Amino nitriles => aldehydes

A more elaborate variation gives a generell amino acid synthesis. If the reaction between an aldehyde and cyanide is done in the presence of ammonia, the product is an a-amino-nitrile ... 

In a modification of the original method. Read (60) replaced a-amino acids with a-amino nitriles. This reaction is sometimes known as Strecker hydantoin synthesis, the term referring to the reaction employed for the synthesis of the a-amino nitrile from an aldehyde or ketone. The cycli2ation intermediate (18) has been isolated in some cases (61), and is involved in a pH-controUed equiUbrium with the corresponding ureide. 

Synthesis from Thiohydantoins. A modification (71) of the Bucherer-Bergs reaction consisting of treatment of an aldehyde or ketone with carbon disulfide, ammonium chloride, and sodium cyanide affords 2,4-dithiohydantoias (19). 4-Thiohydantoias (20) are available from reaction of amino nitriles with carbon disulfide (72). Compounds (19) and (20) can be transformed iato hydantoias. 

Strecker synthesis (Section 27.4) Method for preparing amino acids in which the first step is reaction of an aldehyde with ammonia and hydrogen cyanide to give an amino nitrile, which is then hydrolyzed. 

An a-amino acid 3 can be prepared by treating aldehyde 1 with ammonia and hydrogen cyanide and a subsequent hydrolysis of the intermediate a-amino nitrile 2. This so-called Strecker synthesis - is a special case of the Mannich reaction-, it has found application for the synthesis of a-amino acids on an industrial scale. The reaction also works with ketones to yield a, a -disubstituted a-amino acids. 

The formation of a-amino nitrile 2 is likely to proceed via a cyanohydrin 4 (an a-hydroxy nitrile) as intermediate, which is formed by the addition of hydrogen cyanide to the aldehyde 1 ... 

Alternatively a Mannich-like pathway may be followed (see Mannich reaction), where ammonia reacts with the aldehyde 1 to give an intermediate iminium species, that adds hydrogen cyanide to give the a-amino nitrile 2. The actual mechanistic pathway followed depends on substrate structure and reaction conditions. 

A very efficient and universal method has been developed for the production of optically pue L- and D-amino adds. The prindple is based on the enantioselective hydrolysis of D,L-amino add amides. The stable D,L-amino add amides are effidently prepared under mild reaction conditions starting from simple raw materials (Figure A8.2). Thus reaction of an aldehyde with hydrogen cyanide in ammonia (Strecker reaction) gives rise to the formation of the amino nitrile. The aminonitrile is converted in a high yield to the D,L-amino add amide under alkaline conditions in the presence of a catalytic amount of acetone. The resolution step is accomplished with permeabilised whole cells of Pseudomonas putida ATCC 12633. A nearly 100% stereoselectivity in hydrolysing only the L-amino add amide is combined with a very broad substrate spedfidty. 

A particularly useful variation of this reaction uses cyanide rather than HCN. a-Amino nitriles can be prepared in one step by the treatment of an aldehyde or ketone with NaCN and NH4CI. This is called the Strecker synthesisand it is a special case of the Mannich reaction (16-15). Since the CN is easily hydrolyzed to the acid, this is a convenient method for the preparation of a-amino acids. The reaction has also been carried out with NH3-I-HCN and with NH4CN. Salts of primary and secondary amines can be used instead of NH to obtain N-substituted and N,N-disubstituted a-amino nitriles. Unlike 16-51, the Strecker synthesis is useful for aromatic as well as aliphatic ketones. As in 16-51, the Me3SiCN method has been used 64 is converted to the product with ammonia or an amine. ... 

The analytical data obtained, particularly by the PUMA mass spectrometer on board Vega 1 during the flyby, indicate the presence of a large number of linear and cyclic carbon compounds, such as olefins, alkynes, imines, nitriles, aldehydes and carboxylic acids, but also heterocyclic compounds (pyridines, pyrroles, purines and pyrimidines) and some benzene derivatives no amino acids, alcohols or saturated hydrocarbons are, however, present (Kissel and Krueger, 1987 Krueger and Kissel, 1987). 

