Cyanohydrin anions

The efficiency of the amination methodology of enolates with 0-phoshinylhydroxyl-amine-type reagents was further demonstrated by Boche and Schrodt in the high-yield amination of 0-(trimethylsilyl)cyanohydrin anions with 4c (Scheme 44)". 0-(Trimethyl-silyl)cyanohydrins prepared by treatment of aryl, hetaryl and conjugated aldehydes with trimethylsilyl cyanide were lithiated to the eniminates. This is a practical method that enables the easy conversion of aldehydes to iV,Ai-dimethylamides under mild conditions. 

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... 

The constant of equilibrium 22 may be calculated by several methods. A competitive method was used211 to evalute the equilibrium constant in the formation of cyanohydrin anions of substituted benzaldehydes in DMSO (equilibrium 24). 

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]. 

Cyanohydrin formation was reported for the range of reactions for which k and K have been reported in water.81 This was the first application of NBT to a carbon-carbon bond-forming reaction. The rate-determining step was taken to be the attack of cyanide on the carbonyl compound to give the cyanohydrin anion. The results are summarized in Table 9. 

This reaction can be extended to synthesis of alternating polyol chains found in polyene macrolide antibiotics. Thus reaction of the dibromide 5 with 2 equiv. of the cyanohydrin anion of 6 provides, after reductive cyanation, the protected polyol 7 in good yield. 

DKR of aldehydes via cyanohydrins One-pot (iPr)20 Acetone cyanohydrin + anion exchange resin Pseudomonas sp. lipase + 29... 

The upper half of Figure 9.9 demonstrates that acetone can also be transformed into acetone cyanohydrin (A) by the combined treatment with sodium cyanide and ammonium chloride. Ammonium chloride is a weak acid. Consequently, the protonation of the (nonvolatile) sodium cyanide to the (volatile) hydrocyanic acid occurs to a lesser extent than with the NaCN/H2S04 method (see above). However, ammonium chloride is not acidic enough to activate acetone as the carboxonium ion to the same extent as sulfuric acid. This changes the addition mechanism. As shown in Figure 9.9, it is the cyanide anions that react with the unactivated acetone. Only when the cyanohydrin anions have thus been formed does the ammonium chloride protonate them to yield the neutral cyanohydrin. 

Acid-catalyzed addition of aliphatic, aromatic or heteroaromatic cyanohydrins to ethyl vinyl ether, n-butyl vinyl ether or dihydro-4//-pyran provides base stable, protected cyanohydrin derivatives. Phase transfer catalyzed alkylation of aliphatic cyanohydrins with allylic bromides gave a-substituted a-allyl-oxyacetonitrile. Carbonyl compounds react wiA cyanide under phase transfer catalysis to give cyanohydrin anions, which are trapped by an acyl chloride or ethyl chloroformate to give acyl- or alkoxycarbonyl-protected cyanohydrins respectively. The reduction of the carbonyl group of an acyl cyanide by NaBH4 under phase transfer conditions followed by esterification serves as an alternative route to aldehyde-derived cyanohydrin esters. ... 

The alkylation of protected cyanohydrin anions constitutes an excellent method for ketone synthesis. Generally the anions are generated from aliphatic or aromatic aldehyde protected cyanohyd with LDA under nitrogen at -78 C. The addition of an alkyl halide produces the protected ketone cyanohydrin. The carbonyl group is then liberated by successive treatment with dilute acid and dilute aqueous base. This method is applicable for the synthesis of buflomedil. ... 

The classic SsAi substitution of activated aryl halides by protected cyanohydrin anions provides substituted benzophenones. Another procedure for the arylation of protected cyanohydrin anions involves the use of aromatic substrates activated as their rr-chromium tricarbonyl complexes. - Addition of the anion of (32) to the 1,3-dimethoxybenzene complex, for example, leads principally to the meta-suh-stituted isomer (33 equation 20). Preferential meta regioselectivity is also noted with other -rr-chromium tricarbonyl complexes of arenes. Other arylations of cyanohydrin anions include interesting but synthetically limited additions at the a-position of quinoline N-oxides. In a similar manner, cyanohydrin carbonates of aromatic aldehydes react with A -oxides of quinoline and isoquinoline. ... 

