Dibenzothiophene salt as alkynylating and cyanating agent

Abstract

The present invention describes a new alkynylation and cyanation agent, as well as its preparation and use to introduce nitrile (cyano) or alkyne groups into chemical target molecules by means of an electrophilic reaction. To enable an electrophilic reaction, the chemical backbone of dibenzothiophene was used.

Claims

1. A salt containing a compound of formula I or II: ##STR00019## wherein R.sub.1-R.sub.8 are independently selected from the group consisting of: H, Cl, Br, F, I, NO.sub.2, O—C.sub.1-6 alkyl, SO.sub.3.sup.−, C.sub.1-6 alkyl, C.sub.6-12 aryl, C.sub.6-12 aryl, C.sub.6-12 heteroaryl, CN, COOR*, where R*=H, C.sub.1-6 alkyl, C.sub.6-12 aryl, and COO—; wherein R in Formula II is selected from the group consisting of: H, OMe, silyl groups and optionally substituted C.sub.6 aryl groups, optionally substituted C.sub.3-12 cycloalkyl groups, optionally substituted C.sub.1-20 alkyl groups.

2. The salt according to claim 1, wherein R is an R′.sub.3 silyl group, wherein the three R′ substituents are independently selected from the group consisting of: optionally substituted linear, branched or cyclic C.sub.1-12 hydrocarbon groups optionally having one or more unsaturated bonds and optionally one or more heteroatoms.

3. The salt according to claim 1, wherein R and the three R′ substituents of the R′.sub.3 silyl group are independently selected from the group consisting of: optionally substituted C.sub.4-12 cycloalkenyl groups having one or more unsaturated C—C double bonds, optionally substituted C.sub.6-12 aryl groups, optionally substituted C.sub.3-12 cycloalkyl groups, optionally substituted C.sub.1-20 alkyl groups, optionally substituted C.sub.1-20 alkenyl groups having one or more unsaturated C—C double bonds, optionally substituted C.sub.1-20 alkynyl groups, optionally substituted C.sub.1-20 heteroalkyl groups, optionally substituted C.sub.1-20 heteroalkenyl groups having one or more unsaturated double bonds, optionally substituted C.sub.1-20 heteroalkynyl groups optionally having one or more unsaturated bonds, optionally substituted C.sub.6-12 heteroaryl groups, optionally substituted C.sub.3-12 heterocycloalkyl groups, optionally substituted C.sub.3-12 heterocycloalkenyl groups having one or more unsaturated double bonds.

4. The salt according to claim 1, wherein the compound of formula I or formula II represents the cation and the anion is selected from the group consisting of: triflate (TfO.sup.−); perchlorates; nitrate; Tf.sub.2N; [{3,5-(CF.sub.3).sub.2C.sub.6H.sub.3}.sub.4B].sup.−; PF6.sup.−; BF4.sup.−; B(C.sub.6F.sub.5).sub.4.sup.−; BF.sub.4.sup.−; BR*.sub.4, wherein R* is optionally substituted C.sub.1-6 alkyl, or optionally substituted C.sub.6-12 aryl; 1-carba-closo-dodecaborate(1-) and corresponding compounds; HC(SO.sub.2CF.sub.3).sub.2.sup.− and corresponding compounds; C.sub.60.sup.−; halides; SbF.sub.6.sup.−; Sb.sub.2F.sub.11.sup.− and antimonate compounds; fluorinated alkoxyaluminates; and tosylates.

5. The salt according to claim 1 wherein R is selected from phenyl, toluene, para-methoxyphenyl, naphthyl, triisopropylsilyl, triethylsilyl, trimethylsilyl, tent-butyl dimethylsilyl and tent-butyl diphenylsilyl.

6. A cyanation or alkynylation reaction comprising the steps a) providing a salt containing the compound of formula I or II: ##STR00020## wherein R.sub.1-R.sub.8 are independently selected from the group consisting of: H, Cl, Br, F, I, NO.sub.2, O—C.sub.1-6 alkyl, SO.sub.3.sup.−, C.sub.1-6 alkyl, C.sub.6-12 aryl, O—C.sub.6-12 aryl, C.sub.6-12 heteroaryl, CN, COOR*, where R*=H, C.sub.1-6 alkyl, C.sub.6-12 aryl, and COO.sup.−; wherein R in Formula II is selected from the group consisting of: H, OMe, silyl groups and optionally substituted C.sub.6 aryl groups, optionally substituted C.sub.3-12 cycloalkyl groups, optionally substituted C.sub.1-20 alkyl groups; and b) reacting the salt with a nucleophile (Nu).

