Cyanations imines

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). 

The complex [Co(NH3)5(OS02CF3)]2+ undergoes triflate substitution by cyanate and condensation with acetone to form the unusual bis-bidentate imine complex (213)917 in a reaction reminiscent of the classic Curtis condensation of acetone with ethylenediamine. Apart from the novelty of the synthesis, the reported crystal structure was only the second of a CoN6 complex bearing a cyanate ligand. 

Complexation of an amino acid derivative with a transition metal to provide a cyanation catalyst has been the subject of investigation for some years. It has been shown that the complex formed on reaction of titanium(IV) ethoxide with the imine (40) produces a catalyst which adds the elements of HCN to a variety of aldehydes to furnish the ( R)-cyanohydrins with high enantioselectivity[117]. Other imines of this general type provide the enantiomeric cyanohydrins from the same range of substrates11171. 

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. 

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. 

Diones are normally synthesized from /3-hydroxy acids in two steps first, conversion into carbamates by reaction with sodium cyanate, and then cyclization with thionyl chloride (Scheme 103) (54JCS839). Alternative preparations utilize oxetanes, which may be combined either with isocyanates in the presence of boron trifluoride (68JAP6808278) or with S-alkylthioureas (Scheme 104) (69ZOR1844). In the last example the initial products are imines (224) which may readily be hydrolyzed to the required diones. Similar methods can be applied to the synthesis of tetrahydro-l,3-thiazine-2,4-diones, and, for instance, the 4-oxo-2-thioxo derivative (225) is obtained from /3-propiolactone and dithiocarbamic acid (Scheme 105) (48JA1001). 

Keywords Cyanation, a-Cyanohydrin, a-Aminonitrile, Cyanide, HCN, TMSCN, Lewis acid, Metal-free, Organocatalyst, C=0 bond, C=N bond, Strecker, Reissert, Aldehydes, Ketones, Imines, Aldimines, Ketoimines... 

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. 

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 Feng group showed that organic molecules without an imine bond also seem to be able to catalyze the cyanation of imines [14]. In the presence of (stoichiometric) amount of a chiral N-oxide, 19, addition of trimethylsilylcyanide to several types of aldimine gave the desired a-amino nitriles with enantioselectivity up to 73% ee [14]. For example, (S)-4a is obtained in 95% yield and with 58% ee (Scheme 5.10). In addition to medium enantioselectivity, a drawback of this method is the need for stoichiometric amounts of the chiral N-oxide. The use of trimethylsilylcyanide is also less recommendable than HCN from both atom-economical and industrial considerations. 

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... 

The hydrocyanation of alkenes [1] has great potential in catalytic carbon-carbon bond-formation because the nitriles obtained can be converted into a variety of products [2]. Although the cyanation of aryl halides [3] and carbon-hetero double bonds (aldehydes, ketones, and imines) [4] is well studied, the hydrocyanation of alkenes has mainly focused on the DuPont adiponitrile process [5]. Adiponitrile is produced from butadiene in a three-step process via hydrocyanation, isomerization, and a second hydrocyanation step, as displayed in Figure 1. This process was developed in the 1970s with a monodentate phosphite-based zerovalent nickel catalyst [6],... 

The combination of Me2AlCN and BINOL (1.2 equiv.) also induced the cyanation of imines derived from benzaldehyde, affording the Strecker products in up to 70% ee [76]. Finally, N-allylbenzaldimines have been reported to react with HCN in the presence of chiral ammonium salt catalysts [77, 78]. 

An interesting approach to the generation of l4C-labeled rivastigmine needed for in vivo studies was published by Novartis (Scheme 11).57 The synthesis of 14C-labeled 2 was initiated by l4C-labeled cyanation of iodide 48 to provide 3-methoxybenzo-14C-nitrile (49) in 80% yield. Copper-mediated addition of methyl magnesium bromide to nitrile 49 formed an imine that was hydrolyzed with aqueous HC1 to the corresponding... 

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. 

Nakamura, S., Sato, N., Sugimoto, M., Toru, T. A new approach to enantioselective cyanation of imines with Et2AICN. Tetrahedron Asymmetry 2004, 15,1513-1516. 

Likewise, imine 118 was transformd into 120, a mimic of a conformationally rigid glutamic acid, via cyanide 119 (see Scheme 9.25) [50]. 1-Phenyl-1,1-difluoroacetaldehyde imine 121 was also used as a precursor of 3,3-difluorophenylalanine 123 via cyanide 122, but no diastereoselectivity was observed in the cyanation step (see Scheme 9.26) [51]. 

Base-catalyzed deprotonation-alkylation of trifluoroalanine is not easy because a-trifluoromethylated carbanions readily undergo defluorination in general [90]. Therefore, a-alkylated trifluoroalanines have been prepared either by alkylation of imines obtained from trifluoropyruvates [54, 57]or by Strecker cyanation [56] to trifluoroketimines fol-... 

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