diethyl (E)-but-2-enedioate

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: When the alkene-1,2-dicarboxylic acid compound starting material is an ester, such as diethyl fumarate, the addition of acetic anhydride and hydrogen sulfide proceeds to give the diethyl ester of S-acetylthiosuccinic acid, which on selective deacetylation, suitably by means of aqueous alcoholic ammonia, gives diethyl thiomalate according to this invention, as illustrated in SCHEME 2 below.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tosylmethyl isocyanide (9.8 g, 50 mmol), diethyl fumarate (8.2 mL, 50 mmol) and dry THF (1000 mL) were added dropwise to a stirred suspension of potassium t-butoxide (11.2 g, 100 mmol) and THF (150 mL). The mixture was stirred for 2 hours, saturated NaCl (500 mL) was added, and the mixture was extracted with THF (2×250 mL). The organic layers were dried (Na2SO4), filtered and concentrated in vacuo to give a solid. The solid was recrystallized from MeOH to give the title compound 4.6 g (44%) (mp 148-149° C.). 1H NMR (DMSO) δ1.22 (t, 3H, CH3), 4.18 (q, 2H, CH2), 7.39 (s, 2H, ArH), 11.8 (bs, 1H, NH). the mixture was extracted with THF (2×250 mL) The organic layers were dried (Na2SO4) filtered concentrated in vacuo to give a solid The solid was recrystallized from MeOH

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: By the method of Example 1, diethyl fumarate was reacted at -40° C. with 2 equivalents of ketene diethyl acetal in the presence of 0.2 equivalents of ethyldiisopropylamine and 2 equivalents of diisobutylaluminium chloride. 1H NMR analysis of the reaction mixture showed that the yield was quantitative.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 172 g of diethyl fumarate are slowly added at 65°-70° C. under nitrogen to a mixture of 140 g of diethyl ethanephosphonate in 46 g of ethanol. After a further 3 hours the solvent (excess ethanol and diethyl ether) is removed by vacuum distillation; the crude product is obtained in a yield of 285 g with a 95.7% purity, which corresponds to a theoretical yield of 90.9%. After a further 3 hours the solvent (excess ethanol and diethyl ether) is removed by vacuum distillation

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Poly(propylene fumarate) was synthesized following a two step procedure [11]. First, 1 mole of diethyl fumarate (Acros Organics, Pittsburgh, Pa.) and 3 moles of 1,2 propanediol (Acros Organics) were reacted using 0.01 moles ZnCl2 (Fisher Chemicals, Fair Lawn, N.J.) as a catalyst and 0.002 moles hydroquinone (Acros Organics) as a radical inhibitor. The reaction was run under a nitrogen blanket, producing bis(hydroxypropyl) fumarate as the main product and ethanol as a byproduct. Second, the bis(hydroxypropyl) fumarate was transesterified, producing poly(propylene fumarate) and 1,2 propanediol as a byproduct.

Conditions: temp:24.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a one liter round bottom flask containing a cold (0° C.) slurry of 67.6 g (0.6756 mol) of aminoacetonitrile hydrochloride and 44.2 ml (0.2702 mol) of diethyl fumarate in 300 ml of ethyl acetate, were added dropwise, over one hour, an aqueous solution of 46.6 g (0.6756 mol) of sodium nitrite dissolved in 90 ml of water. The temperature of the reaction mixture was maintained at about 0° C. during the nitrite addition, then warmed to room temperature (24° C.) where the mixture was stirred for about 3 hours. The organic layer was separated from the aqueous layer and then stirred at room temperature overnight to provide a solution of 5-cyano-4,5-dihydro-3H-pyrazole-3,4-dicarboxylic acid diethyl ester dissolved in ethyl acetate. were added dropwise, over one hour The organic layer was separated from the aqueous layer stirred at room temperature overnight

Conditions: temp:24.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 500 ml, 3-neck, round bottom flask containing a cold (0° C.) slurry of 46.26 g (0.5 mol) of aminoacetonitrile hydrochloride and 32.74 ml (0.2 mol) of diethyl fumarate in 200 ml of ethyl acetate, were added dropwise, over one hour, an aqueous solution of sodium nitrite (34.5 g of sodium nitrite dissolved in 90 ml of water). The temperature of the reaction mixture was maintained between 0° C. and 5° C. during nitrite addition and then warmed to room temperature (24° C.), where the mixture was stirred for about 3 hours. The organic layer was separated from the aqueous layer and then stirred at room temperature overnight to provide a solution of title compound dissolved in ethyl acetate. were added dropwise, over one hour The organic layer was separated from the aqueous layer stirred at room temperature overnight

