IE51665B1 - Trimethylsilyloxyethanenitrile intermediates for hypoglycemic 5-substituted oxazolidine-2,4-diones - Google Patents

Description

The compounds within the scope of the above proviso are disclosed in Chem. Ber., 112, 2049 (1979).

The compounds of the invention can be prepared by reacting an aldehyde of the formula R^.CHO with trimethylsilylcarbonitrile in the presence of a catalytic quantity of a Lewis acid, e.g., zinc iodide. A reaction inert solvent (e.g. methylene chloride, ether) is generally used when the aldehyde is a solid, but is optional when the aldehyde is a liquid. The temperature of the reaction is not critical, it being conveniently made up at reduced temperature (e.g. 0-5eC) and allowed to proceed at room temperature for a matter of hours or days, as necessary to achieve complete reaction.

The compounds can be converted to hypoglycemic end products as described in Patent Application No. 51662.

The aldehydes required for the above synthesis are broadly available either commercially, or by literature methods. For example, N-alkylpyrrole-2carbaldehydes are obtained by alkylation of pyrrole5 2-carbaldehyde (Weygand, Organic Preparations, Interscience New York, 1945, p. 403) using conditions specifically exemplified hereinafter for the preparation of Nalkylpyrroles, or by Reimer-Tieman formylation of Nalkylpyrrole (cf Weygand loc. cit.); 3-formylindoles TO are similarly obtained from indoles (cf Boyd and Robson, Biochem J. 29, p. 555 (1935; Shabica et al., J. Am. Chem. Soc. 68, p. 1156 (1946)]; Rosenmund hydrogenation of the corresponding acid chloride [e.g. 3-furaldehyde; Hayes, J. Am. Chem. Soc. 71, 2581 (1949)], from halomethyl compounds by the Sommelet reaction [e.g. 3-thenaldehyde; Campaigne and LaSuer, J. Am. Chem. Soc. 70, 1557 (1948)], formylation [e.g. 2-thenaldehyde, 3-methyl-2-thenaldehyde, 5-methyl-2thenaldehyde; Watson and Michaels, J. Am. Chem. Soc. 72, 1422 (1950), Organic Syntheses 31, 108 (1951); 3bromo-2-thenaldehyde; Elliott et al., J. Chem. Soc.

(C), 2551 (1971)]; reduction of chloromethyl substituted aldehydes [e.g. 5-methyl-2-furaldehyde, Spence and Wild, J. Chem. Soc., 338 (1935)], oxidation of the corresponding alcohol [e.g. 2-thenaldehvde; Emerson - 5 and Patrick, J. Org. Chem., 14, 790 (1949)], interaction 5 of Grignard reagents with orthoformic esters (e.g. 2thenaldehdye; Cagniant, Bull. soc. chim. France 16, 849 (1949)], decarboxylation of alpha-keto acids [e.g. 2-thenaldehyde; Barger and Easson, J. Chem.

Soc., 2100 (1938)], and halogenation [e.g. 2-bromo-310 thenaldehyde; Elliot et al., loc. cit.]; a variety of the presently required aldehydes are further available by the hydrolysis of qem-dihalides, oxidation of primary alcohols, interaction of Grignard reagents with orthoformic esters and other methods known in the art. Additional methods are noted in the Preparations detailed hereinafter.

The following Examples illustrate the invention:51665 - 6 EXAMPLE 1 2-(6-Chloro-8-chromanyl)-2-trimethylsiloxyethanenitrile 6-Chlorochroman-8-carbaldehyde (7 g., 0.036 mole) 5 in 70 ml. of methylene chloride was cooled to 0-5°C.

Zinc iodide (100 mg.) was added, followed by the dropwise addition of trimethylsilylcarbonitrile (4.26 g., 0.043 mole). The reaction mixture was stirred at room temperature for 64 hours, then washed in sequence with 10 three portions of saturated sodium bicarbonate and one of brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield title product as an oil [9.5 g.; ir(CH2Cl2) 2857, 1479, 1215, 1190, 1060 EXAMPLE 2 2-(6-Fluoro-8-chromany1)-2-trimethyls iloxy_ethanenitrile _ By the procedure of Example 1 , 6-fluorochroman8-carbaldehyde (3.2 g., 0.0178 mole) was converted to title product as an oil (4.51 g., m/e 279; ir (CHC1_) 1498, 1205, 1066 cm . - Ί EXAMPLE 3 2-(5-Chloro-2,3-dihydro-7-benzo[b]furanyl)-2trimethylsiloxyethanenitrile -Chloro-2,3-dihydrobenzo[b]furan-7-carbaldehyde 5 (900 mg., 4.9 mmoles) was dissolved in 25 ml. of ether. Zinc iodide (20 mg.) and then trimethylsilylcarbonitrile (970 mg., 9.8 mmoles) were added and the mixture stirred 16 hours at room temperature, then diluted with 50 ml. ether, washed with three portions of saturated sodium bicarbonate and one of brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield title product as an oil [1.4 g.; m/e 283/281; ir(CHCl2> 1479, 1457, 1435, 1180, 866, 848 cm-1].

By the same method 5-fluoro-2,3-dihydrobenzo[b]furan-7-carbaldehyde is converted to 2-(5-fluoro-2,3dihydro-7-benzo[b]furanyl,-2-trimethylsiloxyethanenitrile.

EXAMPLE 4 2-(3-Methyl-5-isoxazolyl,-2-trimethylsiloxyethanenitrile_ By the procedure of Example 1 , 3-methylisoxazole5-carbaldehyde (3.4 g., 0.032 mole) was converted to title product, isolated as an oil (6.5 g., no aldehyde proton by nmr,.