To enhance the efficiency of the cyanide addition, these workers subsequently reported a three-component asymmetric synthesis of amino nitriles that avoids the use of the previously mentioned undesirable stannane [74], Thus, as illustrated in Scheme 6.23, treatment of the requisite aniline and aldehyde with HCN (toxic but cheap and suitable for industrial use) at —45°C in the presence of 2.5 mol% 65 leads to the formation of 67 with 86 % ee and in 80 % yield. As was mentioned above in the context of catalytic asymmetric three-component alkylations of imines (see Scheme 6.18), the in situ procedure is particularly useful for the less stable aliphatic substrates (cf. 71—73, Scheme 6.23). The introduction of the o-Me group on the aniline is reported to lead to higher levels of asymmetric induction, perhaps because with the sterically less demanding aliphatic systems, the imine can exist as a mixture of interconverting cis and trans isomers. 

Strecker reactions provide one of the most efficient methods for the synthesis of a-amino nitriles, which are useful intermediates in the synthesis of amino acids and nitrogen-containing heterocycles. Although classical Strecker reactions have some limitations, use of trimethylsilyl cyanide (TMSCN) as a cyano anion source provides promising and safer routes to these compounds.133-351 Consequently, we focused our attention on tributyltin cyanide (Bu3SnCN), because Bu3SnCN is stable in water and is also a potential cyano anion source. Indeed, the Strecker-type reactions of aldehydes, amines, and Bu3SnCN proceeded smoothly in water (Eq. 9).1361 It should be noted that no surfactants are required in this reaction. Furthermore, Complete recovery of the toxic tin compounds is also possible in the form of bis(tributyltin) oxide after the reaction is over. Since conversion of bis(tributyltin) oxide to tributyltin cyanide is known in the literature, this procedure provides a solution to the problem associated with toxicity of tin compounds. 

Trimethylsilyl trichloroacetate is a useful reagent for the A-trimethylsilylation of amines284. The combined action of primary aliphatic or aromatic amines and trimethylsilyl cyanide on aliphatic or aromatic aldehydes yields a-amino nitriles (equation 93)285,286. 

Sodium cyanide-promoted condensation of aldehyde and amine to afford a-amino nitrile, which may be hydrolyzed to a-amino acid. 

Results from an alternate synthesis of an intermediate amino nitrile (similar to (R,S)-3) that uses a ketone as a reactant instead of the aldehyde 2... 

First published in 1850 [1], the Strecker reaction (Scheme 21) is a convenient tool for the synthesis of a-amino acids. Originally it was reported as a condensation of an aldehyde, ammonia and a cyanide source in buffered aqueous medium to form an a-amino nitrile, which is then hydrolysed to an a-amino acid [47, 48]. 

This work has been extended from aryl and alkyl substituted systems (42) (R = aryl, alkyl) to analogues where R is an amino group, so giving access to synthetic equivalents of the nonstabilized amino nitrile ylides (45). Adducts were obtained in good-to-moderate yield with A-methyhnaleimide (NMMA), DMAD, electron-deficient alkenes and aromatic aldehydes (27,28), and with sulfonylimines and diethyl azodicarboxylate (29). Similarly the A-[(trimethylsilyl)methyl]-thiocarbamates (46) undergo selective S-methylation with methyl triflate and subsequent fluorodesilylation in a one-pot process at room temperature to generate the azomethine ylides 47. 

A similar reaction of 70 leads to an amino nitrile ylide synthon (36,37), which reacts with a range of aromatic and heteoaromatic aldehydes to give the 2-oxazolines (71), but which fails to react with ahphatic aldehydes, simple ketones, or activated alkenes. 

When an aldehyde is allowed to react with an optically active amine and hydrocyanic acid, one of the two diastereomeric amino nitriles, (124a) or (124b), may be formed in excess. To prepare the chiral amino acids (125a) or (125b), the nitriles (124a) and (124b), respectively, are hydrolyzed with mineral acids, whereupon R is split off. However, this asymmetric synthesis of amino acids has no industrial significance. 

In our group the diastereoselective 1,2-addition of organometallic reagents to aldehyde SAMP hydrazones was employed in the synthesis of several alkaloids and we have now extended our method to the efficient asymmetric synthesis of the poison-dart-frog indolizidine alkaloids 2091 and 223J and their enantiomers via a common late-stage intermediate amino nitrile (5R,8R,8aS)-63 [45]. This amino nitrile chemistry had previously been used by Polniaszek and Belmont in the first enantioselective total syntheses of 5,8-disubstituted indolizidine alkaloids [46]. They were able to prepare the indolizidines 205A (65) from 64 in one or two steps (Scheme 1.2.15). 

