2-Cyanoketones, addition

Scheme 6.129 Products prepared from the 121- and 124-catalyzed stereoselective Michael additions of a-chloroacrylonitrile and acrylonitrile to a variety to cyclic a-cyanoketones and acyclic a-substituted cyanoesters.

Exercise 24-11 Nitriles of the type RCH2CN undergo a self-addition reaction analogous to the aldol addition in the presence of strong bases such as lithium amide. Hydrolysis of the initial reaction product with dilute acid yields a cyanoketone, O CN... 

These olefins were transformed into unsaturated acetates by Woodward s protocol with iodine, silver acetate, and acetic acid. Saponification and subsequent oxidation of the liberated alcohols with Collin s reagent resulted in a 2 1 mixture of conjugated enones, 162 and 163, in mediocre yields (Scheme 16). The minor enone 163 was transformed into the cyanoketone 164 by 1,4-addition using... 

Displacement of a cyano group in a-cyanoketones is possible. Treatment of the a-cyanoketone with Sml2 followed by addition of an excess of allyl bromide gave the a-allyl ketone derivative. a-Cyano amines react with allyl bromide and then zinc metal to give homoallylic amines after treatment with dilute acetic acid in... 

Thorpe reaction The addition of the anion that results from the deprotonation of a nitrile compound, to another nitrile group. The resulting imine may be hydrolysed to yield a (3-cyanoketone. If the reaction is performed internally it is known as the Thorpe-Ziegler reaction. 

Deng also successfully applied the C6 —OH catalysts 64a,b to the asymmetric tandem conjugate addition-protonation reactions of the a-cyanoketones or... 

Malonate and related activated methylene compounds have also been used as the nucleophile in conjugate addition/Michael reactions. Taylor and co-workers have developed a new methodology that utilizes (salen)aluminum complexes such as 43 as a catalyst to effect the enantioselective conjugate addition to a,p-unsaturated ketones by a variety of nucleophiles.25 For example, nitriles, nitroalkanes, hydrazoic acids, and azides have found utility in this reaction. Additionally, cyanoacetate (42) has been demonstrated to undergo a highly enantioselective conjugate addition to 41. The Krapcho decarboxylation is then necessary to produce cyanoketone 44, an intermediate in the synthesis of enantioenriched 2,4-cw-di substituted piperidine 45. 

To arrive at the 2-aryl-l-tetralone, Zee-Cheng and Cheng (73JHC85, 73JHC867) used the Claisen-Schmidt aldol condensation of veratral-dehyde 30 and acetopiperone 31 to produce (3, 4 -methylenedioxy)-3,4-dimethoxychalcone 32 quantitatively (Scheme 3). On addition of hydrogen cyanide the cyanoketone 33 was formed, which after basic hydrolysis and... 

Additional examples of the cyclization of f-cyanoketones to 2-chloropyrroles were reported. <94TL5989> The reaction requires an electron-... 

Scheme 4.41 Enantioselective Michael addition of a-alkyl a-cyanoketones to a-chlorocyanoacrylate catalyzed by 84c or 71b.

Michael additions of a-mercaptoacetates to a,P-unsaturated systems, followed by Diekmann or aldol-type cyclization, provide access to hydrothiophenes, such as (1), which are useful precursors for a variety of sulfolenes. Scheme 6.2 [27,115]. The ester group of ketoester (la) can be manipulated to provide a range of substituents. The ketone group can then be reduced to an alcohol, and after this has been eliminated, the resultant dihydropyran can be oxidized to a 3-sulfolene. 3-Cyano-3-sulfolene (4) is of general utility and can be efficiently prepared by this strategy from intermediate cyanoketone (lb) [9,10]. Other sulfolenes can be prepared by analogous methods. 

On the other hand, the enantioselective conjugate addition of a-substituted cyano-acetates and cyanoketones to a,P-unsaturated sulfones has been reported by Deng et al. using bifunctional cupreine 127 as catalyst [270]. Substoichiometric amounts of 127 (20 mol%) catalyze the synthesis of chiral sulfones containing all-carbon... 

Addition of cyanide ion to a,a-dihaloketones results in the formation of cyanoepoxides via cyanohydrin formation and subsequent dehydrobromination [117]. In this way, 3-ch]oro-3-bromopentan-2-one gives a virtually quantitative yield of cyanoepoxide consisting of 35% cis and 65% trans. The product is isomerised by pyridine to give the a-chloro-a-cyanoketone (42) which on further treatment with cyanide ion in aqueous solution gives the dicyanoepoxide (35% cis, 65% trans). 

The use of unsaturated nitriles as Michael acceptors represents a facet of the synthetic utility of cyano-compounds that nicely complements the reactivity discussed above. Michael addition of 2-lithio-1,3-dithianes to a,B-unsaturated nitrile derivatives appears to be of use in the preparation of protected cyanoketones, although the method may be limited by the fact that reactions of substrates unable to stabilise the negative charge of the adduct before workup were difficult to achieve satisfactorily. 

In contrast to the large number of addition reactions to C=0 and C=N double bonds, only a few examples of nucleophilic addition to N=N double bonds have been investigated. As a recent example, excellent enantioselectivities (97-99% ee) were obtained for the aminated products generated by the asymmetric amination of ot-cyanoketones with azodicarboxylates performed in the presence of a chiral thiourea-tertiary amine catalyst used at a low catalyst loading of 1 mol %. 

Gyanogen chloride in dioxane added in a slow stream with stirring and ice-saltcooling at 3-8° to a soln. of l-(N-pyrrolidyl)cyclononene and a little more than 1 mole triethylamine in the same solvent, kept at 3-6° for an additional 2 hrs. and at room temp, overnight 2-cyanocyclononanone. Y 77%, F. cyclic -cyanoketones s. M. E. Kuehne, Am. Soc. 81, 5400 (1959). 

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