7. The cyanation or alkynylation reaction according to claim 6, wherein step a) further comprises a′) Providing a compound of formula III ##STR00021## and reacting the compound of formula III to a salt containing the compound of formula I or II in two reaction steps: Step 1) reacting with an acid anhydride or an ester; and Step 2) subsequent reaction with a reagent selected from the group consisting of: ##STR00022## or A-CN, wnere A is selected from cations, ZnX, MgX, where X═halogen; TMS; BR.sub.2 and BR.sub.3.sup.−, where R=optionally fluorinated O—C.sub.1-6 alkyl, optionally fluorinated C.sub.1-6 aryl, F or H.

8. The cyanation or alkynylation reaction according to claim 7, wherein step a′) further comprises a″) providing a compound of formula IV ##STR00023## and reacting the compound of formula IV to the compound of formula III by reaction with an oxidizing agent, wherein R.sub.1-8 are independently selected from the group consisting of: H, Cl, Br, F, I, NO.sub.2, O—C.sub.1-6 alkyl, SO.sub.3.sup.−, C.sub.1-6 alkyl, C.sub.6-12 aryl, O—C.sub.6-12 aryl, C.sub.6-12 heteroaryl, CN, COOR*, where R* ═H, C.sub.1-6 alkyl, C.sub.6-12 aryl, and COO—.

9. The cyanation or alkynylation reaction according to claim 6, wherein the nucleophile is selected from the group consisting of R.sup.x—H, R.sup.x—S—H, R.sup.x.sub.2—N—H, R.sup.x—C(O)S—H, R.sup.x—C(O)NR.sup.x—H, sulfonamides (R.sup.x—S(O).sub.2NR.sup.x—H), doubly activated methylene compounds, amides, electron-rich aromatics, nitrogen-containing C.sub.5-12 heterocycles, and Ph.sub.3P, wherein R.sup.x is selected from the group consisting of: optionally substituted linear, branched or cyclic C.sub.1-30 hydrocarbon groups optionally containing one or more unsaturated bonds and optionally one or more heteroatoms.

10. The salt according to claim 1 containing the compound having the formula ##STR00024## where TIPS stands for triisopropylsilyl.

11. The salt according to claim 1 containing the compound having the formula ##STR00025## wherein R is triisopropylsilyl and the anion is triflate (TfO.sup.−) in formula I and II.

12. The method of claim 6, wherein in step b) reacting the salt with a nucleophile (Nu) is performed in the presence of a base or a Lewis acid.

13. The method of claim 6, wherein in step b) reacting the salt with a nucleophile (Nu) is performed in the presence of a base or a Lewis acid, wherein the compound of formula I is used, wherein —CN or the compound ##STR00026## binds to the nucleophile.

14. The salt according to claim 1 containing the compound having the formula ##STR00027## wherein R is para-substituted phenyl.

Description

DESCRIPTION OF THE FIGURES

(1) FIG. 1 shows the synthesis of alkynylating agents 3a-f according to the invention, using the following abbreviations Ph=phenyl, TIPS=triisopropylsilyl, and TFO.sup.−=triflate anion. The following conditions were used: a) TfOH (trifluoromethanesulfonic acid), H.sub.2O.sub.2 (1.2 equivalents), 0.fwdarw.50° C., 76% (yield); b) Tf.sub.2O (trifluoromethanesulfonic acid anhydride) (1 equivalent), −50° C., 1 h (not isolated); c) TMS-alkine (1 equivalent), 3a, 87%; 3b, 82%; 3c, 97%; 3d, 81%; 3e, 73%; 3f, 85%.

(2) FIG. 2 shows an X-ray structure analysis of single crystals of 3a (lower figure) and 3f (upper figure). In both thiophene cations, the sulfur atom remains in the area defined by the dibenzothiophene skeleton. However, the C—S bond lengths within the aromatic fragment 1.7897(11) for S1-C6 in 3a and 1.7933(8) for S1-C3 in 3f are significantly longer than in dibenzothiophene (1.740 Å). This is a consequence of the substantial loss of aromaticity at the thiophene ring after binding of the alkynyl group and the subsequent reduction of S1-C3 and S1-C6 binding orders (Wiberg binding indices have been calculated but are not shown). Selected bond lengths [Å] and angles [degrees]; 3a: S1-C1, 1.6871(12); S1-C3, 1.7878(11); S1-C6, 1.7897(11); S1-O1, 3.157(1); O1-C1, 3.179(2); C3-S1-O1, 179.0(1); 3f: S1-C1, 1.6980(9); S1-C3, 1.7933(8); S1-C6, 1.7935(8); S1-O1, 2.972(1); O1-C1, 3.101(1); C6-S1-O1, 177.3(1).

