Strecker reaction TMSCN

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. 

The Strecker reaction of silyl cyanide (H3SiCN) with benzaldehyde A-methylimine (PhCH=NMe), catalysed by an axially chiral 2,2 -bipyridine A,A -dioxide has been explored computationally as a model for the corresponding reaction using TMSCN, PhCH=NCH2Ph, and a biquinoline dioxide.70 The non-catalysed reaction is found to be concerted (via a five-membered ring TS), whereas the catalysis is stepwise, via a hexacoordinate hypervalent silicate. 

As an extension of the successful Strecker reaction under high pressure [83], a heterocyclic version of this reaction was investigated by us but met with very limited success. For example, 1 equivalent of 1,2-diacetylbenzene (152) with 1,2-diaminobenzene (153) and TMSCN (2.4 equivalents) afforded 5,6,11,12-tetrahydro-6,11 -dimethyldibenzo[b,f][ 1,4]diazo-cine-6,ll-dicarbonitrile (154), albeit only in 17% yield in one step. A similar reaction of cyclohexane-1,2-dione (155) with 153 produced 1,2,3,4,5,10-hexahydrophenazine-4a,10a-dicarbonitrile (156) in 13% yield along with the aromatized product, 1,2,3,4-tetrahydrophenazine (157) (Scheme 42). However, similar attempts with other diketones, such as 2,5-hexanedione, 2,3-butadiene, and 9,10-phenanthrenequinone, met with failure, either giving a complex mixture of products or well known and commercially available product possessing a pyrazine skeleton [100]. 

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. 

The assymetric Strecker reaction of diverse imines, including aldimines as well as ketoimines, with HCN or TMSCN provides a direct access to various unnatural and natural amino acids in high enantiomeric excesses, using soluble or resin-linked non-metal Schiff bases the corresponding chiral catalysts are obtained and optimized by parallel combinatorial library synthesis [93]. A rather general asymmetric Strecker-type synthesis of various imines and a, 9-unsaturated derivatives is catalyzed by chiral bifunctional Lewis acid-Lewis base aluminum-containing complexes [94]. When chiral (salen)Al(III) complexes are employed for the hydrocyanation of aromatic substituted imines, excellent yields and enatio-selectivities are obtained [94]. 

The first total synthesis of amiclenomycin, an inhibitor of biotin biosynthesis, was completed by A. Marquet and co-workers. In order to prove its structure unambiguously, both the cis and trans isomers were prepared. The L-amino acid functionality was installed by a Strecker reaction using TMSCN in the presence of catalytic amounts of Znla. The resulting O-TMS protected cyanohydrin was exposed to saturated methanolic ammonia solution, which gave rise to the corresponding a-amino nitrile. Enzymatic hydrolysis with immobilized pronase afforded the desired L-amino acid. 

Kato, N., Suzuki, M., Kanai, M., Shibasaki, M. Catalytic enantioselective Strecker reaction of ketimines using catalytic amount of TMSCN and stoichiometric amount of HCN. Tetrahedron Lett. 2004, 45, 3153-3155. 

The Strecker reaction of 51a and 51b was then investigated. Treatment of 51a with benzylamine in the presence of MS 4A in CH2CI2 affected an imine formation and, upon addition of TMSCN, furnished the a-ainino nitrile 52a in 84% yield witli a moderate selectivity aynkinti = 2 1), The same level of the stereocontrol was observed when. Y-phenoxycarbonyl derivative 51b was employed as the substrate. 

The stereochemical outcome for the Strecker reaction is rationalized by the reaction pathway described in Fig. (22). A preferred conformation of in situ generated imine 57 may be the one in which the bulky carbamate group directs toward cis to the hydrogen atom on the a-methine carbon of the imino group. TMSCN then attacks intramolecularly the Si face of 57 by means of activation through coordination of the imino group to the hypervalent silicon atom. This may result in the preferential formation of the syn isomer over the anti counterpart. 

Under these conditions, 107 was produced exclusively at the expense of 108. It was proposed that nonpolar solvent (toluene) would disfavor the charged intermediate 110, thus favoring the production of 107. For the very electron-deficient 4-amino-pyrimidine, heating a toluene solution to 100 °C in the presence of TsOH or InCl3 was necessary to ensure the formation of imidazol[l,2-a]heterocycles [60], Using TMSCN as a source of both cyanide and isocyanide equivalent, Hulme and coworkers combined the above reaction with the Strecker reaction under microwave irradiation conditions to provide highly functionalized heterocycles [61]. Other... 

The use of cyclodextrins14 has provided the ability to conduct the Strecker reaction with TMSCN in water via supramolecular catalysis involving reversible guest-host interactions. Activation of imine 16 by complexation with the hydroxyl groups present in cyclodextrins was found to work best with p-cyclodextrin. This chemically green reaction could be applied to ketones as well as aldehydes. 

Enantiopure sulfinimines (thiooxime-S-oxides) 44 have been reported to facilitate the asymmetric Strecker reaction.28 Davis found that typical cyanide sources, such as potassium cyanide and TMSCN, did not possess sufficient reactivity for addition to the sulfinimines. Product 46, however, could be obtained using the more Lewis acidic Et2AlCN. Not only did the coordination of the aluminum to the oxygen of the sulfinimine activate the imine toward nucleophilic addition, this complexation also facilitated the delivery of the nitrile (see 45), These results triggered numerous modifications and variations that have enhanced this approach to chiral a-amino acids. 

