the heterocyclyl can be a C.sub.1-C.sub.7 heterocyclyl. When heterocyclyl is a polycyclic ring, the rings comprise at least one heterocyclyl monocyclic ring and the other rings may be fused cycloalkyl, aryl, heteroaryl or heterocyclyl and the point of attachment may be on any available atom or pair of atoms. Examples of heterocycloalkyl include but are not limited to piperidinyl, oxetanyl, morpholino, azepanyl, pyrrolidinyl, azetidinyl, azocanyl, and azasilinanyl. Examples of heterocycloalkylene include but are not limited to dihydropyranyl, dihydrothiopyranyl, and tetrahydropiperidine. Examples of further monocyclic heterocyclyl include but are not limited to azolyl, diazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiophenyl, furanyl, thiazolyl, and isothiazolyl. Examples of polycyclic heterocyclyl include but are not limited to oxa-azabicyclo-heptanyl, oxa-azaspiro-heptanyl, azabicyclo-hexanyl, azaspiro-heptanyl, dihydroquinolinyl, and azaspiro-octanyl.
[0053] The term substituted or substituent represents at each occurrence and independently, one or more oxide, amino, amidino, amido, azido, cyano, guanido, hydroxyl, nitro, nitroso, carbonitrile, urea, alkyl, alkoxy, carboxy (i.e. COOH), alkyl-carboxy (i.e. alkyl substituted with COOH), ester, alkyl as defined herein, alkenyl as defined herein, cycloalkyl as defined herein, aryl as defined herein, heteroaryl as defined herein, or heterocyclyl as defined herein. The substituents of the present disclosure may replace a hydrogen of a carbon of the carbon backbone of a substituted chemical species and/or can interrupt the carbon backbone of the substituted species. For example, a nitrogen may replace a hydrogen resulting in a CH.sub.2CH(NH.sub.2)CH.sub.2 or can interrupt the chain to result in CH.sub.2NH.sub.2CH.sub.2.
[0054] The term chemical linker as used herein refers to a covalent chemical linker that binds to the organophotoredox through R.sub.1 or R.sub.2. The chemical linker can for example be a linker that immobilizes the organophotoredox of the present disclosure to a surface, such as the surface of a bead. The chemical linker may be linked to any suitable functional group. In one example, the functional group can be part of a polymer. The chemical linker of the present disclosure can contain maleimide, sulfhydryl reactive groups, or succinimidyl esters which react with amines. Other suitable chemical linkers are contemplated by the present disclosure as long as the chemical linkers do not interfere with the alkylation reaction.
[0055] In some embodiments, the organophotoredox catalyst of the present disclosure is of formula Ib with R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 as previously defined herein and X.sub.3 being N or CH. R.sub.1 and R.sub.2 are not both H when X.sub.3 is CH.
##STR00004##
[0056] In still further embodiments, the organophotoredox catalyst of the present disclosure is of formula Ic with R.sub.1, and R.sub.2 as previously defined herein and X.sub.3 being N or CH. R.sub.1 and R.sub.2 are not both H when X.sub.3 is CH.
##STR00005##
[0057] In yet further embodiments, the organophotoredox catalyst has a chemical structure according to formula Id with R.sub.1 and R.sub.2 being as previously defined herein. In one example, R.sub.1 and R.sub.2 are each independently selected from H, -Me, OMe, -(chemical linker) and O (chemical linker), and R.sub.1 and R.sub.2 are not both H.
##STR00006##
[0058] In some embodiments, the organophotoredox catalyst is selected from the group consisting of
##STR00007## ##STR00008##
[0059] The organophotoredox catalyst of formulas Ia, Ib, Ic, and Id is activated by protonation of the nitrogen of the quinolone group. Accordingly, once protonated, the activated organophotoredox catalyst of formula Ia becomes formula IIa, formula Ib becomes formula IIb, formula Ic becomes formula IIc and formula IId becomes formula IId. The definitions of the substituent groups of formulas Ia, Ib, Ic, and Id respectively apply to formulas IIa, IIb, IIc, and IId.
##STR00009##
[0060] The organophotoredox catalyst furnishes carbon radicals from an array of attractive precursors and can for example complete the Minisci alkylation when partnered with a cobaloxime chaperone. Moreover, the pronounced photosynthetic capacity of the present catalytic system can be used in other oxidative cross-coupling reactions for carbon bond formations, such as oxidative arene fluoroalkylation and alkene/alkyne dicarbofunctionalization.
[0061] There is provided a process of alkylating a substrate, the process comprises providing a mixture that includes an acid, the substrate and optionally a cobalt, nickel, copper or iron co-catalyst. The metal containing co-catalyst can be elemental or ionic cobalt, nickel, copper or iron, or a molecule containing cobalt, nickel, copper or iron. For example, the co-catalyst can be an organic metallocatalyst such as chloro(pyridine)cobaloxime. The process comprises contacting the organophotoredox catalyst as described herein with the mixture. The co-catalyst, such as a cobalt organophotoredox catalyst, can be included in the mixture or can be linked on a surface or solid substrate through a chemical linker group at R.sub.1 and/or R.sub.2 and brought into contact with the reaction. For example, the organophotoredox catalyst can be linked to a polystyrene (PS) bead or any other suitable catalytic surface with the chemical linker at R.sub.1 and/or R.sub.2. The process further comprises activating the organophotoredox catalyst with a light irradiation to alkylate the substrate and form a CC covalent bond. The substrate is an organic compound preferably containing multiple CH bonds (for example at least 3, preferably at least 5 and more preferably at least 10). In some embodiments, the substrate is an organic compound having a molecular weight of from 50 to 1000 g/mol. In further embodiments, the substrate is an organic compound comprising at least one cyclic group, for example an aromatic cyclic group. In some embodiments the substrate is a compound containing at least 1, at least 2, at least 3, at least 4 or at least 5 carbon atoms each having at least one CH bond. In some embodiments, the substrate is solid or liquid at room temperature. The substrate is a compound capable of performing an alkylation reaction with another compound or with itself (e.g. cyclization reaction).
[0062] The organophotoredox catalyst is also provided as a metallophotoredox catalyst. The organophotoredox catalyst can form a metal containing compound with the co-catalyst (i.e. metallophotoredox catalyst). In such embodiments, the organophotoredox catalyst is of formula Ia, Ib, or Ic with X.sub.3 being N and the metal is a redox active metal. Preferably, the redox active metal is a Lewis acidic transition metal. More preferably, the redox active metal is selected from Ni, Co, Cu or Fe. The metallophotoredox catalyst formed is shown in formulas Ie, If, and Ig with M representing the redox active metal which is preferably Ni, Co, Cu or Fe. The redox active metal M forms donor-acceptor coordination bonds with the nitrogen atoms. In formula Ie, R.sub.1, R.sub.1, R.sub.1, R.sub.2, R.sub.2, R.sup.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, X.sub.1, and X.sub.2 are as previously defined for formula Ia. In formula If, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6 are as previously defined for formula Ib. In formula Ig, R.sub.1, R.sub.2 are as previously defined for formula Ic. The metallophotoredox is formed by stirring a compound containing the redox active metal with the organophotoredox catalyst of formula Ia, Ib, or Ic with X.sub.3 being N, preferably in a molar ratio of 1:2 to 2:1, and more preferably in equimolar amounts.
##STR00010##
[0063] In some embodiments, the process of the present disclosure is performed under inert atmosphere. An inert atmosphere is an atmosphere that will not significantly interfere with the alkylation reaction or the protonation of the organophotoredox. In some embodiments, the inert atmosphere is a gas atmosphere such as N.sub.2, Ar, He, Ne, Kr, orXe. In some embodiments, a co-catalyst is selected from a cobalt catalyst (such as cobalt organocatalyst), a copper catalyst, an iron catalyst or a nickel catalyst. The cobalt organocatalyst may be a cobaloxime such as chloro(pyridine)cobaloxime. In one example, the cobalt organocatalyst is chloro(pyridine)bis(dimethylglyoximato)cobalt (III).
[0064] In some embodiments, the acid is trifluoroacetic acid (TFA) or HCl. However the choice of acid will depend on the type of alkylation and co-catalyst when used. In some embodiments, the role of the acid is to promote the protonation of the nitrogen of the quinoline group of the organophotoredox catalyst.
[0065] An alkylation precursor may be provided in the mixture in order to link an alkylation group of the precursor to the substrate. Examples of alkylation precursors include but are not
limited to trifluoroborate salts such as the potassium salt,
##STR00011##
Boc.sub.2(NH)SO.sub.2-(alkylation group) (Boc=tert-butyloxycarbonyl), NH.sub.3COO-(alkylation group),
##STR00012##
Example 1
[0066] Conjugated heteroaromatic motifs, especially N-heterocycles, are frequently seen in photocatalytic chromophores (formulas III, IV, V). Indeed, isolated heteroarenes, for instance, quinolines, have been capitalized as single-electron oxidants that could oxidize some intractable reactants under photochemical conditions (MeOH, E.sub.red>+3.0 V; Cl.sup., E.sub.red>+2.0 V vs standard calomel electrode (SCE)), albeit requiring energetic ultraviolet photons and restricting the reaction scope only in quinoline functionalization.
##STR00013##
[0067] For the present organophotoredox catalyst design, without wishing to be bound by theory, the C2 and/or C4 positions of quinoline skeletons were engineered with -extended substituents. This advantageous modification moved the absorption of the organophotoredox catalyst to the visible light region and simultaneously blocked their radicophilic sites. The present inventors have found that a simple protonation of the organophotoredox catalyst can exert an effect at least equal to other known alkylation photocatalysts. The organophotoredox catalyst of the present disclosure has a convenient and tunable activation mode that considerably simplifies its synthesis since the exocyclic N-substituents of above-noted counterparts were tethered via nucleophilic displacement or metal-catalyzed cross-couplings. Furthermore, pairing the organophotoredox catalyst with a radical precursor with reasonably low reduction potential improves the current protocols for oxidative Minisci alkylation. To this end, potassium alkyltrifluoroborates (R-BF.sub.3K), was tested in the present example. RBF.sub.3K is structurally diverse, shelf-stable, and a good candidate for evaluating the organophotoredox catalyst of the present disclosure.
[0068] Solvents used in the present example were dried over 4 molecular sieves (beads, 8-12 mesh) and degassed by purging with argon for 30 min. The 4 molecular sieves were purchased from Sigma-Aldrich chemical company and were freshly activated in the oven for 12 h at 380 C. before use. Reagents were purchased from Sigma-Aldrich, Combi-Blocks, TCI America, Oakwood, and Fisher Scientific chemical companies and were used without further purification unless otherwise specified.
[0069] Nuclear magnetic resonance (NMR) spectra, including .sup.1H NMR, .sup.13C NMR, and .sup.19F NMR, were recorded on Bruker 500 MHz spectrometers, using the deuterium lock signal to reference the spectra. The solvent residual peaks, e.g., chloroform (CDCl3: 7.28 ppm and 77.02 ppm), were used as references. All NMR spectra were recorded at room temperature. Gas chromatography-mass spectroscopy (GC-MS) was obtained from the Agilent gas chromatography-mass spectroscopy system with helium (He) as the carrier gas. High-resolution mass spectrometry (HRMS) lifetime was measured by time-correlated single-photon counting (TCSPC), and the decay data was collected on a time-resolved emission spectrometer setup (Fluotime 200) suited with a TCSPC module (PicoHarp 300) (Picoquant GMBH) with time-resolved fluorescence decay and time-resolved anisotropy decay capabilities, monochromator, operated with symphotime software (Picoquant). Electrochemical experiments were performed with HEKA PG 340 potentiostat with Ag/AgCl as the reference electrode. The working electrode was made of glassy carbon, and a Pt wire was used as the counter electrode to complete the electrochemical setup. A scan rate of 20 mV/s was used for all experiments. All the potentials were noted with respect to the Ag/AgCl electrode unless otherwise specified. The reduction potential referenced to the standard calomel electrode (SCE) could be calculated by subtracting 0.039 V from the E(Ag/AgCl). It followed that E(SCE)=E(Ag/AgCl)0.039 V. Electron paramagnetic resonance (EPR) was performed on a Bruker Elexsys E580 X-band EPR Spectrometer. Gas chromatography-thermal conductivity detector (GC-TCD) was conducted on an Agilent 6890N Network Gas Chromatograph for hydrogen gas (H2) analysis using argon (Ar) as the carrier gas.
[0070] Reactions were stirred magnetically unless otherwise specified. Column chromatography was performed with E. Merck silica gel 60 (230-400 mesh). Experiments were conducted in sealed 10 mL pyrextubes. Experiments under light irradiation were performed using a low-pressure 300 W Xe lamp (from Atlas Specialty Lighting, with a PE300BF light bulb from Excelitas) equipped with a water bath (Chemglass Jacketed Beaker, GC-1107-12) for efficient temperature maintenance, and all the reactions were conducted under an inert atmosphere in sealed tubes unless otherwise noted. Quantum yield was measured with a 390 nm PR160L Kessil lamp.