By the same method, isothiazole-5-carbaldehyde is converted to 2-(5-isothiazolyl)-2-trimethylsilylethanenitrile and 5-methylisoxazole-3-carbaldehvde (Kane et al., Japan 62/17,572) is converted to 2-(5-methyl-330 isoxazolyl)-2-trimethylsilylethanenitrile. - 8 EXAMPLE 5 2- ( 3-Furyl) -2-Tr imethylsi-loxyethanenitrile To a mixture of 3-furaldehyde (1.92 g., 20 mmoles) and about 100 mg. of zinc iodide in 25 ml. of ether, trimethylsilylcarbonitrile (4.74 g., 48 mmoles) was added dropwise. The mixture was stirred about 16 hours at room temperature. The reaction mixture was washed sequentially with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to yield 2-(3-furyl)2-trimethylsiloxyethanenitrile [2.2 g.; pnmr/CDCl^/delta 0.2 (s, 9H); 5.4 (s, IH); 6.4 (m, IH); 7.3 (m, IH) ; 7.5 (m, IH)].

EXAMPLE 6 2-(5-Chloro-2-furyl)-2trimethylsiloxyethanenitrile -Chloro-2-furaldehyde (2.7 g., 21 mmoles) was dissolved in 30 ml. of ether. Trimethylsilylcarbonitrile (6.3 ml., 50 mmoles) and zinc iodide (about 50 mg.) were added and the mixture stirred for 1.5 hours at room temperature, at which time tic (hexanezethyl acetate 8:1) indicated complete reaction. Concentration to dryness afforded 2-(5-chloro-2-furvl,-2trimethylsiloxyethanenitrile as an oil (5.5 g.; pnmr/CDC1^/delta: 0.3 (s, 9H); 5.4 (s, IH); 6.1 (d, IH): 6.5 (d, IH)]. - 9 EXAMPLE 7 2-(5-Bromo-2-furyl)-2-trimethylsiloxyethanenitrile -Bromo-2-furaldehyde (1.1 g., 6 mmoles) was dissolved in 50 ml. of ether. A catalytic quantity (about 50 mg.) of zinc iodide was added and then trimethylsilylcarbonitrile (746 mg., 1.2 equiv.) was added dropwise. The reaction was monitored by ir (disappearance of typical carbonyl absorption, and pnmr (disappearance of typical aldehyde proton peak).

After 60 minutes at room temperature, the reaction mixture was washed with saturated sodium bicarbonate, twice with water, and finally with brine, dried over anhydrous sodium sulfate and evaporated to yield 2-(5bromo-2-furyl)-2-trimethylsiloxyethanenitrile as an oil [1.2 g.; pnmr/CDCl-j/delta: 0.3 (s, 9H); 5.6 (s, IH); S.4 (d, IH); 6.6 (d, 1H)J.

EXAMPLE 8 2-(3-Bromo-2-furyl)-2-trimethylsiloxyethanenitrile By the procedure of Example 5 , 3-bromo-2-furaldehyde 2:1 (1.75 g., 10 mmoles) in 50 ml. of ether was reacted with trimethylsilylcarbonitrile (8.8 ml., 70 mmoles, in the presence of about 100 mg. of zinc iodide. At the end of the 16 hour reaction period, the ether supernatant was decanted from solids and evaporated to dryness to yield 2-(3-broreo-2-furyl)-2-trimethylsiloxyethanenitrile [3 g., Rf 0.7 (3:1 hexane:ethyl acetate)]. - 10 EXAMPLE 9 2-(5-Phenyl-2-thienyl)-2trimethylsiloxyethanenitrile S-Phenyl-2-thenaldehyde (0.9 g.) in 35 ml. of 20 ether was reacted with 1 ml. of trimethylsilylcarbonitrile in the presence of about 50 mg. of zinc iodide After 1 hour of stirring at room temperature, tic indicated reaction was complete. Evaporation to dryness gave 2-(5-phenyl-2-thienyl)-2-trimethylsiloxy25 ethanenitrile [1.65 g., 0.5 (5:1 hexane:ethyl acetate with 5% acetic acid)). - ii EXAMPLE 10 2-(2-Thienvl)-2-trimethvlsiloxyethanenitrile By the procedure of Exanple 67 of Patent Application NcS 1662, 2-thenaldehyde (56.1 g., 46.8 ml., 0.5 mole) was reacted 5 for 16 hours with trimethylsilylcarbonitrile (60 ml.) in the presence of zinc iodide (aoproximately 0.5 g.), yielding 2-(2-thienyl)-2-trimethylsiloxyethanenitrile as an oil [92 g.; m/e 211; pnmr/CDClg/delta: 0.2 (s, 9H); 5.8 (s, 1H); 6.9-7.5 (m, 3H) ] .

EXAMPLE 11 2-(3-Methyl-2-thienyl)-2-trimethylsiloxyethanenitrile Following the procedure of Example 67 of Patent Application No. 51662, 3-methyl-2-thenaldehyde (31.6 g., 0.25 mole) was reacted with trimethylsilylcarbonitrile (30 ml.) for 16 hours in the presence of 500 mg. of zinc iodide.

