Nitrile, a,p-Unsaturated

An important biological process is the basis for a general coupling method of aldehydes into symmetncal acyloins, such as BETYROIN. The key catalyst is 5-(2-hydroxyethyl)-4-methyl-l,3-thiazole, an analog of thiamin. Condensation of ketones and aldehydes with excess acetonitrile can be accomplished in a simple way to produce a,p-unsaturated nitriles Cyclohexanone leads to CY-CLOHEXYLIDENEACETONITRILE while benzaldehyde gives CINNA-MONITRILE. 

The cyclization with a,p-unsaturated nitriles has proven effective for the synthesis of 3-aminothiophene 14, a key intermediate for the synthesis of p38 kinase inhibitors."... 

A vinyl ether and an aryl hydrazide react to give compound 72 (83JHC1657). A large number of compounds have been made from a,P-unsaturated nitriles. Crotononitriles react with A-acetylcyanoacetohydrazide and with cyanocinna-monitrile to give compounds such as 73 (91GEP3926770), and compound 74 (90JOC2259), respectively. 

The base-catalyzed joint reaction of nitroalkenes with thiophenol in the presence of aldehydes gives y-phenylthio-P-nitro alcohols in one pot (Eq. 4.5).8 The joint reaction of nitroalkenes with thiols and a,p-unsaturated nitriles (or esters) has also been achieved. (Eq. 4.6).9 P-Nitro sulfides thus prepared show unique reactivity toward nucleophiles or tin radicals. The nitro... 

EvenPd(OAc)2 is not effective in catalyzing the cyclopropanation of a,P-unsaturated nitriles by ethyl diazoacetate. Instead, vinyloxazoles 92 are formed from acrylonitrile or methacrylonitrile by carbenoid addition to the CsN bond 143 Diethyl maleate and diethyl fumarate as well as polyketocarbenes are by-products in these reactions the 2-pyrazoline which would result from initial [3 + 2] cycloaddition at the C=C bond and which is the sole product of the uncatalyzed reaction at room temperature, can be avoided completely by very slow addition of the diazoester... 

Supplemental References for Table 19. Organosilane Reduction of a,p-Unsaturated Nitriles... 

The Michael-type conjugate addition of an alkoxide such as methoxide to an a,p-unsaturated nitrile or aldehyde proceeds in solution quite readily, being complete in 5—10 minutes. In the gas phase however, it was found that reaction (6a) does not occur there is no evidence of the addition product even at the longest trapping times, nor in the unquenched mode. Rather, the sole product observed is due to proton loss from the nitrile, to form a nominal vinyl anion, reaction (6b). 

Tetraalkylammonium bromide was found to be a good catalyst for the conjugate addition of thiols to a,p-unsaturated nitriles, carboxylic esters, ketones, aldehydes, and nitro alkenes. The reactions proceeded rapidly and gave high yields of products (typically, 90%) (160). 

Metalation of 2 with lithium diisopropylamide (LDA) generates diazo(trimethyl-silyl)methyl hthium (3), which reacts with a,p-unsaturated nitrile 36 and phenyl-sulfones (37) to form 3(or 5)-trimethylsilyl-l//-substituted pyrazole 4 that can be desilylated to furnish pyrazoles 5 (Scheme 8.3). 

Clerici et al. studied the reaction of 3-diethylamino-4-(4-methoxyphenyl)-5-vinyl-isothiazole 1,1-dioxides 15 with nitrile oxides and with munchnones. These reactions produced cycloadducts such as 16 and 17 which underwent thermal rearrangement to a, P-unsaturated nitriles <98T11285>. 

Aziridines can add to carbon—carbon multiple bonds. Elevated temperature and alkali metal catalysis are required in the case of nonpolarized double bonds (193—195). On the other hand, the addition of aziridines onto the conjugated polarized double or triple bonds of a,p-unsaturated nitriles (196—199), ketones (197,200), esters (201—205), amides (197), sulfones (206—209), or quinones (210—212) in a Michael addition-type reaction frequendy proceeds even at room temperature without a catalyst. The adducts obtained from the reaction of aziridines with a,p-unsaturated ketones, eg, 4-aziridinyl-2-butanone [503-12-8] from 3-buten-2-one, can be converted to 1,3-substituted pyrrolidines by subsequent ring opening with acyl chlorides and alkaline cyclization (213). 

One of the few examples of a synthetically useful 6-exo-trig cyclization from 3-aza-6-heptenyl radicals is found in the total synthesis of ( )-melinonine-E (159, Scheme 31) by Bonjoch et al. [66]. The cyclization precursor, a,P-unsaturated nitrile 157 was prepared from 1,4-cyclohexanedione monoethylene acetal (156) and tryptamine in 5 steps with 41% overall yield. Initially, when 157 was treated with 1.1 equiv. of n-BujSnH and 0.1 equiv. of AIBN in toluene for 16 h, the expected cyclization to the 2-azabicyclo[3.3.1]nonane ring took place to give 158 only as a minor product, along with its C(14) chloro- and dichloro-substituted derivatives as major products. An additional treatment of the crude mixture with 2.2 equiv. of BujSnH brought about the reduction of the C-Cl bonds to provide nitrile 158 in 38% yield over... 

The base catalyzed reaction of 4-phenyl-l,2-dithiole-3-thione 506 with a,P-unsaturated nitriles affords 6-aminothiopyran-2-thiones. A complex mechanism is postulated for the transformation with elimination of a thioketone from a dithiepin featuring in the key step (Scheme 189) <2003PS(178)2255>. 

Giese and coworkers determined on the basis of experimental results obtained by Scheffold et al. [268, 299] that addition reactions of alkyl bromides 249 to a,p-unsaturated nitriles or esters 248 catalyzed by cobalamine 247 are free radical reactions (Fig. 61) [300], This conclusion was based on the similar cis/trans-selectivities in addition reactions of the 4-tert-butylcyclohexyl radical to different electron-poor alkenes 248 using 247 as a catalyst on one hand and classical tributyltin hydride conditions on the other. The kinetics of the radical addition was determined. 

Effenberger, F. and Oswald, S. 2001b. (i )-Selective hydrolysis of (ii,Z)-a,P-unsaturated nitriles by the recombinant nitrilase AtNITl from Arabidopsis thaliana. Tetrahedron ... 

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