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 900 g of N-Benzyl-N-trimethylsilylmethyl-amine (4654 mmol) were dissolved in 5.6 l THF at 20-25° C. 450 ml of 36% aqueous formaldehyde (5880 mmol, 1.26 equiv.) were added over 15 min, keeping the temperature between 20-25° C. After 15 min, a mixture of 760 ml diethyl fumarate (1 equiv.), 2.25 l THF and 11.2 ml trifluoroacetic acid (0.03 equiv.) was added over 15 min. The reaction mixture was stirred overnight keeping the temperature between 20-30° C. (in process control by GC). 3.5 l of 1N HCl were added, followed by 2.3 l heptane. The aqueous phase was separated and washed with 3.4 l heptane. The heptane phases were washed sequentially with 3.5 l 1N HCl. 4.5 l MTBE were added to the combined aqueous phases. 720 ml of 32% NaOHaq were added (pH 13) under vigorous stirring. The aqueous phase was separated and re-extracted with 4.5 l MTBE. The MTBE phases were washed sequentially with 2.2 l water, combined and concentrated to dryness at 45° C. to give 1.295 kg of crude (rac)-trans-N-benzyl-pyrrolidine-3,4-dicarboxylic acid diethyl ester. If required, the crude cycloadduct can be distilled. between 20-25° C was added over 15 min between 20-30° C. The aqueous phase was separated washed with 3.4 l heptane The heptane phases were washed sequentially with 3.5 l 1N HCl 4.5 l MTBE were added to the combined aqueous phases 720 ml of 32% NaOHaq were added (pH 13) under vigorous stirring The aqueous phase was separated re-extracted with 4.5 l MTBE The MTBE phases were washed sequentially with 2.2 l water concentrated to dryness at 45° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 900 g of N-Benzyl-N-trimethylsilylmethyl-amine (4654 mmol) were dissolved in 5.6 l THF at 20-25° C. 450 ml of 36% aqueous formaldehyde (5880 mmol, 1.26 equiv.) were added over 15 min, keeping the temperature between 20-25° C. After 15 min, a mixture of 760 ml diethyl fumarate (1 equiv.), 2.25 l THF and 11.2 ml trifluoroacetic acid (0.03 equiv.) was added over 15 min. The reaction mixture was stirred overnight keeping the temperature between 20-30° C. (in process control by GC). 3.5 l of 1N HCl were added, followed by 2.3 l heptane. The aqueous phase was separated and washed with 3.4 l heptane. The heptane phases were washed sequentially with 3.5 l 1N HCl. 4.5 l MTBE were added to the combined aqueous phases. 720 ml of 32% NaOHaq were added (pH 13) under vigorous stirring. The aqueous phase was separated and re-extracted with 4.5 l MTBE. The MTBE phases were washed sequentially with 2.2 l water, combined and concentrated to dryness at 45° C. to give 1.295 kg of crude (rac)-trans-N-benzyl-pyrrolidine-3,4-dicarboxylic acid diethyl ester. If required, the crude cycloadduct can be distilled. between 20-25° C was added over 15 min between 20-30° C. The aqueous phase was separated washed with 3.4 l heptane The heptane phases were washed sequentially with 3.5 l 1N HCl 4.5 l MTBE were added to the combined aqueous phases 720 ml of 32% NaOHaq were added (pH 13) under vigorous stirring The aqueous phase was separated re-extracted with 4.5 l MTBE The MTBE phases were washed sequentially with 2.2 l water concentrated to dryness at 45° C.