The reaction mixture was diluted with 200 ml. of methylene chloride and further isolated also according to Example 13 of Patent Application Νο.®1β®2, affording 2-(3-methyl-2-thienyl)-2-trimethylsiloxy-ethanitrile [52 g., 93%; pnmr/CDC13/delta: 0.2 (s, 9H); 2.3 (s, 3H); 5.7 (s, 1H); 6.8 (d, 1H); 7.25 (d, 1H)]. 5166S - 12 EXAMPLE 12 2-(5-Methyl-2-thienyl) 2-trimethylsiloxyethanenitrile -Methyl-2-thenaldehyde (25 g., 0.2 mole), zinc 5 iodide (266 mg.) and 100 ml. of ether were combined and stirred at room temperature. Trimethylsilylcarbonitrile (23.5 g., 0.24 mole) was added dropwise and the reaction mixture stirred for an additional 2 hours. The reaction mixture was diluted with 100 ml. of ether, washed wtih two 50 ml. portions of 5% sodium bicarbonate, washed with two 25 ml. portions of brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to produce 2-(5-methyl-2-thienyl)2-trimethylsiloxyethanenitrile [42 g.; pnmr/CDCl^/delta: 0.2 (s, 9H); 2.2 (s, 3H) ; 5.6 (s, IH) ,· 6.6-7.4 (m, 2H) ] . - 13 EXAMPLE 13 2-(5-Chloro-2-thienyl)-2-trimethylsiloxyethanenitrile -Chlorothenaldehyde (5 g., 34 mmoles) was combined with zinc iodide (50 mg.) and 30 ml. of diethyl ether and cooled to 0’C. Trimethylsilylcarbonitrile (4.04 g., 40 mmoles) was added dropwise and the reaction mixture warmed to room temperature and stirred for 4 hours. Additional equal portions of trimethylsilylcarbonitrile and zinc iodide were added and the reaction stirred an additional 16 hours. The reaction mixture was diluted with ether, washed with two 30 ml. portions of 5% sodium bicarbonate, washed once with 30 ml. of brine, dried over anhydrous magnesium sulfate and evaporated to yield 2-(5-chloro-2-thienyl)-2-trimethylsiloxyethane15 nitrile as an oil [4.0 g., pnmr/CDClj/delta: 0.3 (s, 9H); 5.7 (s, IH); 7.0 (q, 2H)].

By the same method, 3-fluoro-2-thenaldehyde, 4fluoro-2-thenaldehyde, 5-fluoro-2-thenaldehyde, 5fluoro-3-thenaldehye [Gronowitz and Rosen, Chem. Ser. 1, pp. 33-43 (1971); Chem. Abstracts 75, 20080c], 4fluoro-3-thenaldehyde, 4-methoxy-3-thenal3ehyde, and 4-methylthio-3-thenaldehyde are converted, respectively, to 2-(3-fluoro-2-thienyl)-2-triraethylsiloxyethanenitrile, 2-(4-fluoro-2-thienyl)-2-trimethylsiloxyethanenitrile, 2-(5-fluoro-2-thienyl)-2-trimethylsiloxyethanenitrile, 2-(5-fluoro-3-thienyl)-2-trimethylsiloxyethanenitrile, 2-(4-fluoro-3-thienyl)-2-trimethylsiloxyethanenitrile, 2-(4-methoxy-3-thienyl)-2-trimethylsiloxyethanenitrile, 2-(4-methylthio-3-thienyl)-2-trimethylsiloxyethanenitrile. - 14 EXAMPLE 14 2-(4-Bromo-3-thienyl)-2-trimethylsiloxyethanenitrile 4-Bromo-3-thenaldehyde (5.5 g., 29 mmoles) in 75 ml. of methylene chloride was cooled to 0-5aC.

Zinc iodide (50 mg.) was added, followed by the dropwise addition of trimethylsilylcarbonitrile (3.47 g., 35 mmoles) over a 3 minute period. The mixture was warmed to room temperature, stirred for 16 hours, washed twice with saturated sodium bicarbonate, washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield 2-(4-bromo?-thienyl)-2-trimethylsiloxyethanenitrile as an oil (7.6 g, , 90%, m/e 291/289) .

EXAMPLE 15 2-(3-Thienyl)-2-trimethylsiloxyethanenitrile 3-Thenaldehyde (10 g., 0.089 moles), zinc iodide (120 mg.) and ether (60 ml.) were combined and stirred. Trimethylsilylcarbonitrile (10.6 g., 0.107 mole) was added dropwise over 10 minutes and the reaction mixture stirred for 16 hours, diluted with 60 ml. of ether, washed with two 30 ml. portions of 5% sodium bicarbonate, washed with 30 ml. of brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield 2(3-thienyl)-2-trimethylsiloxyethanenitrile as an oil [14.3 g., pnmr/CDClg/delta: 0.2 (9H); 5.6 (IH); 7.0-7.5 (3H)]. - 15 EXAMPLE 16 2-(3-Eromo-2-thienyl)-2-trimethylsiloxyethanenitrile 3-Bromo-2-thenaldehyde (6 g., 31 mmoles, and zinc iodide (50 mg.) were combined with 180 ml. of methylene chloride. Trimethylsilylcarbonitrile (4.0 g., 5.2 ml., 41 mmoles) were added dropwise. The reaction mixture was stirred for 24 hours at room temperature, diluted with 50 ml. of methylene chloride, washed with 60 ml. of 5% sodium bicarbonate and then with 50 ml. of brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield 2-(3-bromo-2-thienyl)-2trimethylsiloxyethanenitrile (7.2 g., oil, m/e 291/289).

