Process for the synthesis of carboxylic acid derivatives

Abstract

The present invention discloses one-pot synthesis of various carboxylic acid derivatives using copper catalyst and sodium cyanide as the cyanide source for bringing in carbonylative coupling in a single step.

Claims

1. A one-step, one-pot process for the synthesis of carboxylic acid or carboxylic acid derivatives comprising the steps of: a. stirring the solution of 0.9-1.1 equivalent aryl halides in dimethylformamide (DMF) optionally in the presence of 0.9-1.3 equivalent nucleophile followed by addition of 1.0-1.2 equivalent sodium cyanide and 10-20 mol % of 1, 10-phenanthroline and 5-25 mol % of copper bromide; and b. quenching the reaction mixture of step (a) to obtain carboxylic acid or carboxylic acid derivatives, wherein the nucleophile is selected from the group consisting of water, phenol, 4-nitro-phenol, 4-methoxybenzyl alcohol, aniline, 2-chloro-aniline, 4-methoxy-aniline, and 2-chloro-benzylamine.

2. The process according to claim 1, wherein the halides are selected from the group consisting of bromobenzene, 3-bromo-toluene, 4-methoxy-bromobenzene, 4-nitro-iodobenzene, 1-(2-bromophenyl)pent-4-en-2-ol, 1-(2-bromo-5-methylphenyl)pent-4-en-2-ol, 1-(2-bromo-5-methoxyphenyl)pent-4-en-2-ol, 1-(2-bromo-5-fluorophenyl)pent-4-en-2-ol, 1-(2,6-dibromo-3,4,5-trimethoxyphenyl)pent-4-en-2-ol, 1-(2-bromopyridin-3-yl)pent-4-en-2-ol, 2-(2,2-dibromovinyl)phenol, 1-(2-bromo-5-fluorophenyl)but-3-en-1-ol, 1-(2-bromo-5-methoxyphenyl)but-3-en-1-ol, 1-(2,5-dibromophenyl)but-3-en-1-ol, 1-(2-bromophenyl)octan-1-ol, 1-(2-bromophenyl)pentan-1-ol, 2-iodobenzoic acid, 1,2-dibromobenzene, and (2-bromophenyl)methanamine.

3. The process according to claim 1, wherein the carboxylic acid or carboxylic acid derivatives are selected from the group consisting of phenyl benzoate, 4-nitrophenyl benzoate, 4-methoxybenzyl benzoate, N-phenylbenzamide, N-(2-chlorophenyl)benzamide, N-(2-chlorobenzyl)benzamide, benzoic acid, phenyl 3-methylbenzoate, phenyl 4-methoxybenzoate, phenyl 4-nitrobenzoate, 3-allylisochroman-1-one, 3-allyl-7-methylisochroman-1-one, 3-allyl-6-methoxyisochroman-1-one, 3-allyl-6-fluoroisochroman-1-one, 6,7,8-trimethoxy-1-oxoisochromane-5-carbonitrile, 6-allyl-5,6-dihydro-8H-pyrano[3,4-b]pyridin-8-one, 2H-chromen-2-one, 3-allyl-5-fluoroisobenzofuran-1(3H)-one, 3-allyl-5-methoxyisobenzofuran-1(3H)-one, 5-bromoisobenzofuran-1(3H)-one, 3-heptylisobenzofuran-1(3H)-one, 3-butylisobenzofuran-1(3H)-one, isobenzofuran-1,3-dione, and 2-benzylisoindoline-1,3-dione.

4. The process according to claim 1, wherein the stirring in step (a) is carried out at temperature ranging from 100 C. to 120 C.

5. The process according to claim 1, wherein the stirring in step (a) is carried out for the period ranging from 10-12 hrs.

6. The process according to claim 1, wherein the quenching in step (b) is carried out using water.

7. The process according to claim 1, wherein yield is in the range of 63 to 96%.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) Present invention provides a high yielding and operationally simple method of preparation of acid derivatives starting from substituted halide in a single step under neutral reaction conditions.

(2) Present invention provides a one-step, one-pot process for the synthesis of carboxylic acid derivatives comprising the steps of: a) Stirring the solution of substituted halides in polar solvent optionally in presence of phenols or alcohols or amines or water as nucleophile followed by addition of sodium cyanide, 1,10-phenanthroline and copper bromide; b) Quenching the reaction mixture of step (a) to obtain carboxylic acid derivatives.

(3) The intermolecular O, N substituted nucleophiles are selected from benzyl amine, p-hydroxy benzaldehyde, substituted or unsubstituted phenols such as phenol, chlorophenol and the like.

