Cyanide addition to imines

Zr-Catalyzed Enantioselective Cyanide Additions to Imines (Strecker Reactions)... 

Catalytic asymmetric cyanide addition to imines constitutes an important C—C bondforming reaction, as the product amino nitriles may be converted to non-proteogenic a-amino acids. Kobayashi and co-workers have developed two different versions of the Zr-catalyzed amino nitrile synthesis [73]. The first variant is summarized in Scheme 6.22. The bimetallic complex 65, formed from two molecules of 6-Br-binol and one molecule of 2-Br-binol in the presence of two molecules of Zr(OtBu)4 and N-methylimidazole, was proposed as the active catalytic species. This hypothesis was based on various NMR studies more rigorous kinetic data are not as yet available. Nonetheless, as depicted in Scheme 6.22, reaction of o-hydroxyl imine 66 with 5 mol% 65 and 1—1.5 equiv. Bu3SnCN (CH2C12, —45 °C) leads to the formation of amino nitrile 67 with 91 % ee and in 92 % isolated yield. As is also shown in Scheme 6.22, electron-withdrawing (— 68) and electron-rich (—> 69), as well as more sterically hindered aryl substituents (— 70) readily undergo asymmetric cyanide addition. 

Scheme 6.22. Zr-catalyzed enantioselective cyanide addition to imines in the presence of Bu3SnCN.

Optically active a-amino acids are prepared by a cyanide addition to imines, known as the Strecker reaction. Several organobase catalysts and metal complex catalysts have been successfully applied to the asymmetric catalytic Strecker amino... 

For detailed studies regarding the mechanism of the Ti-catalyzed cyanide additions to imines promoted by amino acid-based ligands, see Josephsohn NS, Kuntz KW, Snapper ML, Hoveyda AH (2001) J Am Chem Soc 123 11594... 

Like the nitronate ion, the cyanide ion is synthetically equivalent to the aminomethyl carbanion (CH2NH2) , because of the possible reduction of - CN to the - CH2NH2 group. Consequently, the addition of cyanide ion to imines to give a-aminonitriles (Strecker-type reaction) is a viable route to 1,2-diamines. As a matter of fact, a number of diastereoselective and catalytic... 

Cycloaddition to give heterocycles IV. ADDITION TO IMINES AND CYANIDES... 

As the follow up to our studies in connection to the development of Ti-cat-alyzed cyanide additions to meso epoxides [4], we developed the corresponding catalytic enantioselective additions to imines [5]. A representative example is shown in Scheme 1 chiral non-racemic products maybe readily converted to the derived cx-amino acids (not available through catalytic asymmetric hydrogenation methods). In these studies, we further developed and utilized the positional optimization approach effected by examination of parallel libraries of amino acid-based chiral ligands (e.g., 1 and 2). Thus, the facile modularity of these ligands and their ease of synthesis were further exploited towards the development of a new catalytic enantioselective method that delivers various ar-... 

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... 

In 1850, A. Strecker accidently accomplished the first synthesis of the amino acid alanine by mixing of acetaldehyde, ammonia, and HCN and subsequent hydrolysis of the formed adduct [1]. Whereby this three-component-reaction is in general known as the Strecker reaction, the addition of a cyanide source to a preformed imine species is often referred to as the modified Strecker reaction, The so-formed a-amino nitriles, or from cyanide addition to carbonyl compounds the so-obtained cyanohydrins, are versatile building blocks that can be converted, for example, into a-hydroxy carbon acids, amino acids, amino alcohols and diamines. 

Like the Strecker synthesis, the Ugi reaction also involves a nucleophilic addition to an imine as the crucial step in which the stereogenic center of an a-amino acid derivative is formed4. The Ugi reaction, also denoted as a four-component condensation (A), is related to the older Passerini reaction5 (B) in an analogous fashion as the Strecker synthesis is to cyanohydrin formation. In both the Ugi and the Passerini reaction, an isocyanide takes the role of cyanide. 

The addition of cyanide to imines, the Strecker reaction, constitutes an interesting strategy for the asymmetric synthesis of a-amino acid derivatives. Sigman and Jacobsen150 reported the first example of a metal-catalyzed enan-tioselective Strecker reaction using chiral salen Al(III) complexes 143 as the catalyst (see Scheme 2-59). 

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. 

Scheme 6.24. Representative asymmetric additions of cyanide to imines promoted by non-Zr catalysts.

The asymmetric reactions discussed in this chapter may be divided into three different types of reaction, as (1) hydrometallation of olefins followed by the C—C bond formation, (2) two C C bond formations on a formally divalent carbon atom, and (3) nucleophilic addition of cyanide or isocyanide anion to a carbonyl or its analogs (Scheme 4.1). For reaction type 1, here described are hydrocarbonyla-tion represented by hydroformylation and hydrocyanation. As for type 2, Pauson-Khand reaction and olefin/CO copolymerization are mentioned. Several nucleophilic additions to aldehydes and imines (or iminiums) are described as type 3. 

Imine intermediates can be trapped by an added nucleophile. However the only reactions of general preparative value are those in which a carbon-carbon bond is formed. In most other cases the product is unstable under the reaction conditions, reverting to the imine which reacts further. Reactions are best carried out in the flow through cell devised by Moinet and Raoult, illustrated in Figure 8.1 [87]. This cell permits total oxidation of tlie substrate in one pass through the porous anode, tlius exposing the product to further oxidation for only a short time, a-aminonitriles are obtained when cyanide ion is added to the electrolyte [88, 89]. In the case of piperidine ring oxidation, addition to the imine is from the less hindered... 

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