Cyanation Strecker reaction

One of the most important approaches to a-amino acids is based on the Strecker reaction. Although there are already a number of catalytic asymmetric variants, the cyanation of imines still challenges modem organic chemists. 

The cyanation of imines, generally known as the Strecker reaction, has been one of the most aggressively studied transformations of asymmetric catalysis over the past several years. Very recent efforts in this area have resulted in the discovery of several highly efficient catalytic systems capable of providing a-ami-... 

The potential substrates for the Strecker reaction fall into two categories ald-imines (derived from aldehydes, for which cyanide addition results in formation of a tertiary stereocenter) and ketoimines (derived from ketones, for which addition results in a quaternary stereocenter). As in the case of carbonyl cyanation, significant differences are observed between the substrate subclasses. To date, while a few catalyst systems have been found to display broad substrate scope with respect to aldimine substrates, successful Strecker reactions of ketoimines have been reported in only two cases. As is the case for all asymmetric catalytic methodologies, the breadth of the substrate scope constitutes a crucial criterion for the application of the Strecker reaction to a previously unexplored substrate. 

Vallee reported another example of a BINOL-based Lewis acid catalyst for the asymmetric Strecker reaction of ketoimines. While a traditional (BINOL)Ti(IV)-based system provided poor enantioselectivity [61], Sc(BINOL)2Li proved to be highly enantioselective for the cyanation of N-benzyl acetophenonimine (95% ee at 50% conversion, 91% ee at 80% conversion) [62], Unfortunately, results were provided only for a single ketoimine and a single aromatic aldimine, leaving the generality of the methodology in question. 

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 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. 

An important application of oxidation of a C-H bond adjacent to a nitrogen atom is the selective oxidation of amides. This reaction proceeds in the presence of ferf-BuOOH as the oxidant and Ru(II) salts. Thus in the example of Eq. (36), the a-tert-butylperoxy amide of the isoquinoline was obtained, which is an important synthetic intermediate for natural products [138]. This product can be conveniently reacted with a nucleophile in the presence of a Lewis add. Direct trapping of the iminium ion complex by a nudeophile was achieved in the presence of trimethylsilyl cyanide, giving a-cyanated amines as shown in Eq. (37) [45]. This ruthenium/peracid oxidation reaction provides an alternative to the Strecker reaction for the synthesis of a-amino acid derivatives since they involve the same a-cyano amine intermediates. In this way N-methyl-N-(p-methoxyphenyl) glycine could be prepared from N,N-dimethyl-p-methoxyaniline in 82% yield. 

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 catalytic asymmetric cyanation of imines-the Strecker reaction-represents one of the most direct and viable methods for the asymmetric synthesis of a-amino... 

Strecker reaction to establish a new stereocenter is subject to asymmetric induction, capable of creating either a tertiary" or quaternary carbon atom in the presence of 59. The peptido-imine 60 proves to be an excellent ligand for the Ti(IV)-mediated cyanation of aldimines. On catalysis of the bicyclic guanidine 61 the addition of HCN to A-benzhydrylaldimines affords a-amino nitrile derivatives with moderate to good ee. ... 

Peptide-catalysed Cyanations Cyanhydrin Synthesis and Strecker Reactions... 

Discovered in the middle of the 19th century, the Strecker reaction is one of the earliest atom-economic multicomponent reactions. Amino nitriles were simply obtained from ammonia, hydrogen cyanide and an aldehyde. These products are important intermediates for the synthesis of natural and unnatural a-aminoacids. Due to the ever-increased demand for enantioenri-chied a-aminoacids, the asymmetric Strecker reaction has emerged as a viable synthetic method. Since the first report published in 1996, the catalytic enantioselective cyanation of preformed imines was intensively studied and several excellent reviews were devoted to this topic. ... 

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]. 

Recent developments in the catalytic asymmetric cyanation of ketimines. (c) T. Vilaivan, W. Bhanthumnauin, Y. Sritana-Anant, Curr. Org. Chem. 2005, 9, 1315-1392. Recent advances in catalytic asymmetric addition to imines and related C=N systems, (d) S. J. Connon, Angew. Chem. Int. Ed. 2008,47,1176-1178. The catalytic asymmetric Strecker reaction ketimines continue to join the fold. 

Strecker reaction A robust heterogeneous self-supported chiral titanium cluster (SCTC) catalyst applied both in batch and continuous mode [44] enabled imine cyanation as well as a three-component Strecker reaction using the corresponding aldehydes and amines under continuous flow conditions in a PBR giving aminonitriles enantiomeric excess values of up to 98%. 

