BH 3 -Promoted Stereoselective β-Lithiation of N -Alkyl-2-phenylaziridines (original) (raw)

2011, The Journal of Organic Chemistry

A ziridines are widely used as versatile building blocks for the synthesis of a variety of biologically and pharmaceutically important molecules. 1 Several methods for the synthesis of aziridines have been developed, and their use as chiral building blocks has also emerged recently. 2 In the past decade, much interest has been devoted to the development of new methodologies for a regioselective lithiation and functionalization of such substrates. 3 Data from the literature indicate that N-alkyl-2phenylaziridines undergo smooth ortho-lithiation, thus showing the ability of the aziridino group to act as a directing metalation group (DMG). 4 In contrast, trans-N-alkyl-2,3-diphenylaziridines undergo exclusive R-lithiation with a stereochemistry strongly depending on the coordinating ability of the solvents. 5,6 These results have been rationalized, taking into account the crucial role of the aziridine nitrogen dynamics in controlling the R-versus ortho-lithiation competition. 7 Focusing on the deprotonation of simple N-alkyl-substituted aziridines, Vedejs 8 reported the lithiation of a simple unsubstituted aziridine by using BH 3 activation, a procedure originally developed by Kessar 9 to promote the Rmetalation of tertiary amines. A stereochemical analysis of the reaction was consistent with a dominant aziridine lithiation syn to the BH 3 group. 10 Starting from this evidence, and conscious that N-alkyl-2-phenylaziridines undergo exclusive ortho-lithiation, we decided to investigate the lithiation of the corresponding BH 3 complexes lacking the nitrogen lone pair availability. We started our investigation with a careful structural and stereochemical analysis, by NMR and DTF calculations, on the BH 3 complexes of N-alkyl-2-phenylaziridines. 2-Phenylaziridines 1a-d were prepared according to a known procedure 11 and reacted with a 1 M THF solution of BH 3 3 THF complex . The corresponding aziridino-borane complexes 2a-c were obtained as single diastereoisomers in high yields, while attempts to prepare the borane complex of the trityl aziridine 1d were unsuccessful. 12 Before evaluation of the structural analysis of the aziridinoborane complexes, some stereochemical considerations are needed. If one considers that N-alkyl-2-phenylaziridines could undergo nitrogen inversion, two diastereoisomers should, in principle, be expected in the reaction with BH 3 . Nevertheless, previous reports demonstrated that, in N-alkylmonophenylaziridines, the main diastereoisomer is the one that sets the lone pair on the same side of the phenyl ring (dr >98:2). 4-7 With this assumption in mind, the stereochemistry of BH 3 -coordinated Nalkyl-2-phenylaziridines was assigned, taking into account the results of NMR experiments and DFT calculations. reports experimental, calculated, and scaled 1 H and 13 C NMR chemical shifts (ppm) for complexes 2a and 2b bearing the phenyl group and the BH 3 group in a cis relationship. For Table 1. Synthesis of the Aziridino-Borane Complexes 2a-c aziridine 1 R borane complex 2 yield a (%) 1a t-Bu 2a >95 1b Et 2b >95 1c Ph(CH 3 ) 2 C 2c 92 1d (Ph 3 ) 3 C 2d b a Determined on pure isolated products. b The complex was not enough stable for isolation.