(4) Substituted halides are selected from bromobenzene, 3-bromo-toluene, 4-methoxy-bromobenzene, 4-nitro-iodobenzene, 1-(2-bromophenyl)pent-4-en-2-ol (2l), 1-(2-bromo-5-methylphenyl)pent-4-en-2-ol (2m), 1-(2-bromo-5-methoxyphenyl)pent-4-en-2-ol (2n), 1-(2-bromo-5-fluorophenyl)pent-4-en-2-ol (2o), 1-(2,6-dibromo-3,4,5-trimethoxyphenyl)pent-4-en-2-ol (2p), 1-(2-bromopyridin-3-yl)pent-4-en-2-ol (2q), 2-(2,2-dibromovinyl)phenol (2r), 1-(2-bromo-5-fluorophenyl)but-3-en-1-ol (2s), 1-(2-bromo-5-methoxyphenyl)but-3-en-1-ol (2t), 1-(2,5-dibromophenyl)but-3-en-1-ol (2u), 1-(2-bromophenyl)octan-1-ol (2v), 1-(2-bromophenyl)pentan-1-ol (2w), 2-iodobenzoic acid (2x), 1,2-dibromobenzene (2y), (2-bromophenyl)methanamine (2z) and the nucleophile is selected from phenol, 4-nitro-phenol, 4-methoxy benzyl alcohol, aniline, 2-chloro-aniline, 4-methoxy-aniline, 2-chloro-benzylamine.

(5) The carboxylic acid derivatives that can be prepared using the process of the invention may be selected from esters, amides, chroman-1-one, isochroman-1-one, benzofuran-2(3H)-one, isobenzofuran-1,3-dione, isoindoline-1,3-dione, isoindoline 1-one compounds etc.

(6) The carboxylic acid derivatives are selected from phenyl benzoate, 4-nitrophenyl benzoate, 4-methoxybenzyl benzoate, N-phenylbenzamide, N-(2-chlorophenyl)benzamide, N-(2-chlorobenzyl)benzamide, benzoic acid, phenyl 3-methylbenzoate, phenyl 4-methoxybenzoate, phenyl 4-nitrobenzoate, 3-allylisochroman-1-one, 3-allyl-7-methylisochroman-1-one, 3-allyl-6-methoxyisochroman-1-one, 3-ally-6-fluoro isochroman-1-one, 6,7,8-trimethoxy-1-oxoisochromane-5-carbonitrile, 6-allyl-5,6-dihydro-8H-pyrano[3,4-b]pyridin-8-one, 2H-chromen-2-one, 3-ally-5-fluoroisobenzofuran-1(3H)-one, 3-allyl-5-methoxyisobenzofuran-1(3H)-one, 5-bromoisobenzofuran-1(3H)-one, 3-heptylisobenzofuran-1(3H)-one, 3-butyl isobenzofuran-1(3H)-one, isobenzofuran-1,3-dione, 2-benzyl isoindoline-1,3-dione.

(7) In the process for the synthesis of carboxylic acid derivatives stirring is carried out at temperature ranges from 100 C. to 120 C. for 10-12 hrs and dimethylformamide is used as polar solvent.

(8) Dimethylformamide is used as polar solvent and quenching in step (b) is carried out using water. The reaction proceeds smoothly in presence of copper (I) salt in catalytic form. The halides according to the invention are selected from substituted or unsubstituted arylic, allylic, vinylic and alkylic halides and pseudohalides (like OMs, OTf) that have been found to support this transformation. The process of the instant invention as shown in scheme 1a and 1b will find tremendous application in carbonylative coupling processes acting as substitute for the hazardous Carbon monoxide.

(9) The copper-catalyzed carbonylative coupling of halide derivatives in presence of CN source through intermolecular nucleophilic substitution is represented in general scheme 1a.

(10) ##STR00001##

(11) The copper catalyzed carbonylative coupling of halide derivatives in presence of CN source through intramolecular nucleophilic substitution is represented in general scheme 1b.

(12) ##STR00002##

(13) The tentative mechanism may be presumed that reaction sequence may involve a Cu insertion into the CX bond followed by cyanation, then reductive elimination of Cu to give cyanated product which when attacked by O, N substituted nucleophile generates imine that undergoes hydrolysis on quenching the reaction mixture with water to give various carboxylic acid derivatives. The role of NaCN is crucial in the present application in order to obtain carbonylative coupling with a simultaneous CC and CO bond formation.

EXAMPLES

(14) Following examples are given by way of illustration and therefore should not be construed to limit the scope of the invention.

Example 1: General Experimental Procedure for the Preparation of Carboxylic Acid Derivatives (3a-3k)

(15) To a stirred solution of haloarenes 1a-1k (3 mmol) and nucleophiles 2a-2k (3 mmol) in dry DMF (15 mL) was added NaCN (3.3 mmol), CuBr (0.3 mmol, 10 mol %) and 1,10-phenanthroline (0.3 mmol, 10 mol %), the entire solution stirred at 120 C. under N.sub.2 for 12 h (monitored by TLC). The reaction mixture was then cooled to room temperature (25 C.) and excess cyanide was quenched with aq. NaClO.sub.2, diluted with water (10 mL) and EtOAc (15 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (320 mL). The combined organic extracts were washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under reduced pressure to give crude products which were purified by column chromatography [silica gel (230-400 mesh) and petroleum ether: EtOAc (7:3) as an eluent to afford corresponding esters and amides (3a-3k) in 63-76% yield.