However, in contrast to the relatively well-developed cyanation of aldimines, limited reports were related to the cyanation of ketoimines. In this context, Feng et al. have designed a novel Ai, A -dioxide catalyst derived from BINOL and prolinamide in order to be applied as organocatalyst for the asymmetric Strecker reaction of ketoimines with fairly wide substrate scope and excellent enantioselectivities of up to 99% ee (Scheme 3.34)." A low catalyst loading of 2 mol % combined with mild reaction conditions and an operational simplicity made this strategy facile to be used for the synthesis of pharmaceutically important chiral disubstituted a-amino nitriles. 

Inspired from the usage of cyclic peptides for the hydrocyanation of carbonyls, cyclic peptides were applied to the Strecker reaction (Table 30.3) [12, 13]. Employment of 2 to the mechanistically similar Strecker reaction did not provide any asymmetric introduction In the reaction of benzaldehyde (1) catalyzed by 2, proton transfer takes place from HCN to the imidazole residue in 2. The resulting imidazolium ion can serve as an acid catalyst for the asymmetric cyanation of 1 meanwhile, in the case of the Strecker reaction, the more basic benzaldimine (17) becomes protonated directly by HCN without interaction with the catalyst [4j. Thus, replacement of the imidazole function with the more basic guanidine turned... 

Using a-unbranched aldimines for the asymmetric Strecker reaction under PTC, somewhat lower ee s and yields were obtained than with branched analogues. These results can be ascribed to the partial imine hydrolysis and uncatalyzed cyanation of primary and secondary aldimines under PTC [44]. Therefore, N-arylsulfonyl a-amido sulfones 78 were employed for in situ generation of the imines species (Table 30.9). With catalyst 76, generally higher yields and higher enantioselectivities were obtained for various primary and secondary aliphatic N-arylsulfonyl a-amido sulfones 78. 

The Strecker reaction is an efQdent method for the preparation of a-amino acids which was first reported by Adolf Strecker over 100 years ago [120]. Now, several methods for asymmetric cyanations catalyzed by metal-complexes or organocata-lysts have been developed [121-124],... 

Asymmetric phase-transfer catalytic addition of cyanide to C=N, C=0, and C=C bonds has been recently explored, which has been demonstrated to be an efficient method toward the synthesis of a series of substituted chiral nitriles. In this context, Maraoka and coworkers disclosed an enantioselective Strecker reaction of aldimines by using aqueous KCN [140]. In this system, the chiral quaternary ammonium salts (R)-36e bearing a tetranaphthyl backbone were found to be remarkably efficient catalysts (Scheme 12.25). Subsequently, this phase-transfer-catalyzed asymmetric Strecker reaction was further elaborated by use of a-amidosulfones as precursor of N-arylsulfonyl imines. Interestingly, the reaction could be conducted with a slight excess of potassium cyanide [141] or acetone cyanohydrin [40] as cyanide source, and good to high enantioselectivities were observed. In contrast, the asymmetric phase-transfer-catalytic cyanation of aldehydes led to the cyanation products with only moderate enantioselectivity [142]. 

Furthermore, Rueping and coworkers applied their reaction conditions to the cyanation of ketimines [54]. The use of A-benzylated imines derived from aryl-methyl ketones generally gave comparable yields, but lower enantioselectivities. However, this method furnished Strecker products bearing a quaternary stereogenic center, which are valuable intermediates for the preparation of optically active a,a-disubstituted a-amino acids. 

Asymmetric Cyanation of C=N Bonds (Strecker-Type Reaction). . 121... 

Strecker-type reaction of TMS cyanide with chiral sulfinimines gives diastereoselective cyanations at the imine carbon, at —78 °C in DMF, using simple metal-free Lewis base catalysts such as tetraalkylammonium carboxylates.73... 

Aldehydes, ketones, and acetals react with allyltrimethylsilane in the presence of a catalytic amount of BiX3 (X = C1, Br, OTf) to give homoallyl alcohols or homoallyl alkyl ethers (Equation (52)).91-93 The BiX3-catalyzed allylation of aldehydes and sequential intramolecular etherification of the resulting homoallylic silyl ethers are involved in the stereoselective synthesis of polysubstituted tetrahydropyrans (Equation (53)).94,95 Similarly, these Lewis acids catalyze the cyanation of aldehydes and ketones with cyanotrimethylsilane. When a chiral bismuth(m) catalyst is used in the cyanation, cyanohydrines are obtained in up to 72% ee (Equation (54)). a-Aminonitriles are prepared directly from aldehydes, amines, and cyanotrimethysilane by the BiCl3-catalyzed Strecker-type reaction. 

Alder, cyanation, allylation, Michael reaction, and Friedel-Crafts acylation). The same catalyst was also effective in three-component reactions such as Mannich-type reactions, Strecker, and quinoline-forming reactions. The polymer catalyst was recovered and reused many times without loss of activity (Eq. 31). 

---