For the classical Strecker reaction conditions, there are multiple references in the literature that one could use to conduct this reaction.1,47 The following two examples illustrate the modified Strecker reaction using TMSCN and an asymmetric variation of this reaction. 

The Strecker reaction that is the nucleophilic addition of trimethylsilyl cyanide (TMSCN) to imines in water has been developed in the presence of P-CD to afford a-aminonitriles (Figure 4.15a). The use of CD precludes the use of either acid or base, and the catalyst can be recycled a number of times without loss in activity. No reaction... 

The alkali-metal-salt-catalyzed enantioselective Strecker reaction of ketimines (176) with TMSCN has been developed by employing chiral (5)-BNPNa (177) (BNP = 1,1 -binaphthyl- 2,2 -diylphosphate) and PBAP (/ -t-butyl-6>-adamantylphenol) (Scheme 48). The simplicity and facile availability of the catalyst and high enantioselectivities of the reaction made it potentially applicable in synthesis. 

Various oxazoline-based organocatalysts were prepared and applied to enantioselective Strecker reactions of different N-benzhydrylimines with TMSCN. In particular, derivative 156 allowed the synthesis a-amino nitriles in high yield and with excellent chiral induction (13CEJ14224). 

Strecker reaction using trimethylsilyl cyanide (TMSCN) as cyanide source under mild conditions, affording good yield for the final a-aminonitriles 59. The small catalytic charge used in this process is also notable (Scheme 10.16) [56]. 

The same group has also applied a similar methodology to produce carboxamides 66 through an oxidative Strecker reaction of aldehydes, amines, and TMSCN by simply modifying the work-up procedure (Scheme 10.20) [60]. 

The original protocol of a one-pot Strecker reaction was performed in water as reaction solvent, but in subsequent procedures, water has been replaced by organic solvents, such as toluene, dichloromethane, and acetonitrile, or nonconventional solvent, such as ionic liquid [68], especially with TMSCN as cyanide source, to improve the solubility of organic reagents. Although there are also examples performed in aqueous media [69], including water-containing DMF [70], polyethylene... 

Since the toxicity and volatility of HCN are high, these facts limit its extensive and practical application in organic synthesis. In this respect, a number of cyanating agents have been developed to avoid the use of toxic HCN, such as TMSCN [76], (Et0)2P(0)CN [77], Et AlCN [78], BUjSnCN [79], MeCOCN [80], K [Ee-(CN)g] [81], and acetone cyanohydrin [82]. Although TMSCN has been the most widely used in the Strecker reaction, this often requires a Brpnsted or Lewis acids or bases as catalysts [83]. 

In this field, Najera and coworkers developed more recently a three-component Strecker reaction with TMSCN in the absence of solvent and catalyst, which could potentially be applied at an industrial level (Scheme 10.31) [91]. 

The Strecker reaction has been widely studied for the synthesis of a-amino acids. Matsumoto and coworkers reported the multicomponent nncatalyzed Strecker reaction under high pressure in 2005 for the synthesis of quaternary a-amino acids 170 [86]. The reaction of ketones 168, aniline 9a, and TMSCN (169) at 0.6 GPa pressure and SO C afforded the corresponding a-aminonitriles 170 in very good to excellent yields (81-99%) (Scheme 11.36). 

Keywords Strecker reaction, a-aminonitriles, carbonyl compounds, TMSCN, Zr0Cl2.8H20, homogeneous catalyst, one-pot synthesis, multicomponent reaction (MCR), solvent-free, room temperature... 

Dekamin, M. G., and Mokhtari, Z. (2012). Highly efficient and convenirait Strecker reaction of carbonyl compounds and amines with TMSCN catalyzed by MCM-41 anchored sulfonic acid as a recoverable catalyst. Tetrahedron, 68, 922-930. 

A variety of fused 3-aminoimidazoles have been synthesized by Sc(OTf)3-catalyzed Ugi three-component coupling (3CC) reaction in methanol with or without a microwave irradiation [60, 61]. Polymer-supported Sc(OTf)3 have been used in sequential Ugi-Strecker reactions of a-amino-pyridines, aldehydes, and TMSCN... 

Sc(BINOL)2Li, a new chiral heterobimetallic complex, was shown to catalyze addition of a cyanide source (hydrogen cyanide (HCN) and trimethylsilyl cyanide (TMSCN)) to various imines enantioselectively [128]. Moderate to high conversions and enantiomeric excesses were obtained in this Strecker reaction using 10 mol% of the catalyst. High enantioselectivity (84% ee) and quantitative yield were also obtained by the addition of TMSCN to benzaldehyde. 

Following Snapper and Hoveyda s reports, Vilaivan and coworkers employed titanium complex of simple N-salicyl-P-amino alcohol (10 mol%) for catalytic asymmetric Strecker reaction of N-benzyl substituted imines with TMSCN, affording the Strecker adducts in excellent yields and up to >98% ee [229]. The presence of a protic additive is found to be essential to ensure good conversion and reaction rate (Scheme 14.97). 

The application of [(salen)Ti( x-0)]2 catalyst to the Strecker reaction of N-benzyl-idenebenzylamine was reported by North [230]. However, the enantioselectivity was rather low (30% ee). For asymmetric Strecker reaction of ketimine with TMSCN, a combined use of BINOL-Ti complex and N,N,N, N-tetramethylethylene diamine (TMEDA) gave the corresponding product with 59% ee and 80% conversion of the imine substrate [231]. 

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