(16) TABLE-US-00001 TABLE 1 substrates nucleophiles (1a-1k) (2a-2k) Product yields No. (ArX) (1 equiv) (RYH) (1 equiv) (3a-3k) (%) a bromobenzene phenol phenylbenzoate 74 b bromobenzene 4-NO.sub.2-phenol 4-NO.sub.2- 71 phenylbenzoate c bromobenzene 4-OMe 4-OMe- 76 benzylalcohol benzylbenzoate d bromobenzene aniline benzanilide 68 e bromobenzene 2-Cl-aniline 2-Cl-benzanilide 70 f bromobenzene 4-OMe-aniline 4-OMe-benzanilide 63 g bromobenzene 2-Cl-benzylamine 2-Cl-benzylbenzamide 71 h bromobenzene water benzoic acid 70 i 3-Br-toluene phenol 3-Me-phenylbenzoate 68 j 4-MeO- phenol 4-MeO- 71 bromobenzene phenylbenzoate k 4-NO.sub.2- phenol 4-NO.sub.2- 71 iodobenzene phenylbenzoate

Example 2: General Experimental Procedure for the Preparation of Carboxylic Acid Derivatives (3l-3z)

(17) To a stirred solution of haloarenes 2l-2z (3 mmol) in dry DMF (15 mL) was added NaCN (3.3 mmol), CuBr (0.3 mmol) and 1,10-phenanthroline (0.3 mmol), the entire solution stirred at 120 C. under N.sub.2 for 12 h (monitored by TLC). The reaction mixture was then cooled to room temperature (25 C.) and excess cyanide was quenched with aq. NaClO.sub.2, diluted with water (10 mL) and EtOAc (15 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (320 mL). The combined organic extracts were washed with brine, dried over anhyd. Na.sub.2SO.sub.4 and concentrated under reduced pressure to give crude products which was purified by column chromatography [silica gel (230-400 mesh) and petroleum ether: EtOAc (7:3) as an eluent to afford corresponding esters and amides (3l-3z) in 73-96% yield.

(18) TABLE-US-00002 TABLE 2 No. substrates (2l-2z) (1 equiv) products (3l-3z) & Yields (%) l-o R.sub.1 = H, R.sub.2 = H; (21) R.sub.1 = H, R.sub.2 = Me; (2m) R.sub.1 = OMe, R.sub.2 = H; (2n) R.sub.1 = H, R.sub.2 = H; (3l), 84% R.sub.1 = F, R.sub.2 = H; (2o) R.sub.1 = H, R.sub.2 = Me; (3m), 86% R.sub.1 = OMe, R.sub.2 = H; (3n), 87% R.sub.1 = F, R.sub.2 = H; (3o), 88% p (2p) (3p), 84% q (2q) (3q), 84% r 0 (2r) (3r), 81% s-w R.sub.1 = F, R.sub.2 = allyl; (2s) R.sub.1 = OMe, R.sub.2 = allyl; (2t) R.sub.1 = F, R.sub.2 = allyl; (3s), 92% R.sub.1 = Br, R.sub.2 = allyl; (2u) R.sub.1 = OMe, R.sub.2 = allyl; (3t), 85% R.sub.1 = H, R.sub.2 = heptyl; (2v) R.sub.1 = Br, R.sub.2 = allyl; (3u), 78% R.sub.1 = H, R.sub.2 = butyl; (2w) R.sub.1 = H, R.sub.2 = heptyl; (3v), 91% R.sub.1 = H, R.sub.2 = butyl; (3w), 85% x (2x) (3x), 96% y (2y) (3y), 73% Z (2z) (3z), 81% .sup.[c]concomitant reduction of one of the Br to H takes place .sup.[d]2 equiv NaCN used, 1 equiv of benzylamine used as nucleophile.

Example 3: Phenyl Benzoate (3a)

(19) Yield: 74% (0.440 g, 2.222 mmol); Colorless solid; mp. 70 C.; IR (CHCl.sub.3, cm.sup.1): .sub.max 690, 1080, 1260, 1500, 1718, 2980; .sup.1H NMR (200 MHz, CHLOROFORM-d) 7.18-7.30 (m, 3H) 7.39-7.53 (m, 4H) 7.58-7.67 (m, 1H), 8.20 (td, J=1.7 and 6.9 Hz, 2H); .sup.13C NMR (50 MHz, CHLOROFORM-d) 121.7, 125.8, 128.5, 129.4, 129.7, 130.2, 133.5, 151.0, 164.9; Analysis: C.sub.13H.sub.10O.sub.2 requires C, 78.77; H, 5.09; O, 16.14; Found: C, 78.56; H, 5.34; O, 16.10%.

Example 4: 4-nitrophenyl benzoate (3b)

(20) Yield: 71% (0.517 g, 2.127 mmol); Colorless solid; mp. 141 C.; IR (CHCl.sub.3, cm.sup.1): .sub.max 695, 1060, 1206, 1340, 1530, 1740, 3010; .sup.1H NMR (200 MHz, CHLOROFORM-d) ppm 7.43 (td, J=3.2 and 8.9 Hz, 2H) 7.50-7.61 (m, 2H) 7.55 (dt, J=1.6 and 7.6 Hz, 1H) 7.70 (tt, J=1.6 and 7.6 Hz, 1H), 8.19-8.24 (m, 2H), 8.34 (td, J=3.2 and 8.9 Hz, 2H); .sup.13C NMR (50 MHz, CHLOROFORM-d) 122.6, 125.2, 128.6, 128.8, 130.3, 134.2, 145.4, 155.7, 164.0; Analysis: C.sub.13H.sub.9NO.sub.4 requires C, 64.20; H, 3.73; N, 5.76; O, 26.31; Found: C, 64.46; H, 3.54; N, 5.67; O, 26.33%.