EXAMPLE 17 2-(3-BenzoIb]thienyl)-215 trimethylsiloxyethanenitrile Benzo[b]thiophene-3-carbaldehyde [1.8 g., 11 mmoles, J. Chem. Soc. C., pp. 339-340 (1969)] and about 100 mg. of zinc iodide ware combined in 35 ml. of ether. Trimethylsilylcarbonitrile (1.98 g., 20 mmoles) was added dropwise. After approximately 1 hour, the reaction mixture was washed in sequence with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate, filtered and evaporated to yield 2-(3-benzo[b]thienyl)-2-trimethylsiloxyethane25 nitrile [2.5 g., oil, Rf 0.7 (1:2 ethyl acetate:hexane)] . - 16 25 EXAMPLE 18 2-(7-Benzo[b]thienyl)-2trimethylsiloxyethanenitrile Benzo[b]thiophene-7-carbaldehyde [1.3 g., 8 mmoles, J. Org. Chem. 39, 2829 (1974)] was dissolved in 35 ml. of ether. Trimethylsilylcarbonitrile (1.5 ml., mmoles) and zinc iodide (about 50 mg.) were added and the mixture stirred for 1 hour at room temperature, at which time tic indicated conversion was complete.

The reaction mixture was evaporated to dryness, yielding 2-(7-benzo[b]thienyl)-2-trimethylsiloxyethanenitrile [2.2 g., oil; Rj 0.6 (1:5 ethyl acetate:hexane/5% acetic acid)].

EXAMPLE 19 15 3-(4-Methoxy-3-thienyl)-2-trimethylsiloxyethanenitril By the procedure of Example 5 , 4-methoxy-3thenaldehyde (2.6 g., 18.3 mmole) and trimethylsilylcarbonitrile (2.15 g., 21.7 mmole) in 250 ml. of ether in the presence of 50 mg. of zinc iodide was converted to title product as an oil (3.9 g., m/e 241).

EXAMPLE 20 3-(4-Ethoxy-3-thienyl)-2-trimethylsiloxyethanenitrile By the procedure of Example 5 , 4-ethoxy-3-thenaldehyde (8.1 g., 0.052 mole) and trimethysilylcarbonitrile (6.13 g., 0.062 mole) in 300 ml. of ether, in the presence of 50 mg. of zinc iodide, were converted to title product (13 g.) as a viscous oil? pnmr indicated absence of the aldehyde proton. - 17 EXAMPLE 21 2-(4-(n-Propoxy)-3-thienyl]-2trimethylsiloxyethanenitrile By the procedure of Example 5 , 4-(n-propoxy)-35 thenaldehyde (3.1 g., 18 mmoles) and trimethylsilylcarbonitrile (2.28 g., 2.9 ml., 23 mmoles) in 250 ml. of ether, in the presence of 50 mg. of zinc iodide, were converted to title product as an oil (4.6 g.; m/e 269? ir (CH2C12) 2936, 1558 cm-1].

EXAMPLE 22 2-(4-Methoxy-2-methyl-3-thienyl) 2-trimethyIsiloxyethanenitrile By the procedure of Example 5 , 4-methoxy-2methyl-3-thenaldehyde (5.2 g., 33.3 mmoles) and trimethylsilylcarbonitrile (3.96 g., 40 mmoles) in 350 ml. of ether, in the presence of 50 mg. of zinc iodide, were converted to title product, isolated as a viscous oil [7.3 g.; m/e 255; ir (CH2C12) 1575, 1204, 1075 cm-1].

The following Preparations illustrate the preparation of certain starting materials:20 - 18 PREPARATION 1 6-Chlorochroman Mossy zinc (75 g.), 7.5 g. of mercuric chloride, 125 ml. of water and 4 ml. of cone, hydrochloric acid were combined, shaken for 5 minutes, allowed to settle, and liquids decanted from the resulting amalgamated zinc. A mixture of 100 ml. of water and 126 ml. of cone, hydrochloric acid and then 6-chloro-4-chomanone (15 g.) were added to the metal, and the mixture re10 fluxed for 1.5 hours, cooled to room temperature, decanted from the zinc and the decant extracted with three portions of ether. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil (14 g.). The oil was chroma15 tographed on 400 g. of silica gel using 9:1 hexane: ether as eluant tic monitoring and 15 ml. fractions. Clean product fractions were combined and evaporated to yield title product as an oil [8.72 g.; pnmr/CDCl^/ delta (ppm) 2.0 (m, 2H), 3.7 (t, 2H), 4.1 (t, 2H), 6.9 (ra, 3H); m/e 170/168; Rf 0.88 (2:1 hexane: ether,]. - 19 PREPARATION 2 6-Chlorochroman-8-carbaldehyde Product of the preceding Preparation (8.6 g., 0.051 mole) in 75 ral. of methylene chloride was cooled 5 in an ice-water bath. Titanium tetrachloride (19.34 g., 11.2 ml., 0.102 mole) was added, followed by the dropwise addition of 1,1-dichloromethyl methyl ether (6.2 g., 0.054 mole). The reaction mixture was stirred at 0* for 30 minutes, then slowly poured into 400 ml. of saturated sodium bicarbonate. The aqueous phase was extracted with three fresh portions of methylene chloride. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield title product [7.9 g.; m.p. 8315 86°C.; pnmr/CDCl3/delta (ppm) 2.0 (m, 2H), 2.8 (t, 23), 4.2 (t, 23), 7.1-7.5 (m, 2H), 10.2 (s, IH), m/e 198/ 196] . - 20 PREPARATION 3 6-Fluorochroman By the procedures of Preparation 1 , 6-fluoro-4chroraanone (15 g.) was converted to chromatographed 65 fluorochroman [5.7 g.; oil; pnmr/CDCl^/delta (ppm) 2.0 (m, 2H,, 3.8 (t, 2H), 4.1 (t, 2H,, 6.8 (m, 35); Rf 0.68 (2:1 hexane:ether); m/e 152).

