Hydrogen cyanide conjugate addition

Cyanide addition has also been done under Lewis acid catalysis. Triethylaluminum-hydrogen cyanide and diethylaluminum cyanide are useful reagents for conjugate... 

The conjugate addition of hydrogen cyanide, generated in situ from KCN and acetic acid to (i-mesityl ketones, gives high yields of the corresponding oxo nitriles in aqueous ethanol (Eq. 10.19).41... 

Copper-catalyzed monoaddition of hydrogen cyanide to conjugated alkenes proceeded very conveniently with 1,3-butadiene, but not with its methyl-substituted derivatives. The most efficient catalytic system consisted of cupric bromide associated to trichloroacetic acid, in acetonitrile at 79 °C. Under these conditions, 1,3-butadiene was converted mainly to (Z )-l-cyano-2-butene, in 68% yield. A few percents of (Z)-l-cyano-2-butene and 3-cyano-1-butene (3% and 4%, respectively) were also observed. Polymerization of the olefinic products was almost absent. The very high regioselectivity in favor of 1,4-addition of hydrogen cyanide contrasted markedly with the very low regioselectivity of acetic acid addition (vide supra). Methyl substituents on 1,3-butadiene decreased significantly the efficiency of the reaction. With isoprene and piperylene, the mononitrile yields were reduced... 

Many of the synthetic routes derived for pregabalin (2) before 2003 have relied on classical chiral resolution of either an intermediate or the final racemic 3-isobutyl GABA (43). In 2003, Jacobsen and co-workers published their work on a novel enantio-selective synthesis of pregabalin (2) (Sammis and Jacobsen, 2003). The Harvard group was able to promote conjugate addition of hydrogen cyanide into the unsaturated imide... 

The addition of hydrogen cyanide (HCN) to carbon-carbon double bonds activated by electron-withdrawing groups in the presence of a base as a catalyst (a variation of the Michael Reaction) has been known for a long time. Nitriles were also obtained by hydrocyanation of branched olefins, such as isobutylene and trimethylethylene, in vapor phase reactions in particular the reactions over alumina (3) and cobalt-on-alumina (4) were reported in the late 1940s and early 1950s. Addition of HCN to conjugated dienes in the presence of cuprous salts (vapor and liquid phase) was reported as early as 1947 (5). 

There are many addition reactions of a,(3-unsaturated aldehydes, ketones, and related compounds that are the same as the carbonyl addition reactions described previously. Others are quite different and result in addition to the alkene double bond. Organometallic compounds are examples of nucleophilic reagents that can add to either the alkene or the carbonyl bonds of conjugated ketones (see Section 14-12D). Hydrogen cyanide behaves likewise and adds to the carbon-carbon double bond of 3-butene-2-one, but to the carbonyl group of 2-butenal ... 

Except for the well-documented conjugate additions of diethylaluminum cyanide,92 triethylaluminum-hydrogen cyanide and Lewis acid-tertiary alkyl isonitriles,93 examples of Lewis acid catalyzed conjugate additions of acyl anion equivalents are scant Notable examples are additions of copper aldimines (233),94, 94b prepared from (232), and silyl ketene acetals (234)940 to a,(3-enones which afford 1,4-ketoal-dehydes (235) and 2,5-diketo esters (236), respectively (Scheme 37). The acetal (234) is considered a glyoxylate ester anion equivalent. 

Androst-is-en-iy-ones (9) readily add methanol, hydrogen cyanide, etc., with stereospecific i5j8-attachment (10) of the nucleophile [265]. The stereochemistry of conjugate addition to both Ai -20-ketones and A S-i -ketones follows the same pattern as for electrophilic attack upon the A - and A -enolic derivatives respectively of 17-0x0- and 16-0x0 steroids (p. 167). AU these reactions probably depend upon a combina-... 

Addition of hydrogen cyanide to an olefin can be accomplished under catalysis with dicobalt octacarbonyl at 130° at a pressure of 25-200 atmospheres. Best results are obtained with terminal olefins, conjugated dienes, which give mainly 1,4-addition products, and with Diels-Alder adducts of cyclopentadiene, which give mixtures and/or position isomers. 

HCN also adds to alkenes in the presence of an appropriate catalyst (Arthur et al., 1954 Jackson and Level, 1982). Thus, cobalt carbonyl leads to Markownikov addition, for example, 1-propene yields isopropyl cyanide in approximately 75% yield. HCN adds to alkynes in the presence of metal complexes, and the use of a nickel complex may lead to syn addition (Jackson and Level, 1983 Jackson et al., 1988). Hydrogen cyanide reacts with conjugated dienes, the mechanism involving a TT-allyl intermediate. The course of addition is complex and may lead to more than one product (Keim et al., 1982). 

Addition of hydrogen cyanide. As one step in a total synthesis of effect conjugate addition of hydrogen cyanide to the intermediate... 

The conjugate base of hydrogen cyanide is the cyanide ion ( C=Ns). Cyanide ion is a strong base and a strong nucleophile. It attacks ketones and aldehydes to give addition products called t anohydrins. The mechanism is a base-catalyzed nucleophilic addition attack by cyanide ion on the carbonyl group, followed by protonation of the intermediate. 

Almost every nucleophilic reagent that adds at the carbonyl carbon of a simple aldehyde or ketone is capable of adding at the j8 carbon of an a,/3-unsaturated carbonyl compound. In many instances when weaker nucleophiles are used, conjugate addition is the major reaction path. Consider the following addition of hydrogen cyanide ... 

Pentenenitrile is first rapidly isomerized by the nickel catalyst to 4-pentenenit-rile. Addition of hydrogen cyanide then affords adiponitrile as the major product. This is fortunate, as the unwanted conjugated 2-pentenenitrile is thermodynamically more stable than either the 3- or the 4-isomer. The favourable initial course of the isomerization is thought to be controlled by the formation of a cyclic intermediate or transition state in which the nitrile group coordinates to nickel. 

As part of a projected synthesis of corrins, a simple synthesis of y-substi-tuted y-butyrolactams via the conjugate addition of hydrogen cyanide to unsaturated ketones is described contrary to a much earlier report, the )S-cyanohydrin (101) is not produced, but a mixture of the two butyro-lactams (102) and (103) is isolated, (103) being convertible into (102) by reaction with basic cyanide solution. Reaction of one of those, (102), with potassium t-butoxide in t-butyl alcohol gave, inter alia, the semi-corrinoid (104), These transformations are outlined in Scheme 35. 

Hydrogen cyanide also undergoes conjugate addition... 

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