Example 5: 4-methoxybenzyl benzoate (3c)

(21) Yield: 76% (0.552 g, 2.280 mmol); Colorless solid; mp. 91 C.; IR (CHCl.sub.3, cm.sup.1): .sub.max 693, 1075, 1270, 1500, 1720, 2990; .sup.1H NMR (200 MHz, CHLOROFORM-d) 3.80 (s, 3H), 5.28 (s, 2H), 6.89 (td, J=2.9 and 8.6 Hz, 2H), 7.35-7.45 (m, 4H), 7.53 (tt, J=1.7 and 7.1 Hz, 1H), 8.04 (td, J=1.7 and 7.1 Hz, 2H); .sup.13C NMR (50 MHz, CHLOROFORM-d) 55.1, 66.4, 113.9, 128.2, 129.5, 129.6, 130.0, 130.3, 132.8, 159.6, 166.2; Analysis: C.sub.15H.sub.14O.sub.3 requires C, 74.36; H, 5.82; O, 19.81; Found: C, 74.35; H, 5.78; O, 19.87%.

Example 6: N-phenylbenzamide (3d)

(22) Yield: 68% (0.402, 2.040 mmol); Colorless solid; mp. 163 C.; IR(CHCl.sub.3, cm.sup.1): .sub.max690, 780, 1305, 1430, 1530, 1600, 1670, 3330; .sup.1H NMR (200 MHz, CHLOROFORM-d) ppm 6.63-6.77 (m, 2H), 7.13 (tt, J=1.6 and 8.4 Hz, 2H), 7.32-7.65 (m, 5H), 7.86 (td, J=1.6 and 6.4 Hz, 2H); .sup.13C NMR (100 MHz, CHLOROFORM-d) 115.1, 118.6, 120.2, 124.6, 127.1, 128.8, 129.1, 129.3, 131.8, 135.1, 138.0, 146.3, 165.5; Analysis: C.sub.13H.sub.11NO requires C, 79.17; H, 5.62; N, 7.10; O, 8.11; Found: C, 79.95; H, 5.54; N, 7.13; O, 7.38%.

Example 7: N-(2-chlorophenyl)benzamide (3e)

(23) Yield: 70% (0.486 g, 2.099 mmol); Colorless solid; mp. 101 C.; IR (CHCl.sub.3, cm.sup.1): .sub.max 690, 788, 1310, 1415, 1510, 1600, 1680, 3310; .sup.1H NMR (200 MHz, CHLOROFORM-d) 7.07 (dt, J=1.3 and 7.4 Hz, 1H), 7.29-7.59 (m, 5H), 7.93 (td, J=1.3 and 6.1 Hz, 2H), 8.45 (br. s., 1H), 8.58 (dd, J=1.6 and 8.3 Hz, 1H); .sup.13C NMR (100 MHz, CHLOROFORM-d) 121.5, 122.9, 124.6, 127.1, 127.9, 128.9, 128.9, 132.1, 134.6, 134.8, 165.0; Analysis: C.sub.13H.sub.10ClNO requires C, 67.40; H, 4.35; Cl, 15.30; N, 6.05; O, 6.91 Found: C, 67.87; H, 4.23; Cl, 15.18; N, 6.20; O, 6.52%.

Example 8: N-(4-methoxyphenyl)benzamide (3f)

(24) Yield: 63% Colorless solid; IR (CHCl.sub.3, cm.sup.1): .sub.max 690, 708, 1320, 1411, 1530, 1610, 1670, 3210; .sup.1H NMR (200 MHz, CHLOROFORM-d) 9.8 (s, 1H), 6.8-8.0 (m, 9H), 3.8 (s, 3H).

Example 9: N-(2-chlorobenzyl)benzamide (3g)

(25) Yield: 71% (0.523 g, 2.130 mmol); Colorless solid; mp. 99 C.; IR (CHCl.sub.3, cm.sup.1): .sub.max 688, 785, 1316, 1400, 1520, 1678, 3320; .sup.1H NMR (200 MHz, CHLOROFORM-d) 4.70 (d, J=5.4 Hz, 2H), 6.73 (br. s., 1H) 7.20-7.26 (m, 2H) 7.35-7.52 (m, 5H) 7.77 (dd, J=1.6 and 8.2 Hz, 2H); .sup.13C NMR (100 MHz, CHLOROFORM-d) 42.0, 127.0, 127.1, 128.6, 128.9, 129.6, 130.4, 131.5, 133.7, 134.3, 135.7, 167.2; Analysis: C.sub.14H.sub.12ClNO requires C, 68.44; H, 4.92; Cl, 14.43; N, 5.70; O, 6.51 Found: C, 68.87; H, 4.23; Cl, 14.78; N, 5.20; O, 6.92%.