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 2:1 mixture of 2-(cyclopenten-1-yl)-1-(triisopropylsilyl)pyrrole and 3-(cyclopenten-1-yl)-1-(triisopropylsilyl)pyrrole (1.16 g, 4.01 mmol) and diethyl fumarate (0.75 g, 4.36 mmol) was heated under nitrogen to 150° C. for 64 h, affording the crude Diels-Alder adduct as an amber oil. The pure Diels-Alder adduct could be isolated by chromatography on silica gel (hexanes-ether 90:10). NMR (CDCl3) δ 6.68 (d, 1H), 6.16 (d, 1H), 4.20 (m, 4H), 3.95 (d, 1H), 2.91 (t, 2H), 2.49 (m, 1H), 2.09 (m, 1H), 1.73 (m, 2H), 1.48 (septet, 3H), 1.30 (2t, 6H), 1.27 (d, 9H), 1.07 (d, 9H). MS m/e 462 (M+H)+. DDQ (2.2 g, 9.7 mmol) was added in three portions to a benzene solution (16 mL) of the crude Diels-Alder adduct at 50° C. until no starting material remained (TLC and NMR). After 8 h, the mixture was filtered through Celite®. The precipitate was rinsed with benzene, and the filtrate was evaporated to give 1.52 g of a black solid. This was chromatographed on silica gel (hexanes-ether 15:85 to 20:80) to give the product (380 mg, 21% yield, 35% yield from 2-isomer) as a colorless oil. NMR (CDCl3) δ 7.42 (d, 1H), 7.05 (d, 1H), 4.40 (2q, 4H), 3.20 (t, 2H), 3.12 (t, 2H), 2.17 (quintet, 2H), 1.67 (septet, 3H), 1.39 (t, 3H), 1.36 (t, 3H), 1.20 (d, 18H). MS m/e 458 (M+H)+. affording the crude Diels-Alder adduct as an amber oil The pure Diels-Alder adduct could be isolated by chromatography on silica gel (hexanes-ether 90:10) the mixture was filtered through Celite® The precipitate was rinsed with benzene the filtrate was evaporated

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 2:1 mixture of 2-(cyclopenten-1-yl)-1-(triisopropylsilyl)pyrrole and 3-(cyclopenten-1-yl)-1-(triisopropylsilyl)pyrrole (1.16 g, 4.01 mmol) and diethyl fumarate (0.75 g, 4.36 mmol) were heated under nitrogen to 150° C. for 64 h, affording the crude Diels-Alder adduct as an amber oil. The pure Diels-Alder adduct could be isolated by chromatography on silica gel (hexanes-ether 90:10). NMR (CDCl3) δ 6.68 (d, 1H), 6.16 (d, 1H), 4.20 (m, 4H), 3.95 (d, 1H), 2.91 (t, 2H), 2.49 (m, 1H), 2.09 (m, 1H), 1.73 (m, 2H), 1.48 (septet, 3H), 1.30 (2t, 6H), 1.27 (d, 9H), 1.07 (d, 9H). MS m/e 462 (M+H)+. DDQ (2.2 g, 9.7 mmol) was added in three portions to a benzene solution (16 mL) of the crude Diels-Alder adduct at 50° C. until no starting material remained (TLC and NMR). After 8 h, the mixture was filtered through Celite®. The precipitate was rinsed with benzene, and the filtrate was evaporated to give 1.52 g of a black solid. This was chromatographed on silica gel (hexanes-ether 15:85 to 20:80) to give the product (380 mg, 21% yield, 35% yield from 2-isomer) as a colorless oil. NMR (CDCl3) δ 7.42 (d, 1H), 7.05 (d, 1H), 4.40 (2q, 4H), 3.20 (t, 2H), 3.12 (t, 2H), 2.17 (quintet, 2H), 1.67 (septet, 3H), 1.39 (t, 3H), 1.36 (t, 3H), 1.20 (d, 18H). MS m/e 458 (M+H)+. affording the crude Diels-Alder adduct as an amber oil The pure Diels-Alder adduct could be isolated by chromatography on silica gel (hexanes-ether 90:10) the mixture was filtered through Celite® The precipitate was rinsed with benzene the filtrate was evaporated

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 1,4-dihydro-2,3-benzoxathiin 3-oxide (2.0 g, 11.9 mmol) in toluene (20 mL) was added diethyl fumarate (3.9 mL, 23.8 mmol). Upon completion of addition, the reaction mixture was heated to 110° C. for 16 h under nitrogen. The solvent was removed under vacuum to yield a residue. The residue was purified by silica gel chromatography eluting with 10% ethyl acetate in hexane to yield the title compound (2.1 g, 64%). 13C NMR (400 MHz, CDCl3) δ 174.1, 133.7, 128.3, 126.1, 60.5, 42.3, 42.0, 31.6, 14.3, 14.0. 1H NMR (400 MHz, CDCl3) δ 7.04-7.15 (m, 4H), 4.18 (m, 4H), 3.12 (dd, J=2.6, 12.4 Hz, 2H), 2.87-3.03 (m, 4H), 1.27 (t, J=7.5 Hz, 6H). MS [M+Na]+, 299. Upon completion of addition The solvent was removed under vacuum to yield a residue The residue was purified by silica gel chromatography eluting with 10% ethyl acetate in hexane