2-Cyano-2- propionic acid

Similar results were obtained on reduction of 3,4,5-trimethylisoxa-zole/ Further examples of such a cleavage were found later. Thus, j8-(3-halogenoisoxazol-5-yl) propionic acids (163) on treatment with sodium amalgam give a mixture of S-cyano-y-ketovaleric and succinic acids (163—> 164) The reaction can be interpreted as a result of... 

Aromatization of 8-(cyano or ethoxycarbonyl)-2-oxo-2,3,4,4a,7,8-hexa-hydropyrido[l,2-A][l,2]oxazine-8-carbonitriles 12 by treatment with CS2CO3 resulted the formation of (2-pyridyl)propionic acids 13 (00OL4007). Application of other bases, e.g. DBU, NEt3, Dowex 1X8-400 ion-exchange resin afforded (2-pyridyl)propionic acids in irreproducible or considerably lower yields. 

A mixture of 100 g of ethyl 2-cyano-2-(5H-[ 1 ] benzopyrano [2,3-b] -py rid in-7-y I [propionate, 500 ml of glacial acetic acid and 200 g of concentrated hydrochloric acid is refluxed for 48 hours. The reaction mixture is concentrated, and the residue is dissolved in hot water. The solution is adjusted to pH 2 to 3 by addition of 10% sodium hydroxide. The resulting crystalline precipitate Is washed thoroughly with water, and recrystallized from aqueous dioxane to give 74 g of 2-(5H-[1] benzopyrano [2,3-b] -pyridin-7-y I [propionic acid as white crystals melting at 183°Cto 183.5°C. 

Abbreviations N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA), L(+)-2 amino-3-phosphonopropionic acid (L-AP3), 6-cyano-7-nitroqninoxaline (CNQ5Q, 2,3-dihydroxy-6-nitro-7-sulfamyl-benzo-f-quinoxaline (NBQX), 3-(2-carboxypiperazin-4-yl)-propyl-l-phosphonic acid (CPP), 7 Chlorokynnreic... 

Beccalli et al. reported a new synthesis of staurosporinone (293) from 3-cyano-3-(lH-indol-3-yl)-2-oxo propionic acid ethyl ester (1464) (790). The reaction of 1464 with ethyl chlorocarbonate and triethylamine afforded the compound 1465, which, on treatment with dimethylamine, led to the corresponding hydroxy derivative 1466. The triflate 1467 was prepared from 1466 by reaction with trifluoromethanesulfonic anhydride (Tf20) in the presence of ethyldiisopropylamine. The palladium(O)-catalyzed cross-coupling of the triflate 1467 with the 3-(tributylstannyl)indole 1468 afforded the vinylindole 1469 in 89% yield. Deprotection of both nitrogen atoms with sodium ethoxide in ethanol to 1470, followed by photocyclization in the presence of iodine as the oxidizing agent provided the indolocarbazole 1471. Finally, reductive cyclization of 1471 with sodium borohydride-cobaltous chloride led to staurosporinone (293) in 40% yield (790) (Scheme 5.248). 

Scheme 7 Alternative mechanism for asymmetric decarboxylation of 2-cyano-2-(6-methoxy-naphth-2-yl)propionic acid in the synthesis of Naproxen involving a pre-association mechanism.

A mixture of 5 parts l-(3-cyano-3,3-diphenylpropyl)-4-(2-oxo-l-benzimidazolinyl)piperidine, 7.5 parts propionic acid anhydride and 80 parts benzene is stirred and refluxed for 16 hours. After cooling, the reaction mixture is washed twice with 100 parts water. The aqueous layer is dried over potassium carbonate, filtered and evaporated. The residue is recrystallized from 60 parts of ether, yielding 4 parts crude l-(3-cyano-3,3-diphenylpropyl)-4-(2-oxo-3-propionyl-l-benzimidazolinyl)piperidine. This crop is recrystallized from 20 parts m-methyl-2-pentanone 4-ethyl-2-pentanone, yielding l-(3-... 

Crystallization-induced asymmetric transformation has already been described by Leuchs in 1913 during the resolution of 2-(2-carboxybenzyl)-l-indanone with brucine.34 In this case spontaneous racemization occurred. More recently researchers at Sanofi observed spontaneous racemization during the resolution of 3-cyano-3-(3,4-dichlorophenyl)propionic acid (7), most likely as a result of the basic resolving agent [>-(-)-N-1 n etli y I g I near nine [d-(-)-MGA] (8) (Scheme 7.6).35 The enantiopure cyano acid, obtained in 91% overall yield, is subsequently reduced to (+)-4-amino-3-(3,4-dichlorophenyl)-l-butanol (9), a key intermediate in the phase 2 synthesis of tachykinin antagonists. 

In an extension of these studies (55JA3844), the synthesis of 5,6-dimethoxyindole-3-propionic acid was achieved by reductive cyclization of 3-cyano-3-(2-nitro-4,5-dimethoxyphenyl) propanoate esters with H2 over 10% Pd/C in ethyl acetate. This approach was later revisited for the preparation of ethyl 2-(5,6-dimethoxyindol-3-yl)acetate 14 (80SYN663) (Scheme 3). 

CliHi5N, Tricyclo[3.3.1.1 Idecane-1-carbonitrile, 45B, 175 C11H15NO, 3-Cyano-4-exo-protoadamantanol, 46B, 172 CliHigO, Tricyclo[5.3.1.0 ]undecan-5-one, 43B, 235 Cl1H1g03, 2-Methyl-3-(3 -hydroxy-bicyclo[2.2.1]-2 -heptylidenyl)propionic acid, 45B, 176... 

The decarboxylation of aminomalonic acid derivatives constitutes a classical route to proteinogenic and non-proteinogenic amino acids. In 2003, Brunner et al. [16] explored the potential of the 9-ep/-cinchonine-benzamides previously designed [14], in the decarboxylation of A-acetylaminomalonic acid derivatives 22a-c. Selected examples presented in Scheme 3.8 indicate that a number of 9-epi-cinchonine-benzamides reached acceptable levels of enantioselectivity, up to 71%. hi contrast to 2-cyano-2-aryl propionic acids 14 and 20,9-ept-cinchonine-benzamides 19b, c and f gave rather disappointing results with A-acetylaminomalonic acids... 

Figure 40 Preparation of p-cyano-a-amino-L-propionic acid by O-acetylserine sulfhydrolase from Bacillus stearothermophilus CN3.

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