[0071] To establish a proof of concept, slightly excessive potassium cyclohexyltrifluoroborate (2a, Cy-BF.sub.3K, E.sub.red=+1.5 V vs SCE) was opted to alkylate lepidine (1a) in the presence of trifluoroacetic acid (TFA), chloro(pyridine)bis(dimethylglyoximato)cobalt (III) ([Co(dmgH).sub.2(py)]Cl) (Co, formula VI) and a quinolone photocatalyst (QN) in dioxane under visible light irradiation (Scheme 1). (Cy=cyclohexyl)
##STR00014##
##STR00015##
[0072] The quinoline photocatalyst tested as well as the results for each are summarized in Table 1. The yield was determined by nuclear magnetic resonance (NMR).
TABLE-US-00001 TABLE 1 Quinoline photocatalyst results Name of QN Yield of compound Structure of QN catalyst compound compound 3 DPQN
[0073] The reactions were performed with compound 1a (0.10 mmol, 1.0 equiv), compound 2a (0.15 mmol, 1.5 equiv), QN (5.0 mol, 5.0 mol %), [Co(dmgH).sub.2(py)]Cl (5.0 mol, 5.0 mol %), TFA (0.20 mmol, 2.0 equiv) in dioxane (1.5 mL, 0.067 M) under N.sub.2 at about 37 C. and irradiated by >395 nm light for 20 hours.
[0074] As set out in Table 1, DPQN.sup.2,4-di-OMe, DPQN.sup.4-OMe, DPQN.sup.2-OMe, and DPQN.sup.2-Me showed good results with yields of at least 65% whereas the remaining compounds tested all had an inadequate yield of 25% or less. DPQN.sup.2,4-di-OMe had the best yield at 96% and was further tested by reducing the loading concentration from 5.0 mol % to 0.025 mol %. The yield obtained with the loading concentration of 0.025 mol % of DPQN.sup.2,4-di-OMe was 84%. Because of the instrumental role of cationization for enhancing the photocatalytic performance, electron-donating groups are beneficial. Furthermore, locating the electron-releasing substituents on DPQN could structurally correlate with the donor-acceptor patterns of acridiniums. Unsurprisingly, the yield of compound 3 dropped when an electron-withdrawing group (CF.sub.3) resided on the DPQN parent structure. On the contrary, the productivity was significantly elevated when using methylated and methoxylated DPQNs (i.e. DPQN.sup.2,4-di-OMe, DPQN.sup.4-OMe, DPQN.sup.2-OMe, and DPQN.sup.2-Me). Without wishing to be bound by theory, -Me and OMe combat the susceptibility of catalysts towards radical attack, therefore conferring stability against their deactivation. This can therefore explain why DPQN.sup.2,4-di-OMe ranked as the most robust and efficient photocatalyst in the series tested (Table 1), giving a very high yield of the cyclohexylation product even at 0.025 mol % loading, albeit for a longer reaction time (72 h).
[0075] Removal of either aryl handle from DPQNs completely suppressed the reaction, presumably due to the unmatched photoabsorptive profiles or the non-productive consumption of radical intermediates. Control experiments showed that photocatalyst, cobalt, acid, light and inert atmosphere were important for this photoinduced oxidative cross-coupling reaction. Other boron reagents were ineffective, which might attribute to their prohibitive oxidation potentials (E.sub.red>+2.5 V vs SCE for cyclohexylboronic acid, Cy-B(OH).sub.2 and its pinacol ester, Cy-Bpin). Notably, among some commercial photocatalysts evaluated, [Ru(bpy).sub.3](PF.sub.6).sub.2, Eosin Y, Rose bengal, and Rhodamine 6G brought poor results of the Minisci alkylation (0%, 25%, 0% and 0% yields respectively).
[0076] Further experimentation according Scheme 1 was performed by varying different conditions as detailed in Table 2 below.
TABLE-US-00002 TABLE 2 Experimental conditions and results QN Co Acid (equiv) Solvent (mL) Yield (%) DPQN [Co(dmgH).sub.2(py)]Cl TFA (3.0) Dioxane (1.0) 59 DPQN.sup.2-CF3 [Co(dmgH).sub.2(py)]Cl TFA (3.0) Dioxane (1.0) 16 DPQN.sup.2-Me [Co(dmgH).sub.2(py)]Cl TFA (3.0) Dioxane (1.0) 63 DPQN.sup.2-OMe [Co(dmgH).sub.2(py)]Cl TFA (3.0) Dioxane (1.0) 68 DPQN.sup.4-OMe [Co(dmgH).sub.2(py)]Cl TFA (3.0) Dioxane (1.0) 67 DPQN.sup.2,4-di-OMe [Co(dmgH).sub.2(py)]Cl TFA (3.0) Dioxane (1.0) 73 DPQN.sup.2,4-di-OMe [Co(dmgH).sub.2(py)]Cl TFA (3.0) Dioxane (1.5) 93 DPQN.sup.2,4-di-OMe [Co(dmgH).sub.2(py)]Cl TFA (2.0) Dioxane (1.5) 96 DPQN.sup.2,4-di-OMe [Co(dmgH).sub.2(py)]Cl TFA (1.0) Dioxane (1.5) <5 DPQN.sup.2,4-di-OMe [Co(dmgH).sub.2(py)]Cl Dioxane (1.5) 0 DPQN.sup.2,4-di-OMe [Co(dmgH).sub.2(py)]Cl TFA (2.0) MeCN (1.5) 51 DPQN.sup.2,4-di-OMe [Co(dmgH).sub.2(py)]Cl TFA (2.0) EtOAc 86 DPQN.sup.2,4-di-OMe [Co(dmgH).sub.2(py)]Cl TFA (2.0) Dioxane (1.5) <5 (under air) DPQN.sup.2,4-di-OMe [Co(dmgH).sub.2(py)]Cl TFA (2.0) Dioxane (1.5) 0 (at room temperature in the dark) DPQN.sup.2,4-di-OMe [Co(dmgH).sub.2(py)]Cl TFA (2.0) Dioxane (1.5) 0 (at 80 C. in the dark) [Co(dmgH).sub.2(py)]Cl TFA (2.0) Dioxane (1.5) 0 DPQN.sup.2,4-di-OMe TFA (2.0) Dioxane (1.5) 0 DPQN.sup.2,4-di-OMe [Co(dmgH).sub.2(py)]Cl HCl (2.0) Dioxane (1.5) 30 DPQN.sup.2,4-di-OMe [Co(dmgH).sub.2(py)]Cl AcOH (2.0) Dioxane (1.5) 0 DPQN.sup.2,4-di-OMe CoCl.sub.2 TFA (2.0) Dioxane (1.5) <5 DPQN.sup.2,4-di-OMe Co(dmgBF.sub.2).sub.2 TFA (2.0) Dioxane (1.5) 82
[0077] Therefore, 1.0 equiv heteroarene, 1.5 equiv R-BF.sub.3K, 5.0 mol % DPQN.sup.2,4-di-OMe, 5.0 mol % [Co(dmgH).sub.2(py)]Cl and 2.0 equiv TEA in dioxane (0.067 M) under argon with visible light irradiation (>395 nm) were the preferred conditions. The synthesis of DPQN.sup.2,4-di-OMe was explored and it was found that DPQN.sup.2,4-di-OMe can be prepared in a multigram scale (56%, 2.9 g) via the facile aldehyde-alkyne-amine (A.sup.3) couplings with a Lewis acid (LA) (scheme 2). Its structure was unambiguously confirmed by X-ray crystallography (
##STR00026##
[0078] An advantage of DPQN.sup.2,4-di-OMe is its reduced cost compared to current commercial catalysts. Table 3 below details the price of the chemicals to synthesize DPQN.sup.2,4-di-OMe. Based on Table 3, the cost for 2.92 g of DPQN.sup.2,4-di-OMe could be estimated to be $212 CAD, and its unit price would be $7.3 CAD/100 mg, which is significantly lower than the acridinium catalyst ($145 CAD/100 mg from Sigma Aldrich and 4CzIPN $762 CAD/100 mg from Sigma Aldrich).
TABLE-US-00003 TABLE 3 Cost summary for DPQN.sup.2,4-di-OMe synthesis Unit price (CAD) from Chemical Sigma Aldrich Quantity Cost (CAD) 4-anisaldehyde 0.21$/g.sup. 2.0 g $0.42 Aniline 0.035$/g.sup. 1.4 g $0.049 4-ethynylanisole .sup.67$/g 3.0 g $201 MgSO.sub.4 0.043$/g.sup. 0.90 g $0.039 Fe(OTf).sub.3 .sup.52$/g 0.18 g $9.3 AcOH 0.025$/mL 1.3 mL $0.033 CH.sub.2Cl.sub.2 0.11$/mL 5.0 mL $0.55 Toluene 0.020$/mL 15 mL $0.30
[0079] Furthermore, in terms of the catalyst synthesis, the preparation of DPQN.sup.2,4-di-OMe photocatalyst is advantageous because of a shorter synthetic time length and using reagents that are easy to handle. In general, the synthesis of acridinium catalysts involves multiple steps for a long reaction time, in which the N-functionalization is realized by nucleophilic substitution or metal-catalyzed cross-coupling. In addition, the synthesis is often accomplished by Grignard reactions. In contrast, in the present example a two-step aldehyde-alkyne-amine coupling reaction was designed for the diarylquinoline catalyst preparation, wherein the starting materials are readily available and convenient to handle. Furthermore, N-substitution is unnecessary in the procedure since the catalyst could be easily activated under typical Minisci acidic conditions.
[0080] Henceforth in the present example, DPQN.sup.2,4-di-OMe with chloro(pyridine)bis(dimethylglyoximato)cobalt (III) was used as the catalyst system unless otherwise specified. This catalyst system was first used to investigate the alkylation of lepidine 1a with various R-BF.sub.3K (Table 4). The reaction conditions were 4-Me-DPQN (0.10 mmol, 1.0 equiv), potassium alkyltrifluoroborate (R-BF.sub.3K, 0.15 mmol, 1.5 equiv), DPQN.sup.2,4-di-OMe (5.0 mol, 5.0 mol %), [Co(dmgH).sub.2(py)]Cl (5.0 mol, 5.0 mmol %), and TFA (0.20 mmol, 2.0 equiv) in dioxane (1.5 mL, 0.067 M) under light irradiated at 37 C. for 20 h under N.sub.2. Yields in the table refer to the isolated yields unless otherwise specified. For compound 6, ethyl acetate (EtOAc) was used as the solvent. For compound 17, 3.0 equiv R-BF.sub.3K was used.
[0081] A broad spectrum of R-BF.sub.3K, including 1, 2 and 3 ones, were proven viable in this transformation. Simple alkyl groups such as the isopropyl, sec-butyl, n-pentyl, and tert-butyl could be installed, providing the elaborated lepidines smoothly (compounds 4 to 7), so as the four to six-membered cyclic substituents (compounds 8 and 9). The bridged reagents like 1-adamantyl and 2-norbonyl ones were heteroarylated successfully, which afforded the target products compounds 10 and 11 in good to excellent yields. Functionalized alkyltrifluoroborates bearing ester, ketone, ethereal, carbamoyl, benzyloxy, allyloxy, and propargyloxy groups were also compatible, and the lepidine was decorated in satisfactory yield (compounds 12 to 22).
##STR00027##
TABLE-US-00004 TABLE 4 Alkylation of lepidine Compound number Compound product obtained Yield 4
[0082] Further scope examination with different heteroaromatic pharmacophores with Cy-BF.sub.3K (compound 2a) as the coupling partner was conducted (Scheme 4). Unless otherwise specified the reaction conditions were: heteroarene (Het-H, 0.10 mmol, 1.0 equiv), potassium alkyltrifluoroborate (R-BF.sub.3K, 0.15 mmol, 1.5 equiv), DPQN.sup.2,4-di-OMe (5.0 mol, 5.0 mol %), [Co(dmgH).sub.2(py)]Cl (5.0 mol, 5.0 mmol %), and TFA (0.20 mmol, 2.0 equiv) in dioxane (1.5 mL, 0.067 M) under light irradiated at 37 C. for 20 h under N.sub.2. For compounds 24, 28, 33, 34, 35, and 39-43 3.0 equiv R-BF.sub.3K was used. For compounds 29, 36, and 37 4.0 equiv RBF.sub.3K was used. For compounds 33-37 and 42 3.0 equiv TFA was used. For compound 29 EtOAc was the solvent and the reaction was run for 40 h. For compound 29 a ratio Mono:di=10:1 was obtained where mono is a C2 alkylation and di is both a C2 and C4 alkylation. For compound 30 a ratio C1:C3=6.2:1 was obtained where C1 is the alkylation at C1 and C3 is the alkylation at C3. For compound 37 the yield was determined by NMR. As shown in Table 5, a variety of substituents on heterocycles like cyano, halo, ketone, alkoxy, ester, sulfonamido, amino, amido groups and others were well tolerated in this reaction (23 to 52). Other than quinoline compounds, elaboration of isoquinoline, pyridine, bipyridine, phenanthroline, phenanthridine, benzimidazole, benzothiazole, thiazole, quinoxalinone and quinazolinone were shown to be effective (compounds 30 to 43). Yields in the tables below refer to the isolated yields unless otherwise specified.
