Nitriles, amino

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 ... 

TABLE n-36. 2,5-DIAMINOTHIAZOLE DERfVATIVES FROM a-AMINO-NITRILES AND ISOTHIOCYANaTES. 

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. 

Chlorosulfonyl isocyanate is an excellent alternative to alkaline cyanates ia the preparation of hydantoias from stericaHy hindered or labile amino nitriles (62). Imino derivatives similar to (18) can also be obtained by addition of sonitnles to imines followed by treatment with a cyanate (63). 

Substitution of alkaline cyanates by isocyanates allows the preparation of 3-substituted hydantoias, both from amino acids (64) and amino nitriles (65). The related reaction between a-amino acids and phenyl isothiocyanate to yield 5-substituted 3-phenyl-2-thiohydantoiQS has been used for the analytical characterization of amino acids, and is the basis of the Edman method for the sequential degradation of peptides with concomitant identification of the /V-terminal amino acid. 

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. 

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. 

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. 

Several examples exist for the conversion of 5-aminothiazoles into the corresponding thiazolopyrimidines. Shaw and Butler report the formation of aminothiazole thiocarboxyamide 27 from the thioamide 26 and carbon disulphide using Cook and Heilbron s procedure. Methylation of 27 gave carboxythioimidate 28 which then reacted with sodium hydroxide to give amino-nitrile 29, and with formic acid and acetic anhydride to give the thiazolopyrimidine 30. 

Good yields of pyrido[2,3-d]pyrimidiries (37) were also oblaiiied by the action of formamide on o-amino nitriles (36). Reduction of 2-amino-4,6-dimethylnicotinitrilc yields the 3-aminomcthyl compound (38). Acylation to the 3-aoylaminomethyl derivative (39), followed by cyolization, by means of heat or phosphoryl chloride, yielded the dihydropyrido[2,3-d]pyrimidines (40). ... 

Among the most successful classes of asymmetric acyl anion equivalents are the dioxane-containing a-amino nitriles 99 introduced by Enders and coworkers. These are deprotonated by EDA, and the resulting anions act as efficient equivalents of RCO for addition to a, (3-unsaturated esters [90AG(E)179],... 

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 ... 

Reaction of cyanohydrin 4 with ammonia leads to formation of a-amino nitrile 2, which can easily be hydrolyzed to give the corresponding a-amino acid 3 ... 

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. 

Platinum, palladium, and rhodium will function well under milder conditions and are especially useful when other reducible functions are present. Freifelder (23) considers rhodium-ammonia the system of choice when reducing -amino nitriles and certain )5-cyano ethers, compounds that undergo extensive hydrogenolysis under conditions necessary for base-metal catalysis. 

Reductions of nitronitriles situated to favor interaction are apt to involve both functions (S4,93). Hydrogenation of o-nitrobenzonitrile over either palladium or platinum gave o-aminobenzamide (78), with the amide oxygen transferred from the nitro group (66). On the other hand, l-amino-2-cyanonaphthalene gave the amino amide on reduction over Pt02, but the amino nitrile over palladium (82). 

The BF3 Et20-catalyzed aziridination of compounds 47 (Scheme 3.15) with a diazo ester derived from (R)-pantolacetone gave aziridine-2-carboxylates 48 [59]. The reaction exhibited both high cis selectivity (>95 <5) and excellent diastereose-lectivity. Treatment of a-amino nitrile 49 (Scheme 3.16) with ethyl diazoacetate in the presence of 0.5 equivalent of SnCl4 afforded aziridines 50 and 51 in 39% yield in a ratio of 75 25 [60]. 

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. 

The Strecker methodology has similarly been applied to chain extension at C-6 of dialdopy-ranoses, e.g., on the D-galactohexodialdopyranose derivative 42S. When nontertiary amines are used instead of ammonia, the conversions proceed with considerable diastereoselection in favor of the (6.S )-f-glycero-diastcreomcr. The best results arc reported for benzylamine, which gives the diastereomeric amino nitriles in a ratio of 91 9. 

Diastereoselective amino nitrile formation from the following ulose may, however, be attributed to thermodynamic control. Flash chromatography of the product provides only one ri bo-derivative28. 