(3) Based on these observations, it is assumed that the first step of the alkynyl transfer reaction is an alpha or beta attack on the triple bond.

(4) B3LYP/6-31G*-calculations of 3a showed that the sulfur atom carries an almost complete positive charge (+0.946e).

(5) FIG. 3 shows the yields of alkynylation reactions with the alkynylating agent of the invention, using the following abbreviations: Ph=phenyl, TIPS=trilsopropylsilyl, OMe=OCH.sub.3, Boc=tert-butyloxycarbonyl, TFO.sup.−=triflate anion. For thiols and amides, the reactions were performed at room temperature, whereas methylene groups required 60° C. as reaction temperature. Reagents 3a-e and 3f were used in excess (1.5 equivalents and 1.2 equivalents, respectively). All reactions were quenched after 12 h. The yields refer to the isolated products.

(6) FIG. 4 shows the results of isotope labeling experiments. An isotope-labeled phenyl-substituted alkyne synthon 37 is reacted with bistriflate 6 (see FIG. 1) to form the agent 3a* of the invention and then reacted with p-(methoxy)benzylthiol, or a ketoester, or an N-phenyl-tosylamine, using the following conditions a) −50° C..fwdarw.−15° C., 7 h, 90% yield; b) p-(methoxy)benzylthiol (1 equivalent), Cs.sub.2CO.sub.3 (1 equivalent), CH.sub.2Cl.sub.2, room temperature; c) ketoester (1 equivalent), Cs.sub.2CO.sub.3 (1 equivalent), CH.sub.2Cl.sub.2, 60° C.; d) N-phenyl-tosylamine (1 equivalent), Cs.sub.2CO.sub.3 (1 equivalent), CH.sub.2Cl.sub.2, room temperature.

(7) The analysis of compound 10* shows complete retention of the .sup.13C at its original position in 3a*. The result is either consistent with a direct attack of the thiol at the a position of 3a* and simultaneous elimination of dibenzothiophene, or with the reaction of the S nucleophile at the β-carbon, followed by exclusive 1,2 migration of the thio group. The NMR spectrum of aminoalkine 32* shows that the labeled carbon atom is bound to the nitrogen atom. This is only consistent with an attack of the amide at the β-position of alkyne 3a, followed by exclusive 1,2-phenyl group migration. The nucleophilic attack at the β-position can also explain the mixed products 19*, since the migration ability of phenyl and tertiary alkyl radicals is known to be comparable. However, the coexistence of a and 6-attack pathways cannot be excluded.

(8) FIG. 5 shows the results of isotope labeling experiments. An isotope-labeled TIPS-substituted alkyne synthon 38 is reacted with bistriflate 6 (see FIG. 1) to form the agent 3f* according to the invention and then reacted with p-(methoxy)benzylthiol, or a ketoester, or an N-phenyl-tosylamine, using the following conditions a) −50° C..fwdarw.0° C., 7 h, 85% yield; b) p-(methoxy)benzylthiol (1 equivalent), Cs.sub.2CO.sub.3 (1 equivalent), CH.sub.2Cl.sub.2, room temperature; c) ketoester (1 equivalent), Cs.sub.2CO.sub.3 (1 equivalent), CH.sub.2Cl.sub.2, 60° C.; d) N-phenyl-tosylamine (1 equivalent), Cs.sub.2CO.sub.3 (1 equivalent), CH.sub.2Cl.sub.2, room temperature. In FIG. 5c, “S” stands for dibenzothiophene. The labeling is as follows: 1=β attack; 2=β addition product; 3=S elimination step +1,2 shift; 4=α attack; 5=α addition product; 6=S elimination step.

(9) The TIPS group was selected because 1,2-migration of silicon moieties in vinylcarbenoids is known to be significantly faster than that of alkyl- or sulfur-based substituents. 3f* was obtained and used as a 3:1 mixture of the isotopomers. In the reaction of 3f* with p-(methoxy)benzylthiol to obtain 9, the main product obtained was that in which the more strongly labeled carbon atom was still attached to the silicon moiety. This result means that for sulfur-based nucleophiles, the most likely is an a attack. The same observations were made for C- or N-based nucleophiles.

