IE51666B1

IE51666B1 - Carboximidate intermediates for hypoglycemic 5-substituted oxazolidine-2,4-diones

Info

Publication number: IE51666B1
Application number: IE819/85A
Authority: IE
Original assignee: Pfizer
Priority date: 1980-07-28
Filing date: 1981-07-27
Publication date: 1987-02-04
Also published as: IE51664B1; IE51665B1; IE51663B1; IE842427L; IE850819L; IE850702L

Description

This application is a divisional from Patent Application No. 516 6S.lt relates to certain methanecarboximidate intermediates which are useful in the preparation of the hypoglycemic end products of said application.

Thus according to the invention there are provided compounds of the formula:.%7 R8 {j OR wherein R is (03-03)alkyl; and R6 is either (a) Ν' t R1 R’ R1 wherein R* is (03-04)alkyl or phenyl, (b) wherein W is hydrogen or halo, and n is 1 or 2; (c) wherein Q is sulfur or oxygen; and V is hydrogen or (C3-C3)alkyl; or wherein Y is sulfur or oxygen; X is hydrogen, halo, methyl, phenyl, benzoyl or (C.-C,)alkoxy; X1 is hydrogen 2 x ·» or methyl; and X is hydrogen or halo; 8 and R and R are both H. - 4 The carboximidates(D) of the invention are conveniently prepared from the corresponding aldehydes by the sequence:- (C) The aldehyde (A) is converted to the cyanohydrin 5 ( c ) by standard procedures (e.g. via the bisulfite adduct, which is reacted with cyanide in a two phase, aqueous-organic solvent system). Alternatively, -the aldehyde is converted -to the -trimethylsilyl cyanohydrin ( B) by reaction with -trimethylsilylcarbonitrile in the presence of a catalytic guantity 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. 0-5°C.) and allowed to proceed at room temperature for a matter of hours or days, as necessary to achieve complete reaction.

If desired, the trimethylsilyl ether can be hydrolyzed to cyanohydrin, conveniently at reduced temperature (e.g. -10°C.) in a two phase strong aqueous acid/organic s olvent system. - 5 Either the cyanohydrin (C) or the trimethylsllyl ether (B) is converted to the carboximidate (DJ by strong acid catalyzed alcoholysis (using strictly anhydrous conditions). A convenient method is to simply dissolve the nitrile in alcohol which has been saturated with hydrogen chloride) and allow the solution to stand until carboximidate formation is complete. Temperature is not critical, although lower temperatures (e.g. 0-25’C.) generally lead to 10 more optimal yields.

The aldehydes reguired for the above syntheses are broadly available either commercially, or by literature methods. For example, N-alkylpyrrole-2carbaldehydes are obtained by alkylation of pyrrole2-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 •20 axe .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))7 Rosenmund hydrogenation of the corresponding acid chloride [e.g. 3-furaldehyde; Hayes, J. Am. Chem. Soc. 71, 2581 (1949)], ficom'halonethyl compounds hy the Scmnelet reaction [e.g. 3-thenaldehyde; Campaigne and LaSuer, J. Am. Cnem. 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 ehloromethyl substituted aldehydes [e.g.' 5-methyl-2-furaldehyde, Spence and Wild, J. Chem. Soc., 338 (1935)], oxidation of the corresponding alcohol [e.g. 2-thenaldehyde; Emerson - 6 and Patrick, J. Org. Chem., 14, 790 (1949)] , interaction of Grignard reagents with orthoformic esters (e.g. 2thenaldehyde; Cagniant, Bull. soc. chim. Prance 16, 849 (1949)], decarboxylation of alpha-keto acids [e.g. 25 thenaldehyde; Barger and Easson, Ji Chem. Soc., 2100 (1938)], and halogenation [e.g. 2-bromo-3-thenaldehyde; Elliot et al., loc. cit.]; a variety of the presently required aldehydes are further available by the hydrolysis of gem-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 intermediates can be converted to oxazolidine-2,4dione hypoglycemic agents as described in the said Application 15 No. 516 6 2.

The following Examples illustrate the invention:51666 EXAMPLE 1 2-(6-Chloro-8-chromanyl,-2-trimethylsiloxy--— 6~Chlorochroman-8-carbaldehyde (7 g., 0.036 mole) 5 in 70 ml. of methylene chloride was cooled to 0-5’C.

Zine 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 seguence with 1° 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.f ir(CE,Cl,) 2857, 147S, 1215, 1190, 1060 -1 22 cm x).

EXAMPLE 2 Ethyl 1-(6-Chloro-S-chromanyl)-1-hydroxymethanecarboximidate Hydrochloride To cold (0-5’C.), saturated ethanolic hydrogen chloride (250 ml.) there was added, in a dropwise •20 manner, product of the preceding Example (9.29 g·.) in 15 ml. of ethanol, keeping the temperature below 10’C. The -mixture was stirred at 0-5’C. for 35 minutes and then evaporated to an oil.. Crystallization from ethanol—ether gave title product [5.7 g.; m.p. 12525 -127’ (dec); m/e 271/269].

