Cyanohydrins Subject

Hydroxyl Group. The OH group of cyanohydrins is subject to displacement with other electronegative groups. Cyanohydrins react with ammonia to yield amino nitriles. This is a step in the Strecker synthesis of amino acids. A one-step synthesis of a-amino acids involves treatment of cyanohydrins with ammonia and ammonium carbonate under pressure. Thus acetone cyanohydrin, when heated at 160°C with ammonia and ammonium carbonate for 6 h, gives a-aminoisobutyric acid [62-57-7] in 86% yield (7). Primary and secondary amines can also be used to displace the hydroxyl group to obtain A/-substituted and Ai,A/-disubstituted a-amino nitriles. The Strecker synthesis can also be appHed to aromatic ketones. Similarly, hydrazine reacts with two molecules of cyanohydrin to give the disubstituted hydrazine. 

There are expressions of uncertainty concerning the mechanism of the first step of the Strecker amino acid synthesis13-17. The reaction can proceed via the formation of an imine and subsequent nucleophilic attack of cyanide (path ). Alternatively, it has been speculated that the reaction of the aldehyde with hydrogen cyanide furnishes a cyanohydrin (path ), which then is subjected to a nucleophilic displacement of the hydroxy group by the amino function. 

Complexation of an amino acid derivative with a transition metal to provide a cyanation catalyst has been the subject of investigation for some years. It has been shown that the complex formed on reaction of titanium(IV) ethoxide with the imine (40) produces a catalyst which adds the elements of HCN to a variety of aldehydes to furnish the ( R)-cyanohydrins with high enantioselectivity[117]. Other imines of this general type provide the enantiomeric cyanohydrins from the same range of substrates11171. 

In 1903, Lapworth described his findings of the action of potassium cyanide on benzaldehyde [28], He postulated that cyanide adds to benzaldehyde to form V, followed by proton transfer of the a-labile hyd rogen, forming intermediate VI which is now referred to as an acyl anion equivalent. Addition to another molecule of benzaldehyde occurs to form VII (Scheme 1). The unstable cyanohydrin of benzoin VII then collapses to form benzoin and potassium cyanide. Additionally, Lapworth tested the reversibility of the addition of cyanide to benzaldehyde by first forming hydroxybenzyl cyanide (protonated variant of V) and subjecting it to benzaldehyde and base, in which benzoin was recovered. 

Names in small capital letters refer to the titles of individual preparations. A number in ordinary bold-face type denotes the volume. A number in bold-face italics refers to a page which gives preparative directions for substances formed either as principal products or as by-products numbers in ordinary type indicate pages on which a compound or a subject is mentioned in connection with other preparations. For example. Acetone cyanohydrin, SO, 42, 43, indicates that acetone cyanohydrin is mentioned on page 42, and that directions for its preparation are given in detail on page 43, of Volume 20. 

Cyanosilylations of carbon-oxygen and carbon-nitrogen double bonds with cyanosilanes are very important synthetic reactions since the products, cyanohydrin silyl ethers and a-amino nitriles, serve as synthetic intermediates for a variety of natural products. A number of studies on these subjects have been reported in the last decade however, this review does not deal with carbonyl and imine cyanosilylations due to the availability of recent reviews and limited... 

Cyanide ions react with aldehydes and ketones to yield cyanohydrins (Kiliani) (Fig. 2-28). Hydrolysis of the cyanohydrins gives aldonic acids, which can be reduced to aldoses. Kiliani reaction thus opens the possibility for chain lengthening of aldoses. Because of the formation, of a hydroxyl group in place of the aldehyde group a new asymmetric center is generated. It is to be observed, however, that the reaction is subject to so-called asymmetric induction, which means that the diastereoisomers are formed in unequal proportions. 

Carbonyl addition reactions include hydration, reduction and oxidation, the al-dol reaction, formation of hemiacetals and acetals (ketals), cyanohydrins, imines (Schiff bases), and enamines [54]. In all these reactions, some activation of the carbonyl bond is required, despite the polar nature of the C=0 bond. A general feature in hydration and acetal formation in solution is that the reactions have a minimum rate for intermediate values of the pH, and that they are subject to general acid and general base catalysis [121-123]. There has been some discussion on how this should be interpreted mechanistically, but quantum chemical calculations have demonstrated the bifunctional catalytic activity of a chain of water molecules (also including other molecules) in formaldehyde hydration [124-128]. In this picture the idealised situation of the gas phase addition of a single water molecule to protonated formaldehyde (first step of Fig. 5) represents the extreme low pH behaviour. 

