Strecker synthesis conditions

It is of course surprising that amino acids can be obtained via the Strecker synthesis, purines from the condensation of HCN, pyrimidines from the reaction of cyanoacetilene with urea, and sugars from the autocatalytic condensation of formaldehyde. The synthesis of chemical constiments of contemporary organisms by non-enzymatic processes under laboratory conditions does not necessarily imply that they were either essential for the origin of life or available in the primitive environment. However, the significance of prebiotic simulation experiments is... 

Strecker synthesis attempts have been made to optimize the reaction conditions [4b] and to achieve stereoselective syntheses [4c-hJ. Usually chiral amines such as 7 have been employed, which can, for example, on reaction with 6 be converted to the thiophene-substituted amino acid 8 [4c]. 

The H CN (or CN, if the reaction is done under basic conditions) synthon has been mainly used to extend the carbon chain by one carbon. For example, cyanide ion has been used in the synthesis of amino acids labelled in the carboxylate group. This is accomplished using the high pressure-high temperature modification of the Bucherer-Strecker synthesis. In this reaction, bisulphite addition complex of an aldehyde reacts with cyanide ion in the presence of ammonium carbonate to form a hydantoin, which is then converted into the amino acid by basic hydrolysis (equation 61). 

The addition reaction of carbon-11 labelled cyanide ion to the bisulphite addition adduct of an aldehyde has been extended to prepare carbon-11 labelled amines. Maeda and coworkers prepared both p- and m-octopamine [2-(p-and m-hydroxyphenyl)-2-hydroxyethyl-amine] from the corresponding benzaldehyde by reducing the cyanohydrin formed in the reaction between the appropriate benzaldehyde and cyanide ion both under enzymatic conditions and by the basic modification of the Bucherer-Strecker synthesis, with borane-THF. The synthesis of / -octopamine is presented in equation 64. 

As many of the classical multicomponent reactions, the Strecker synthesis also takes advantage of the versatile chemistry of the initially formed imine. The formation of the amino nitrile, however, is reversible under the reaction conditions which usually results in lower yields. This problem was elegantly solved in the Bucherer-Bergs variation,3 4-376 where the initially formed aminonitrile is irreversibly trapped by formation of a hydantoin as depicted in Scheme 1.8 (entry b). 

Recently, a general aminocatalytic synthesis of aldimines catalysed by pyrrolidine has been described. DABCO was the catalyst of choice for isomerisation of 5-hydro yl-2,3-dienoate. ° The Strecker synthesis of a-amino acids is one of the simplest and most atom economical reactions. Tri-methylsilyl cyanide has been widely used for this purpose. Recently, Feng and coworkers have used a catal) c amount of tetramethylguanidine (TMG) to carry out the Strecker reaction of aldehydes and ketones under solvent-free conditions. ... 

Since the introduction of the first peptide organocatalyst in the 1980s, a considerable number of new peptide frameworks have been developed that are able to effectively catalyse several important transformations including alcohol esterifications, 1,4-conjugate additions, aldol reactions, Strecker synthesis, asymmetric cyanohydrin synthesis and alkene epoxidation are discussed. A few successful examples of solid-supported peptides and reactions in ball milling under solvent-free conditions have been demonstrated. These methods combine the advantages of being economically and environmentally friendly processes. 

Most of the elementary reactions in the classic MCRs are equilibrium processes. Therefore, thermodynamic factors can significantly impact the reaction pathways in addition to the reaction kinetics. A classic example is the Strecker synthesis of a-amino nitrile 9 from aldehydes, amines, and cyanide (Scheme 15.5). The key step in this reaction is the nucleophilic addition of cyanide to the in situ formed iminium. However, condensation of a carbonyl compound with an amine leading to iminium is an equilibrium process, especially under aqueous conditions. Therefore, the desired addition reaction is in competition with direct addition of cyanide to the aldehyde, leading to cyanohydrin 10. However, since the formation of both 9 and 10 were reversible, only the more stable adduct 9 was produced at the expense of cyanohydrin 10 under thermodynamically controlled conditions. 

First of all, two examples of the change in selectivity of catalytic reactions performed in "silent" or ultrasound conditions should be recalled (for a discussion, see Ch. 4, p. 145). The classical paper by Ando 2 refers to the reaction between benzyl bromide and potassium cyanide on alumina in toluene. In the sonochemical reaction, the main product is benzyl cyanide, while in a silent condition it is the Friedel-Craft adduct. When the Strecker synthesis of a-amino nitriles from an aldehyde, potassium cyanide, and an amine in acetonitrile is performed with alumina and ultrasound, the main product (selectivity = 90%) is the a-amino nitrile. In the same conditions, except for the absence of ultrasoimd, the selectivity for the same product is only 64%. If ultrasound is used without alumina, the selectivity is 23%, and 6% if only stirring is used. 

Combined use of alumina and ultrasound facilitates the first step of the Strecker synthesis imder non-aqueous conditions, starting from carbonyl compounds, salts of amines, and solid potassium cyanide in acetonitrile. The desired product is formed more selectively than when the activation methods are employed separately. 

Hajipour, A. R., Ghayeb, Y., and Sheikhan, N. (2010). Zr(HS04)4 catalyzed one-pot Strecker synthesis of a-amino nitriles from aldehydes and ketones under solvent-liee conditions. J. Iran. 

Synthesis.—Optimum conditions have been systematically worked out for the preparation of the spiro-4-thiohydantoin (217) from cyclohexanone hydrolysis of (217) leads to the corresponding a-amino-acid. " This overall Bucherer-Bergs reaction is a useful alternative to the classical Strecker synthesis and hopefully the optimum conditions found will be applicable to other ketones. Hydrolysis of 5-substituted hydantoins can be effected enzymatically, giving optically active a-amino-acids of varying purity. ... 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

Strecker reactions are among the most efficient methods of synthesis of a-amino nitriles, useful intermediates in the synthesis of amino acids [73] and nitrogen-containing heterocycles such as thiadiazoles, imidazoles, etc. [74]. Although classical Strecker reactions have some limitations, use of trimethylsilyl cyanide (TMSCN) as a source of cyano anion provides promising and safer routes to these compounds [73b,75]. TMSCN is, however, readily hydrolyzed in the presence of water, and it is necessary to perform the reactions under strictly anhydrous conditions. BusSnCN [76], on the other hand, is stable in water and a potential source of cyano anion, and it has been found that Strecker-type reactions of aldehydes, amines, and BuaSnCN proceed smoothly in the presence of a catalytic amoimt of Sc(OTf)3 in water [77]. No surfactant was needed in this reaction. The reaction was assumed to proceed via imine formation and successive cyanation (it was confirmed that imine formation was much faster than cyanohydrin ether formation under these reaction conditions) again the dehydration process (imine formation) proceeded smoothly in water. 

The enantioselective total synthesis of (-)-hemiasterlin, a marine tripeptide with cytotoxic and antimitotic activity, was achieved by E. Vedejs and co-workers. The asymmetric Strecker reaction was used to construct the key tetramethyltryptophan subunit. The aldehyde substrate was first converted to the corresponding chiral imine with (R)-2-phenylglycinol under scandium triflate catalysis. The addition of tributyltin cyanide resulted in the formation of a-amino nitriles as an 8 1 mixture of diastereomers. Subsequently the cyano group was converted to a primary amide, and the chiral auxiliary was removed under catalytic hydrogenation conditions. 

Addition to C=N bond. Strecker-type synthesis, the addition of MesSiCN to imines, on extending to AT-phosphinoyl ketimines is enantioselective in the presence of 86, and the optimal conditions involve the addition of 10 mol% of MCPBA. ... 

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