PREPARATION 4 6-Fluorochroman-8-carbaldehyde 10 By the procedures of Preparation 2, the product of the preceding Preparation (5.5 g., 0.036 mole) was converted to title product initially isolated as a viscous oil which was crystallized from hexane (3.4 g.; m.p. 54-57°C.; m/e 180). - 21 PREPARATION 5 3-Hethyl-5-isoxazolecarboxamide 3-Methyl-5-isoxazolecarboxylic acid (20 g.) was refluxed for 10 hours in 350 ml. of thionyl chloride, then stirred at room temperature for 16 hours, clarified by filtration and evaporated to an oil. The oil was multiply triturated with hot hexane, and the combined hexane triturates evaporated to yield acid chloride (16.2 to 21 g.) as a solid.

With stirring, acid chloride prepared in the manner (35 g.) was added portionwise to 300 ml. of cone, ammonium hydroxide at room temperature. After granulating for 1 hour, title product was recovered by filtration (24.2 g., m.p. 180-182°C.).

PREPARATION 6 3-Methyl-5-isoxazolecarbonitrile Product of the preceding Preparation (5 g.) was mixed thoroughly with phosphorous pentoxide (10 g.) and placed in an oil bath preheated to 140®. The bath temperature was increased to 200°C. and title product recovered by distillation in vacuo [2.9 g., ir(film) nitrile band at 2220 cm1, no amide peak in the 1700 cm-1 region]. - 22 PREPARATION 7 3-Methyl-5-isoxazolecarbaldehyde Product of the preceding Preparation (1.08 g., 0.01 mole) was dissolved in 25 ml. of ether and cooled 5 to -40°C. Diisobutylaluminum hydride (12 ml. of IM in hexane, 0.012 mole) was added at -40°C. over a 15 minute period. The mixture was stirred at -30° to -35°C. for 10 minutes. Keeping the temperature at -20°C., 60 ml. of ethyl acetate was added. Keeping the temperature at -25°C., methanol (15 ml.) was added dropwise, and keeping the temperature below -20°C., ml. of 6N hydrochloric acid was added. The reaction mixture was warmed to 5°C. and the organic phase washed with 25 ml. of water and evaporated to an oil. The oil was chromatographed on 50 ml. of silica gel using 1:1 ether:hexane as eluant. Product fractions were combined and evaporated to yield title product (0.42 g.; m.p. 39-41°C.). A small sample further purified by sublimation had m.p. 43-45°C. - 23 PREPARATION 8 -Chlorobenzofb]furan-2-carboxylic Acid 5-Chlorosalicylaldehyde (31.3 g., 0.2 mole) was dissolved in 200 ml. of 2-butanone. Potassium carbo5 nate (82.9 g., 0.6 mole) and then diethyl 2-bromoraalonate (95.6 g., 0.4 mole) were added and the mixture heated to reflux for five hours, then cooled, filtered from salts, and concentrated to an oil. The oil was partitioned between 500 ml. of 10% sulfuric acid and 500 ml. of ether. The aqueous layer was extracted with two 250 ml. portions of fresh ether. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to a second oil. The second oil was dissolved in 400 ml. of 10% ethanolic potassium hydroxide, heated at reflux for 1 hour and concentrated to solids. The solids were dissolved in 1500 ml. of water, filtered from trace insoluble matter, acidified with 6N hydrochloric acid and precipitated solids recovered by filtration. Purified title product was obtained by repulping the solids in 1 liter of water (19 g., m.p. 259-262’C., m/e 198/196).

By the same procedure, 5-fluorosalicyaldehyde and 6-chlorosalicylaldehyde are converted, respectively, to -fluorobenzo[b]furan-2-carboxylie acid and 6-chlorobenzofb]furan-2-carboxylic acid. - 24 PREPARATION 9 5-Chlorobenzo[b]furan Title compound of the preceding Preparation (7.8 g.) was combined with copper powder (700 mg.) and quinoline (50 ml.) and the mixture heated to reflux for 50 minutes, then cooled to room temperature and diluted with 500 ml. of ether. Insolubles were removed by filtration and the filtrate washed in sequence with five 200 ml. portions of 2N hydrochloric acid and one of brine, dried over anhydrous magnesium sulfate and concentrated to an oil (6.2 g.). The oil was chromatographed through 200 g. of silica gel using ether as eluant and 300 ml. fractions. Fractions 1 and 2 were combined and evaporated to yield title product as an oil (6.1 g.).

By the same procedure the other benzofurancarboxylic acids of the preceding Preparation are converted to 5fluorobenzo[b]furan and 6-chlorobenzo[b]furan. 81665 - 25 PREPARATION 10 -Chloro-2,3-dihydrobenzo[b] furan Vd/C (5%, 12.2 g.) in 400 ml. of acetic acid was prehydrogenated at atmospheric pressure and 25 °C.

Title compound of the preceding Preparation (6,1 g.) in 100 ml. of acetic acid was added and hydrogenation continued until slightly more than 1 equivalent of hydrogen had been consumed. Catalyst was recovered by filtration over diatomaceous earth. The filtrate was neutralized with saturated potassium carbonate and extracted with four 200 ml. portions of ether. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to an oil. The oil was chromatographed on 400 g. silica gel using hexane-3% ether as eluant, 15 ml. fractions and tic monitoring. Pure product fractions 70-90 were combined and evaporated to yield title product [2.15 g.; oil; Rf 0.32 (hexane); m/e 156/154].