EXAMPLE 3 2_ (-5-Fluoro-8-chromanyl) -.2-trimethyj.siloxy__ethanenitrile___ By the procedure of Example 1, 6-fluorochroraan5 6-carbaldehyde (3-.2 g., 0.0178 mole) was converted to -title mroduct as an oil [*4.31 g., m/e .279; ir (CHClg) 1498, 1205, 1066 cm*1].

EXAMPLE 4 Ethyl 1-(6-Fluoro-8-chromanyl)-1-hydroxyyo methanecarboximidate Hydrochloride Using a reaction time, of 1 hour at 0-5’C., the procedure of Example 2 was employed to convert product of the preceding Example (4.4 g.) to title product [4.1 g.; m.p. 124-126’C. (dec); m/e 253], EXAMPLE 5 2-(5-Chloro-2,3-dihydro-7-benzo[b]furanyl)-2trimethylsiloxyethanenitrile_ -Chloro-2,3-dihydrobenzo[b]furan-7-carbaldehyde (900 mg., 4.9 mmoles) was dissolved in 25 ml. of 2o ether. Sine 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 cm1].

By the same method 5-fluoro-2,3-dihydrobenzo[b]30 furan-7-carbaldehyde is converted to 2-(5-fluoro-2,3dihydro-7-benzo[b]furanyl)-2-trimethylsiloxyethanenitrile.

EXAMPLE 6 Ethyl 1-(5-Chloro-2,3-dihydro-7-benzo[b]furanyl)-1-hydroxymethanecarboximidate Hydrochloride By the procedure of Example 2 , title compound of the preceding Example (1.37 a.) was converted to title product. The initially isolated solids were repulped twice in ether to obtain purified product [1.28 g.f m.p. 149-152’C. (dec); m/e 257/255; ir(KBr) 3162, 2875, 1650, 1524, 1458 cm1).

By the same method the fluoro compound of the preceding Example is converted to ethyl l-(5-fluoro2,3-dihydro-7-benzo[b]furanyl)-1-hydroxymethanecarboximidate hydrochloride.

EXAMPLE 7 2-(3-Methyl-5-isoxazolyl)-2-trimethylsilylethanenitrile _______ By the procedure of Example 1 , 3-methylisoxazole5-carbaldehyde (3.4 g., 0.032 mole) was converted to 20 title product, isolated as an oil (6.5 g., no aldehyde proton by nmr).

By the same method, j.sothiazole-5-carbaldehyde is converted to 2-(5-thiazolyl)-2-trimethylsilylethanenitrile and 5-roethylisoxazole-3-carbaldehyde (Kane et al., Japan 62/17,572) is converted to 2-(5-methyl-3isoxazolyl)-2-trimethylsilylethanenitrile. - 10 EXAMPLE 8 Ethyl 1-Hydroxy-1-(3-methyl-5-isoxazolyl)methanecarboximidate Hydrochloride Title product of the preceding Example (6.5 g.) was dissolved in cold, saturated ethanolic hydrogen chloride (50 ml.) and held at 5°C. for 16 hours.

Title product was recovered by filtration (3.3 g., m.p. 119-121°C.). 3y thA same method, the other -products of the preceding Example nre converted to ethyl 1-hydroxy-l(5-isothiazolyl)methanecarhoximidate hydrochloride and euhyl 1-hydroxy-l-(5-methyl-3-isoxazolyl Jmethanecarboximidate hydrochloride.

EXAMPLE 9 15 2-(3-Puryl)-2-Trimethvlsiloxyethanenitrile 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/CDCl3/delta 0.2 (s, 9H); 5.4 (s, IB); 6.4 (ro, IH); 7.3 (m, IB); 7.5 (m, IB)]. - 11 EXAMPLE 10 Ethyl l-Bydroxy-l-(3-furyl)methanecarhoximidate Hydrochloride 2-(3-Furyl)-2-trimethylsiloxyethanenitrile (l.D g.) was dissolved in 10 ml. of saturated ethanolic hydrogen chloride at 0-5’C. The resulting solution •was held at about 5’C. for 16 hours. The reaction •mixture was concentrated to about half volume and diluted with ether. Filtration, with ether wash, gave 10 ethyl 1-hydroxy-l-(3-furyl)methanecarboximidate hydrochloride (746 mg.? m.p. 113-115’C.; m/e 169).

EXAMPLE 11 2- (5-Chlcro-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 xine iodide (about 30 mg.) were added and the mixture stirred for 1.5 hours at room temperature, at which time tic (hexane:ethyl acetate 8si) indicated complete reaction. Concentration to dryness afforded 2-(5-chloro-2-furyl)-2trimethylsiloxyethanenitrile as an oil (5.5 g.? pnmr/CDC13/delta: 0.3 (s, 93)? 5.4 (s, IE); 6.1 (d, 13)? 6.5 (d, IH)]. - 12 EXAMPLE 12 Ethyl l-(5-chloro-2-furyl)-lhydroxymethanecarboximidate Hydrochloride 2-(5-Chloro-2-furyl)-2-trimethylsiloxyethanenitrile 5 (2.3 g.) was dissolved in saturated ethanolic hydrogen chloride (25 ml.) at O’C. The solution was held for 2.5 hours at about 5°C. and then concentrated to oil. Trituration with 20 ml. of ether afforded crystalline ethyl 1-(5-chloro-2-furyl)-l-hydroxymethanecarboximidate hydrochloride (1.2 g.; m.p. 112-114°C.; m/e 203).