If X in Scheme 41 represents a cyanide group (X = CN) the rearrangement of the anion leads to a cyanohydrin anion as the product, which can yield a carbonyl function directly.The reaction is not only known for allylic ethers but also for propargylic ethers, giving access to allenic carbonyl compounds in the latter case (equation 39). ... 

Garcia et alf have described the synthesis of a-hydroxy- y-lactones by the alkylation of protected cyanohydrin anions with epoxides. 

Reaction of (50) with alkyl halides gives exclusive a-alkylation. With aldehydes and ketones, a-addi-tion again takes place to give (52) via intramolecular silyl transfer with concomitant loss of lithium cyanide (c/. 25 Scheme 30). Treatment of (52) with p-Ts0H H20 gives the cyclopentenone annelation product. The allylic cyanohydrin anion (53) also gives a-adducts upon treatment with aldehydes and ketones at -78 °C, whereas reaction with electrophiles at 0 C affords -y-adducts (c/. 25). 

The other route uses a silyl-protected cyanohydrin anion for the formation of the ketoester. The corresponding bromoester, prepared as shown in Scheme 21, reacts with the anion of a cyanohydrin to give, after hydrolysis, an ester which was transformed into trichostatin A in 4.8% overall yield. 

Formation of PQ + in alkaline solutions containing paraquat is not restricted to the simple examples noted above. Thus cyanohydrin anions are rapidly oxidized by paraquat in a sequence [(183) and (184)] which involves overall oxidation of aromatic aldehydes to... 

Metals supply a very soft electron to the C-4 of pyridines or pyridinium ions (57). Interestingly, viologens can be reduced by cyanohydrin anions (58). 

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. 

In our first study, we examined the effect of added alcohols on the solubility of benzalde-hyde in water and on the rate of the benzoin condensation in water. We saw — in a plot with 15 points - that there was a good parallel between the log of the solubility and the log of the rate constant effect (increased solubility and decreased rate with added alcohols in water). Since the effect of added alcohols on the solubility ofbenzaldehyde simply reflects the antihydrophobic role of the additives, this must also be true of the rate effects. That is, apparently there was no extra effect relating to solvation of charges in the rate changes with additives they simply reflected the fact that the transition state for the benzoin condensation -under these conditions the transition state occurs during the addition of the cyanohydrin anion to the aldehyde - is less stabilized by additives than is the starting material. Some... 

The protection of carbonyl functions by reaction with trimethylsilyl cyanide to form the cyanohydrin trimethylsilyl ethers is subject to catalysis by potassium cyanide in the presence of 18-crown-6, tetrabutylammonium cyanide or resin bound tetraalkyl-ammonium cyanide [27, 29]. The nucleophilic cyanide ion is believed to attack the carbonyl yielding a cyanohydrin anion. This anion is silylated by trimethylsilyl cyanide with generation of an equivalent of cyanide anion. The sequence is shown in equation 7.13. Accordingly, 3-pentanone and 4- -butylcyclohexanone are cyanosil-... 

Protected cyanohydrin anions also behave as acyl carbanion equivalents, and this method can be extended to aj3-unsaturated derivatives (5). The reaction of yet another type of acyl carbanion equivalent (6) with esters gives products of type (7), which are useful for the synthesis of novel heterocyclic compounds. Species of type (8 Y = 0,S), are further modified acyl carbanion equivalents, and behave towards carbonyl compounds as synthetic equivalents of the Wittig reagents PhaP = C(YR)CHO. Compounds (9) are j8-acylvinyl anion equivalents. ... 

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