Nitriles 3-Hydroxynitriles

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 nitrilase from cyanobacterium Synechocystis sp. PCC6803 was found to effect the stereoselective hydrolysis of phenyl-substituted /3-hydroxy nitriles to (S)-enriched /3-hydroxy carboxylic acids. The enzyme also effected the conversion of y-hydroxynitrile, albeit with lesser enantioselectivity (Table 8.10). Interestingly, this enzyme was also was found to hydrolyze aliphatic dinitriles, such that for 1,2-dicyanoethane and 1,3-dicyanopropane the... 

The hydroxynitrile lyase (HNL)-catalysed cyanohydrin reaction is a useful method to synthesize enantiopure a-hydroxy nitriles and the corresponding a-hydroxy acids. However, small ketones, such as 2-butanone, are converted with low selectivities, due to the poor discrimination between methyl and ethyl. ... 

The production of optically active cyanohydrins, with nitrile and alcohol functional groups that can each be readily derivatized, is an increasingly significant organic synthesis method. Hydroxynitrile lyase (HNL) enzymes have been shown to be very effective biocatalysts for the formation of these compounds from a variety of aldehyde and aliphatic ketone starting materials.Recent work has also expanded the application of HNLs to the asymmetric production of cyanohydrins from aromatic ketones. In particular, commercially available preparations of these enzymes have been utilized for high ee (5)-cyanohydrin synthesis from phenylacetones with a variety of different aromatic substitutions (Figure 8.1). 

Chiral cyanohydrins are versatile intermediates in the synthesis of a-hydroxy acids, /3-amino alcohols, amino nitriles, a-hydroxy ketones and aziridines. For the synthesis of enantiopure cyanohydrins, the use of hydroxynitrile lyases is currently the most effective approach.Application of an organic-solvent-free system allows thermodynamically hindered substrates to be converted with moderate to excellent yields. With the use of the highly selective hydroxynitrile lyase from Manihot esculenta, the syntheses of several acetophenone cyanohydrins with excellent enantioselectivities were developed (Figure 8.2). (5)-Acetophenone cyanohydrin was synthesized on a preparative scale. ... 

The nitrile group in the readily available a-hydroxynitriles (the cyanohydrins) may also be similarly hydrolytically converted into a carboxyl group to afford a convenient synthesis of a-hydroxy acids (Expt 5.168). 

Despite acetonitrile s feeble acidity (pATa ca 29) compared with enolizable aldehydes (67, pA s 16-17), the combination of a simple ruthenium complex, [RuCp(PPli3)2]+, and diazabicycloundecane (DBU) brings about a nitrile-selective deprotonation to give /I-hydroxynitriles (68).274 A mechanism is proposed in which DBU, aldehyde, and acetonitrile can displace triphenylphosphines, with the metal centre activating acetonitrile to convert it to an NC-CFU- ligand (proposed intermediate, 69). A nickel-diarylamidodiphosphine complex (70) also catalyses this transformation in the presence of DBU.275... 

The organoindium reagent, prepared from indium metal and bromoacetonitrile, reacts with carbonyl compounds in the presence of chlorotrimethylsilane to give /3-hydroxy nitriles (Scheme 93),336 337 Similarly, indium-mediated coupling of bromoacetonitrile or 2-bromopropionitrile with a variety of aromatic acyl cyanides affords the corresponding aromatic a-cyanoketones in moderate to good yields under mild and neutral conditions (Equation (86)).338 Carbonyl compounds are efficiently transformed into 2,2-dichloro-3-hydroxynitriles by the action of trichloroaceto-nitrile and indium(i) bromide (Scheme 94).339 Bromocyanomethylation of carbonyl compounds is also achieved by the reaction of dibromoacetonitrile and indium(i) bromide.340... 

Although nitriles lack an acyl group, they are considered acid derivatives because they hydrolyze to carboxylic acids. Nitriles are frequently made from carboxylic acids (with the same number of carbons) by conversion to primary amides followed by dehydration. They are also made from primary alkyl halides and tosylates (adding one carbon) by nucleophilic substitution with cyanide ion. Aryl cyanides can be made by the Sandmeyer reaction of an aryldiazonium salt with cuprous cyanide. a-Hydroxynitriles (cyanohydrins) are made by the reaction of ketones and aldehydes with HCN. 

You met a way of making nitriles—from HCN (or NaCN + HC1) plus aldehydes the hydroxynitrile products are known as cyanohydrins. 

In particular, the use of hydroxynitrile lyase has proved to be a general and reliable method for obtaining a-hydroxy nitriles of both configurations [22]. An interesting approach is the Upase- and baseacyl-cyanohydrin for a synthetic DKR [23]. This is a combination of two reaction systems the dynamic, base-catalyzed equiUbrium between acetone cyanohydrin, acetone, HCN, aldehyde and a racemic cyanohydrin and the lipase-catalyzed enantioselective and irreversible acylation of the hydroxyl group. The combination yields the... 

Tapper, B.A. and Butler, G.W. (1971) Oximes, nitriles and 2-hydroxynitriles as precursors in the biosynthesis of cyanogenic glucosides. Biochem.., 124, 935-41. 

Oxiranes yield oxazolines with nitriles in the presence of strong acids. The reaction proceeds with inversion, with complete stereospecificity. A new application of the Ritter reaction has been reported the opening of epimeric steroid-16,17-oxiranes in acidic medium with acetonitrile. The reactions of unsaturated hydroxynitriles formed from a-ethylenic oxiranes have been investigated. Numerous publications have appeared on the kinetics of reactions with carboxylic acids and their derivatives. ° ... 

In a new approach 3-aminopyridazines are formed from acetylenic hydroxynitriles that add hydrazine and subsequently cyclize [Eq. (19)]. The reaction may also form pyrazolines or pyrazoles, depending on the starting nitrile. 

Since 1970, a new class of cyano compounds has been isolated from certain seed oils that are of interest as some members, like cyanogenic glycosides, liberate HCN on enzymic or mild chemical hydrolysis All the authenticated compounds occur in several genera of the Sapindaceae (soapberry) family " and they can comprise up to 50% v/v of the extract, e.g. in kusum seed oil. These cyanolipids are mono- or di-esters of mono- or dihydroxy-nitriles and 4 types are known (Figure 22). The chain length of the fatty acid moiety, which may be saturated or not (e.g. commonly from oleic acid), can be C14 to C22 with C18 and C20 predominant and the double bond in type 3 can be Z or E, but structural variations are few. After hydrolysis the a-hydroxynitriles derived from types 1 and 4 are cyanogenic. In many plant species one type occurs to the virtual exclusion of the others thus type 1 accumulates in Allophyllus and Paullina spp, whereas type 2 is characteristic of... 

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