EXAMPLE13. 2-(5-Bromo-2-furyI)-2-trimethylsiloxyethanenitrile -3rorao-2-furaldehyde (1.1 g., 6 mmoles) was dissolved in 50 ml. of ether. A catalytic guantity (about 50 mg.) of zinc iodide wasadded and then trimethylsilylcarbonitrile (746 mg., 1.2 eguiv.) 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 25 oil [1.2 g.; pnmr/CDClg/delta: 0.3 (ε, 9B)? 5.6 (s, IE); 6.4 (d, IE); 6.6 (d, IB)]. 51686 - 13 EXAMPLE 14.

Ethyl 1-(5-3romo-2-furyl)-1tiydroxymethanecarboximiaate Hydrochloride Following the procedure of Example 10 , except that the reaction mixture was not concentrated prior to addition of ether, 2-(5-bromo-2-furyl)-2-trimethylsiloxyethanenitrile (1.2 g.) was converted to ethyl 1(5-bromo-2-furyl)-1-hydroxymethanecarboximidate hydrochloride (480 mg., m.p. 120-122’C., m/e 247, 249). A less pure second crop (235 mg., m.p. 104-106*0.) was recovered by evaporation of mother licuor and trituration of the residue with ether.

EXAMPLE 15 2-(3-Bromo-2-furvl)-2-trimethylsiloxyethanenltrile 3y -the procedure of Example 9 , 3—bromo-2— furaldehyde (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-bromo-2-furyl)~2-trimethylsiloxyethanenitrile [3 g., Sf 0.7 (3:1 hexanetethyl acetate)].

EXAMPLE 16 Ethyl l-(3-Bromo-2-furyl)-lhydroxymethanecarboximidate Hydrochloride 2-(3-Bromo-2-furyl)-2-trimethoxysilylethanenitrile (6.8 g.) was dissolved in 70 ml. of saturated ethanolic hydrogen chloride at O’C. and maintained at about 5’C. for 2 hours. Concentration to dryness and trituration with acetone afforded ethyl l-(3-bromo-2-furyl)-1hydroxymethanecarboximidate hydrochloride 14.4 g., m.p. 117-119’ (dec.)]. - 14 EXAMPLE 17 2- (2-Furyl)-2-trimethylsiloxyethanenitrile 2-Furaldehyde (24 g., 0.25 mole) was cooled to 0-5°C., zinc iodide (500 mg.) was added and the mixture stirred. Trimethylsilylcarbonitrile (30 ml.) was added dropwise. The mixture was allowed to warm to rocm temperature and stirred for approximately 64 hours at room temperature. The reaction mixture was diluted with methylene chloride, extracted twice with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, treated with activated carbon, filtered and evaporated to yield 2-(2-furyl)-2-trimethyl siloxyethanenitrile as an oil [36 g., 74%; pnmr/CDCl^/ delta: 0.2 (s, 9E); 5.6 (s, IH); 6.4 (m, IH); 6.6 (m, IH); 7.4 (d,· IH)] .

EXAMPLE 18 Ethyl 1-(2-Furvl)-1-hydroxymethanecarboximidate Following the procedure of Example 10, 2-(2furyl)-2-trimethylsiloxyethanenitrile (15 g.) was reacted with saturated ethanolic hydrogen chloride, except that a reaction time of about two hours -was employed. Crude product was isolated by -evaporating the reaction -mi-xture to an oil. The oil was partitioned in -400 ml. of chloroform and saturated sodium bicarbonate. Tbe chloroform was washed twice with fresh saturated sodium bicarbonate, washed-once with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to yield ethyl 1-(2-furyl)-1hydroxymethanecarboximidate as an oil [10.6 g., 81·%; pnmr/CDCl^/delta: 1.3 (t, 3H); -4.1 (g, 23); 5.1 (s, IH); -4.8-5.2 (m, IH); 6.3 (m, 2Ξ); 7.3 (d, 13)]. - 15 EXAMPLE 19 2-(5-Phenyl-2-thienyl)-2triroethylsiloxyethanenitrile -Phenyl-2-thenaldehyde (0,9 g.) in 35 ml. of ether was reacted with 1 ml. of trimethylsilylcarbonitrile in the presence of about 50 ng. of zinc iodide. After 1 hour of stirring at room 'temperature, tie indicated reaction was complete. Evaporation to dryness gave 2-(5-phenyΣ-2-thieny1)-2—trimethylsiloxyethanenitrile [1.65 g., Rj 0.5 (5:1 hexane: ethyl acetate with 5% acetic acid)].

EXAMPLE 20 Ethyl 1-Hydroxy-1-(5-phenyl-2-thienyl)methanecarboximidate Hydrochloride 2-(5-Phenyl-2-thienyl)-2-trimethylsiloxyethanenitrile (1.6 g.) was dissolved in 30 ml. of cold, saturated ethanolic hydrogen chloride and maintained at 0 to 5*C. for about 17 hours. The reaction mixture was evaporated to dryness and triturated with ethyl acetate to yield ethyl 1-hydroxy-1-(5-phenyl-2-thienyl)methanecarboximidate hydrochloride [0.9 g.i pnmr/DMSO/ delta: includes 1.1 (3H); 4.0 (2H); 5.2 (IH); 6.5 (IE)].