##STR00047##
TABLE-US-00005 TABLE 5 Alkylation of heteroarenes Compound number Compound structure Yield 23
[0083] To showcase the robustness of the heteroarene functionalization method of the present disclosure, the alkylation (with Cy-BF.sub.3K) of substrates with high molecular complexity was evaluated (Scheme 4, Table 6). Unless otherwise specified the reaction conditions: heteroarene (Het-H, 0.10 mmol, 1.0 equiv), potassium alkyltrifluoroborate (RBF.sub.3K, 0.15 mmol, 1.5 equiv), DPQN.sup.2,4-di-OMe (5.0 mol, 5.0 mol %), [Co(dmgH)z(py)]Cl (5.0 mol, 5.0 mmol %), and TEA (0.20 mmol, 2.0 equiv) in dioxane (1.5 mL, 0.067 M) under light irradiated at 37 C. for 20 h under N.sub.2. For compounds 44-47, 51 and 52 3.0 equiv RBF.sub.3K was used. For compounds 44, 45, 47, 48, 51 and 52 3.0 equiv TEA was used. For compound 50 a ratio Mono:di=1:1 was obtained and for compound 52 a ratio Mono:di=2:1 was obtained where mono is only a C2 alkylation and di is a C2 and C6 alkylation.
[0084] Encouragingly, cyclohexylation of dichloropurine provided the expected product 44 in moderate yield. Couplings of pyridines consisting of alanine, pyrrolidine, and menthol moieties proceeded efficiently (compounds 45, 46, and 50). The more structurally complex pyridine derivatives were also successfully applied in the present protocol. For example, loratadine and roflumilast, which were registered for allergy medications and phosphodiesterase-4 (PED-4) inhibition, respectively, were transformed into the desirable products with their carbamate or amide group remained untouched (compounds 51 and 52). Other bioactive examples including the antifungal agent voriconazole and the marketed isoquinoline-based vasodilator, fasudil, were utilized directly without functional group protection (compounds 47 and 48). Finally, cinchonine, which is quinoline-cored and bears both hydroxyl and amino groups, was easily modified the present protocol (compound 49).
TABLE-US-00006 TABLE 6 Complex substrates results Compound number Compound structure Yield 44
[0085] DPQN.sup.2,4-di-OMe was characterized by several spectroscopic techniques to collect some PP of its photophysical parameters. Five formulated solutions were prepared with degassed dioxane in 10 mL volumetric flasks. For flask A, DPQN.sup.2,4-di-OMe (17.1 mg, 0.05 mmol) and TEA (3.8 L, 0.05 mmol) were added; for flask B, DPQN.sup.2,4-di-OMe (17.1 mg, 0.050 mmol) was added; for flask C, DPQN (14.1 mg, 0.050 mmol) and TEA (3.8 L, 0.050 mmol) were added; for flask D, DPQN.sup.2-CF3 (17.5 mg, 0.050 mmol) and TEA (3.8 L, 0.050 mmol) were added; for the flask E, potassium cyclohexyltrifluorobo-rate (2a, 47.5 mg, 0.25 mmol) and tetrabutylammonium tetrafluoroborate (Bu4NBF4, 82.3 mg, 0.25 mmol) were added. All these flasks were diluted to 10 mL to set the concentration to be 5.0 mM, 5.0 mM, 5.0 mM, 5.0 mM, and 25.0 mM, respectively.
[0086] UV-vis and fluorescence spectra demonstrated that the positively charged DPQN.sup.2,4-di-OMe absorbed strongly above 395 nm and emitted mostly at around 455 nm, with the intersection at 441 nm (
[0088] A quartz cuvette (1.0 cm1.0 cm3.5 cm) was added 0.20 mL of the 5.0 mM solution from flask A and was diluted to 2.0 mL with dioxane as a 0.50 mM solution, which was then irradiated at 395 nm. Duplicate experiments were performed with the addition of 2.0, 4.0, 6.0, 8.0 L 25 mM solution from flask E before being diluted to 2.0 mL. The resulting stacked UV-vis fluorescence emission spectra is shown in
[0089] Cyclic voltammogram (CV) showed that the redox processes of neutral DPQN.sup.2,4-di-OMe was electrochemically reversible (E.sub.1/2([QN]/[QN.sup.])=0.95 V vs SCE), while it was irreversibly reduced in the presence of TFA (E.sub.p/2([QN-H.sup.+]/[QN-H.sup.]=0.81 V vs SCE) (
[0090] A quartz cuvette (1.0 cm1.0 cm3.5 cm) was added 0.20 mL of the 5.0 mM solution from flask A and was diluted to 2.0 mL with dioxane as a 0.50 mM solution, which was then irradiated at 395 nm. Duplicate experiments were performed with the addition of 2.0, 4.0, 6.0, 8.0 L 25 mM solution from flask E before being diluted to 2.0 mL. The resulting fluorescence emission spectra is shown in
[0091] A quartz cuvette (1.0 cm1.0 cm3.5 cm) was filled with 0.20 of the 5.0 mM solutions from flasks A and diluted to 2.0 mL with dioxane as a 0.5 mM solution, which was then submitted to the fluorescence lifetime spectrometer for the experiment. The solution was excited at 375 nm, and the photon counts were recorded at 450 nm. Monoexponentially fitting trend line gave the lifetime =2.070.01 ns, as shown in
[0092] Secondly, to rationalize the advantageous effect of methoxy substituents on the protonated DPQN.sup.2,4-di-OMe and further elucidate the proton activation concept, the electronically neutral and deficient variants (DPQN and DPQN.sup.2-CF3) as well as the non-protonated form of DPQN.sup.2,4-di-OMe were selected as representative catalysts for more investigations. Interestingly, the stronger visible light absorption of protonated DPQN.sup.2,4-di-OMe could be directly visualized under ambient conditions as its neutral form and the other two in acidic media were basically colorless. Such differences were even more obvious under light irradiation since proton-activated DPQN.sup.2,4-di-OMe gave a much brighter luminescence (
[0093] A quartz cuvette (1.0 cm1.0 cm3.5 cm) was added 2.0 mL of the abovementioned 5.0 mM solutions from flasks A and successively diluted to 2.5 mM, 1.25 mM, and 0.625 mM with dioxane to perform UV-vis experiments. Duplicated experiments were performed with solutions from flasks B to D, and the absorptions of different catalytic solutions (DPQN.sup.2,4-di-OMe, DPQN.sup.2,4-di-OMe+TFA at 1:1, DPQN.sup.2-CF3+TFA at 1:1, and DPQN+TFA at 1:1) at 395 nm were plotted, as shown in
[0094] A quartz cuvette (1.0 cm1.0 cm3.5 cm) was added 2.0 mL of the abovementioned 5.0 mM solutions from flasks A and successively diluted to 2.5 mM, 1.25 mM, and 0.625 mM with dioxane to perform UV-vis experiments. Duplicated experiments were performed with solutions from flasks B to D, and the absorptions of different catalytic solutions at 395 nm were plotted and are shown in
[0095] While the quenching effect was observed with protonated DPQN.sup.2,4-di-OMe no prominent quenching was observed with other DPQN solutions from flasks B to D. The Stern-Volmer plots of each DPQN solution are shown in
[0096] These results emphasized the significance of electron-releasing substituents on the diarylquinoline framework and the presence of an acid, which synergistically augmented the photoproductivity of DPQN.sup.2,4-di-OMe.
[0097] Next, to gain insight into the overall reaction process, a light on-and-off experiment was performed. To a 10 mL pyrex microwave tube equipped with a Teflon-coated magnetic stirring bar were added heteroarene (1a, 13.3 L, 0.10 mmol, 1.0 equiv), potassium cyclohexyltrifluoroborate (2a, 28.5 mg, 0.15 mmol, 1.5 equiv), DPQN.sup.2,4-di-OMe (1.7 mg, 5.0 mmol, 5.0 mol %) and [Co(dmgH)2(py)]Cl (2.0 mg, 5.0 mmol, 5.0 mol %). The tube was sealed with a rubber septum, evacuated and backfilled with argon three times before dioxane (1.5 mL) was injected. To the mixture was then added TFA (15.3 L, 0.20 mmol, 2.0 equiv) in the glovebox, and the tube was sealed again by an aluminum cap with a septum, which was taken out from the glovebox and stirred at 37 C., with or without a 300 W Xe lamp (with a 395 nm filter) irradiation, as the time period indicated in
[0098] The experiment indicated that continuous light irradiation was needed for the reaction since a minimal increase of product yield persisted in the dark (
TABLE-US-00007 TABLE 7 Results of the light on/off experiment Time (h) Light Conversion of 1a to 3 (%) 1 On 38 2 Off 38 4 On 49 5 Off 50 7 On 62 8 Off 62 10 On 69
[0099] Furthermore, electron paramagnetic resonance (EPR) provided direct evidence for the existence of open-shell species. Two 10 mL pyrex microwave tubes equipped with Teflon-coated magnetic stirring bars were added 5,5-dimethyl-1-pyrroline-N-oxide (DMPO, 11.3 mg, 0.10 mmol, 1.0 equiv), potassium alkyltrifluoroborate (2a, 19 mg, 0.10 mmol, 1.0 equiv), and DPQN.sup.2,4-di-OMe (34.1 mg, 0.10 mol, 1.0 equiv). The tubes were sealed with rubber septa, evacuated and backfilled with argon three times before dioxane (1.0 mL) was injected. To the mixture was then added TFA (7.7 L, 0.10 mmol, 1.0 equiv) in the glovebox and sealed again by an aluminum cap with a septum, which was taken out from the glovebox and stirred at 37 C. with or without light irradiation of a 300 WXe lamp with a 395 nm filter. After 2 h, the reactions were taken for electron paramagnetic resonance (EPR) analysis. Under light irradiation, Cy. was trapped by 5,5-dimethyl-1-pyrroline-N-oxide (DMPO, compound 56), whose EPR spectrum was fully consistent with the literature and a simulation performed (compound 57), while such a response was silenced in the dark (Scheme 7,
##STR00078## ##STR00079##
##STR00080##
##STR00081##
[0100] Taken together, a reaction mechanism was proposed and shown in Scheme 9. Driven by the visible light irradiation, the excited diarylquinoline, [QN-H.sup.+]*, underwent a reductive quenching by the R-BF.sub.3K compound 2, generating two radical intermediates, alkyl radical I and heteroaryl radical [QN-H]*. While the former nucleophilic carbon radical I attacked the protonated heteroarene to give a radical cation III, the latter [QN-H].sup. (E.sub.p/2([QN-H.sup.+]/[QN-H*]=0.81 V vs SCE) reduced the cobaloxime [Co.sup.III] into [Co.sup.II](E.sub.red([Co.sup.III]/[Co.sup.II]=0.16 V vs SCE) via single electron transfer (SET) and regenerated the active catalyst [QN-H.sup.+]. Concurrently, formal HAT occurred between III and [Co.sup.II], which delivered [Co.sup.III-H] and the desired alkylated product 3-H.sup.+ after rearomatization. The [Co.sup.IIIH] then reduced the H.sup.+ and closed the catalytic cycle via releasing H.sub.2.
##STR00082##
[0101] The facile access of different DPQN congeners, which were immobilized on the commercially available amino-modified polystyrene (PS) beads via amide coupling, allowed the convenient preparation of solid-supported organophotocatalysts DPQN.sup.2,4-di-OR@PS (Formula VII). To a 10 mL glass vial equipped with a Teflon-coated magnetic stirring bar were added p-hydroxybenzaldehyde (610.6 mg, 5.0 mmol, 1.0 equiv), aniline (465.7 mg, 5.0 mmol, 1.0 equiv), and anhydrous MgSO4 (300.9 mg, 2.5 mmol, 0.50 equiv). Then, CH.sub.2Cl.sub.2 (5.0 mL) was added to the reaction mixture, which was stirred at room temperature. After 2 h, the MgSO.sub.4 was filtered and washed with CH.sub.2Cl.sub.2, and the filtrate was concentrated in a 20 mL glass vial to dryness to afford the crude imine, which was directly used without further purification.