Example 10: Benzoic Acid (3h)

(26) Yield: 70% (0.256 g, 2.098 mmol); Colorless solid; mp. 123 C.; IR (CHCl.sub.3, cm.sup.1): .sub.max700, 1280, 1320, 1410, 1690, 3200; .sup.1H NMR (400 MHz, ACETONE-d.sub.6) ppm 7.43-7.48 (m, 2H), 7.50-7.55 (m, 1H), 7.93-7.96 (m, 2H); .sup.13C NMR (50 MHz, Acetone) 30.2, 128.3, 129.1, 132.1, 135.3, 169.1; Analysis: C.sub.7H.sub.6O.sub.2 requires C, 68.85; H, 4.95; O, 26.20 Found: C, 68.82; H, 4.97; O, 26.21%.

Example 11: phenyl 3-methylbenzoate (3i)

(27) Yield: 68% (0.433 g, 2.041 mmol); Colorless oil; .sup.1H NMR (200 MHz, CHLOROFORM-d) ppm 2.45 (s, 3H), 7.16-7.30 (m, 3H), 7.34-7.46 (m, 4H), 7.98-8.01 (m, 2H); .sup.13C NMR (50 MHz, CHLOROFORM-d) 21.0, 121.5, 125.5, 127.0, 128.2, 129.1, 129.2, 130.4, 134.0, 137.9, 150.8, 164.7; Analysis: C.sub.14H.sub.12O.sub.2 requires C, 79.23; H, 5.70; O, 15.08 Found: C, 79.12; H, 5.97; O, 14.91%.

Example 12: phenyl 4-methoxybenzoate (3j)

(28) Yield: 71% (0.485 g, 2.130 mmol); Colorless solid; mp. 70 C.; .sup.1H NMR (200 MHz, CHLOROFORM-d) ppm 3.89 (s, 3H), 6.97 (td, J=3.5 Hz and 9.1 Hz, 2H), 7.15-7.29 (m, 3H), 7.35-7.46 (m, 2H); .sup.13C NMR (125 MHz, CHLOROFORM-d) 55.4, 113.8, 121.8, 123.2, 125.7, 129.4, 132.3, 151.1, 163.9, 164.7; Analysis: C.sub.14H.sub.12O.sub.3 requires C, 73.67; H, 5.30; O, 21.03 Found: C, 73.75; H, 5.13; O, 21.12%.

Example 13: phenyl 4-nitrobenzoate (3k)

(29) Yield: 71% (0.518 g, 2.130 mmol); Colorless solid; mp. 128 C.; .sup.1H NMR (200 MHz, CHLOROFORM-d) ppm 7.16-7.50 (m, 5H), 8.36 (s, 4H); .sup.13C NMR (125 MHz, CHLOROFORM-d) 122.8, 123.8, 129.8, 131.3, 131.9, 134.6, 148.9, 151.0, 162.9; Analysis: C.sub.13H.sub.9NO.sub.4 requires C, 64.20; H, 3.73; N, 5.76; O, 26.31 Found: C, 64.38; H, 3.52; N, 5.81; O, 26.29%.

Example 14: 3-allylisochroman-1-one (3l)

(30) Yield: 86% (0.474 g, 2.521 mmol); Colorless oil; IR (CHCl.sub.3, cm.sup.1): .sub.max 745, 1118, 1281, 1723, 2918, 3077; .sup.1H NMR (200 MHz, CHLOROFORM-d) 2.45-2.72 (m, 2H) 2.87-3.07 (m, 2H) 4.51-4.62 (m, 1H), 5.13-5.24 (m, 2H), 5.79-5.97 (m, 1H) 7.21-7.56 (m, 3H), 8.07 (dd, J=0.8 and 7.7 Hz, 1H); .sup.13C NMR (125 MHz, CHLOROFORM-d): 32.5, 39.2, 77.6, 118.8, 125.2, 127.3, 127.6, 130.3, 132.3, 133.6, 138.9, 164.9; HRMS (ESI+, m/z): calcd for (C.sub.12H.sub.12O.sub.2).sup.+ [(M+Na).sup.+] 211.0727; found: 211.0730; Analysis: C.sub.12H.sub.12O.sub.2 requires C, 76.57; H, 6.43; O, 17.00 Found: C, 76.58; H, 6.33; O, 17.09%.

Example 15: 3-allyl-7-methylisochroman-1-one (3m)

(31) Yield: 86% (0.521 g, 2.579 mmol); Colorless oil; IR (CHCl.sub.3, cm.sup.1): .sub.max 774, 921, 1082, 1194, 1723, 2923, 3078; .sup.1H NMR (200 MHz, CHLOROFORM-d) 2.39 (s, 3H), 2.51-2.68 (m, 2H), 2.82-2.94 (m, 2H), 4.48-4.61 (m, 1H), 5.12-5.23 (m, 2H), 5.77-6.00 (m, 1H) 7.10 (d, J=7.7 Hz, 1H) 7.32 (d, J=7.7 Hz, 1H), 7.90 (s, 1H); .sup.13C NMR (50 MHz, CHLOROFORM-d) 20.9, 32.1, 39.2, 77.7, 118.7, 124.8, 127.2, 130.4, 132.4, 134.4, 135.9, 137.3, 165.2; HRMS (ESI+, m/z): calcd for (C.sub.13H.sub.14O.sub.2).sup.+ [(M+Na).sup.+] 225.0884; found: 225.0886; Analysis: C.sub.13H.sub.14O.sub.2 requires C, 77.20; H, 6.98; O, 15.82 Found: C, 77.38; H, 6.83; O, 15.79%.