EXAMPLE 21 2-(2-Thienvl)-2-trimethvlsiloxyethanenitrile By the procedure of Example Π, 2-thenaldehyde (56.1 g., 46.8 ml., 0.5 mole) was reacted for 16 hours with trimethylsilylcarbonitrile (60 ml.) in-the presence of zinc iodide (approximately 0.5 g.), yielding 2-(2-thienyl)-2-trimethylsiloxyethanenitrile as an oil [92 g.; m/e 211; pnmr/CDCl3/fielta: 0.2 (s, SB); 5.8 (s, IH); 6.9-7.5 (m, 3H)]. - 16 EXAMPLE 22 Ethyl 1-Hydroxy-I-(2-thienyl)methanecarboximidate 2-(2-Thienyl)-2-trimethylsiloxyethanenitrile (45 5.) was dissolved in 450 ml. of absolute ethanol.

The solution was cooled to 0-5°C. and perfused with hydrogen chloride for 40 minutes. The mixture was kept at about 5°C. for 16 hours and evaporated to dryness. The residue was triturated with four 200 ml. portions of ether, and then partitioned between 400 ml. of methylene chloride and saturated sodium bicarbonate. The organic phase was washed twice with saturated sodium bicarbonate, treated with activated carbon, filtered and concentrated to yield ethyl 1-hydroxy-l(2—thienyl)methanecarboximidate as-an oil which solidified on standing [10 g.; pnmr/CDCl^/delta: 1.2 (t, 3H); 4.1 (q, 2H); 5.2 (s, IH), 5.9 (s, IH)? 6.8-7.3 (ro, 3E); 7.3-8.1 (s, IH)). - 17 EXAMPLE 23 2-(3-Methyl-2-thienyl)-2-trimethylsiloxyethanenitrile Following the procedure of Example 17, 3-methyl2-thenaldebyde (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, affording 2-(3-methy1-2-thienyl)-2-trimethylsiloxy10 ethanenitrile [52 g., 93%; pnmr/CDClg/delta: 0.2 (s, 9E); 2.3 (S, 3S); 5.7 (s, IH); 6.6 (d, IB); 7.25 (d, IE)].

EXAMPLE 24 Ethyl l-3ydroxy-l-T3-methyl-215 thienyl)methanecarboximidate 2-(3-Methyl-2-thienyl)-2-trimethylsiloxyethanenitrile (13 g.) was added dropwise to 100 ml. of cold ethanol, saturated with hydrogen chloride, keeping the temperature at 0-4°C. After 1 hour at 0-4*C., -the reaction mixture was evaporated to dryness. The residue was triturated three times with 100 ml. portions of ether, and then partitioned between 300 ml. of methylene chloride and saturated sodium bicarbonate. The separated methylene chloride layer was washed with two additional portions of saturated sodium bicarbonate, 'dried over anhydrous magnesium sulfate, filtered and evaporated to yield -ethyl 1-hydroxy-l-(3-methyl-2thienyl)methanecarboximidate [8.0 g., 69%; m.p. 73-76°C.; m/e 199). - 18 EXAMPLE 25 2-(5-Methyl-2-thienyl)-2-trimethy1s iloxyeth anenitrile -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-methy1-2-thienyl)2-trimethylsiloxyethanenitrile (42 g.? pnmr/CDCl3/delta: 0.2 (s, 95)? 2.2 (s, 3H); 5.6 (s, 15); 6.6-7.4 (m, 2E)) .

EXAMPLE 26 Ethyl 1-Hydroxy-l-(5-methyl-2-thienyl )methanecarboximidate Hydrochloride With cooling to 0-5’C., -ethanol (550 ml.) was saturated with hydrogen chloride. 2—(5-Methyl—2thienyl)-2-trimethylsiloxyethanenitrile (42 g.) was dissolved in portions and the -solution maintained st O’C. for 2.5 hours. The reaction, mixture was evaporated to dryness and the residue triturated with diethyl .ether to provide ethyl 1-hydroxy-l-(5-methyl-2-thienyl)— methanecarboximidate hydrochloride—[33 g.-; m.-p. 122-123’C., pnmr/DMSO/delta: - 1.1-1.-6 (3H); 2.5 (35)? 4.6 (25)? 5.9 (1H)7 -6.6-72 (2H)J. - 19 EXAMPLE 27 2-(5-Chloro-2-thienyl)-2-trimethvls iloxyethanenitrile -Chlorothenaldehyde (5 g., 34 mmoles) was combined with zinc iodide (50 mg.) and 30 ml. of diethyl ether and cooled to O’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-triwethylsiloxyethane15 nitrile as an oil [4.0 g., pnmr/CDClg/delta: 0.3 (s, 9Ξ),· 5.7 (s, IS); 7.0 (g, 2B}].