[0102] To the crude imine were sequentially added 4-ethynylanisole (1.3 mL, 10 mmol, 2.0 equiv), Fe(OTf).sub.3 (62.9 mg, 375 mol, 2.5 mol %), toluene (5.0 mL) and AcOH (428.9 mL, 0.75 mmol, 1.5 equiv). The reaction mixture was gradually heated from 90 C. to 140 C. (Scheme 10). After being stirred at 140 C. for 16 h, the insolubles were filtered with a short celite pad and washed with EtOAc. The filtrate was basified with sat NaHCO.sub.3 (aq) and extracted with EtOAc. The organic layer was dried over an-hydrous MgSO4 and concentrated. The residue was then purified by column chromatography (Hex:EtOAc=10:1 to 5:3) and recrystallized with pentane/Et2O to afford the pure DPQN.sup.2-OR-4-OMe (0.41 g, 25%).
##STR00083##
[0103] To a 10 mL pyrex microwave tube equipped with a Teflon-coated magnetic stirring bar were added DPQN.sup.2-OR-4-OMe (163.7 mg, 0.50 mmol, 1.0 equiv), 6-bromohexanoic acid (84 L, 0.60 mmol, 1.2 equiv), 10 wt % KOH (1.25 mL), sat K.sub.2CO.sub.3 (0.50 mL), and EtOH (1.5 mL). After being stirred at 120 C. for 16 h, the reaction mixture was acidified with 18 wt % HCl to pH 5.0 to 6.0 and extracted with EtOAc. The organic layer was dried over anhydrous MgSO.sub.4 and concentrated. The residue was then purified by column chromatography (Hex:EtOAc=10:1 to 5:3) and recrystallized with pentane/Et.sub.2O to afford the pure DPQN.sup.2-OR-4-OMe (66.3 mg, 30%).
[0104] To a 10 mL glass vial equipped with a Teflon-coated magnetic stirring bar were added DPQN.sup.2-OR-4-OMe (44.1 mg, 0.10 mmol, 1.0 equiv) and dichloroethane (5.0 mL), which was followed by the dropwise addition of oxalyl chloride (16 L, 0.20 mmol, 2.0 equiv) and 1 drop dimethylformamide. After being stirred for 6 h, to the reaction mixture were added (aminomethyl)polystyrene (250 mg, Sigma Aldrich, purchase ID:515620) and Et.sub.3N (0.70 mL, 0.50 mmol). After being stirred at 50 C. for 8 h, the reaction was quenched by benzoyl chloride (87 L, 0.75 mmol, 7.5 equiv) and Et.sub.3N (292 L, 0.75 mmol, 7.5 equiv), and kept stirring at 50 C. After 2 h, the insoluble beads were washed with MeOH, water, acetone, and CH.sub.2Cl.sub.2. After drying at 60 C. for 3 h, pale yellow DPQN.sup.2,4-di-OR@PS beads were obtained (408.1 mg). The filtrate was concentrated and taken for .sup.1H NMR analysis using CH.sub.2Br.sub.2 as the internal standard, which showed that 69% of the starting DPQN.sup.2-OR-4-OMe was recovered.
[0105] The increased weight of PS beads after the reaction (250 mg vs 408.1 mg) comes from 1) installation of DPQN.sup.2-OR-4-OMe) the benzoyl protecting groups of the amine residues on the surface. We assumed that the non-recovered DPQN.sup.2-OR-4-OMe (31%, 0.031 mmol) were all on the PS beads. Therefore, the loading of DPQN.sup.2-OR-4-OMe on DPQN2,4-di-OR@PS is 0.031 mmol/408.1 mg=7.6.Math.10-5 mmol/mg.
[0106] Robustness tests showed that the DPQN.sup.2,4-di-OR@PS in only 0.50 mol % loading could be used for oxidative Minisci alkylation five times after simple filtration (Scheme 11, Table 8). Compound 1a was alkylated with compound 2a (1.5 eq.) with a catalyst system of 0.50 mol % DPQN.sup.2-OR-4-OMe @PS and 5.0 mol % of chloro(pyridine)bis(dimethylglyoximato)cobalt (III). The standard conditions of light stimulus (>395 nm), TFA (2.0 equiv) dioxane (0.067 M) at room temperature for 20 h were applied.
##STR00084##
##STR00085##
TABLE-US-00008 TABLE 8 Recycle cycle number NMR yield of compound 3 1 86% 2 84% 3 77% 4 65% 5 50%
[0107] The photosynthetic versatility and generality of DPQN.sup.2,4-di-OMe-based oxidative coupling platform were further explored by harnessing its oxidatively initiated reactivities with more radical alkylating reagents (Table 9). In terms of radical donors, C.sub.4-alkylated Hantzsch esters showed comparable productivity in heteroaromatic CH substitution in place of the R-BF.sub.3K (Table 9). Most of the prior established (fluoro)alkylation methods using sulfinate-derived radicals were operated with oxidants. Through the present dual catalytic platform, (fluoro)alkylated products, including tert-butylated lepidine (compound 7), the high-value trifluoromethylated dipeptide (compound 58) and difluoromethylated caffeine (compound 59), were obtained in an H.sub.2-releasing manner. A TfNHNHBoc reagent was exploited to expedite the trifluoromethyl radical, which was captured by 1,3,5-trimethoxybenzene to afford compound 60. Interestingly, when the non-protected Boc-hydrazide was applied directly, the tert-butylated product was obtained. The quinoline/cobalt co-catalyzed system could also accommodate other attractive alkylating reagents, which liberated the desired radicals driven by either restoring aromaticity or extruding CO.sub.2 (Table 9).
[0108] Of equal importance, other types of DPQN.sup.2,4-di-OMe-catalyzed photoreactions were investigated with Cy-BF.sub.3K and suitable radical acceptors with unsaturated bondings (Tables 9 and 10). Giese-type addition of cyclohexyl radical (Cy.sup.) to electron-poor CC double bond was found amenable, which could trigger a cascade radical addition to the pendent benzene ring and accomplish the tandem alkene dicarbofunctionalization. Accordingly, the synthesis of several fused heterocycles was succeeded under the optimal conditions (compounds 61 to 64, Tables 9 and 10). The cyclisation was catalyzed prior to the Giese-type addition and together formed a cascade reaction. Similarly, alkyne could behave as the SOMOphile, furnishing the polycyclic arene smoothly by the photochemical manifold (compound 65).
TABLE-US-00009 TABLE 9 Results for the alkylation with alkylation precursors Compound Synthesized compound (i.e. number alkylated substrate) Alkylation precursor Yield 37
TABLE-US-00010 TABLE 10 Results for substrate internal cyclisation Compound Synthesized compound (i.e. number alkylated substrate) Substrate for cyclisation/alkylation Yield 61
[0109] It is noted that in the present example, stoichiometric chemical oxidants were unnecessary for balancing the redox status in all cases of oxidative couplings above. Collectively, the present example illustrated the tremendous synthetic capabilities of compounds of formula I, and particularly DPQN.sup.2,4-di-OMe. DPQN.sup.2,4-di-OMe is a photoredox catalyst based on diarylquinoline, which was enabled oxidatively initiated alkylation chemistry. Furthermore, DPQN.sup.2,4-di-OMe was successfully synthesized via a three-component coupling of the corresponding aldehyde, alkyne and amine (scheme 2). The present example has established a visible light-mediated dehydrogenative Minisci alkylation between heteroarene and a numerous carbon radical precursors in a catalytic combination of formula I and cobaloxime. The present catalyst system of formula I and cobaloxime empowers a set of photoredox reactions for CC bond formation without chemical oxidants, wherein, the carbon radicals were intercepted by other radical acceptors for different synthetic purposes. The computed S0-T1 gap of DPQN2,4-di-OMe estimated its triplet energy (ET) to be 52.2 kcal/mol, which was similar to its structurally related acridinium photocatalysts, indicating that it serves as a prominent photosensitizer for triplet energy transfer (EnT).
[0110] In the following experiments, photoreactions with DPQN.sup.2,4-di-OMe in the absence of a co-catalyst (i.e. no cobalt organocatalyst) were performed. Scheme 12 shows the alkylation reaction between the substrate -trifluoromethylstyrene and Cy-BF.sub.3K. To a 10 mL pyrex microwave tube equipped with a Teflon-coated magnetic stirring bar were added alkyl -trifluoromethylstyrene (0.10 mmol, 1.0 equiv), potassium cyclohexyltrifluoroborate (28.5 mg, 0.15 mmol, 1.5 equiv), and DPQN.sup.2,4-di-OMe (1.7 mg, 5.0 mmol, 5.0 mol %). The tube was sealed with a rubber septum, evacuated and backfilled with argon three times before dioxane (1.5 mL) was injected into the reaction tube. Then, to the mixture was added TFA (7.7 mL, 0.10 mmol, 1.0 equiv) in the glovebox. After that, the reaction tube was sealed with an aluminum cap with a septum, which was taken out from the glovebox and stirred at 37 C. under a 300 W Xe lamp irradiation with a 395 nm filter. After 20 h, the reaction mixture was basified with saturated NaHCO.sub.3 aqueous solution, extracted with EtOAc, filtered through a short pad of MgSO.sub.4, and concentrated to obtain the crude product. The product was isolated by preparative thin-layer chromatography.
##STR00118##
[0111] Scheme 13 shows the procedure for the coupling of benziodoxolones and cyclohexyltrifluoroborate. To a 10 mL pyrex microwave tube equipped with a Teflon-coated magnetic stirring bar were added alkenyl/alkynyl alkyl benziodoxolones (0.10 mmol, 1.0 equiv), potassium cyclohexyltrifluoroborate (28.5 mg, 0.15 mmol, 1.5 equiv), and DPQN.sup.2,4-di-OMe (1.7 mg, 5.0 mmol, 5.0 mol %). The tube was sealed with a rubber septum, evacuated and backfilled with argon three times before dioxane (1.5 mL) was injected into the reaction tube. Then, to the mixture was added TFA (7.7 mL, 0.10 mmol, 1.0 equiv) in the glovebox. After that, the reaction tube was sealed with an aluminum cap with a septum, which was taken out from the glovebox and stirred at 37 C. under a 300 W Xe lamp irradiation with a 395 nm filter. After 20 h, the reaction mixture was basified with saturated NaHCO.sub.3 aqueous solution, extracted with EtOAc, filtered through a short pad of MgSO.sub.4, and concentrated to obtain the crude product. The product was isolated by preparative thin-layer chromatography.
##STR00119##
[0112] Scheme 14 shows the procedure for BocN=NBoc and Cy-BF.sub.3K. To a 10 mL pyrex microwave tube equipped with a Teflon-coated magnetic stirring bar were added di-tert-butyl azodicarboxylate (23.0 mg, 0.10 mmol, 1.0 equiv), potassium cyclohexyltrifluoroborate (28.5 mg, 0.15 mmol, 1.5 equiv), and DPQN.sup.2,4-di-OMe (1.7 mg, 5.0 mmol, 5.0 mol %). The tube was sealed with a rubber septum, evacuated and backfilled with argon three times before dioxane (1.5 mL) was injected into the reaction tube. Then, to the mixture was added TFA (7.7 mL, 0.10 mmol, 1.0 equiv) in the glovebox. After that, the reaction tube was sealed with an aluminum cap with a septum, which was taken out from the glovebox and stirred at 37 C. under a 300 W Xe lamp irradiation with a 395 nm filter. After 20 h, The reaction mixture was basified with saturated NaHCO.sub.3 aqueous solution, extracted with EtOAc, filtered through a short pad of MgSO.sub.4, and concentrated to obtain the crude product. The product was isolated by column chromatography.
##STR00120##
[0113] Scheme 15 shows the procedure for the coupling of alkyl sulfonothioates/sulfonoselenoate and cyclohexyltrifluoroborate. To a 10 mL pyrex microwave tube equipped with a Teflon-coated magnetic stirring bar were added alkyl sulfonothioate/sulfonoselenoate (0.10 mmol, 1.0 equiv), potassium cyclohexyltrifluoroborate (28.5 mg, 0.15 mmol, 1.5 equiv), DPQN.sup.2,4-di-OMe (1.7 mg, 5.0 mmol, 5.0 mol %) and [Co(dmgH).sub.2(py)]Cl (2.0 mg, 5.0 mmol, 5.0 mol %). The tube was sealed with a rubber septum, evacuated and backfilled with argon three times before dioxane (1.5 mL) was injected into the reaction tube. Then, to the mixture was added TFA (7.7 mL, 0.10 mmol, 1.0 equiv) in the glovebox. After that, the reaction tube was sealed with an aluminum cap with a septum, which was taken out from the glovebox and stirred at 37 C. under a 300 W Xe lamp irradiation with a 395 nm filter. After 20 h, The reaction mixture was basified with saturated NaHCO.sub.3 aqueous solution, extracted with EtOAc, filtered through a short pad of MgSO.sub.4, and concentrated to obtain the crude product. The product was isolated by preparative thin-layer chromatography or column chromatography.