Example 16: 3-allyl-6-methoxyisochroman-1-one (3n)

(32) Yield: 87% (0.569 g, 2.610 mmol); Colorless oil; IR (CHCl.sub.3, cm.sup.1): .sub.max 778, 917, 1027, 1260, 1606, 1716, 2920, 3076; .sup.1H NMR (200 MHz, CHLOROFORM-d) 2.48-3.04 (m, 4H), 3.86 (s, 3H), 4.49-4.60 (m, 1H), 5.16-5.24 (m, 2H), 5.83-6.00 (m, 1H), 6.70 (d, J=2.4 Hz, 1H), 6.87 (dd, J=2.4 and 8.3 Hz, 1H), 8.02 (d, J=8.3 Hz, 1H); .sup.13C NMR (50 MHz, CHLOROFORM-d) 32.7, 39.1, 55.4, 77.4, 112.0 113.4, 117.5, 118.7, 132.3, 132.4, 141.2, 163.7, 165.3; HRMS (ESI+, m/z): calcd for (C.sub.13H.sub.14O.sub.3).sup.+ [(M+Na).sup.+] 241.0831; found: 241.0835; Analysis: C.sub.13H.sub.14O.sub.3 requires C, 71.54; H, 6.47; O, 21.99 Found: C, 71.58; H, 6.53; O, 21.89%.

Example 17: 3-allyl-6-fluoroisochroman-1-one (3o)

(33) Yield: 88% (0.536 g, 2.640 mmol); Colorless oil; IR (CHCl.sub.3, cm.sup.1): .sub.max 667, 755, 1107, 1267, 1615, 1725, 2919, 3079; .sup.1H NMR (200 MHz, CHLOROFORM-d) 2.45-2.72 (m, 2H) 2.84-3.08 (m, 2H), 4.51-4.65 (m, 1H), 5.16-5.25 (m, 2H), 5.78-5.99 (m, 1H), 6.93 (dd, J=2.3 and 8.1 Hz, 1H), 7.06 (dt, J=2.3 and 8.1 Hz, 1H), 8.10 (dd, J=5.6 and 8.6 Hz, 1H); .sup.13C NMR (125 MHz, CHLOROFORM-d) 32.6, 39.1, 77.5, 114.3, 115.3, 119.1, 121.5, 132.1, 133.3, 141.9, 164.0, 166.8; HRMS (ESI+, m/z): calcd for (C.sub.12H.sub.11O.sub.2F).sup.+ [(M+Na).sup.+] 229.0632; found: 229.0635; Analysis: C.sub.12H.sub.11O.sub.2F requires C, 69.89; H, 5.38; F, 9.21; O, 15.52 Found: C, 69.95; H, 5.54; F, 9.13; O, 15.38%.

Example 18: 6,7,8-trimethoxy-1-oxoisochromane-5-carbonitrile (3p)

(34) Yield: 84% (0.663 g, 2.520 mmol); yellowish solid; mp. 107 C.; IR (CHCl.sub.3, cm.sup.1): .sub.max 802, 1036, 1130, 1579, 1677, 1713, 2922, 2949; .sup.1H NMR (200 MHz, CHLOROFORM-d) 3.31 (t, J=8.5 Hz, 2H), 3.85 (s, 3H), 3.95 (s, 3H), 4.04 (s, 3H), 4.65 (t, J=8.5 Hz, 2H); .sup.13C NMR (125 MHz, CHLOROFORM-d) 27.4, 61.4, 61.8, 62.2, 65.7, 100.3, 113.8, 115.2, 141.2, 145.1, 159.6, 159.7, 161.2; HRMS (ESI+, m/z): calcd for (C.sub.13H.sub.13NO.sub.5).sup.+ [(M+Na).sup.+] 286.0691; found: 286.0693; Analysis: C.sub.13H.sub.13NO.sub.5 requires C, 59.31; H, 4.98; N, 5.32; O, 30.39 Found: C, 58.95; H, 4.57; N, 5.27; O, 31.21%.

Example 19: 6-allyl-5,6-dihydro-8H-pyrano[3,4-b]pyridin-8-one (3q)

(35) Yield: 84% (0.476 g, 2.518 mmol); yellow oil; .sup.1H NMR (200 MHz, CHLOROFORM-d) 2.29-2.73 (m, 4H), 5.05-5.19 (m, 2H), 5.23 (s, 1H), 5.79-5.96 (m, 1H), 7.27 (dd, J=4.9 and 7.6 Hz, 1H), 7.92 (dd, J=1.5 Hz and 7.6 Hz, 1H), 8.28 (dd, J=1.5 and 4.9 Hz, 1H); .sup.13C NMR (125 MHz, CHLOROFORM-d) 40.4, 42.0, 69.3, 118.9, 122.4, 133.3, 134.0, 140.4, 147.7, 151.5; Analysis: C.sub.9H.sub.6O.sub.2 requires C, 73.97; H, 4.14; O, 21.89; Found: C, 73.94; H, 4.17; O, 21.89%.