By the same method, 3-fluoro-2-thenaldebyde, 4fluoro-2-thenaldehyde, 5-fluoro-2-thenaldehyde, 5fluoro-3-thenaldehye [Gronowitz and Rosen, Chem. Ser. 1, pp. 33-43 (1971)7 Chem. Abstracts 75, 20080c], 4fluoro-3-thenaldehyde, -4-»ethoxy-3-thenaldehyde, and 4-methylthio-3-thenaldebyde are converted, respectively, to 2-(3-fluoro-2-thienyl)-2-triroethylsiloxyethanenitrile,· 2-(4-fluoro-2-thienyl)-2-trimefhylsiloxyethanenitrile, 2-(5-fluoro-2-thienyl)-2-trimethylsiloxyethanenitrile, -2-(5-fluoro-3-thienyl )-2-trimethylsiloxyethanenitrile, 2- (4-fluoro-3-thienyl,-2-trimethyl siloxyethanenitrile, 2-(4-methoxy-3-thienyl)-2-trimethylsiloxyethanenitrile, 2- (4-methyl thio-3-thienyl) -2-trimethylsiloxyethanenitrile. - 20 EXAMPLE 28.

Ethyl 1-(5-Chloro-2-thienyl)-1hydroxymethanecarboximidate Hydrochloride 2-(5-Chloro-2-thienyl)-2-trimethylsiloxyethane5 nitrile (4 g.) was dissolved in absolute ethanol (100 ml.). The solution was cooled to 0-5°C. and saturated with hydrogen chloride. The reaction mixture was held for 16 hours at 0°C., evaporated to dryness and triturated with ether to yield solid ethyl 1-(510 chloro-2-thienyl)-1-hydroxymethanecarboximidate hydrochloride [3 g., pnmr/DMSO/delta: 1.2 (3H); 4.2 (2E); .3 (IH); 6.6 (15); 6.9 (IE); 7.4 (IH); 8.4 (IE)]. 3y the same method, the other nitriles of the preceding Example are converted to ethyl l-(3-fluoro15 2-thienyl)-1-hydroxymethanecarboximidate hydrochloride, ethyl 1-(4-fluoro-2-thienyl)-1-hydroxymethanecarboximidate hydrochloride, ethyl 1-(5-fluoro-2-thienyl)-1hydroxymethanecarboximidate hydrochloride, ethyl 1-(5fluoro-3-thienyl)-l-hydroxymethanecarboxiniidate hydrochloride, ethyl 1-(4-fluoro-3-thienyl)-l-hydroxymethanecarboximidate hydrochloride, ethyl 1-hydroxy-l(4-methoxy-3-thienyl)methanecarboximidate hydrochloride and 1-hydroxy-l—(4-methylthio-3-thienylmethanecarboximidate hydrochloride. - 21 EXAMPLE 29 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 0-5eC.

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-bromo3-thienyl)-2-trimethylsiloxyethanenitrile as an oil (7.6 g., 90%, m/e 291/289).

EXAMPLE 30 Ethyl .1-(4-Bromo-3-thienyl)1-hydroxymethanecarboximidate 2-(4-3romo-3-thienyl)-2-trimethylsiloxyethanenitrile (7.5 g.) in 200 ml. of ethanol, cooled in- an ice bath, was perfused with hydrogen chloride for 45 minutes. •20 After an additional 20 minutes at 0-5’C. the reaction •mixture was evaporated to dryness and triturated -with ether to yield the hydrochloride salt of the product as a hygroscopic solid. The salt was taken up in a mixture of methylene chloride and saturated sodium bicarbonate. The separated methylene chloride layer was washed twice with saturated sodium bicarbonate, washed with 'brine, dried over anhydrous magnesium sulfate, filtered and evaporated to yield ethyl 1-(4bromo-3-thienyl)-1-hydroxymethanecarboximidate as an oil (6.1 g., 89%, m/e 265/263).. - 22 EXAMPLE 31 2- (3-Thienyl) -2-trimethylsilox'yechanenitrile 3-Thenaldehyde (10 □ 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 ΙΟ—thienyl ) -2-trimethylsiloxyethanenitrile as an oil [14.3 g., pnmr/CDCl3/delta: 0.2 (9H); 5.6 (1H); 7.0-7.5 (3H)].

