Cyano ketones formation

A facile synthesis of 5-substituted 3-aminopyrrole-2-carboxylates has been developed wherein condensation of diethyl aminomalonate with a-cyano ketones 46 was facilitated by prior formation of the p-toluenesulfonyl enol ether 47 <00JOC2603>. Addition of the amine component is followed by cyclization and decarboxylation to afford the pyrroles 48. 

Application of the Beckmann cleavage route to the preparation of 18-norandrostan-17-ones185 (219) has been improved by intermediate formation of the 13-carboxy-13,17-seco-nitriles (217), which cyclized with base to form the 13a- and 13/3-isomers of the a-cyano-ketone (218) and thence the 18-nor-13a- and -13/3-androstan-17-ones (219).186 A similar reaction sequence has been employed for... 

The formation of cyano ketones by this method is illustrated by the conversion of phenacyl halides to the corresponding nitriles. Ring closure to cyclopropane derivatives is a side reaction which has been encountered with y-halo ketones. Benzalacetophenone dibromide is converted by alcoholic potassium cyanide to the fi-cyaao ketone, the a-halogen atom being reduced. Several a-chloro ketones have been found to yield a-cyano epoxides. ... 

In the reaction of 2-hydroxyalkyl halides with cyanide ions the intermediate formation of oxiranes can give rise to rearrangement products. Epoxides may also be encountered if CN ions are reacted with a-halo ketones (Scheme On heating with quaternary ammonium halides in acetonitrile or DMSO at 80-130 C these cyanooxiranes (3) are converted into 2-cyano ketones (4). Phenacyl bromide, in contrast, gives rise to 3-oxo-3-phenylpropionitrile (5) on treatment with cyanide ions. Not much is known about the reaction of the corresponding a-halo sulfides with cyanide ethylthioacetonitrile was obtained from the chloro sulfide by treatment with Hg(CN)2. ... 

Readily available A A -dimethyldithiocarbamoylacetonitrile (15) is alkylated by alkyl halide and aqueous base longer reaction times lead to high-yield dialkylation. Elimination of the cyano and dithiocarbamoyl groups with consequent aldehyde or ketone formation is achieved simply on reaction with sodium hydroxide in hot ethanol or on treatment with A -bromosuccinimide (Scheme 20). ... 

For example, condensation of the 5-cyano ketone 146 with methyl [ C ]cyanoacetate gave (Figure 7.36) a-[ C]cyanobenzo[a]quinolizin-2-yUdeneacetate derivative 147 in 52% yield. Reduction of the double bond followed by selective de-methoxycarbonylation provided the dinitrile, a key intermediate in the synthesis of carbon-14-labeled 4a-hydroxy-allo-berbane (148) . Despite loss of half of the label during formation of the final ring by Thorpe-Ziegler condensation, this route was considered superior to the alternative longer route. 

The intramolecular formation of 18-cyano-20-ketones in 30-50% yield from 20-cyanohydrins in the hypoiodite reaction is particularly interesting. The reaction is considered to occur through the following steps ... 

Unfortunately, it quickly became apparent that a shortfall in this proposal was an inability to prepare the desired vinyl halide 25 in a straightforward and selective manner [19]. In contrast, we reasoned that the selective formation of an enol sulfonate, such as the enol triflate 26a, could be controlled by judicious tuning of enolization conditions starting from the corresponding ketone, and that such an enol sulfonate would possibly be a substrate for a palladium-mediated coupling (Scheme 9.17). In this way a common intermediate from the previously defined synthesis, that is, the racemic ketone rac-13 or its cyano equivalent rac-5 could be used to generate the required enamide. 

Alkyl-3-cyano-4-hydroxythiophenes 625 were obtained from the reaction of 2,3-allenenitriles 610 with mercaptoacetates 622. The presence of the ester group leads to the formation of cyclic ketones 623, which undergo migration of the C=C and C=0 bonds to form thiophenes 625 [276]. 

Suzuki and co-workers achieve aromatic substitution of fluoroarenes with a variety of aldehydes in good yields [91, 92], Imidazolilydene carbene formed from 143 catalyzes the reaction between 4-methoxybenzaldehyde 22a and 4-fluoroni-trobezene 141 to provide ketone 142 in 77% yield (Scheme 20). Replacement of the nitro group with cyano or benzoyl results in low yields of the corresponding ketones. The authors propose formation of the acyl anion equivalent and subsequent addition to the aromatic ring by a Stetter-like process forming XXVIII, followed by loss of fluoride anion to form XXIX. 

Cyano-substituted ethylenes react in a different way with aliphatic ketones. The orientation of photochemical cycloaddition (4.661 is the opposite of that found for electron-rich alkenes, and the reaction is highly stereoselective (4.69) in the early stages. These processes involve the formation and subsequent decay of an excited complex (exciplex) from the (n,n ) singlet state of the ketone and the alkene. Aryl ketones undergo intersystem crossing so efficiently that such a singlet-state reaction is rarely observed, but the reaction of a benzoate ester with an electron-rich alkene 14.70 rnay well be of this type, with the ester acting as electron-acceptor rather than electron-donor. 

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