By the same procedure, the other benzofurans of the preceding Preparation are converted to 5-fluoro2,3-dihydrobenzo[b]furan and 6-chloro-2,3-dihydrobenzofb]furan. - 26 10 PREPARATION 11 -Chloro-2, 3-dihydrobenzo(b]furan-7-carbaldehyde By the procedure of Preparation 1 , title compound of the preceding Preparation (2.1 g.) was converted to crude product contaminated with an isomeric aldehyde. Purified title product was obtained by digesting the crude product in 50 ml. of boiling hexane, filtering and cooling the filtrate [0.93 g.; m.p. 79-81’C.; Rf 0.55 (chloroform); m/e 184/182].

By the same method the 5-fluoro compound of the preceding Preparation is converted to 5-fluoro-2,3dihydrobenzo(b]furan-7-carbaldehyde. - 27 PREPARATION 12 3-Furaldehyde 3-Furylmethanol (19.6 g., 0.2 mole) in 50 ml. of methylene chloride was added dropwise to a slurry of pyridinium chlorochromate (64.5 g., 0.3 mole) in 450 ml. of methylene chloride. The exothermic reaction, which led to vigorous reflux, was controlled by occasional cooling with an ice-bath. By the end of 60 minutes, gummy solids had precipitated. The reaction mixture was diluted with 600 ml. of ether and the supernatant separated by a combination of decantation and filtration. The filtrate was passed through Florisil(Registered Trade Mark - synthetic magnesium silicate) contained in a short column, with ether as eluant. Collected fractions were combined and evaporated to an oil. Distillation of the oil provided 3-furaldehyde (7.6 g.j b.p. 68-72°C./40-45 mm.).

Alternatively, this aldehyde is prepared by Rosenmund reduction of 3-furoic acid chloride [Hayes, J. Am. Chem. Soc. 71, 2581 (1949)].

PREPARATION 13 2-(2-Furyl)-1,3-dioxolane 2-Furaldehyde (42 ml., 0.5 mole), ethyleneglycol (50 ml., 0.9 moles) and p-toluenesulfonic acid (about 200 mg.) were combined in 150 ml. of toluene and the mixture refluxed for 6 hours while collecting byproduct water in a Dean-Stark trap. The mixture was cooled, diluted with 500 ml. of ether, and clarified by filtration. The filtrate was washed with 200 ml. of saturated sodium bicarbonate and the organic phase again clarified by filtration. This second filtrate was washed with 200 ml. of water, and the organic layer concentrated to dryness, affording 2-(2-furyl)1,3-dioxolane as an oil (45 g.). - 28 PREPARATION 14 2-(5-Chloro-2-furyl)-1,3-dioxolane 2-(2-Furyl)-1,3-dioxolane (14 g., 0.1 mole) was dissolved in 100 ml. of tetrahydrofuran and the 5 solution cooled to -25° to -20°C. Maintaining this temperature range, butyl lithium in hexane (45 ml. of 2.2M, 0.1 mole) was added over a period of 10 minutes. The mixture was allowed to warm to 0°C. over 25 minutes and rechilled to -30°C. While maintaining a temperature range of -30° to -25°C., hexachloroethane (23.7 g., 0.1 mole) in 50 ml. of tetrahydrofuran was added over 5 minutes. The reaction mixture was warmed to room temperature, stirred for 1.5 hours, recooled to 5°C., and diluted slowly with 500 ml. of water.

Product was extracted into ether (2 x 500 ml.) and recovered as an oil (15.8 g.) by evaporation to dryness. The oil was chromatographed on a 200 ml. volume of silica gel, using 8:1 hexane:ethyl acetate as eluant and monitoring by silica gel tic with the same eluant. The early, product containing fractions were combined and evaporated to yield purified 2-(5chloro-2-furyl)-1,3-dioxolane as an oil [5 g.; 0.6 (8:1 hexane:ethyl acetate)].

PREPARATION 15 -Chloro-2-furaldehyde 2-(5-Chloro-2-furyl)-1,3-dioxolane (4.8 g.) was dissolved in 20 ml. of ether. 6N Hydrochloric acid (10 ml.) was added and the two-phase mixture stirred for 1 hour at room temperature. The ether phase was separated, washed with water and evaporated to yield 5-chloro-2-furaldehyde as an oil (2.8 g.).

S1665 - 29 PREPARATION 16 5-Bromo-2-furylcarboxamide -Bromo-2-furoic acid (20 g.) was refluxed for 3 hours with 60 ml. of thionyl chloride, and the corresponding acid chloride isolated as an oil by concentration. The acid chloride was added dropwise to 150 ml. of stirring, concentrated ammonium hydroxide. Filtration afforded 5-bromo-2-furylcarboxamide (17.0 g., m.p, 140-143'C.).

PREPARATION 17 -Bromo-2-fury1carbonitrile -Bromo-2-furylcarboxamide (10 g.) was combined with 50 ml. of phosphorus oxychloride and refluxed for 24 hours. The mixture was poured onto ice, the product extracted into ether, which on evaporation gave 5-bromo-2-furylcarbonitrile as an oil (6.4 g.).