EXAMPLE 32 Ethyl l-Eydroxv-l-(3-thienyl)methanecarboximidate At 0-5°C., 2-(3-thienyl)-2-trimethylsiloxyethanenitrile (14.3 g.) was dissolved portionwise in 500 ml.. of ethanol, previously saturated with hydrogen chloride at 0-5’C. The solution was held at O’C. for 16 hours, and the product isolated as the hydrochloride salt by evaporation of the reaction mixture to dryness ,and trituration of the residue with .ether. The salt was taken up in 400 ml. of chloroform and 100 ml. of saturated sodium bicarbonate. The separated chloroform layer was washed with an additional 100 ml. of saturated sodium bicarbonate, washed with brine, dried over magnesium sulfate, filtered and evaporated to yield ethyl 1-hydroxy-l- (3-thienyl) methanecarboximidate [12.5 g., pnrar/CDClj/Selta: 1.0-1.3 (3H); -4.8-5.3 (2H); 5.0 (1H); 6.9-7.2 (3E), 7.3-8.0 (1H)]. - 23 EXAMPLE 33 2-(3-Sron)p-2-thienyl) -2-trimethylsiloxyethanenitrile 3-Sromo-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 34 Ethyl 1-(3-Bromo-2-thienyl)-1hydroxvmethanecarboximidate Bydrochloride At 0°C., 2-(3-bromo-2-thienyl)-2-trimethylsiloxyethanenitrile (7.0 g., 24 moles) was dissolved in 210 ml. of ethanol saturated at 0*C. with hydrogen chloride. After stirring for 30 minutes at the same temperature, -the reaction mixture was evaporated to dryness. Trituration of the solid residue with ether afforded ethyl l-(3~bromo-2-thienyl)-l-hydroxymethanecarboximidate hydrochloride (7.0 g., m.p. 120-122°C.) .· - 24 EXAMPLE 35 2-(3-Benzo[b]thienyl)-2trimethylsiloxyethanenitrile Benzo[b]thiophene-3-carbaldehyde [1.8 g., 11 mmoles, 5 J. Chem. Soc. C., ρρ. 339-340 (1969)] and about 100 mg. of zinc iodide were 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-trimethylsiloxyethanenitrile (2.5 g., oil, Rx 0.7 (1:2 ethyl acetate:hexane)].

EXAMPLE- 36' Ethyl l-(3-Benzo[b]thienyl)-1hvdroxymethanecarboximidate Hydrochloride With cooling in an ice-water bath, 2-(3-benzo[b]thienyl)-2—trimethylsiloxyethanenitrile {2.3 g.) was dissolved in 10 ml. of saturated ethanolic hydrogen chloride, and held for 16 hours -at .about 5’C. The' reaction mixture was evaporated -to dryness and -triturated with ether to yield 1-(3-benzo[b]thienyl)-1-hydroxymethanecarboximidate hydrochloride (2.2 g., m.p. 128-131’C., m/e 235). 5X666 - 25 EXAMPLE 37 2-(7-Benzo[b]thienyl)-2trimethylsiloxyethanenitrile Benzo[bjthipphene-7-carbaldehyde [1.3 g., 8 mmoles, 5 2. Org. Chem. 39, 2829 (1974)] was dissolved in 35 ml. of ether. Trimethylsilylcarbonitrile (1.5 ml., .12 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 12.2 g., oil; Rf 0.6 (1:5 ethyl acetate;hexane/5% acetic acid)]. .

EXAMPLE 38 15 Ethyl 1-(7-Benzo[b)thienyl)-1hydroxyrnethanecarboximidate Hydrochloride By the procedure of Example 36 , 2-(7-benzo[bjthienyl) -2-trimethylsiloxyethanenitrile (2.1 g.), using 35 ml. of saturated ethanolic hydrogen chloride, was converted to ethyl l-(7-benzo[b]thienyl-l-hydroxymethaneearboximidate hydrochloride (1.1 g., m.p. 120-122’C.), after crystallization from acetone.

EXAMPLE 39 3-(4-Methoxy-3-thienyl)-2-trimethvlsiloxyethanenitrile By the procedure of Example 9 , 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). - 26 EXAMPLE 40 Methyl l-Eydroxv-l-(4-methoxy_3-thienyl) methanecarboximidate Hydrochloride Saturated methanolic hydrogen chloride (100 ml.) 5 was maintained at 0-5°C. in an ice bath. Title product of the preceding Example (3.9 g.) in 20 ml. of methanol was added dropwise and the mixture held for 1 hour at 0-5°C. The reaction mixture was concentrated to solids and the residue triturated with ether to yield the title product [2.76 g., m.p. 94-99°C. (dec.)]. Reerystallization from methanol-ether gave purified title product [1.51 g.; m.p. 112-114 (dec.)? m/e 201].

EXAMPLE 41 3-(4-Ethoxy-3-thienyl)-2-trimethvlsiloxyethanenltril ι By the procedure of Example 9, 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.

EXAMPLE 42, Ethyl 1-Hydroxy-l-(4-ethoxy-3-thienyl)methanecarboximidate Hydrochloride Osing ethanol in place of methanol, but otherwise the procedure of Example 40 , product of the preceding 25 Example (13 g.) was converted to title compound [9.23 g., m.p. 126-128° (dec.)j. - 27 EXAMPLE 43 2-[4-(n-Propoxy)-3-thienyl)-2trimethyls iloxyethanenitrile.

By the procedure of Example 9 , 4-(n—propoxy)-35 uhenaldehyde (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 259; ir (CHjClj) 2936, 1558 cm1).

EXAMPLE 44 Ethyl l-Hydroxy-l-[4-(n-propoxy)3—thienvl3 methanecarboximidate Bydrochloride Using a reaction time of 20 minutes after completion of -the addition, the procedure of Example 42 was 15 used to convert the product cf the preceding Example (4.5 g.) into -title product of the present Example [3.05 g.,».p. 127-129’C. (dec,)].