To a solution of 2.5 g (8.56 mmol) of methyl 4,6-0-(S/5)-benzylidene-2-deoxy-2,2-diniethyl-a-D-3-hexulopy-ranoside, in 100 mL of CH3OH in a stainless steel pressure bottle are added 7 g (130 mmol) of NI14C1 and 8 g (123 mmol) of potassium cyanide. The mixture is cooled to — 78 "C and, under an ammonia gas stream, it is stirred for 30 min. The bottle is then carefully closed and the mixture is stirred for 1 week. The CH3OH is evaporated, and the residue dissolved in CH2C l2, then filtered. Flash chromatography (CII,CI2/hexanc/EiOAc 80 19 1) affords the pure crystalline amino nitrile yield 2 g (73%) mp 152 154°C [a] ,° +1.21 (CHC13). 

This contrary stereochemistry in the Bucherer - Bergs reaction of camphor has been attributed to steric hindrance of e.w-attack of the cyanide ion on the intermediate imine. Normally, equatorial approach of the cyanide ion is preferred, giving the axial (t>Mr/o)-amino nitrile by kinetic control. This isomer is trapped under Bucherer-Bergs conditions via urea and hydan-toin formation. In the Strecker reaction, thermodynamic control of the amino nitrile formation leads to an excess of the more stable compound with an equatorial (e.w)-amino and an axial (endo)-cyano (or carboxylic) function13-17. 

Auxiliary-controlled Streeker syntheses have so far only been carried out with amines serving as the chiral components. In the first asymmetric Streeker synthesis a solution of sodium cyanide, ( — )-(S)-a-methylbeuzylamine and its hydrochloride in water was mixed with a methanolie solution of acetaldehyde and stirred for five days. Hydrolysis of the resulting amino nitrile and subsequent hydrogenolysis furnished L-alanine with 90% optical purity 38-39-85. 

The asymmetric Strecker synthesis of a-amino nitriles from Schiff bases of a-methylbenzyl-aminc is improved by the use of trimethylsilyl cyanide, instead of hydrogen cyanide and by promotion of the transformation with a Lewis acid, preferably zinc chloride43. Thus, from the butyraldimine 2, the amino nitrile is synthesized with a yield of 98.5% and an ee of 68.5%. 

Interestingly, when R1 and R2 are hydrogens, the -configurated amino nitriles 1 arc obtained, whereas one or two methoxy substituents on the aromatic ring leads to (S)-diastereomers. This surprising effect is caused by the preferential crystallization of the (R)- or the (.S )-diastereomers, respectively. If the pure diastereomers of 1 are dissolved in methanol, equilibration occurs. On concentration, the optically pure diastereomer again crystallizes from the solution45. 

In asymmetric Strecker synthesis ( + )-(45,55 )-5-amino-2,2-dimethyl-4-phenyl-l,3-dioxane has been introduced as an alternative chiral auxiliary47. The compound is readily accessible from (lS,25)-2-amino-l-phcnyl-l,3-propancdioI, an intermediate in the industrial production of chloramphenicol, by acctalization with acetone. This chiral amine reacts smoothly with methyl ketones of the arylalkyl47 or alkyl series48 and sodium cyanide, after addition of acetic acid, to afford a-methyl-a-amino nitriles in high yield and in diastereomerically pure form. 

Usually, the reaction is carried out at 60 °C in methanol. After addition of acetic acid and on cooling, the diastereomerically pure amino nitrile crystallizes from the reaction mixture. If crystallization docs not occur, the mixture is stirred in the open vessel until precipitation of the pure diastereomer takes place. 

The method is very useful for the synthesis of physiologically interesting a-mcthylamino acids, e.g., methyl dopa from the 3,4-dimethoxybenzyl derivative. The excellent stereoselection achieved in the process, however, is caused by the preferential crystallization of one pure diastereomerfrom the equilibrium mixture formed in the reversible Strecker reaction. Thus, the pure diastcrcomers with benzyl substituents, dissolved in chloroform or acetonitrile, give equilibrium mixtures of both diastereomers in a ratio of about 7 347. This effect has also been found for other s-methylamino nitriles of quite different structure49. If the amino nitrile (R1 = Bn) is synthesized in acetonitrile solution, the diastereomers do not crystallize while immediate hydrolysis indicates a ratio of the diastereomeric amino nitriles (S)I(R) of 86 1447. 

Transformation of the amino nitriles to the corresponding amino acids, with removal of the dioxane ring, is carried out in two steps. Treatment with concentrated hydrochloric acid results in the hydrolysis of both the nitrile and the acetal group, and in cyclization to the corresponding 3-substituted 5-hydroxyniethyl-3-methyl-2-oxo-6-phenylmorpholinc hydrochlorides. Oxidative cleavage with 2 N sodium hydroxide solution, air and Raney nickel at 120 CC (ca. 30 h) delivers the hydrochlorides of the free a-methylamino acids in high yield. 

---