##STR00121##
[0114] Table 11 shows additional cyclohexyl addition performed without co-catalyst but with DPQN.sup.2,4-di-OMe (1.7 mg, 5.0 mmol, 5.0 mol %) and [Co(dmgH).sub.2(py)]Cl (2.0 mg, 5.0 mmol, 5.0 mol %). The cyclohexyl additions summarized in Table 11 used Cy-BF.sub.3K as the alkylation precursor.
TABLE-US-00011 TABLE 11 Cyclohexyl addition without a co-catalyst Substrate with Cy addition Substrate Yield
[0115] Scheme 16 shows the procedure for a trifluoromethylation. The organophotoredox catalyst used was a phenyl pyridine quinolone with two OMe groups (PPQN.sup.2,4-di-OMe) as shown in scheme 17 which shows the equilibrium between the organophotoredox catalyst and the nickel complex that can form (metallophotoredox catalyst). To a 10 mL pyrex microwave tube equipped with a Teflon-coated magnetic stirring bar were added NiCl.sub.2.Math.glyme (1.1 mg, 5.0 mol, 5.0 mol %) and PPQN.sup.2,4-di-OMe(1.7 mg, 5.0 mol, 5.0 mol %) in DCM (0.50 mL), which was stirred for 30 minutes to pre-form the complex. The volatiles were then removed under vacuum. Afterward, to a reaction tube were added 1,3,5-trimethoxybenzene (16.8 mg, 0.10 mmol, 1.0 equiv), NaSO.sub.2CF.sub.3 (46.8 mg, 0.30 mmol, 3.0 equiv) and K.sub.2S.sub.2O.sub.8(27.0 mg, 0.10 mmol, 1.0 equiv). The tube was sealed with a rubber septum, evacuated and backfilled with argon three times before DMSO (1.0 mL) was injected into the reaction tube. Then, the tube was moved in the glovebox, where it was sealed with an aluminum cap with a septum. After that, it was taken out from the glovebox, stirred at 37 C. and irradiated by a Kessil lamp (.sub.max=390 nm, 50 W). After 20 h, the reaction mixture was filtered through a short pad of silica gel, and concentrated to obtain the crude product. The product was isolated by preparative thin-layer chromatography or column chromatography.
##STR00136##
##STR00137##
[0116] Scheme 18 shows a pinacol coupling with PPQN.sup.2,4-di-OMe. To a 10 mL pyrex microwave tube equipped with a Teflon-coated magnetic stirring bar were added NiCl.sub.2-glyme (1.1 mg, 5.0 mol, 5.0 mol %) and PPQN.sup.2,4-di-OMe(1.7 mg, 5.0 mol, 5.0 mol %) in DCM (0.50 mL), which was stirred for 30 minutes to pre-form the complex. The volatiles were then removed under vacuum. Afterward, to a reaction tube were added benzophenone (36.4 mg, 0.20 mmol, 2.0 equiv) and (n-Bu).sub.3N (55.5 mg, 0.30 mmol, 3.0 equiv). The tube was sealed with a rubber septum, evacuated and backfilled with argon three times before N,N-dimethylformamide (DMF) (1.0 mL) was injected into the reaction tube. Then, the tube was moved in the glovebox, where it was sealed with an aluminum cap with a septum. After that, it was taken out from the glovebox, stirred at 37 C. and irradiated by a Kessil lamp (.sub.max=390 nm, 50 W). After 20 h, the reaction mixture was quenched by water, extracted by EtOAc. The collected organic layers were combined and concentrated to obtain the crude product. The product was isolated by preparative thin-layer chromatography or column chromatography.
##STR00138##
Example 2
[0117] A photoactive ligand is shown herein to complex with a series of transition metals and serve as a two-in-one metallophotoredox catalyst. This bifunctional system is compatible with a diverse pool of nucleophilic and electrophilic coupling partners and highly enabling in visible-light-driven CC and CX bond formations. Upon complexation, the metal-ligand assembly was shown to switch on its photoexcitation mode, exhibiting potent photochemical properties under light irradiation while preserving its cross-coupling capability. Such a merger brings additional benefits of improving the reaction efficiency since the metal centers neighbor the nascent radicals, thus, better managing the interlocked cycles mediated by light and metal, respectively. Moreover, in transition Metal catalysis, the light facilitates some elementary yet orthogonal organometallic steps simultaneously (e.g., transmetallation, oxidative addition, and reductive elimination) via open-shell intermediacy. The present example shows the design of such versatile ligands, the metal complex of which can confine the dual metallophotoredox reactivities (e.g., electron, energy, and radical transfers) into a singular catalytic entity. Under the monocatalytic conditions tested herein, a diverse reactivity profile was accessed simply by changing the metal precatalysts and coupling partners, thereby improving the synthetic proficiencies for reactions of high interest.
[0118] Nickel/bipyridine, due to its versatility and availability, enjoys a privileged role as the TM catalyst. However, the fact that most of these complexes feature strong absorptivity only in the ultraviolet region, which is governed by the ligand-oriented p-p* transition, dictated the presence of an external photocatalyst (PC) for visible light absorption. Besides, compared with those coordinatively saturated PCs, the short-lived excited state of substitution-labile nickel complexes and their slow photokinetics of intersystem crossing (ISC) compromised their photosynthetic application in their own right. Likewise, the studies on the photocatalysis of other non-noble metal coordination compounds lagged behind.
[0119] In light of these limitations, it was hypothesized that engineering the bipyridine scaffold could provide an alternative avenue to enlighten the nickel photochemistry, therefore, enabling some previously elusive transformations in the classic regime of nickel/bipyridine catalysis. Considering Example 1 which showed that diarylquinolines could behave as efficient PCs upon Brnsted acid activation, it was investigated whether the repurposed diarylquinolinium with an embedded bipyridine motif could impart similar photochemical reactivities when chelating with Lewis acidic TMs. The chemical possibilities of metalated diarylquinolinium were expanded herein, and were geared with the capacity of fragment couplings owing to the vacant coordination sites.
[0120] The synthesis of several 4-phenyl-2-(pyridin-2-yl)quinolines (PPQNs) was performed. Different members in this ligand set were prepared from two readily available and low-cost ketone building blocks (see the two compounds below) via Friedlsnder condensation.
##STR00139##
[0121] In contrast to other synthetic routes for bipyridine modifications, noble metals are absent in the present case, therefore, circumventing issues caused by metal residues and simplifying their purification.
[0122] Solvents used in the present Example were stored over 4 molecular sieves (beads, 8-12 mesh) and degassed by purging with argon for 30 min. The 4 molecular sieves were purchased from Sigma-Aldrich and activated in the oven for 12 h at 380 C. before use. Reagents were purchased from Sigma-Aldrich, Combi-Blocks, TCI America, Oakwood, and Fisher Scientific and used without further purification unless otherwise specified.
[0123] Nuclear magnetic resonance (NMR) spectra, including .sup.1H NMR, .sup.13C NMR, and .sup.19F NMR, were recorded on Bruker 500 MHz spectrometers, using the deuterium lock signal to reference the spectra. The solvent residual peaks, e.g., chloroform (CDCl.sub.3: 7.28 ppm and 77.02 ppm), were used as references. Data was reported as follows: multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, quint=quintet, m=multiplet, dd=doublet of doublet, etc), coupling constant (J/Hz) and integration. All NMR spectra were recorded at room temperature.
[0124] Gas chromatography-mass spectroscopy (GC-MS) was obtained from the Agilent gas chromatography-mass spectroscopy system with helium (He) as the carrier gas. Highresolution mass spectrometry (HRMS) was conducted by using atmospheric pressure chemical ionisation (APCI) or electro-spraying ionisation (ESI) and was performed by McGill University on a Thermo-Scientific Exactive Orbitrap. Protonated/deprotonated molecular ions (MH).sup.+ or sodium adducts (M+Na).sup.+ were used for empirical formula confirmation. Electrochemical experiments were performed with HEKA PG 340 potentiostat with Ag/AgCl as the reference electrode. The working electrode was made of glassy carbon, and a Pt wire was used as the counter electrode to complete the electrochemical setup. A scan rate of 100 mV/s was used for all experiments. All the potentials were noted with respect to the Ag/AgCl electrode unless otherwise specified. The reduction potential referenced to the standard calomel electrode (SCE) was calculated by subtracting 0.039 V from the E(Ag/AgCl). It followed that E(SCE)=E(Ag/AgCl)0.039 V.
[0125] Reactions were stirred magnetically and conducted in 10 mL pyrex sealed tubes under an inert atmosphere unless otherwise specified. Experiments under light irradiation were performed using a 390 nm PR160L Kessil lamp equipped with a cooling fan for efficient temperature maintenance. Column chromatography was performed with E. Merck silica gel 60 (230-400 mesh).
[0126] Dimethoxylated PPQN (PPQN.sup.2,4-di-OMe) was first prepared on a gram scale (scheme 19), and its solid-state structure was confirmed by X-ray crystallography (
##STR00140##
TABLE-US-00012 TABLE 12 Crystal data and structure refinement for PPQN.sup.2,4-di-OMe by X-ray crystallography Empirical formula C.sub.22H.sub.18N.sub.2O.sub.2 Formula weight 342.38 Temperature 298(2) Crystal system triclinic Space group P-1 a/ 6.38850(10) b/ 10.9059(2) c/ 13.2352(3) / 106.3910(10) / 94.7820(10) / 98.7600(10) Volume/.sup.3 866.53(3) Z 2 .sub.calcg/cm.sup.3 1.312 /mm.sup.1 0.679 F(000) 360.0 Crystal size/mm.sup.3 0.221 0.088 0.048 Radiation CuK ( = 1.54178) 2 range for data collection/ 7.024 to 144.55 Index ranges 7 h 6, 13 k 13, 16 l 16 Reflections collected 25833 Independent reflections 3414 [R.sub.int = 0.0615, R.sub.sigma = 0.0320] Data/restraints/parameters 3414/0/238 Goodness-of-fit on F2 1.052 Final R indexes [I >= 2 (I)] R.sub.1 = 0.0512, wR.sub.2 = 0.1330 Final R indexes [all data] R.sub.1 = 0.0856, wR.sub.2 = 0.1774 Largest diff. peak/hole/e .sup.3 0.25/0.20
[0127] Unless otherwise specified, Ni.sup.2+/PPQN.sup.2,4-di-OMe was made by pre-stirring equimolar NiCl.sub.2.Math.1,2-dimethoxyethane (DME) and PPQN.sup.2,4-di-OMe, and a 390 nm Kessil lamp was used as light source. Ni.sup.2+/PPQN.sup.2,4-di-OMe was confirmed by X-ray crystallography (
TABLE-US-00013 TABLE 13 Crystal data and structure refinement for Ni2+/PPQN2,4- di-OMe by X-ray crystallography Empirical formula C.sub.32H.sub.34N.sub.2NiO.sub.7 Formula weight 617.32 Temperature 298(2) K Crystal system monoclinic Space group P2.sub.1/n a/ 16.6157(3) b/ 7.83850(10) c/ 23.5227(4) / 90 / 104.3440(10) / 90 Volume/.sup.3 2968.14(8) Z 4 .sub.calcg/cm.sup.3 1.381 /mm.sup.1 1.366 F(000) 1296.0 Crystal size/mm.sup.3 0.171 0.049 0.045 Radiation CuK ( = 1.54178) 2 range for data collection/ 5.884 to 145.002 Index ranges 20 h 20, 9 k 7, 29 l 29 Reflections collected 56727 Independent reflections 5882 [Rint = 0.0960, Rsigma = 0.0379] Data/restraints/parameters 5882/0/385 Goodness-of-fit on F2 1.045 Final R indexes [I >= 2 (I)] R.sub.1 = 0.0474, wR.sub.2 = 0.1247 Final R indexes [all data] R.sub.1 = 0.0710, wR.sub.2 = 0.1482 Largest diff. peak/hole/e .sup.3 0.40/0.33
[0128] Three reactions were tested (schemes 20-22 where DMO=dimethylsulfoxide and DMF=N,N-dimethylformamide) and yields were determined by .sup.1H NMR using dibromomethane as internal standard. For each of schemes 20-22 tris(2,2-bipyridyl)ruthenium (II) (Ru(bpy).sub.3.sup.2+) was used as a control photocatalyst and the yields are shown in Table 14.