SXAMPLE 45 2-(4-Methoxy-2-methyl-3-thienyl)2*~'i-r^llle'thyl siloxyethanenitrile By the procedure of Example 9 , 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 (CSCl,) 1575, 1204, 1075 cm1]. δίθθθ - 28 EXAMPLE 46 Ethyl 1-Hydroxy-I-(4-methoxy-2-methyl-3thienyl)methanecarboximidate Hydrochloride The procedure of Example 42 was applied to the 5 product of the preceding Example (*7.2 g.) to produce .8 g. of a mixture of title compound and the corresponding ethoxy ether (estimated by pnmr to be a linnt 40% methyl ether and 60% ethyl ether; showing both m/e 243 and 229).

A portion of this mixture (2.5 g.) was taken into 100 ml. of methanol, cooled -to 0-5‘C., and perfused with hydrogen chloride for 1 hour. After 1 hour additional stirring at 0°C., the reaction miwtnrc .«as evaporated to a viscous oil. Crystallization from 15 ether gave title product [2.1 g.; m.p. 123-125®C. (dec.); m/e 229].

The corresponding methyl imidate ester of the title product is obtained by directly reacting tbe product of the preceding Example with methanolic hydrogen 20 chloride according to the procedure of Example''40.,? EXAMPLE 47 Ethyl 1-(Hydroxy)-1-(4-Ethoxy-2-methyl-3thienyl)methanecarboximidate Hydrochloride A portion of the mixed methyl and ethyl ethers of 25 the preceding Example (2.5 g.) was taken into 100 ml. of ethanol and cooled to 0°C. The cold solution was oerfused with hydrogen chloride for 1 hour, stirred for an additional hour at 0°C. and evaporated to an oil. The oil was crystallized by trituration with 30 ether. Repulping in ether gave title product [2.07 g., m.o. 105-107°C. (dec.); m/e 243]. - 29 The following Preparations illustrate the synthesis of certain starting materials :PRSPARATIOK 1 6-Chiorochroman Mossy zinc (75 g.), 7.5 g. of mercuric chloride, 125 ml. of water and 4 ml. of cone, hydrochloric acid were comhined, 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 acxd and then 6-chloro-4-chomanone (15 g.) were added to the metal, and the mixture refluxed for 1.5 hours, cooled to room temperature, decanted from the zinc and the decant extracted with three portions of ether. The comhined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil (14 g.). The oil was chromatographed on 400 g. ef silica gel using 9:1 hexane: ether as eluant tic monitoring and 15 ml. fractions. Clean product fractions were comhined and evaporated to yield title product as an oil [8.72 g.; pnmr/CDCl^/ delta (ppm) 2.0 (m, 25), 3.7 (t, 2H), 4.1 (t, 2B), 6.9 (m, 3H); m/e 170/168; Rf 0.88 (2:1 hexane: ether)]B1666 - 30 PREPARATION 2 6-Chlorochroman-8-carbaldehyde Product of the preceding Preparation (8.6 g., 0.051 mole) in 75 ml. of methylene chloride was cooled 5 in an ice-water bath. Titanium tetrachloride (12.34 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 agueous 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 86eC.; pnmr/CDC13/delta (ppm) 2.0*(m, 25), 2.8 (t, 25), 4.2 (t, 25), 7.1-7.5 (m, 2H), 10.2 (s, 15), m/e 198/ 196] .

S1666 - 31 PREPARATION 3 6-Fluorochroman By the procedures of Preparation 1 , 6-fluoro-4chromanone (15 g.) was converted to chromatographed 65 fluorochroman [5.7 g.; oil? pnmr/CDClg/delta (ppm) 2.0 (m, 2H), 3.8 (t, 2H), 4.1 (t, 2H), 6.8 (m, 3H)j 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). - 32 PREPARATION 5 3-Methyl-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 comhined 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. 1BO-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 hath temperature was increased to 200°C. and title product recovered hy distillation in vacuo [2.S g,, ±r(£ilm) nitrile band at 2220 cm , no «mj de peak in the 2700 cn”1, region]..

S1666 - 33PRSPARATIOK 7 3-Methyl-5-isoxa2olecarbaldehvde 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 6K 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. - 34 PREPARATION 8 -Chlorobenzofb]furan-2-carboxylic Acid -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-bromomalonate (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 wafer, 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-carboxylic acid and 6-ehloroben2o[b]furan-2-carboxylic acid. - 35 PREPARATION 9 -Chlorobenzo[b)furan Title compound of the preceding Preparation (7.8 g.) was combined with copper powder (700 mg.) and guinoline (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 seguence 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 axe converted to 5fluorobenzo[b]furan and 6-chlorobenzo[b)furan. - 36 PREPARATION 10 -Chloro-2,3-aihyarobenzo[b]furan Pd/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 Ereparation are converted to 5-xluoro7.1 ^-di'hydr-nhgngn [h] furan and 6—chloro-2,3-dihydrobenzo [b]furan. - 37 PREPARATION 11 -Chloro-2,3-dihydrobenzofb]furan-7-carbaldehyde By the procedure of Preparation 2, title compound of the preceding Preparation (2.1 g.) was converted to 5 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.