The Strecker synthesis is the one-carbon homologation of an aldehyde to the a-amino nitrile. Robert Cunico of Northern Illinois University in DeKalb reports (Tetrahedron Lett. 44 8025, 2003) a modified Strecker leading directly to the amide of the a-amino acid. 

In the Strecker synthesis an aldehyde is converted to an a-amino acid with one more carbon atom by a two-stage procedure in which an a-amino nitrile is an intermediate. The a-amino nitrile is formed by reaction of the aldehyde with ammonia or an ammonium salt and a source of cyanide ion. Hydrolysis of the nitrile group to a carboxylic acid function completes the synthesis. 

Peptide thioesters (Section 15.1.10) are generally prepared by coupling protected amino acids or peptides with thiols and are used for enzymatic hydrolysis. Peptide dithioesters, used to study the structures of endothiopeptides (Section 15.1.11), may be prepared by the reaction of peptide nitriles with thiols followed by thiolysis (Pinner reaction). Peptide vinyl sulfones (Section 15.1.12), inhibitors of various cysteine proteases, are prepared from N-protected C-terminal aldehydes with sulfonylphosphonates. Peptide nitriles (Section 15.1.13) prepared by dehydration of peptide amides, acylation of a-amino nitriles, or the reaction of Mannich adducts with alkali cyanides, are relatively weak inhibitors of serine proteases. 

Shibasaki and co-workers applied (BINOL)Al(III)-derived catalyst 5a, previously developed for the cyanation of aldehydes [28], to the asymmetric Strecker reaction. This catalyst proved to be highly enantioselective for both aromatic and a,p-unsaturated acyclic aldimines (>86% ee for most substrates) (Scheme 8) [63-65]. Aliphatic aldimines underwent cyanide addition with lower levels of enantioselectivity (70-80% ee). A significant distinction of 5 relative to other catalysts is, undoubtedly, its successful application to the hydrocyanation of quinolines and isoquinolines, followed by in situ protection of the sensitive cx-amino nitrile formed (this variant of the Strecker reaction is also known as the Reissert reaction [66]). Thus, Shibasaki has shown that high enantioselectivities (>80% ee for most substrates) and good yields are generally obtainable in the Reissert reaction catalyzed by 5b [67,68]. When applied to 1-substituted... 

The original Strecker procedure is the reaction of an aldehyde with ammonia and then with hydrogen cyanide to form the a-amino nitrile. This intermediate may also be obtained by reacting the aldehyde cyanohydrin with ammonia, but a more convenient method is to treat the aldehyde in one step with ammonium chloride and sodium cyanide. The a-amino acid is obtained when the amino nitrile is hydrolysed under either acidic or basic conditions the former are usually preferred. The preparation of a-phenylglycine (R = Ph) from benzalde-hyde is typical of the general procedure (cognate preparation in Ept 5.181). 

When applied to formaldehyde, however, the reaction is somewhat anomalous in that methyleneaminoacetonitrile (CH2=N CH2-CN), the condensation product derived from the aldehyde and the amino nitrile, is formed (Expt 5.181). The free amino nitrile is obtained by careful basification of its sulphate salt, which is formed when methyleneaminoacetonitrile is treated with concentrated sulphuric acid in ethanol. Details of the hydrolysis of the amino nitrile (as the sulphate) under basic conditions are given. Barium hydroxide is used, the excess of which is finally removed by precipitation as the sulphate to facilitate the isolation of the glycine formed. 

The Strecker reaction is a three-component reaction of an aldehyde (or ketone), ammonia (86, or another amine) and hydrogen cyanide (87, or equivalents) to give a-amino nitriles and, after hydrolysis, a-amino acids (Scheme 9.16). 

As actually carried out, the aldehyde was converted to the amino nitrile by treatment with an aqueous solution containing ammonium chloride and potassium cyanide. Hydrolysis was achieved in aqueous hydrochloric acid and gave valine as its hydrochloride salt in 65% overall yield. 

The Strecker reaction [1] starting from an aldehyde, ammonia, and a cyanide source is an efficient method for the preparation of a-amino acids. A popular version for asymmetric purposes is based on the use of preformed imines 1 and a subsequent nucleophilic addition of HCN or TMSCN in the presence of a chiral catalyst [2], Besides asymmetric cyanations catalyzed by metal-complexes [3], several methods based on the use of organocatalysts have been developed [4-14]. The general organocatalytic asymmetric hydrocyanation reaction for the synthesis of a-amino nitriles 2 is shown in Scheme 5.1. 

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