Example 20: 2H-chromen-2-one (3r)

(36) Yield: 81% (0.355 g, 2.430 mmol); Colorless liquid; IR (CHCl.sub.3, cm.sup.1): .sub.max 820, 1104, 1180, 1610, 1710, 3030; .sup.1H NMR (200 MHz, CHLOROFORM-d) 6.43 (d, J=9.4 Hz, 1H), 7.28-7.57 (m, 4H), 7.77 (d, J=9.4 Hz, 1H); .sup.13C NMR (50 MHz, CHLOROFORM-d) 116.7, 116.9, 118.8, 124.4, 127.8, 131.8, 143.5, 154.0, 160.8; Analysis: C.sub.9H.sub.6O.sub.2 requires C, 73.97; H, 4.14; O, 21.89; Found: C, 73.94; H, 4.17; O, 21.89%.

Example 21: 3-allyl-5-fluoroisobenzofuran-1(3H)-one (3s)

(37) Yield: 92% (0.530 g, 2.760 mmol); Colorless oil; IR (CHCl.sub.3, cm.sup.1): .sub.max 988, 1100, 1247, 1483, 1604, 1624, 1766, 3100; .sup.1H NMR (200 MHz, CHLOROFORM-d) 2.62-2.78 (m, 2H), 5.12-5.25 (m, 2H), 5.48 (t, J=6.1 Hz, 1H), 5.65-5.86 (m, 1H), 7.12-7.28 (m, 2H), 7.89 (dd, J=4.8 and 8.1 Hz, 1H); .sup.13C NMR (50 MHz, CHLOROFORM-d) 38.2, 79.2, 109.3, 117.2, 119.8, 122.2, 127.8, 130.6, 151.9, 163.6, 168.7; Analysis: C.sub.11H.sub.9FO.sub.2 requires C, 68.75; H, 4.72; F, 9.89; O, 16.65; Found: C, 68.82; H, 4.97; O, 26.21%.

Example 22: 3-allyl-5-methoxyisobenzofuran-1(3H)-one (3t)

(38) Yield: 85% (0.518 g, 2.551 mmol); Colorless oil; IR (CHCl.sub.3, cm.sup.1): .sub.max 692, 1073, 1103, 1259, 1605, 1744, 2997; .sup.1H NMR (200 MHz, CHLOROFORM-d) ppm 2.56-2.81 (m, 2H), 3.91 (s, 3H), 5.15-5.25 (m, 2H), 5.42 (t, J=6.1 Hz, 1H), 5.68-5.89 (m, 1H), 6.87 (d, J=1.6 Hz, 1H), 7.02 (dd, J=1.6 and 8.5 Hz, 1H), 7.80 (d, J=8.5 Hz, 1H); .sup.13C NMR (50 MHz, CHLOROFORM-d) 38.8, 55.7, 79.3, 106.1, 116.2, 118.7, 119.6, 127.2, 131.3, 152.0, 164.5, 169.8; Analysis: C.sub.12H.sub.12O.sub.3 requires C, 70.58; H, 5.92; O, 23.50; Found: C, 70.61; H, 5.67; O, 23.72%.

Example 23: 5-bromoisobenzofuran-1(3H)-one (3u)

(39) Yield: 78% (0.498 g, 2.338 mmol); Colorless solid; mp. 162 C.; .sup.1H NMR (200 MHz, CHLOROFORM-d) ppm 5.30 (s, 2H), 7.68 (t, J=3.7 Hz, 2H), 7.77-7.81 (m, 1H); .sup.13C NMR (50 MHz, CHLOROFORM-d) 68.8, 124.9, 125.6, 127.1, 129.2, 132.7, 148.2, 169.7; Analysis: C.sub.8H.sub.5BrO.sub.2 requires C, 45.11; H, 2.37; Br, 37.51; O, 15.02 Found: C, 45.65; H, 2.24; Br, 38.13; O, 13.98%.

Example 24: 3-heptylisobenzofuran-1(3H)-one (3v)

(40) Yield: 91% (0.633 g, 2.728 mmol); Colorless oil; .sup.1H NMR (200 MHz, CHLOROFORM-d) ppm 0.88 (t, J=3.5 Hz, 3H), 1.27-1.47 (m, 10H), 1.66-1.82 (m, 1H), 1.96-2.12 (m, 1H), 5.46 (dd, J=4.0 and 7.4 Hz, 1H), 7.41-7.55 (m, 2H), 7.66 (dt, J=1.6 and 7.6 Hz, 1H). 7.88 (d, J=7.6 Hz, 1H); .sup.13C NMR (50 MHz, CHLOROFORM-d) 14.0, 22.5, 24.8, 29.0, 29.3, 31.7, 34.7, 81.2, 121.6, 125.6, 126.2 128.9, 133.8, 150.0, 170.3; Analysis: C.sub.15H.sub.20O.sub.2 requires C, 77.55; H, 8.68; O, 13.77 Found: C, 77.58; H, 8.71; O, 13.71%.