PREPARATION 18 5-Bromo-2-furaldehyde -Bromo-2-furylcarbonitrile (2.3 g., 13 mmoles) was dissolved in 50 ml. of ether and cooled, under nitrogen, to -10'C. Diisobutylaluminum hydride (1.9 g., 13 mmoles) as a 25% solution in toluene was added dropwise, maintaining the temperature near -10“C. The reaction was allowed to warm to room temperature and allowed to stir about 6 hours. The reaction mixture was cooled to 0° to 5’C., diluted with 1 ml. of methanol, acidified with 3N hydrochloric acid, washed with water, and evaporated to yield 5bromo-2-furaldehyde (1.2 g., m.p. 74-76'C.). - 30 PREPARATION!9 3-Bromo-2-furaldehyde Phosphorus oxychloride (6.5 g., 70 mmoles) was added to dimethylformamide (5.4 g., 70 mmoles) at 0° to 10°C. The resulting slurry was diluted with 10 ml. of ethylene dichloride. Maintaining the mixture near 10°C., 3-bromofuran (9.2 g., 63 mmoles) was added.

The reaction mixture was then heated to 58-60’C. for 1 hour and then recooled to 10°C. Sodium acetate -10 trihydrate (15 g.) dissolved in 25 ml. of water was added slowly, with good stirring, keeping the temperature 10° to 30°C. The mixture was reheated to 68-72°C for 20 minutes, cooled to room temperature, and diluted with 20 ml. of water. Product was extracted 15 into 75 ml. of ether, and the ether back-washed with water and concentrated to yield 3-bromo-2-furaldehyde as an oil [0.9 g., R^ 0.65 (3:1 hexane:ethyl acetate)] PREPARATION20 5-Phenyl-2-thenaldehyde 1-Phenylthiophene [1.6 g., 0.01 mole, prepared according to J. Am. Chem. Soc. 46, 2339 (1924)] was dissolved in 20 ml. of tetrahydrofuran and cooled to -40°C. Butyl lithium in hexane (4.5 ml. of 2.2M, was added over 3 minutes, maintaining the temperature -40° to -30°C. The mixture was warmed to 0°C. and then cooled to -40°C. Dimethylformamide (1.2 ml., mmole) was added, maintaining the temperature -40° to -30°C. The mixture was warmed to room temperature and held for 0.5 hour, recooled to 0°C., quenched with 30 6 ml. of 6N hydrochloric acid, diluted with 10 ml. of water, and extracted with 20 ml. of ether. Evaporation of the ether extract to dryness gave crude product (1.9 g.). Reerystallization from about 35 ml. of hexane gave purified 5-phenyl-2-thenaldehyde 35 (7.9 g., m.p. 90-92°C.). - 31 PREPARATION 21 4-Bromo-3-thenaldehyde 3,4-Dibromothiophene (15 g., 0.062 mole, J. Org. Chem. 36, 2690 (1971)] in 20 ml. of ether was cooled to -70’C. and butyl lithium in hexane (34.8 ml. of 2.1M, 0.073 mole) added dropwise over 5 minutes.

After stirring for 5 minutes at -70’C., the solution was transferred, via nylon tubing under nitrogen pressure, to a solution of dimethylformamide (6.8 g., 0.093 mole) in 35 ml. of ether. The resulting mixture was heated to reflux for 2 hours, cooled to room temperature, washed in sequence with two portions of IN hydrochloric acid, one of saturated sodium bicarbonate and one of brine, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The oil was twice distilled to yield 4-bromo-3thenaldehyde (5.7 g., b.p. 81-84’C./0.8 mm., m/e 192/190). - 32 PREPARATION 22 Methyl 4-Methoxy-3-thenoate Methyl 4-acetoxy-3-thenoate (U.S. Patent 3,144,235; g.) was dissolved in 20 ml. of methanol and added 5 to 100 ml. of methanol containing 0.31 ml. of concentrated sulfuric acid. The mixture was refluxed for 4 days, then neutralized with 0.6 g. of sodium acetate and solvent removed by evaporation. The residue was taken up in 200 ml. of ether. The ether solution was washed sequentially with two 50 ml. portions of water, two 50 ml. portions of IN sodium hydroxide and two 50 ml. portions of brine, dried over anhydrous magnesium sulfate, filtered and evaporated to an oil which crystallized on standing (4.35 g.; m.p. 64-66°C).

When this reaction was worked up after only day only a low yield of the desired product (2.2 g) was isolated. The two IN sodium hydroxide extracts were combined and acidified, precipitating methyl 4hydroxy-3-thenoate (5.13 g.). When this alcohol was dissolved in 100 ml. of methanol containing 0.3 ml. of concentrated sulfuric acid and refluxed for 3 days, the above work-up afforded title product (2.10 g., m.p. 64-66°C.). - 33 PREPARATION 23 1-(4-Methoxy-3-thienyl)methanol Methyl 4-methoxy-3-thenoafce (O.S. Patent 4,144,235; 3.9 g., 23 mmoles) was dissolved in 50 ml. of toluene and cooled in an acetone-dry ice bath. Diisobutyl aluminum hydride (46 ml. of IM in hexane, 46 mmoles) was added dropwise over 30 minutes. The mixture was stirred for an additional 2 hours at the bath temperature and then allowed to warm to room temperature. Keeping the temperature below 30°C., methanol (14.7 g., 18,6 ml., 0.46 mole) was slowly added. The mixture was then stirred for 16 hours at room temperature, by which time a granular precipitate had formed. The mixture was filtered over diatomaceous earth with methanol wash. The combined filtrate and washes were concentrated to yield the title product as an oil (2.8 g., m/e 144).