##STR00141##
##STR00142##
##STR00143##
TABLE-US-00014 TABLE 14 Yield for schemes 20-22 Catalyst Ni.sup.2+/PPQN.sup.2,4-di-OMe Ru(bpy).sub.3.sup.2+ Scheme 20 50% 64% Scheme 21 50% 87% Scheme 22 67% 69%
[0129] The Ni.sup.2+/PPQN.sup.2,4-di-OMe was able to furnish the desired products in all cases and with a yield that was comparable with the regularly used Ru(bpy).sub.3.sup.2+ PC. The success in verifying the competence of Ni.sup.2+/PPQN.sup.2,4-di-OMe in photocatalysis established the concept of a two-in-one metallophotoredox cross-couplings. Mechanistically, Ni.sup.2+/PPQN.sup.2,4-di-OMe could mimic conventional metallophotocatalytic systems with separated roles where part of the Ni.sup.2+/PPQN.sup.2,4-di-OMe mediates the transition Metal catalytic cycles, and the rest sustains the photochemical reactions via SET or EnT. Alternatively, the role-unification scenario in which one single Ni.sup.2+/PPQN.sup.2,4-di-OMe controls all metallophotoredox cross-coupling steps via direct excitation could also be plausible.
[0130] The SM cross-coupling between iodobenzene and potassiumbenzyltrifluoroborate was tested. The cross-coupling reaction proceeded smoothly with 5.0 mol % Ni.sup.2+/PPQN.sup.2,4-di-OMe under Kessil 390 nm light-emitting diodes (LEDs) irradiation, resulting in a 65% yield of diphenylmethane (scheme 23).
##STR00144##
[0131] The reaction of Scheme 23 was repeated with 1.0 mol % of [Ir] which is an abbreviation for [4,4-bis(1,1-dimethylethyl)-2,2-bipyridine-N1,N1]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate, without light, without NiCl.sub.2.Math.DME, without ligand, without base or under air instead of argon. The reaction of Scheme 23 was also repeated with different catalysts instead of PPQN.sup.2,4-di-OMe, namely the compounds listed below. The resulting yields are presented in Table 15.
##STR00145##
TABLE-US-00015 TABLE 15 Yields for Scheme 23 and other conditions tested Condition Yield Scheme 23 66% Scheme 23 with 1.0 mol % of [Ir] 21% Scheme 23 without light 0% Scheme 23 without NiCl.sub.2DME 0% Scheme 23 without ligand 0% Scheme 23 without base 8% Scheme 23 under air instead of argon 0% Scheme 23 with PPQN instead of PPQN.sup.2,4-di-OMe 32% Scheme 23 with PPQN.sup.4-OMe instead of PPQN.sup.2,4-di-OMe 44% Scheme 23 with PPQN.sup.4-t-Bu instead of PPQN.sup.2,4-di-OMe 20% Scheme 23 with DPQN instead of PPQN.sup.2,4-di-OMe 0% Scheme 23 with dtbpy instead of PPQN.sup.2,4-di-OMe 0% Scheme 23 with diOMebpy instead of PPQN.sup.2,4-di-OMe trace
[0132] Changing the ligands impacted the reaction outcome considerably as the nonsubstituted PPQN, its monomethoxy (PPQN.sup.4-OMe), and mono-tert-butyl (PPQN.sup.4-t-Bu) variants gave dramatically lower yields. Interestingly, the monodentate DPQN, an organophotoredox catalyst, was ineffective in this coupling reaction, which indicated the importance of bidentate chelation. Commercially available bipyridines (dtbpy and diOMebpy) did not provide the desired reactivities. The addition of extra PC, [Ir(dFCF.sub.3ppy).sub.2(bpy)]PF.sub.6 decreased the efficiency of SM coupling in our case, presumably owing to the competing light absorption with Ni.sup.2+/PPQN.sup.2,4-di-OMe. Control experiments indicated that light, metal, ligand, base, and inert atmosphere were all indispensable to realize this transformation efficiently.
[0133] Based on the determined optimal reaction conditions, substrate scope studies with an array of aryl halides and RBF.sub.3K under Ni.sup.2+/PPQN.sup.2,4-di-OMe metallophotocatalysis were initiated. To begin, the performance of aromatic halides bearing different substitution patterns, including iodides, bromides, and chlorides, was assessed. First, the catalyst was synthesized by pre-stirring PPQN.sup.2,4-di-OMe (3.4 mg, 10 mol, 10 mol %) and NiCl.sub.2.Math.DME (2.2 mg, 10 mol, 10 mol %) in DMSO (0.50 mL) in a 10 mL pyrex microwave tube for 30 min (scheme 24, oxidative photocatalysis). 1,3,5-Trimethoxybenzene (16.8 mg, 0.10 mmol, 1.0 equiv), NaSO.sub.2CF.sub.3 (46.8 mg, 0.30 mmol, 3.0 equiv) and K.sub.2S.sub.2O.sub.8 (27.0 mg, 0.10 mmol, 1.0 equiv) were then added. The tube was then sealed with a rubber septum, degassed by three freeze-pump-thaw cycles, back-filled with argon, and stirred at room temperature under the 53 W 390 nm LED irradiation. After 20 h, to the reaction mixture was added brine, which was extracted with EtOAc, filtered through a short pad of MgSO.sub.4, and concentrated to afford the crude product. The .sup.1H NMR yield was determined using CH.sub.2Br.sub.2 as the internal standard to be 50% and 0% in a negative control condition without irradiation.
##STR00146##
[0134] As explained above, the catalyst was synthesized by pre-stirring PPQN.sup.2,4-di-OMe (3.4 mg, 10 mol, 10 mol %) and NiCl.sub.2.Math.DME (2.2 mg, 10 mol, 10 mol %) in DMF (1.0 mL) in a 10 mL pyrex microwave tube for 30 min. Benzophenone (36.4 mg, 0.20 mmol, 1.0 equiv) and tributylamine (143 L, 111.0 mg, 0.60 mmol, 3.0 equiv) were then added (scheme 25, reductive photocatalysis). The tube was then sealed with a rubber septum, degassed by three freeze-pump-thaw cycles, back-filled with argon, and stirred at room temperature under the 53 W 390 nm LED irradiation. After 20 h, to the reaction mixture was added brine, which was extracted with EtOAc, filtered through a short pad of MgSO.sub.4, and concentrated to afford the crude product. The .sup.1H NMR yield was determined using CH.sup.2Br.sup.2 as the internal standard to be 50% and the negative control without irradiation had a 0% yield.
##STR00147##
[0135] In another experiment, the catalyst was synthesized by pre-stirring PPQN.sup.2,4-di-OMe (1.7 mg, 5.0 mol, 5.0 mol %) and NiCl.sub.2.Math.DME (1.1 mg, 5.0 mol, 5.0 mol %) in CH.sub.2Cl.sub.2 (1.0 mL) in a 10 mL pyrex microwave tube for 30 min as explained above. (E)-Stilbene (18.0 mg, 0.10 mmol, 1.0 equiv) and MeCN (1.0 mL) were then added (scheme 26, energy-transfer photocatalysis). The tube was then sealed with a rubber septum, degassed by three freeze-pump-thaw cycles, back-filled with argon, and stirred at room temperature under the 53 W 390 nm LED irradiation. After 20 h, the reaction mixture was passed through a short pad of silica gel and concentrated to afford the crude product. The .sup.1H NMR yield was determined using CH.sup.2Br.sup.2 as the internal standard to be 67% and the negative control without irradiation had a 0% yield.
##STR00148##
[0136] Control experiments for the above three reactions (Schemes 24-26) were performed by replacing the NiCl.sub.2 with a Brnsted acid (trifluoroacetic acid, TFA, used in this case), schemes 27-30. Under otherwise standard conditions, aromatic trifluoromethylation and olefin E/Z isomerisation proceeded smoothly, which was consistent with the previous experiments showing that the diarylquinolinium enables oxidative photoredox catalysis and energy-transfer catalysis.
##STR00149##
##STR00150##
##STR00151##
##STR00152##
[0137] However, reductive pinacol coupling was unsuccessful with protonated or Zn.sup.2+-activated PPQN.sup.2,4-di-OMe. Since organic base n-Bu.sub.3N was used as the terminal reductant in this transformation, its competition with PPQN.sup.2,4-di-OMefor strong Brnsted acids or Lewis acids might deactivate the photoredox system and also undermine its single-electron transfer. Therefore, the moderately Lewis acidic Ni.sup.2+ was uniquely enabling in this reductive coupling. As such, transition metals might not be needed herein. However, using the Ni.sup.2+/PPQN.sup.2,4-di-OMe instead of its Brnsted acid salt analogues here, it was aimed to demonstrate its capability in oxidative, reductive and energy-transfer photocatalysis. Once these properties were confirmed and assuming Ni.sup.2+/PPQN.sup.2,4-di-OMe behaved similarly to common bipyridyl nickel(II) transition metal catalysts, Ni.sup.2+/PPQN.sup.2,4-di-OMe should, in principle, be able to manage the dual metallophotoredox cross-couplings as a singular entity.
[0138] The synthesis of the PPQN.sup.2,4-di-OMe ligand was performed as per scheme 19 and explained above. The following procedure was applicable to all the couplings of aryl halides and benzyltrifluoroborates unless otherwise noted. The catalyst was synthesized by prestirring PPQN.sup.2,4-di-OMe (3.4 mg, 10 mol, 5.0 mol %) and NiCl.sub.2.Math.DME (2.2 mg, 10 mol, 5.0 mol %) in CH.sub.2Cl.sub.2 (1.0 mL) in a 10 mL pyrex microwave tube for 30 min. The solvent was evacuated before aryl halide (0.20 mmol, 1.0 equiv), potassium benzyltrifluoroborate (0.30 mmol, 1.5 equiv), acetone (1.9 mL), MeOH (0.10 mL), and 2,6-lutidine (81 L, 75.0 mg, 0.70 mmol, 3.5 equiv) were added (scheme 31). The tube was then sealed by a rubber septum, degassed by three freeze pump-thaw cycles, back-filled with argon, and stirred at room temperature under the 53 W 390 nm LED irradiation. After 20 h, the reaction mixture was passed through a short pad of silica gel and concentrated to afford the crude product. The product was purified by preparative thin layer chromatography. Unless otherwise specified, a 390 nm Kessil lamp was used as light source. The percent yield represents purified product unless otherwise specified.
[0139] Scheme 31 shows a generic reaction with an electrophile compound containing a halogen group X and a nucleophile containing a benzyl potassium trifluoroborate group. Different electrophiles and nucleophiles were tested as per scheme 31 and the yield results are shown in Table 16.
##STR00153##
TABLE-US-00016 TABLE 16 Results of scheme 31 with different electrophiles and nucleophiles Entry Product # Electrophile Nucleophile yield 1
[0140] A site-selective SM cross-coupling was also accomplished (scheme 32) using the same reaction conditions as scheme 31, affording the mono-debrominated product (yield of 31%) as the paracyclophane precursor.
##STR00187##
[0141] In general, (hetero)aryl electrophiles with electron-withdrawing (ketone, ester, amide, trifluoromethyl, sulfonamide, and nitrile) and -donating (methoxy) groups were all tolerated under the tested conditions (entries 1-14 in Table 16). The product yields of electron-deficient iodides (entries 1-4 in Table 16) outweighed the electron-rich (entry 5 in Table 16) and naphthyl ones (entry 6 in Table 16). Different aryl (entries 7-10 in Table 16) and heteroaryl (entries 11-13 in Table 16) bromides were proven effective coupling partners with the benzyl trifluoroborate, and so was the 2-pyridyl chloride (entry 14 in Table 16).
[0142] Regarding the R-BF.sub.3K scope, various benzyltrifluoroborates, including those substituted by methyl (entries 15-16 in Table 16), p-extended (entries 17-22 in Table 16), chloro (entries 23-24 in Table 16), methoxy (entries 25-29 in Table 16), nitrile (entry 30 in Table 16), trifluoromethyl (entry 31 in Table 16), and trifluoromethoxy (entry 32 in Table 16) groups, were examined, delivering the diarylmethanes in moderate to excellent yields. In many cases, aryl bromides and iodides resulted in similar yields (entries 15-26 in Table 16). Noticeably, the bromo handle in entry 29 (Table 16) remained intact, setting the stage for iterative cross-couplings. In addition, trifluoroborate entry 33 (Table 16) with benzothiophene, a moiety found in bioactive structures, also afforded the expected product in high yield.
[0143] Various Ni/PPQN.sup.2,4-di-OMe-catalysed metallophotoredox cross-couplings were tested. More specifically, redox-neutral CC bond-forming reactions were attempted with the same Ni-based transformative platform as explained above. Unless otherwise specified the couplings were conducted on a 0.20 mmol scale, a 390 nm Kessil lamp was used as light source. The >25% yield represents purified product, and yield <25% refers to NMR yield with dibromomethane as internal standard.
