Cyanohydrin anions addition reactions

The above system failed entirely when nonstabilized carbanions such as ketone or ester enolates or Grignard reagents were used as carbon nucleophiles, leading to reductive coupling of the anions rather than alkylation of the alkene. However, the fortuitous observation that the addition of HMPA to the reaction mixture prior to addition of the carbanion prevented this side reaction1 extended the range of useful carbanions substantially to include ketone and ester enolates, oxazoline anions, protected cyanohydrin anions, nitrile-stabilized anions3 and even phenyllithium (Scheme 3).s... 

In both reactions cyanide has usually been employed as catalyst [231, 232], Under these conditions, the acyl anion equivalent is represented by the tautomeric form XIX of the cyanohydrin anion which results from addition of cyanide to an aldehyde (Scheme 6.104). In nature, this type of Umpolung is performed enzymatically, with the aid of the cofactor thiamine pyrophosphate 226 (vitamin Bl, Scheme 6.105) [232, 233]. 

While the addition/oxidation and the addition/protonation procedures are successful with ester enolates as well as more reactive carbon nucleophiles, the addition/acylation procedure requires more reactive anions and the addition of a polar aprotic solvent (HMPA has been used) to disfavor reversal of anion addition. Under these conditions, cyano-stabilized anions and ester enolates fail (simple alkylation of the carbanion), but cyanohydrin acetal anions are successful. The addition of a cyanohydrin acetal anion to l,4-dimethoxynaphthalene-Cr(CO)3 occnrs by kinetic control at C-/3 in THF/HMPA and leads to the O -diacetyl derivative after methyl iodide addition and hydrolysis of the cyanohydrin acetal. Monoacylation of 1,4-dimethoxynaphthalene-Cr(CO)3 has been achieved nsing the seqnence of reactions shown in eqnation (126). ... 

Benzoin condensation can be considered to occur through a formal Knoevenagel type addition (Scheme 47). The key step of the reaction is the loss of the aldehydic proton, which gives rise to the cyanohydrin anion. In this case the acidity of the proton is increased by the electron-withdrawing power of the cyano group. 

Hustedt and Pfeil in 1961 noticed the difference in sensitivity toward the presence of protic solvents between the asymmetrical synthesis induced by cinchona cations and by the enzyme [74]. In the years thereafter Pfeil and co-workers published several important contributions to the synthetic usefulness of the enzyme. They found that the presence of the tightly but not covalently bound FAD molecule in the enzyme is essential, both for its stability and for its activity. The apoenzyme is catalytically inactive, but activity can be fully regenerated by addition of FAD in its oxidized form [28]. A reaction scheme was proposed for the asymmetrical synthesis as depicted in Scheme 2, in which the carbonyl compound first forms a complex with the chiral catalyst. This complex then reacts in a rate-determining step with a cyanide ion. In a third, fast, step the complexed cyanohydrin anion is protonated by HCN. 

The most general methods for the syntheses of 1,2-difunctional molecules are based on the oxidation of carbon-carbon multiple bonds (p. 117) and the opening of oxiranes by hetero atoms (p. 123fl.). There exist, however, also a few useful reactions in which an a - and a d -synthon or two r -synthons are combined. The classical polar reaction is the addition of cyanide anion to carbonyl groups, which leads to a-hydroxynitriles (cyanohydrins). It is used, for example, in Strecker s synthesis of amino acids and in the homologization of monosaccharides. The ff-hydroxy group of a nitrile can be easily substituted by various nucleophiles, the nitrile can be solvolyzed or reduced. Therefore a large variety of terminal difunctional molecules with one additional carbon atom can be made. Equally versatile are a-methylsulfinyl ketones (H.G. Hauthal, 1971 T. Durst, 1979 O. DeLucchi, 1991), which are available from acid chlorides or esters and the dimsyl anion. Carbanions of these compounds can also be used for the synthesis of 1,4-dicarbonyl compounds (p. 65f.). 

The addition of eCN is reversible, and tends to lie over in favour of starting materials unless a proton donor is present this pulls the reaction over to the right, as the equilibrium involving the cyanohydrin is more favourable than that involving the intermediate anion (32) ... 