Example 25: 3-butylisobenzofuran-1(3H)-one (3w)

(41) Yield: 87% (0.496 g, 2.610 mmol); Colorless oil; .sup.1H NMR (200 MHz, CHLOROFORM-d) 0.91 (t, J=6.3 Hz, 3H), 1.26-1.52 (m, 4H), 1.71-1.82 (m, 1H), 1.98-2.12 (m, 1H), 5.46 (dd, J=4.1 and 7.2 Hz, 1H), 7.50 (dd, J=7.2 and 9.8 Hz, 2H), 7.67 (t, J=7.2 Hz, 1H), 7.88 (d, J=7.8 Hz, 1H); .sup.13C NMR (50 MHz, CHLOROFORM-d) 13.8, 22.4, 26.8, 34.4, 81.1, 121.6, 125.6, 126.2, 128.9, 133.8, 150.0, 170.2; Analysis: C.sub.12H.sub.14O.sub.2 requires C, 75.76; H, 7.42; O, 16.82; Found: C, 75.54; H, 7.57; O, 16.89%.

Example 26: isobenzofuran-1,3-dione (3x)

(42) Yield: 96% (0.426 g, 2.878 mmol); Colorless solid; mp. 131 C.; IR (CHCl.sub.3, cm.sup.1): .sub.max 667, 758, 1052, 1307, 1604, 1748, 1772, 2924; .sup.1H NMR (200 MHz, CHLOROFORM-d) 7.77 (dd, J=2.0 and 6.0 Hz, 2H), 7.89 (dd, J=2.0 and 6.0 Hz, 2H); .sup.13C NMR (100 MHz, CHLOROFORM-d) 123.6, 132.7, 134.28, 167.7; HRMS (ESI+, m/z): calcd for (C.sub.8H.sub.5O.sub.3).sup.+ 149.0232; found: 149.0233; Analysis: C.sub.8H.sub.4O.sub.3 requires C, 64.87; H, 2.72; O, 32.40; Found: C, 64.82; H, 2.77; O, 32.41%.

Example 27: 2-benzylisoindoline-1,3-dione (3y)

(43) Yield: 73% (0.396 g, 2.187 mmol); Colorless solid; mp. 115 C.; IR(CHCl.sub.3, cm.sup.1): 717, 1062, 1331, 1391, 1453, 1715, 1764, 2853, 2924; .sup.1H NMR (200 MHz, CHLOROFORM-d) 4.84 (s, 2H), 7.24-7.45 (m, 5H), 7.69 (dd, J=2.9 and 5.6 Hz, 2H), 7.84 (dd, J=2.9 and 5.6 Hz, 2H); .sup.13C NMR (50 MHz, CHLOROFORM-d) 41.6, 123.3, 127.8, 128.7, 132.2, 133.9, 136.4, 167.9; HRMS (ESI+, m/z): calcd for (C.sub.15H.sub.11O.sub.2NNa).sup.+ [(M+Na).sup.+] 260.0678; found: 260.0682; Analysis: C.sub.15H.sub.11NO.sub.2 requires C, 75.94; H, 4.67; N, 5.90; O, 13.49; Found: C, 75.87; H, 4.33; N, 5.98; O, 13.82%.

Example 28: isoindolin-1-one (3z)

(44) 1H NMR (CDCl3, 400 MHz) 4.41 (s, 2H), 7.41-7.53 (m, 4H), 7.81 (d, J=7.6 Hz, 1H); .sup.13C NMR (CDCl3, 100 MHz) (ppm) 45.7, 123.2, 123.7, 128.0, 131.7, 132.1, 143.6, 172.0.

Example 29: Intramolecular Carbonylative Coupling of 1-(2-bromophenyl)pent-4-en-2-ol Optimization Studiesa

(45) ##STR00019##

(46) TABLE-US-00003 TABLE 3 CuBr-catalyzed carbonylative coupling of bromobenzene with phenol using NaCN as C.sub.1 source: optimization studies Temp. Yield Entry Catalyst CN source (equiv.) ( C.) (%).sup.b 1. CuCN (1.0) 150 28 2. CuCN (2.0) 150 53 3. CuCN (3.0) 150 85 (trace).sup.c 4. CuCN (3.5) 150 85 5. CuCN (3.0) 120 48 6. Cu(OAc).sub.2 K.sub.4[Fe(CN).sub.6] (0.5) 110 trace 7. CuBr NaCN (1.1) 150 70 8. CuBr + NaCN (1.1) 110 84 1,10-phenanthroline (0.1) 9. CuBr + NaCN (1.1) 110 70 L-proline (0.1) .sup.aAlcohol1a (1 equiv), Catalyst (10 mol %), CN source, 12 h. .sup.bIsolated yield after column chromatography purification. .sup.cDMSO used as solvent.

(47) It is worth mentioning that intramolecular reactions afforded products in better yields than intermolecular reactions.

ADVANTAGES OF THE INVENTION

(48) A facile process for carbonylative coupling. Hazardous Carbon monoxide free carbonylation reaction. One-step, one-pot and simple process for carbonylative coupling. The present invention reports Cu catalyzed preparation of various carboxylic acid derivatives from arylic, vinylic and alkylic halide using NaCN as the cyanide source for bringing in carbonylative coupling in a single step. This process will find tremendous application in carbonylative coupling processes acting as substitute for the hazardous Carbon monoxide.