##STR00188##
[0144] As per scheme 33 above, the catalyst was synthesized by pre-stirring PPQN.sup.2,4-di-OMe (3.4 mg, 10 mol, 5.0 mol %) and NiCl.sub.2.Math.DME (2.2 mg, 10 mol, 5.0 mol %) in CH.sub.2Cl.sub.2 (1.0 mL) in a 10 mL pyrex microwave tube for 30 min. The solvent was evacuated before 4-iodobenzonitrile (45.8 mg, 0.20 mmol, 1.0 equiv), Hantzsch ester (189.0 mg, 0.60 mmol, 3.0 equiv), acetone (1.9 mL), MeOH (0.10 mL), and 2,6-lutidine (81 L, 75.0 mg, 0.70 mmol, 3.5 equiv) were added. The tube was then sealed with a rubber septum, degassed by three freeze-pump-thaw cycles, back-filled with argon, and stirred at room temperature under the 53 W 390 nm LED irradiation. After 20 h, the reaction mixture was passed through a short pad of silica gel and concentrated to afford the crude product. The product was purified by preparative thin-layer chromatography. The yield obtained is shown in Table 17. The yields obtained for the control conditions: without transition metal, without ligand or without light are also shown in Table 17.
##STR00189##
[0145] As per scheme 34 above, the catalyst was synthesized by pre-stirring PPQN.sup.2,4-di-OMe (3.4 mg, 10 mol, 5.0 mol %) and NiCl.sub.2.Math.DME (2.2 mg, 10 mol, 5.0 mol %) in CH.sub.2Cl.sub.2 (1.0 mL) in a 10 mL pyrex microwave tube for 30 min. The solvent was evacuated before potassium benzyltrifluoroborate (119.0 mg, 0.60 mmol, 3.0 equiv) and tetrahydrofuran (THF) (1.0 mL) were added. The tube was sealed with a rubber septum, degassed by three freeze-pump-thaw cycles, and back-filled with argon. Benzoyl chloride (23.2 L, 28.1 mg, 0.20 mmol, 1.0 equiv) was then added via a syringe. The reaction mixture was stirred at room temperature under the 53 W 390 nm LED irradiation. After 20 h, the reaction mixture was passed through a short pad of silica gel and concentrated to afford the crude product. The product was purified by preparative thin-layer chromatography. The yield obtained is shown in Table 17. The yields obtained for the control conditions: without transition metal, without ligand or without light are also shown in Table 17.
##STR00190##
[0146] As per scheme 35 above, the catalyst was synthesized by pre-stirring PPQN.sup.2,4-di-OMe (3.4 mg, 10 mol, 5.0 mol %) and NiCl.sub.2.Math.DME (2.2 mg, 10 mol, 5.0 mol %) in CH.sub.2Cl.sub.2 (1.0 mL) in a 10 mL pyrex microwave tube for 30 min. The solvent was evacuated before butadiene monoxide (16.2 L, 14.0 mg, 0.20 mmol, 1.0 equiv), potassium benzyltrifluoroborate (79.2 mg, 0.40 mmol, 2.0 equiv), acetone (1.9 mL), and MeOH (0.10 mL), and 2,6-lutidine (81 L, 75.0 mg, 0.70 mmol, 3.5 equiv) were added. The tube was sealed with an aluminium cap with a septum, degassed by three freeze-pump-thaw cycles, back-filled with argon, and stirred at room temperature under the 53 W 390 nm LED irradiation. After 20 h, the reaction mixture was passed through a short pad of silica gel and concentrated to afford the crude product. The product was purified by preparative thin-layer chromatography. The yield obtained is shown in Table 17. The yields obtained for the control conditions: without transition metal, without ligand or without light are also shown in Table 17.
##STR00191##
[0147] As per scheme 36 above, the catalyst was synthesized by pre-stirring PPQN.sup.2,4di-OMe (3.4 mg, 10 mol, 5.0 mol %) and NiCl.sub.2.Math.DME (2.2 mg, 10 mol, 5.0 mol %) in N,N-dimethylacetamide (DMA, 1.0 mL) in a 10 mL pyrex microwave tube for 30 min. The solvent was evacuated before iodobenzene (40.8 mg, 0.20 mmol, 1.0 equiv), piperidine (39 L, 34.0 mg, 0.40 mmol, 2.0 equiv), and 1,4-diazabicyclo[2.2.2]octane (DABCO, 44.9 mg, 0.40 mmol, 2.0 equiv) were added. The tube was sealed with an aluminium cap with a septum, degassed by three freeze-pump-thaw cycles, back-filled with argon, and stirred at room temperature under the 53 W 390 nm LED irradiation. After 20 h, the reaction mixture was passed through a short pad of silica gel and concentrated to afford the crude product. The product was purified by preparative thin-layer chromatography. The yield obtained is shown in Table 17. The yields obtained for the control conditions: without transition metal, without ligand or without light are also shown in Table 17.
##STR00192##
[0148] As per scheme 37 above, the catalyst was synthesized by pre-stirring PPQN.sup.2,4-di-OMe (6.8 mg, 20 mol, 10 mol %) and NiCl.sub.2.Math.DME (4.4 mg, 20 mol, 10 mol %) in DMF (2.0 mL) in a 10 mL pyrex microwave tube for 30 min. 4-lodobenzonitrile (45.8 mg, 0.20 mmol, 1.0 equiv), Boc-Pro-OH (37.6 mg, 0.30 mmol, 1.5 equiv) and Cs.sub.2CO.sub.3 (130.0 mg, 0.40 mmol, 2.0 equiv) were then added. The tube was then sealed with a rubber septum, degassed by three freeze-pump-thaw cycles, back-filled with argon, and stirred at room temperature under the 53 W 390 nm LED irradiation. After 20 h, to the reaction mixture was added brine, which was extracted with EtOAc, filtered through a short pad of MgSO.sub.4, and concentrated to afford the crude product. The product was purified by preparative thin-layer chromatography. The yield obtained is shown in Table 17. The yields obtained for the control conditions: without transition metal, without ligand or without light are also shown in Table 17.
##STR00193##
[0149] As per scheme 38 above, the catalyst was synthesized by pre-stirring PPQN.sup.2,4-di-OMe (6.8 mg, 20 mol, 10 mol %) and NiCl.sub.2.Math.DME (4.4 mg, 20 mol, 10 mol %) in DMF (0.50 mL) in a 10 mL pyrex microwave tube for 30 min. 4-Bromobenzonitrile (36.4 mg, 0.20 mmol, 1.0 equiv), H.sub.2O (144 L, 144.0 mg, 8.0 mmol, 40 equiv), i-Pr.sub.2NEt (N,N-Diisopropylethylamine, 70 L, 51.7 mg, 0.40 mmol, 2.0 equiv), and MeCN (0.50 mL) were then added. The tube was then sealed with a rubber septum, degassed by three freeze-pump-thaw cycles, back-filled with argon, and stirred under the 53 W390 nm LED irradiation. After 20 h, to the reaction mixture was added brine, which was extracted with EtOAc, filtered through a short pad of MgSO.sub.4, and concentrated to afford the crude product. The yield obtained is shown in Table 17. The yields obtained for the control conditions: without transition metal, without ligand or without light are also shown in Table 17.
##STR00194##
[0150] As per scheme 39 above, the catalyst was synthesized by pre-stirring PPQN.sup.2,4-di-OMe (3.4 mg, 10 mol, 5.0 mol %) and NiCl.sub.2.Math.DME (2.2 mg, 10 mol, 5.0 mol %) in DMA (2.0 mL) in a 10 mL pyrex microwave tube for 30 min. 4-lodobenzonitrile (46.0 mg, 0.20 mmol, 1.0 equiv) and sodium ptoluenesulfinate (TsSO.sub.2Na, 71.0 mg, 0.40 mmol, 2.0 equiv) were then added. The tube was then sealed with a rubber septum, degassed by three freeze-pump-thaw cycles, back-filled with argon, and stirred at room temperature under the 53 W 390 nm LED irradiation. After 20 h, to the reaction mixture was added brine, which was extracted with EtOAc, filtered through a short pad of MgSO.sub.4, and concentrated to afford the crude product. The product was purified by preparative thin-layer chromatography. The product was purified by preparative thin-layer chromatography. The yield obtained is shown in Table 17. The yields obtained for the control conditions: without transition metal, without ligand or without light are also shown in Table 17.
##STR00195##
[0151] As per scheme 40 above, the catalyst was synthesized by pre-stirring PPQN.sup.2,4-di-OMe (6.8 mg, 20 mol, 10 mol %) and Ni(PPh.sub.3).sub.2Cl.sub.2 (13.0 mg, 20 mol, 10 mol %) in MeOH (1.0 mL) in a 10 mL pyrex microwave tube for 30 min. Diphenylphosphine oxide (40.4 mg, 0.20 mmol, 1.0 equiv), iodobenzene (44 L, 81.6 mg, 0.40 mmol, 2.0 equiv), and Cs2CO3 (130.4 mg, 0.40 mmol, 2.0 equiv) were added. The tube was sealed with a rubber septum, degassed by three freeze-pump-thaw cycles, and back-filled with argon. The reaction mixture was stirred at room temperature under the 53 W 390 nm LED irradiation. After 20 h, the reaction mixture was passed through a short pad of silica gel and concentrated to afford the crude product. The product was purified by preparative thin-layer chromatography. The yield obtained is shown in Table 17. The yields obtained for the control conditions: without transition metal, without ligand or without light are also shown in Table 17.
##STR00196##
[0152] As per scheme 41, the catalyst was synthesized by pre-stirring PPQN.sup.2,4-di-OMe (6.8 mg, 20 mol, 10 mol %) and NiCl.sub.2.Math.DME (4.4 mg, 20 mol, 10 mol %) in CH.sub.2Cl.sub.2 (1.0 mL) in a 10 mL pyrex microwave tube for 30 min. The solvent was evacuated before 4-chlorobenzaldehyde (28.2 mg, 0.20 mmol, 1.0 equiv), allyl acetate (64 L, 60.0 mg, 0.60 mmol, 3.0 equiv), i-Pr.sub.2Net (104 L, 77.6 mg, 0.60 mmol, 3.0 equiv), MeCN (0.90 mL), and H.sub.2O (0.10 mL) were added. The tube was sealed with a rubber septum, degassed by three freeze-pump-thaw cycles, and backfilled with argon. The reaction mixture was stirred at room temperature under the 53 W 390 nm LED irradiation. After 20 h, the reaction mixture was passed through a short pad of MgSO.sub.4 and concentrated to afford the crude product. The product was purified by preparative thin-layer chromatography. The yield obtained is shown in Table 17. The yields obtained for the control conditions: without transition metal, without ligand or without light are also shown in Table 17.
##STR00197##
[0153] As per scheme 42 above, the catalyst was synthesized by pre-stirring PPQN.sup.2,4-di-OMe (3.4 mg, 10 mol, 5.0 mol %) and NiCl.sub.2.Math.DME (2.2 mg, 10 mol, 5.0 mol %) in CH.sub.2Cl.sub.2 (1.0 mL) in a 10 mL pyrex microwave tube for 30 min. The solvent was evacuated before 4-bromobenzonitrile (36.4 mg, 0.20 mmol, 1.0 equiv), NaN.sub.3 (65.0 mg, 1.0 mmol, 5.0 equiv), Et3N (28 L, 20.2 mg, 0.40 mmol, 2.0 equiv), followed by MeOH (1.25 mL) and H.sub.2O (0.75 mL), were added. The tube was sealed with a rubber septum, degassed by three freeze-pump-thaw cycles, and back-filled with argon. The reaction mixture was stirred under the 53 W 390 nm LED irradiation. After 20 h, the reaction mixture was passed through a short pad of silica gel and concentrated to afford the crude product. The product was purified by preparative thin-layer chromatography. The yield obtained is shown in Table 17. The yields obtained for the control conditions: without transition metal, without ligand or without light are also shown in Table 17.
TABLE-US-00017 TABLE 17 Yields obtained for the reactions of schemes 33-42 Control, without Control, without Control, without Reaction Standard transition metal ligand light Scheme 33 85% 0% 0% 0% Scheme 34 41% 0% 0% 0% Scheme 35 52% 0% 0% 0% Scheme 36 53% 0% 8% 0% Scheme 37 55% 0% 0% 0% Scheme 38 90% 0% 23% 0% Scheme 39 62% 0% 0% 0% Scheme 40 51% 0% 16% 0% Scheme 41 62% 0% 0% 0% Scheme 42 56% 12% 18% 0%
[0154] In place of RBF.sub.3K, Hantzsch's ester, which was derived from the corresponding aldehydes, was also shown as an efficacious radical source for the Ni-catalyzed metallophotoredox C(sp.sup.3)-C(sp.sup.2) cross-coupling (scheme 33). Under light irradiation, aroyl chloride and alkenyl epoxide were found compatible with the nickel photocatalysis, extending the electrophile scope and giving aryl alkyl ketone and allylic alcohol as desired products (schemes 34 and 35).