PREPARATION 24 4-Methoxy-3-thenaldehyde Pyridinium chlorochromate (6.4 g., 29.7 mmoles) was dissolved in 100 ml. of methylene chloride and added in one portion to a solution of the product of the preceding Preparation 2.8 g., 19.8 mmoles) also in 100 ml. of methylene chloride. The reaction mixture was stirred at room temperature for three hours, diluted with 200 ml. of ether and decanted from the black precipitate. The precipitate was washed with two 100 ml. portions of ether. The combined decant and washes were filtered, washed in sequence with two portions of IN hydrochloric acid, one portion of water, two portions of IN sodium hydroxide and one portion of brine, dried over anhydrous magnesium sulfate, filtered and concentrated to yield title product as an oil [2.6 g.; m/e 142; ir (CH2C12) 1688, 1544 cm-1]. - 34 PREPARATION 25 Ethyl 4-Ethoxy-3-thenoate Following the approximate procedure of U.S. 4,144,235, methyl 4-acetoxy-3-thenoate (20 g.) was dissolved in 240 ml. of ethanol and 0.62 ml. of concentrated sulfuric acid was added. The reaction mixture was gently refluxed for 79 hours, then neutral ized with sodium acetate (1.2 g.) and evaporated to an oil. The latter was partitioned between 400 ml. of ether and 50 ml. of water. The organic layer was separated and washed in sequence with 75 ml. of water, three 50 ml. portions of IN sodium hydroxide· and two 75 ml. portions of brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield title product as an oil [14.9 g., pnmr indicates entirely ethyl ester, no methyl ester].

PREPARATION 26 1-(4-Ethoxy-3-thienyl) methanol By the procedure of Preparation 23 , the product of the preceding Preparation (14 g. ) was converted to title product as an oil (9.15 g.).

PREPARATION 27 4-Ethoxy-3-thenaldehyde By the procedure of Preparation 24, the product of the preceding Preparation (9.15 g.) was converted to the title product, initially isolated as an oil which quickly crystallized on cooling (8.18 g.; m.p. 42-45’C.; m/e 156; ir (KBr) 3090, 2977, 1688 cnT1] . - 35 10 PREPARATION 28 n-Propyl 4-(n-Prcpoxy)-3-thenoate By the procedure of Preparation 25, using a reaction reflux time of 10 days, methyl 4-acetoxy-3thenoate (6 g.) in 750 ml. of 1-propanol containing 0.19 ml. of concentrated sulfuric acid was converted to title product as an oil (5.4 g.; m/e 228).

PREPARATION 29 1-[4-(n-Propoxy)-3-thienyl)methanol By the procedure of Preparation 23, the product of the preceding Preparation (5.4 g.) was reduced to title compound, isolated as an oil (3.44 g.; m/e 172).

PREPARATION 30 4-(n-Propoxy)-3-thenaldehyde) By the procedure of Preparation 24, the product of the preceding Preparation (3.34 g.) was converted to title compound [3.19 g.; m/e 170; ir (CH2C12) 1689, 1539 cm-1].

PREPARATION 31 Ethyl 4-Methoxy-2-methyl-3-fchenoate Ethyl 4-hydroxy-2-methyl-3-thenoate [Chem. Ber. 48, p. 593 (1915); 7.8 g.) was combined with 600 ml. of methanol and 0.25 ml. concentrated sulfuric acid and refluxed for 21 hours. The reaction mixture was evaporated to an oil, taken up in 500 ml. of ether, washed with two 50 ml. portions of IN sodium hydroxide and then one of brine, dried over anhydrous magnesium sulfate, and evaporated to yield title product as an oil (7.8 g.; m/e 200; pnmr/CDClg includes singlet OCH^ protons at 3.9 ppm). The product is contaminated with a minor portion of the corresponding methyl ester. - 36 PREPARATION 32 (4-Methoxy-2-methyl-3-thienyl)methanoi The product of the preceding Preparation (7.8 g., 0.039 mole) was dissolved in 100 ml. of hexane and 75 ml. of toluene and cooled to -78°C. Diisobutyl aluminum hydride (78 ml. of IM in hexane, 0.078 mole) was added dropwise over 40 minutes. The mixture was stirred for 2 hours at -78°C., warmed to room temperature and stirred for an additional 16 hours. Methanol (25.0 g., 31.6 ml., 0.78 mole) was added dropwise to the reaction mixture, keeping the temperature below 3O’C. After stirring 1.5 hours at room temperature, the reaction mixture was clarified by filtration over diatomaceous earth, with thorough methanol wash and repulp of the cake and finally methylene chloride wash. The combined filtrate and washes were dried over anhydrous magnesium sulfate, filtered and evaporated to yield title product as an oil (5.56 g.; m/e 158; ir (CH Cl ) 3598, 1582, 1708 cm-1).

PREPARATION 33 4-Methoxy-2-methyl-3-thenaldehyde By the procedure of Preparation 24, the product of the preceding Preparation (5.4 g., 0.034 mole) was converted to title compound isolated as an oil (5.23 g.; R 0.36 (chloroform)].

Claims (2)

1. CLAIMS:1. A compound of the formula R' wherein R' is (C^-C^)alkyl or phenyl; (b) wherein W is hydrogen or halo, and n is 1 or 2; wherein Q is sulfur or oxygen; and V is hydrogen or (C^-C^Jalkyl; or wherein Υ is sulfur or oxygen; X is hydrogen, halo, methyl, phenyl, benzoyl or (C^-C^)alkoxy; X 1 is hydrogen or methyl; and X 2 is hydrogen or halo; with 5 the proviso that the group

2. A compound of the formula given and defined in Claim 1, which is any one of those specifically hereinbefore mentioned. Dated this the 19th day of March, 1985 F.R. KELLY & CO. BY:-EXECUTIVE 27 Clyde Road, Ballsbridge, Dublin 4. AGENTS FOR THE APPLICANTS.