This reaction of aromatic aldehydes, ArCHO, resembles the Cannizzaro reaction in that the initial attack [rapid and reversible—step (1)] is by an anion—this time eCN—on the carbonyl carbon atom of one molecule, the donor (125) but instead of hydride transfer (cf. Cannizzaro, p. 216) it is now carbanion addition by (127) to the carbonyl carbon atom of the second molecule of ArCHO, the acceptor (128), that occurs. This, in common with cyanohydrin formation (p. 212) was one of the earliest reactions to have its pathway established— correctly —in 1903. The rate law commonly observed is, as might be expected,... 

Addition of a cyanohydrin acetal anion to [(benzene)Cr(CO)3] followed by reaction with allyl bromide produces the cyclohexadiene derivative (73) in 94% yield, which undergoes a Diels-Alder reaction rapidly to give a tricyclic framework (74). After quenching with methyl iodide and disassembling of the cyanohydrin group, the diketone (75) is obtained in 50% yield overall (equation 51).125 These products are obviously interesting as potential intermediates for synthesis. 

In 2000, Kagan and Holmes reported that the mono-lithium salt 10 of (R)- or (S)-BINOL catalyzes the addition of TMS-CN to aldehydes (Scheme 6.8) [52]. The mechanism of this reaction is believed to involve addition of the BI NO Late anion to TMS-CN to yield an activated hypervalent silicon intermediate. With aromatic aldehydes the corresponding cyanohydrin-TMS ethers were obtained with up to 59% ee at a loading of only 1 mol% of the remarkably simple and readily available catalyst. Among the aliphatic aldehydes tested cyclohexane carbaldehyde gave the best ee (30%). In a subsequent publication the same authors reported that the salen mono-lithium salt 11 catalyzes the same transformation with even higher enantioselectivity (up to 97% Scheme 6.8) [53], The only disadvantage of this remarkably simple and efficient system for asymmetric hydrocyanation of aromatic aldehydes seems to be the very pronounced (and hardly predictable) dependence of enantioselectivity on substitution pattern. Furthermore, aliphatic aldehydes seem not to be favorable substrates. 

Addition of acyl anion equivalents (propenal d reagents) to ketones provides general access to a -hy-droxy enones. In an application of this method to pentaimulation, the trimethylsilyl- or ethoxyethyl-pro-tected cyanohydrins of a, -enals were used." The derived tertiary acetates undergo elimination (p-TsOH/benzene) to the divinyl ketones which cyclize in the acidic reaction medium (equation 25)." In some cases the a -hydroxy or a -silyloxy enones underwent cyclization but in much lower yields. Substitution in the ring and on the double bonds is compatible. 

Anions of protected cyanohydrins of aliphatic, aromatic or a,3-unsaturated aldehydes undergo 1,4-addition to cyclic and acyclic enones. The synthetic utility of protected cyanohydrins in 1,4-addition depends on regioselectivity, since a competing reaction is 1,2-addition to Ae carbonyl group. The regioselectivity of these reactions (1,4- versus 1,2-addition) is dependent on the structure of the protected cyanohydrin, the enone and the reaction solvent. Some general principles which influence die regioselectivity can be defined. 

An interesting variant of these Michael-type additions is the 1,6-addition of the anion of type (29) to a dienyl sulfone as a route to tagetones and 1,4-addition to nitrostyrene to form 3-nitro ketones. A key step in a synthesis of 11-deoxyanthracyclinone involves the regioselective reaction of complexed styrene with lithiated protected acetddehyde cyanohydrin. ... 

The ElcB mechanism is rare in practice when the elimination reaction would result in a carbon/carbon double bond. When a carbon/oxygen double bond is to be formed then it is far more common. For example, the ElcB mechanism is found in the reverse of the cyanohydrin formation reaction. You will recall that the forward reaction involves the addition of a cyanide anion to a carbonyl group. Write down the pathway for the reverse reaction, i.e. the elimination reaction. 

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