(10) FIG. 6a shows the synthesis of a cyanation agent according to the invention, using the following abbreviations: TMS=trimethylsilyl, and TF.sub.2O=trifluoromethanesulfonic acid anhydride, and TfO.sup.−=triflate. The following synthesis was performed: Trifluoromethanesulfonic acid anhydride (1.00 equivalents) was slowly added to a solution of dibenzo[b,d]thiophene-5-oxide (1.00 equivalents) in dry dichloromethane (10 mL/mmol) at −50° C. The reaction mixture was stirred at −50° C. for 1 h, then trimethylsilyl cyanide (1.00 equivalents) was added dropwise at −50° C. The reaction mixture was stirred at −50° C. for another 2 h, then allowed to warm up to room temperature and stirred for 0.5 h at this temperature. The resulting mixture was then filtered under nitrogen pressure and the solid residue was washed three times with dry dichloromethane (3×5 mL/mmol) and dried under high vacuum to remove solvent residue. The desired product was obtained as white powder. .sup.1H NMR (300 MHz, CD.sub.3CN) δ 8.56 (dd, J=8.4, 0.9 Hz, 2H), 8.35 (dd, J=7.8, 1.2 Hz, 2H), 8.04 (td, J=7.5, 1.2 Hz, 2H), 7.89-7.83 (m, 2H); .sup.13C NMR (75 MHz, CD.sub.3CN) δ 141.71, 137.18, 133.70, 129.98, 127.24, 126.40, 121.87 (q, .sup.1J.sub.C-F=318.5 Hz), 103.87. m/z calculated by HRMS (high resolution mass spectrometry) for C.sub.13H.sub.8NS.sup.+[M-OTf.sup.−]: [M-OTf−]: 210.0372, found (ESI) 210.0365.

(11) FIG. 6b shows the yields of the cyanation reactions.

(12) The invention is explained in more detail below with reference to the figures:

(13) The approach according to the invention is based on the reaction of dibenzothiophene 4 (see scheme in FIG. 1) with hydrogen peroxide in the presence of e.g. trifluoromethanesulfonic acid (Tf-OH) to obtain the corresponding S-oxide 5, which subsequently leads to an orange suspension of bistriflate 6 in a reaction with e.g. one equivalent of trifluoromethanesulfonic acid anhydride (see also Fascione et al., Chem. Eur, 12012, 18, 2987-2997). Bistriflate 6 can then be reacted, for example, by adding a TMS (trimethylsilane)-protected alkyne to the reaction mixture, which resulted in a slow formation of a slightly yellow solution of 5-(alkynyl)dibenzothiophenium triflates 3a-f as white solids after distilling off the solvent and washing with dry diethyl ether (Et.sub.2O) (see FIG. 1). The syntheses could be performed on a multigram scale and showed good to excellent yields. Diagnostic features of the compounds 3a-f are low field shifted .sup.13C-NMR signals of the alkyne carbon atom, the beta carbon to the sulfur being more strongly shifted to the low field (105-110 ppm) and the alpha carbon atom being found at δ=63-69 ppm, the acetylene at δ=73.2 ppm.

EXAMPLES

(14) Nuclear Magnetic Resonance (NMR) experiments

(15) .sup.13C-NMR spectra were recorded in deuterated chloroform (CDCl.sub.3) and deuterated DCM (CD.sub.2Cl.sub.2) (Bruker AV300 and Bruker AV500).

(16) Cited Literature: Fascione et al., Chem. Eur. J. 2012, 18, 2987-2997. Höfer et al., J. Pol. Sci: Part A: Pol. Chem. 2009, 47, 3419-3430. Ochiai, et al., Org. Biomol. Chem. 2003, 1, 1517-1521. Talavera et al.: “Dihalo(imidazolium)sulfuranes: A Versatile Platform for the Synthesis of New Electrophilic Group-Transfer Reagents”, J. Am. Chem. Soc. 2015, 137, 8704-8707. Zhdankin et al.: “1-(Organosulfonyloxy)-3(1H)-1,2-benziodoxoles: Preparation and Reactions with Alkynyltrimethylsilanes”, J. Org. Chem 1996, 61, 6547. WO 2017/001245 A1 WO 2016/107578 A1 WO 2016/087879 A1