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Enantioselective reactions of a wide variety of benzyl nitriles with N-tosylimines catalyzed by novel chiral 1,3-bis(imidazolin-2-yl)benzene-palladium(II) [Phebim-Pd(II)] complexes have afforded the respective products in high yield with good enantioselectivity. A reaction mechanism is proposed based on X-ray crystal structures of palladium complexes.
Enantioselective reactions of a wide variety of benzyl nitriles with N-tosylimines catalyzed by novel chiral 1,3-bis(imidazolin-2-yl)benzene-palladium(II) [Phebim-Pd(II)] complexes have afforded the respective products in high yield with good enantioselectivity. A reaction mechanism is proposed based on X-ray crystal structures of palladium complexes.
The enantioselective aza-Morita-Baylis-Hillman (aza-MBH) reaction of a,b-unsaturated carbonyl compounds or nitriles with imines is a powerful method for the preparation of synthetically useful chiral a-methylidene-b-amino carbonyl compounds or nitriles. Therefore, there are many reports on the catalytic enantioselective aza-MBH reaction for a,b-unsaturated carbonyl compounds.[1] However, the catalytic enantioselective aza-MBH reaction with acrylonitriles is still not fruitful, [2] even though the obtained b-amino nitriles are chiral precursors to b-amino carboxylic acids and 1,3-diamines. [3,4] The first enantioselective aza-MBH reaction of acrylonitrile with imines was reported by Shi and coworkers.[5] They reported that using organocatalysts derived from cinchona alkaloids for the reaction of imines with acrylonitrile afforded a-methylidene-b-aminonitriles in moderate yield (32-40 %) with up to 68 % ee. Adolfsson and Balan reported the three-component aza-MBH reaction between benzaldehyde, tosylamide, and acrylonitrile with 15 mol % of the same organocatalyst and 2 mol % of Ti(OiPr) 4 to give the product in 45 % yield with 53 % ee.[6] Despite the pioneering results achieved for the enantioselective aza-MBH reaction of acrylonitrile with imines, a more efficient catalytic system with regards to reactivity and selectivity is still highly desirable. However, the enantioselective aza-MBH reaction of acrylonitrile with imines is not a trivial task because of the low reactivity and high polymerization ability of acrylonitrile in comparison with a,b-unsaturated carbonyl compounds. Therefore, the enhancement of the electrophilicity of acrylonitrile by coordination of transition metal catalysts to the cyano group has become an attractive approach for the activation of acrylonitrile. Although there are many reports for the enantioselective aza-MBH reaction using chiral Lewis bases, to the best of our knowledge, there is only one report for the catalytic enantioselective aza-MBH reaction using chiral Lewis acids together with achiral Lewis bases. In 2010, Shibasaki and co-workers reported a highly enantioselective aza-MBH reaction of acrylates using La(OiPr) 3 /linked-binol complexes in combination with an achiral nucleophilic Lewis base. [7] On the other hand, we recently developed a highly enantioselective reaction of a-cyano carbanions with imines catalyzed by chiral bis(imidazoline)/palladium(II) pincer complexes. [8][9][10] In this catalyst system, palladium pincer complexes enhance the acidity of the a-protons of alkylnitriles to give palladium ketenimides, which react with imines (Scheme 1). We expected that the bis(imidazoline)/palladium system can be applied to the aza-MBH reaction of acrylonitrile with imines; the chiral palladium pincer complexes should coordinate to acrylonitrile, thus increasing its electrophilicity, then an achiral Lewis base would attack the b-position of acrylonitrile. The generated palladium ketenimide should react with imines to give chiral a-methylene-bamino nitriles. We herein report t...
Chiral b-amino nitriles are versatile synthetic intermediates that are readily transformed into optically active compounds such as b-amino acids, and 1,3-diamines. [1] The asymmetric addition of alkyl nitriles to imines provides a straightforward route to such compounds. [2] Although many methods for the asymmetric Mannich reaction have been described, [3] the use of less nucleophilic alkyl nitriles as the nitrile species is a continuing challenge; [4][5][6] one reason for this issue is the poor acidity of the a protons of alkyl nitriles. [5,6] One strategy to solve this problem is the use of an N-metalloketene imine, generated from cyanocarboxylic acid or benzyl nitrile, as an active intermediate; two catalytic asymmetric systems have been reported for such Mannich reactions. [4b,d] As an alkyl nitrile equivalent, silyl ketene imines [7] (SKIs) are competent nucleophiles that can react to form C-substituted nitriles (Scheme 1). Moreover, owing to their unique structure and ready racemization, SKIs are attractive substrates for the construction of vicinal tertiary and quaternary stereogenic carbon centers, [8] which are difficult to synthesize. [9] Since Fu and co-workers reported the first asymmetric acylation of SKIs, [10a] they have become attractive nucleophiles for asymmetric catalytic reactions. [10] The asymmetric aldol-type reaction of SKIs has been reported. [10b,c,e] However, there is only a limited number of examples of the asymmetric addition of SKIs to aldimines and the addition of SKIs to similar substrates has proven somewhat more difficult to achieve and is generally characterized by a narrow substrate scope; the only asymmetric system, which uses stoichiometric quantities of a chiral silicon Lewis acid as the promoter, was reported by Leighton and co-workers. [11] Therefore, the development of a general and efficient asymmetric Mannich reaction of SKIs is particularly desirable. We have recently developed chiral N,N'-dioxide/metal catalysts, which we used for a variety of asymmetric transformations, [12] one of which is the three-component, [13] one-pot addition of N-aryl imines. [14] Herein, we describe a practical and highly efficient Mannich reaction of SKIs to address the challenges mentioned above. A three-component, one-pot method involving the use of a chiral N,N'-dioxide scandium(III) catalyst under mild reaction conditions was developed for the synthesis of bamino nitriles. The desired products, which contain a quaternary stereogenic center, were generated in excellent yield and stereoselectivity (up to 95 % yield, > 95:5 d.r., 97 % ee). The procedure is convenient as no exclusion of air and moisture is required.In the initial study, the reaction between aldimine 1 a [15] and SKI 2 a was performed in EtOAc at À20 8C with 10 mol % of a Lewis acid catalyst, which was prepared in situ from Sc(OTf) 3 and chiral N,N'-dioxide ligand L1. The desired bamino nitrile 3 a was obtained in moderate yield and enantioselectivity and extremely low diastereoselectivity (56:44 d.r.; Table 1, entry ...
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