[0155] Satisfactorily, Ni.sup.2+/PPQN.sup.2,4-di-OMe-catalyzed CX bond formation was amenable by pairing some heteroatomic nucleophiles with various aromatic halides. In this category, Ni.sup.2+/PPQN.sup.2,4-di-OMe enabled the photoamination of unactivated aryl iodide with an aliphatic amine in a good yield (scheme 36), although electronically biased aryl halides were frequently needed in known metallophotoredox CN cross-couplings. Encouragingly, phenol and its derivatives were obtained under mild conditions from the coupling reactions with O-nucleophiles, such as carboxylic acid and water (schemes 37-38). Harsh conditions such as strong bases and elevated temperatures were often required for the same synthetic purposes. C(sp.sup.2)-S and C(sp.sup.2)-P bond formation was feasible by harnessing the two-in-one NiPC, providing diarylsulfone and triarylphosphine via Ullmann-type couplings (schemes 39-40).
[0156] Moreover, the catalytic versatility of Ni.sup.2+/PPQN.sup.2,4-di-OMe reached beyond redoxneutral transformations, enabling a Nozaki-Hiyama-Kishi (NHK)-type cross-electrophile coupling between aldehyde and allylic ester with tertiary amine as the organic sacrificial reductant (scheme 41). The reductive aromatic amination with azide as the N-source also proceeded efficiently with the Ni-metallophotocatalyst (scheme 42). Due to the high value of primary anilines and the lack of general metallophotoredox protocols to access themvia cross-couplings, the present catalytic method is a valuable addition to the primary aniline synthesis toolbox. It is to be noted that, in schemes 33-42, an inconsequential quantity of products were observed if the metal, ligand, or light was omitted (control conditions, Table 17).
[0157] The use of Zn instead of Ni was tested in a metallophotoredox Suzuki coupling with Zn.sup.2+/PPQN.sup.2,4-di-OMe. Zn.sup.2+/PPQN.sup.2,4-di-OMe was made by pre-stirring equimolar ZnCl.sub.2.Math.1,2-dimethoxyethane (DME) and PPQN.sup.2,4-di-OMe and a 390 nm Kessil lamp was used as light source. The metallophotoredox Suzuki coupling was performed as per Scheme 43 shown below. The no product was obtained (yield of 0%).
##STR00198##
[0158] The reactions of schemes 33-42 were repeated with the same conditions but Zn.sup.2+/PPQN.sup.2,4-di-OMe was used instead of Ni.sup.2+/PPQN.sup.2,4-di-OMe. No product was obtained (yield of 0%) except for the reaction of scheme 34 were a 6% yield was obtained. In all the Ni-catalysed metallophotoredox cross-couplings tested herein, zinc was proven inefficient, indicating the transition-metal-catalysed redox chemistry was only viable in the presence of redox-active metals like nickel. In the dark, all the redox-neutral CC and CX couplings and reductive cross-electrophile CC coupling did not proceed, showing the indispensable role of photoexcitation in these transformations. Accordingly, the product formation was significantly inhibited when replacing Ni.sup.2+ with redox-innocent Zn.sup.2+. The present results thus illustrate the essential cooperation between the redox-active Ni.sup.2+/PPQN.sup.2,4-di-OMe and light excitation, which did not only simplify the conditions of Ni-metallophotoredox cross-couplings but also broadened the ground-state chemistries of nickel catalysis.
[0159] To elucidate some mechanistic underpinnings of Ni.sup.2+/PPQN.sup.2,4-di-OMe metallaphotocatalysis, spectroscopic analysis and computational calculations were performed. All computations were performed using linear response time-dependent DFT (TD-DFT) with the 6-311G* basis set in a Gaussian 16 software package.
[0160] First, Ni.sup.2+/PPQN.sup.2,4-di-OMe was characterized by ultraviolet-visible (UV-vis) spectroscopy, which showed a prominent absorption peak (.sub.max=385 nm) of violet and blue light and overlapped consistently with the emission spectrum of 390 nm Kessil lamp (
[0161] In line with the control experiments, Ni.sup.2+, free PPQN.sup.2,4-di-OMe, as well as the Ni.sup.2+/dtbpy and Ni.sup.2+/diOMebpy counterparts were of weak absorptivity in the same region. Cyclic voltammetry (CV) featured distinct electrochemical patterns of Ni.sup.2+/PPQN.sup.2,4-di-OMe relative to its metal and ligand components (
[0162] Additionally, the coordination between Ni.sup.2+ and PPQN.sup.2,4-di-OMe was ascertained by the solid-state structure of their complex (
[0163] The ground state geometry was optimised using DFT, and the excited states were calculated with linear response time-dependent DFT (TDDFT) at the optimised ground state geometry. All calculations were performed with the Gaussian 16 package (Rev. C.01) using the PBEO functional and the 6-311G* basis set. Grimme's D3BJ dispersion correction was used to improve calculation accuracy. The optimised structures of Ni(PPQN.sup.2,4-di-OMe)Cl.sub.2 are shown in
TABLE-US-00018 TABLE 18 Summary of the energies for each orbital calculated Orbital label Energy Orbital 122 -HOMO 6.683788 eV Orbital 740 -HOMO 6.434968 eV Orbital 123 -LUMO 2.751196 eV Orbital 741 -LUMO 2.711818 eV
[0164] The merging PPQN.sup.2,4-di-OMe and earth-abundant first-row metals such as iron, cobalt, and copper enriches the base-metal photochemistry and brings more fruitful transformation reactions. This was demonstrated in schemes 44-48 shown below and the yields are summarized in Table 19 below.
##STR00199##
[0165] The catalyst was synthesized by pre-stirring PPQN.sup.2,4-di-OMe (6.8 mg, 20 mol, 10 mol %) and Fe.sub.2(SO.sub.4).sub.3(4.0 mg, 10 mol, 5.0 mol %) in 1,2-dichloroethane (DCE) (2.0 mL) in a 10 mL pyrex microwave tube for 30 min. Carboxylic acid (65.6 mg, 0.20 mmol, 1.0 equiv) and N-fluorobenzenesulfonimide(NFSI, 126 mg, 0.40 mmol, 2.0 equiv) were added. The tube was sealed with a rubber septum, degassed by three freeze-pump-thaw cycles, and back-filled with argon. The reaction mixture was stirred at room temperature under the 53 W 390 nm LED irradiation. After 20 h, the reaction mixture was passed through a short pad of silica gel and concentrated to afford the crude product. The product was purified by preparative thin-layer chromatography. The yield obtained is shown in Table 19. The yields obtained for the control conditions: without transition metal, without ligand or without light are also shown in Table 19. As shown in scheme 44, the combination of the PPQN.sup.2,4-di-OMe and simple ferric salt promoted the decarboxylative fluorination of the estrone-derived carboxylic acid which exemplified a convenient route to prepare the valuable monofluoromethoxylated product.
##STR00200##
[0166] The catalyst was synthesized by pre-stirring PPQN.sup.2,4-di-OMe (6.8 mg, 20 mol, 10 mol %) and CoBr.sub.2 (4.4 mg, 20 mol, 10 mol %) in DMF (0.90 mL) in a 10 mL pyrex microwave tube for 30 min. 4-Chlorobenzaldehyde (28.2 mg, 0.20 mmol, 1.0 equiv), allyl acetate (64 L, 60.0 mg, 0.60 mmol, 3.0 equiv), i-Pr.sub.2NEt (104 L, 77.6 mg, 0.60 mmol, 3.0 equiv), and H.sub.2O (0.10 mL) were added. The tube was sealed with a rubber septum, degassed by three freeze-pump-thaw cycles, and back-filled with argon. The reaction mixture was stirred at room temperature under the 53 W 390 nm LED irradiation. After 20 h, to the reaction mixture was added brine, which was extracted with EtOAc, filtered through a short pad of MgSO.sub.4, and concentrated to afford the crude product. The product was purified by preparative thin-layer chromatography. The yield obtained is shown in Table 19. The yields obtained for the control conditions: without transition metal, without ligand or without light are also shown in Table 19. Analogous to the Ni metallaphotocatalysis, the Co.sup.2+/PPQN2,4-di-OMe also derived the reductive allylation of the aldehyde with the allyl ester in the presence of tertiary amine (scheme 45), providing more flexibility for the retrosynthetic planning of allylic alcohol preparation. In tandem with PPQN.sup.2,4-di-OMe, copper was also catalytically viable for several metallaphotoredox reactions.
##STR00201##
[0167] The catalyst was synthesised by pre-stirring PPQN.sup.2,4-di-OMe (6.8 mg, 20 mol, 10 mol %) and Cu(BF.sub.4).sub.2.Math.H.sub.2O (5.2 mg, 20 mol, 10 mol %) in MeCN (2.0 mL) in a 10 mL pyrex microwave tube for 30 min. N-Sulfonyl imine (47.8 mg, 0.20 mmol, 1.0 equiv) and potassium benzyltrifluoroborate (59.4 mg, 0.30 mmol, 1.5 equiv) were added. The tube was sealed with a rubber septum, degassed by three freeze-pump-thaw cycles, and back-filled with argon. The reaction mixture was stirred at room temperature under the 53 W 390 nm LED irradiation. After 20 h, the reaction mixture was passed through a short pad of silica gel and concentrated to afford the crude product. The product was purified by preparative thin-layer chromatography. The yield obtained is shown in Table 19. The yields obtained for the control conditions: without transition metal, without ligand or without light are also shown in Table 19.
##STR00202##
[0168] The catalyst was synthesized by pre-stirring PPQN.sup.2,4-di-OMe (3.4 mg, 10 mol, 5.0 mol %) and Cu(MeCN).sub.4BF.sub.4 (11.2 mg, 30 mol, 15 mol %) in DMA (1.0 mL) in a 10 mL pyrex microwave tube for 30 min. 4-lodobenzonitrile (45.8 mg, 0.10 mmol, 1.0 equiv) and sodium p-toluenesulfinate (TsSO.sub.2Na, 178.2 mg, 1.0 mmol, 5.0 equiv) were added. The tube was then sealed with a rubber septum, degassed by three freeze-pump-thaw cycles, back-filled with argon, and stirred at room temperature under the 53 W 390 nm LED irradiation. After 20 h, to the reaction mixture was added brine, which was extracted with EtOAc, filtered through a short pad of MgSO.sub.4, and concentrated to afford the crude product. The product was purified by preparative thin-layer chromatography. The yield obtained is shown in Table 19. The yields obtained for the control conditions: without transition metal, without ligand or without light are also shown in Table 19.
##STR00203##
[0169] The catalyst was synthesized by pre-stirring PPQN.sup.2,4-di-OMe (6.8 mg, 20 mol, 10 mol %) and Cu(MeCN).sub.4PF.sub.6 (7.4 mg, 20 mol, 10 mol %) in DMA (2.0 mL) in a 10 mL pyrex microwave tube for 30 min. N-Methyl-N-phenylmethacrylamide (35.0 mg, 0.20 mmol, 1.0 equiv) was added. The tube was sealed with a rubber septum, degassed by three freeze-pumpthaw cycles, and back-filled with argon. Benzoyl chloride (46.4 L, 28.1 mg, 0.40 mmol, 2.0 equiv) was then added via a syringe. After 20 h, to the reaction mixture was added brine, which was extracted with EtOAc, filtered through a short pad of MgSO4, and concentrated to afford the crude product. The product was purified by preparative thin-layer chromatography. The yield obtained is shown in Table 19. The yields obtained for the control conditions: without transition metal, without ligand or without light are also shown in Table 19.
[0170] With a common Cu(I) source (Cu(MeCN).sub.4BF.sub.4), the Cu.sup.+/PPQN.sup.2,4-di-OMe-mediated radical addition to imine (scheme 46), aromatic sulfonylation (scheme 47) as well as alkene dicarbofunctionalization (scheme 48) was performed successfully, which furnished the desired products accordingly (schemes 46-48).
TABLE-US-00019 TABLE 19 Yields obtained for the reactions of schemes 44-48 Control, Control, Control, without without without Reaction Standard transition metal ligand light Scheme 44 45% 15% 0% 0% Scheme 45 53% 0% 0% 0% Scheme 46 61% 7% 0% 0% Scheme 47 52% 0% 30% 0% Scheme 48 59% 0% 0% 0%
[0171] The NMR characterization of the compounds synthesized in the present Example are presented in Table 20.
TABLE-US-00020 TABLE 20 NMR characterization of compounds Compound Characterization
[0172] In conclusion, it is reported herein a well-tailored photoactive ligand, PPQN.sup.2,4-di-OMe, that was designed for a wide range of metallaphotoredox cross-coupling reactions. The TM complexes of PPQN.sup.2,4-di-OMe, including Fe, Co, Ni, and Cu, were highly enabling in photocatalytic CC and CX bond-forming transformations, either in a redox-neutral or net reductive fashion. These simple metal pyridyl catalysts were bifunctional, concurrently serving as PCs and traditional metal catalysts. Thus, such a synergistic activation mode increases the variety of base-metal photocatalysis and represents a complementary strategy for the current mainstay of binary meta llaphotoredox systems, which consist of two discrete catalytic entities for separate functions.