Hydroxy nitriles from aldehydes

A cyanohydrin is an organic compound that contains both a cyanide and a hydroxy group on an aUphatic section of the molecule. Cyanohydrias are usually a-hydroxy nitriles which are the products of base-cataly2ed addition of hydrogen cyanide to the carbonyl group of aldehydes and ketones. The lUPAC name for cyanohydrias is based on the a-hydroxy nitrile name. Common names of cyanohydrias are derived from the aldehyde or ketoae from which they are formed (Table 1). 

Oxynitrilase (Hydroxy Nitrile Lyase, HNL) Cyanohydrins from Aldehydes... 

The hydroxy acids obtained from aldehydes will contain the group,. —CH(OH) —COOH, and are thus secondary alcohols while those obtained from ketones will contain the group, =C(OH) —COOH, and are tertiary alcohols. These reactions are of especial importance in connection with the poly-hydroxy aldehydes and ketones, which, as we shall find, are the sugars. The cyan hydrines, or hydroxy acid nitriles, which are the intermediate products in these reactions, are not isolated as such, the reaction being completed without interruption. 

From Aldehydes.— Aldehydes and ketones by the hydrogen cyanide reaction yield cyan-hydrine compounds which are nitriles of hydroxy acids. When such an hydroxy acid nitrile is treated with ammonia the hydroxyl group is replaced by the amino group forming the nitrile of the amino acid, the amino acid itself being obtained on hydrolysis of the nitrile. 

The one-pot synthesis of Y-hydroxy-a, 3-unsaturated nitriles 82 starting from aldehydes 49 and arylsulfonylacetonitriles 79 has been carried out in the presence of Si(), (Cll ) , Mu. (Scheme 3.23). ... 

Aromatic aldehydes react with sodium hydrogen sulfite to yield bisulfite compounds. Further reaction with sodium cyanide forms the hydroxy nitrile (cyanohydrin), which can sometimes be formed directly from the aldehyde by reaction with hydrogen cyanide (Scheme 6.11). 

Enantioselective cyanomethylation. Cyanomethylzinc bromide, prepared by reaction of BrCH2CN with Zn/Cu, adds to aryl aldehydes in the presence of (S)-l (1 equiv.) to give / -hydroxy nitriles in 87-93% ee. If only 0.3 mol% of (S)-l is present the optical yield is markedly decreased (in the case of QIlsCHO cc falls from 93 to 78%). Therefore, 1 serves both as a ligand and a catalyst. 

MJnsaturated acids are rarely formed from -hydroxy acids by means of dehydrating agents, which, instead, afford lactides and anhydrides or, with loss of formic acid, aldehydes. However,, / -unsaturated nitriles can be obtained from a-hydroxy nitriles (cyanohydrins) by means of thionyl chloride45 or phosphorus(v) oxide,46 and are readily hydrolysed to the corresponding <%,/ -unsaturated acids. 

Very closely related to decarbonylation of an -hydroxy acid is the Wohl degradation, in which an -hydroxy aldehyde is degraded to the aldehyde with one fewer carbon atoms. This starts from the oxime, which is converted by removal of water into the hydroxy nitrile, whence elimination of hydrogen cyanide — analogous to that of carbon monoxide and water from an -hydroxy acid — affords the lower aldehyde ... 

Carbonyl compounds from a-amino nitriles. A synthesis of a-hydroxy enones from the a-amino nitrile derivatives of enals starts from alkylation with aldehydes and the hydrolysis of the products. ... 

Optically active aldehydes are available in abundance from amino and hydroxy acids or from carbohydrates, thereby providing a great variety of optically active nitrile oxides via the corresponding oximes. Unfortunately, sufficient 1,4- or 1,3-asymmetric induction in cycloaddition to 1-alkenes or 1,2-disubstituted alkenes has still not been achieved. This represents an interesting problem that will surely be tackled in the years to come. On the other hand, cycloadditions with achiral olefins lead to 1 1 mixtures of diastereoisomers, that on separation furnish pure enantiomers with two or more stereocenters. This process is, of course, related to the separation of racemic mixtures, also leading to both enantiomers with 50% maximum yield for each. There has been a number of applications of this principle in synthesis. Chiral nitrile oxides are stereochemicaUy neutral, and consequently 1,2-induction from achiral alkenes can fully be exploited (see Table 6.10). 

In basic chemicals, nitrile hydratase and nitrilases have been most successful. Acrylamide from acrylonitrile is now a 30 000 tpy process. In a product tree starting from the addition of HCN to butadiene, nicotinamide (from 3-cyanopyridine, for animal feed), 5-cyanovaleramide (from adiponitrile, for herbicide precursor), and 4-cyanopentanoic acid (from 2-methylglutaronitrile, for l,5-dimethyl-2-piperidone solvent) have been developed. Both the enantioselective addition of HCN to aldehydes with oxynitrilase and the dihydroxylation of substituted benzenes with toluene (or naphthalene) dioxygenase, which are far superior to chemical routes, open up pathways to amino and hydroxy acids, amino alcohols, and diamines in the first case and alkaloids, prostaglandins, and carbohydrate derivatives in the second case. 

A simultaneous reduction-oxidation sequence of hydroxy carbonyl substrates in the Meerwein-Ponndorf-Verley reduction can be accomplished by use of a catalytic amount of (2,7-dimethyl-l,8-biphenylenedioxy)bis(dimethylaluminum) (8) [33], This is an efficient hydride transfer from the sec-alcohol moiety to the remote carbonyl group and, because of its insensitivity to other functionalities, should find vast potential in the synthesis of complex polyfunctional molecules, including natural and unnatural products. Thus, treatment of hydroxy aldehyde 18 with 8 (5 mol%) in CH2CI2 at 21 °C for 12 h resulted in formation of hydroxy ketone 19 in 78 % yield. As expected, the use of 25 mol% 8 enhanced the rate and the chemical yield was increased to 92 %. A similar tendency was observed with the cyclohexanone derivative. It should be noted that the present reduction-oxidation sequence is highly chemoselective, and can be utilized in the presence of other functionalities such as esters, amides, rert-alco-hols, nitriles and nitro compounds, as depicted in Sch. 10. 

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