Unraveling the Synthetic Utility of the Regio- and Stereoselective Lithiation of Aziridines

Abstract

The chemistry and synthetic utility of lithiated aziridines are discussed. Lithiated aziridines can be easily generated and captured by electrophiles, leading to more highly functionalized derivatives. Nitrogen dynamics and complexation phenomena play crucial roles in determining the regiochemistry of the lithiation process of aziridines and the stereochemistry of the reactions of the resulting lithiated species with electrophiles. Bench experiments combined with spectroscopic investigations and density-functional theory calculations are particularly useful in elucidating the chemistry of aziridines in their carbanionic form and in unraveling new aspects of the chemistry of aziridines.The aziridine structural motif occurs frequently in natural products and in biologically active substances, and aziridines are common intermediates in organic synthesis. 1 Aziridines are readily accessible 2 in enantiomerically enriched forms and they are mainly used as electrophiles, taking advantage of their predictable, highly regioselective, ring-opening reactions with nucleophiles. Studies on lithiated epoxides and aziridines by my group and others have also demonstrated that there are many other less conventional, but nevertheless useful, reactions that these small-ring heterocycles can undergo. Indeed, when treated with strong bases such as lithium amides or organolithiums, aziridines can undergo α-deprotonation at the aziridine ring carbons to form lithiated derivatives that can be captured with an electrophile to give more substituted products. This lithiation-electrophile trapping sequence, which has been named the aziridinyl anion methodology and has been developed over the last twenty years, parallels the oxiranyl anion methodology. [3][4][5][6] Among the methods developed for the generation of aziridinyl anions are tin-lithium exchange in organotin aziridines, desulfinylation of sulfinyl aziridines, desilylation of silylaziridines, and deprotonation of easily available parent aziridines. 4e Of these, the deprotonation of simple and easily available aziridines remains by far the most convenient and efficient method for generating α-aziridinyl anions.

Stille Coupling of an Aziridinyl Stannatrane

“…We did not investigate the dimerization pathway at the mechanistic level, but control experiments established that formation of 14 is independent of palladium. Thus, reaction of 8 with CuDPP (1 equiv, DMF, 16 h) in the absence of halide substrate or palladium source gave the same alkene 14 , a finding that implicates metal exchange between 8 and CuDPP as the initiating event leading to 14 . The undesired dimerization did not interfere in the case of the iodoacrylate coupling to 12 , presumably because the Stille pathway is relatively fast.…”

“…Evidently, the increased s -character in the Sn–C bond due to the strained ring together with the adjacent nitrogen electron pair are responsible for the relatively greater polarization in the Sn–C bond of 8 . At the extreme, such an effect might induce carbenoid generation by α-elimination and/or conversion to dimeric alkenes as observed by Hodgson et al in the case of lithiated aziridines at −78 to 0 °C . However, crude 8 was quite stable under inert conditions and survived refluxing toluene over 2 days.…”

Palladium-Catalyzed Cross-Coupling of Aziridinylmetal Species, Generated by Sulfinyl–Magnesium Exchange, with Aryl Bromides: Reaction Optimization, Scope, and Kinetic Investigations

“…In order to access a range of functionalized aziridine products, a conceptually appealing strategy is to transform an already constructed aziridine scaffold. To date, such functionalization has been achieved through the generation of aziridinyl anions followed by reaction with, typically highly reactive, electrophiles . The required aziridinyl metal species have been generated by two approaches: direct deprotonation and exchange of a suitable functional group .…”

“…The required aziridinyl metal species have been generated by two approaches: direct deprotonation and exchange of a suitable functional group . Deprotonation of aziridines with organolithium and lithium amide bases can proceed with high regio- and stereoselectivity, which is determined by the structure of the aziridine. , In a complementary, alternative approach, metal-functional group exchange has been shown to afford aziridinyl anions at the preassigned position. ,, Utilizing such aziridinylmetal intermediates, Satoh disclosed a copper(I)-mediated alkylation reaction with reactive alkyl halides . Vedejs recently reported the seminal example of catalytic cross-coupling of an aziridinyl metal species with aryl and vinyl halides (Scheme a) .…”

Synthesis ofcis-C-Iodo-N-Tosyl-Aziridines using Diiodomethyllithium: Reaction Optimization, Product Scope and Stability, and a Protocol for Selection of Stationary Phase for Chromatography

“…To date this has largely been achieved through the formation of aziridine anions followed by reaction with electrophiles. 20 Deprotonation of unstabilized monosubstituted aziridines can occur regio- and stereoselectively: occurring trans to the substituent at the least hindered position for alkyl-aziridines, or at the benzylic position for aryl-aziridines. 21 Functional group exchange has also been demonstrated to be an effective method for generating aziridinyl anions, which react with electrophiles at the predefined position.…”