By the method of Preparation 3, the 6-chloro compound is converted to ethyl 2-(6-chloro~2,3-dihydro-7benzo[b]furanyl)-2-oxoacetate; then by the method of Preparation 4 to ethyl 2-(6-chlaro-2,3-dihydro-7-benzo[b]furanyl)-2-bydroxyacetate. - 38 PREPARATION 3.2 3-Furalaehvde 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 (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.; b.p. 66-72°ε./40-45 mm.,.

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

PREPARATION 13 2-(2-Furvl)-1,3-dioxolane 2-Turaldehyde (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.). - 39 PREPARATION 14 2-(5-Chloro-2-furyl)-1,3-dioxolane 2-{2-Furyl)-l,3-dioxolane (14 g., 0.1 mole) was dissolved in 100 ml. of tetrahydrofuran and the solution cooled to -25° to -20eC. 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 0eC. 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. Tbe 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)-l,3-dioxolane as an oil [5 g.; R^ 0-6 (8:1 hexane:ethyl acetate)]PREPARATION 15 5-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 ana evaporated to yield 5-chloro-2-furaldehyde as an oil (2-8 g.)51666 - 40 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-furylcarbonitrile -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 -3romo-2-furylcarbonitrile (2,3 g., 13 mmoles) •29 was dissolved'in 50 ml. of ether and cooled, under nitrogen, -to -10°C. .Diisobutylaluminum hydride (l.S 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 -25 temperature and allowed -to stir about 6 hours. The reaction mixture was cooled -to 0° -to 3'°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.’74-76oC.). - 41 PREPARATION 19 ' 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 trihydrate (15 g.) dissolved in 25 ml. of water was ' added slowlyi with good stirring, keeping the temperature 10’ to 3«’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 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., Rf 0.65 (3:1 hexane:ethyl acetate)]. - 42 PREPARATION 20 5-Phenvl-2-thenaldehyde 1-Phenylthiophene [1.6 g., 0.01 mole, prepared according to J. Am. Chem. Soc. 46, 2339 (1924)] was 5 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 -40oC. Dimethylformamide (1.2 ml., 10 15 mmole) was added, maintaining the temperature —40® το -30°C. The mixture was warmed to room temperature and held for 0.5 hour, recooled to 0°C., quenched with 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-pheny1-2—thenaldehyde (0.9 g., m.p. 90-92’C.). - 43 PREPARATION 21 4-Bromo-3-thenaldehvde 3,4-Dibromothiophene [15 g., 0.0S2 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 -70C., 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 ar. oil. The oil was twice distilled to yield 4-bromo-3thenaldehyde (5.7 g., b.p. 81-B4eC./0.8 mm., m/e 192/190). 16 6 6 - 44 PREPARATION 22 Methyl 4-Methoxy-3-thenoate Methyl 4-acetoxy-3-thenoate (D.S. Patent 3,144,235 10 g.) was dissolved in 20 ml. of methanol and added 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.). - 45' PREPARATION 23 1-( 4-Metho?:y-3-thienvl) methanol Methyl 4-methoxy-3-thenoate (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 chioroehrornate (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 Example (2.8 g., 19.6 mmoles) also in 100 ml. cf 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 seguence 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 (CH^Clj) 1688, 1544 era-1]. - 46 PREPARATION 25 Ethyl 4-Ethoxy-3-thenoate Following the approximate procedure of D.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-Sthoxy-3-thenaldehyde By the procedure of Preparation 24, the product of the preceding Preparation (5.15 g.) was converted to the title product, initially isolated as an oil which quickly crystallized on cooling 18.28 g.; m.p. 42-45°C.; m/e 156; ir (KBr) 3090, 2977-, 1688 cm1]. - 47 PREPARATION 28 n-Propyl 4-(n-Propoxy)-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 (CE^Cl^) 1689, 1539 cm1].

PREPARATION 31 Ethyl 4-Methoxy-2-roethvl-3-thenoate 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.B g.; m/e 200; pnmr/CDCl3 includes singlet OCHj protons at 3.9 ppm). The product is contaminated with a minor portion of the corresponding methyl ester. - 48 PREPARATION 3 2 (4-Methoxy-2-methvl-3-thienyl)methanol The product of the preceding Preparation (7.8 σ., 0.039 mole) was dissolved in 100 ml. of hexane and 5 75 ml. of toluene and cooled to -78°C. Diisobutyl aluminum hydride (78 ml. of 1M 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 30°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 (CE2C12) 3598, 1582, 1708 cm-1).

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

Claims

1. CLAIMS:1. A compound of the formula wherein 5 2 R is (C,-C-)alkyl? and 6 X «3 R is either.-- M 0- . 1 R' OCH 1 R' or X I R' wherein R* is (C^-cpalkyl or phenyl, (b) wherein W is hydrogen or halo, and n is 1 or 2; (c) V - 50 wherein Q is sulfur or oxygen; (^-Cg) alkyl; or and V is hydrogen or (d) x wherein Y is sulfur or oxygen; X is hydrogen, halo,

2. 5 methyl, phenyl, benzoyl or (C.-C.)alkoxy; X 1 is hydrogen 2 1 J or methyl; and X is hydrogen or halo;

3. 7 8 and R and R are both H.