This nitrilase dynamic kinetic resolution (DKR) methodology depends on the availability of highly enantioselective biocatalysts that generate a minimum amount of amide. This latter issue may seem trivial and has long been disregarded somewhat, but reports of modest amounts of amide co-products date back to the early days of nitrilase enzymology. Only recently has the subject come under more intense scrutiny [3-5] and has a relationship with the stereochemistry of the nitrile been demonstrated [3, 5]. Hence, we set out to investigate the enantiomer and chemical selectivity of nitrilases in the hydrolysis of a representative set of cyanohydrins. 

Three cyanohydrins (la-c) (see Table 16.1) were subjected to hydrolysis in the presence of a number of nitrilases (Figure 16.2). The reactants included the standard substrate mandelonitrile (la) and its o-chloro derivative (lb), which is of... 

To aqcuire more insight in amide formation we undertook to study the hydrolysis of enantiomerically pure cyanohydrins. Nitrile le racemises too readily but the stereochemical integrity of (R)- and (S)-la could be maintained with careful adjustment of the reaction conditions (pH 6, 0°C). Thus, enantiomerically pure (R)- and (S)-la were subjected to hydrolysis in the presence of PfNLase (see Figure 16.9) [5]. It became clear that only 11% of amide was formed from the (R)-enan-tiomer, whereas the (S)-enantiomer was hydrolyzed into 55% amide and 45% acid under otherwise identical conditions (see Figure 16.9). Stereochemical integrity was fully maintained under the reaction conditions and 3a and 4a were formed with complete retention of configuration, as would be expected. 

Diketones often are protected as enol ethers or enamines and these selectively functionalized compounds may be subjected to complementary transformations (Scheme 94). Also silylenes can be prepared from diketones and -hydroxycarbonyl compounds by reaction with dimethyldicyanosilane. Naturally, these blocking groups are relatively sensitive to hydrolysis. On the other hand, partial solvolysis can open a route to monoprotected derivatives (e.g. 101), usually blocked at the sterically less demanding carbonyl function as 0-silyl cyanohydrins (see Scheme 95). Deprotection is finally achieved with silver fluoride in THF. 

Amines. Chiral a-amino acids are obtained from cyanohydrins via a Mitsunobu reaction employing A-f-butoxycarbonyl-A-(2-trimethylsilyl)ethylsulfonamide as the nucleophile. The a-aminonitrile derivatives thus generated are hydrolyzed with acid. By means of an intramolecular displacement (3-hydroxy acids are transformed into (3-amino acids. Thus, subjecting the derived 0-benzylhydroxamides to Mitsunobu reaction conditions leads to (3-lactams which are readily processed (LiOH H, Pd/C). 

The higher-carbon sugars formed the subject matter of the first review to appear in this Series on that occasion, particular attention was devoted to the Fischer cyanohydrin synthesis which, until 1942, had been the only method available for preparing these sugars. Since that time, considerable advances have been made in the field of the higher sugars, notably in the development of new synthetic methods and in determination of the role played by heptoses, especially sedoheptulose, in natural systems. Moreover, the recently reported isolations of the first naturally occurring... 

Radical-mediated deiodination, methanolysis of the acetate and subsequent oxidation of the resulting alcohol furnished the ketone 43 in 87% total yield. Transformation of 43 into the corresponding cyanohydrin acetate under ordinary conditions resulted in the formation of a diastereomeric mixture 44 and 45. However, only the kinetically favored cyanohydrin acetate 44 was obtained when treated with hydrogen cyanide and pyridine. Treatment of the nitrile 44 with HCl gas afforded the amide 46, which was subjected to alkaline hydrolysis followed by esterification of the resulting carboxyhc acid with diazomethane to furnish 5 in 11% overall yield from 27. 

Scheme 19 depicts an experimental test for the detection of non-equilibrium radical reactions. At issue was whether there would be a complete equilibration of the radical intermediates (2ax and 2eq) under the reaction conditions. Each diastereomeric cyanohydrin (lax or leq) was subjected separately to various reductive decyanation conditions and the product ratios (3ax 3eq) were determined. It was found that each... 

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