The Conjugate Addition of HCN

The Aldol Cyclization 877 The Conjugate Addition of HCN 879 The Conjugate Addition of an Amine 879 The Michael Addition 880 The Mannich Reaction 882... 

Diethylaluminium cyanide is a valuable reagent for the conjugate addition of HCN to o , 3-unsaturated carboxylic acid derivatives [120]. Steroidal conjugate esters are somewhat resistant to HCN addition even with this powerful reagent and optimum yields of only 36-50% were obtained. With aj3-unsaturated acid chlorides and acid cyanides, however, the reaction proceeds smoothly in toluene at room temperature and, after hydrolysis the 0-cyanoacid was obtained in 71—73% yield. Conjugated steroidal thiocarboxylic S-esters react under similar conditions to give the product in yields of 85-87%. 

The conjugate addition of HCN to a,P-unsaturated ketones can be done using diethylaluminum cyanide, (C2H5)2Al—CN, followed by acid workup. Write the structure of the addition product for each of the following reactants. 

The 1,4 conjugate addition of HCN to a, d-unsaturated ketones has received partictUar attention, because of its selectivity in the steroid field [2S). Alkyl aluminum cyanides are used as catalysts in these reactions. Two methods have been developed which allow either thermodynamic (Equation (39 or kinetic control (Equation (40)) of the addition stereochemistry (Nagata reaction). 

Palladium-catalyzed hydrocyanation of olefins has been reported [31]. However, the corresponding reactions with conjugated dienes have not been reported explicitly. The analogous nickel-catalyzed hydrocyanation of conjugated dienes has been described [32] and is the basis for the commercial adiponitrile process. In this case, it has been shown [33] that the overall addition of HCN to the 1,3-diene occurs with cis stereochemistry consistent with path B in Scheme 8-1. 

The efficiency of diethylaluminum cyanide for conjugate addition of HCN is evident from results reported by Nagata and Yoshioka2 for the reaction of (1) to give the nitrile (2). In benzene-toluene at 0° it took only 5 min. for the reaction to... 

As expected, conjugate addition of HCN predominates leading to 3-pentenenitrile as the major product of the first step, proceeding through a nickel Tr-allyl intermediate. Some... 

Ruthenium Conjugate addition of HCN to enones R CH=CHCOR (R = -, s-, and f-alkyl, Ph R = aryl, heteroaryl, alkyl, alkenyl), catalysed by the Ru(II) complex (289a) or (289b) (0.01-0.5 mol%) in combination with PhOLi, has been shown to produce )3-cyano ketones R CH(CN)CH2COR with <98% ee at -20 to 0°C in Bu OMe. No 1,2-adducts were detected. ... 

Cyanide ion acts as a carbon nucleophile in the conjugate addition reaction. The pK of HCN is 9.3, so addition in hydroxylic solvents is feasible. An alcoholic solution of potassium or sodium cyanide is suitable for simple compounds. 

In order to obtain adiponitrile, 2 should isomerize to 4, and not to the thermodynamically more stable 3 (stabilised by the energy of conjugation). The thermodynamic ratio is 2 3 4 = 20 78 1.6 [6], The isomerization of 2 to 4 happens to be favorably controlled by the kinetics of the reactions the reaction 2 to 4 reaches equilibrium, but the reaction 2 to 3 does not. Note that the nickel complex not only is responsible for the addition of HCN but that it is also capable of catalysing selectively the isomerisation. The final step is the addition of HCN to 4 to give 5, adiponitrile. 

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). 

In Chapter 10 we discussed conjugate addition to unsaturated carbonyl compounds in contrast to direct addition to the carbonyl group. A classic illustration is the addition of HCN to butenone. Two products can be formed. 

In consequence, addition to the ethylenic carbon atom (1) often occurs in these conjugate systems with reagents that do not usually add to ethylenic double bonds. Thus the cyanide ion of HCN, the sulfite ion of bisulfites, the nitrogen of hydroxylamine and of ammonia, and the alkyl group of organometallic compounds are all... 

The reaction proceeds in general stereospecifically as a cA-addition. Equation (9) shows exemplarily the addition of deutero-HCN (DCN 34) to hex-l-yne 33. The cA-position of deuterium and the cyano group is found in both branched (35) and linear (36) products. When dimethyl acetylenedicarboxylate is used as the substrate, the product of anti-addition is formed. This indicates a change in the mechanism as a result of the electron-withdrawing effect of the two functional groups in direct conjugation with the triple bond [62]. 

In the first stage Lewis acids are absent and further hydroeyanation of the monoolefm products 3-PN 40 and 2M3BN 41 does not readily oeeur. The monoeyanation of butadiene is similar to HCN addition to olefins. An individual feature of hydrocyanation of conjugated dienes is the intermediate appearance of TT-allylic complexes 43, which participate in the successive carbon-carbon coupling. Equations (12) and (13) demonstrate the reaction of butadiene with the hydrido-nickel complex 42 leading to formation of nitrile 40 (a) and explain the generation of byproducts, i.e., the branched nitrile 41 via an alternative pathway (b) [68-70]. 

The commercial process run by Solvay Duphar, based on the work of van der Gen,41 uses an aqueous extract of almond meal for (R)-126 and the sorghum enzyme for (S)-126. Again a two-phase system (H20/Et20) is used and the rather unstable cyanohydrins, that may racemise by reversible loss of HCN, are stabilised by conversion to silyl ethers such as 129-131. The last example shows that direct is preferred to conjugate addition. 

Because hydrocyanic acid is behaving as a Bronsted-Lowry acid, it will require some species to accept a proton. Here the proton acceptor is water, as is often the case. This allows us to write the equilibrium for the HCN solution. Once it is written, we identify the conjugate pairs by noting which species differ by only the addition or subtraction of a proton. 

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