Lithiation of N -Alkyl-( o -tolyl)aziridine: Stereoselective Synthesis of Isochromans § (original) (raw)

Synthesis of Optically Active Arylaziridines by Regio- and Stereospecific Lithiation of N -Bus-Phenylaziridine

Organic Letters, 2009

r,r-Disubstituted aziridines can be produced in good yields by selective lithiation of N-tert-butylsulfonyl-2-phenylaziridine (n-BuLi/TMEDA, Et 2 O) at the benzylic position and subsequent trapping with a range of electrophiles. Repetition of the lithiation/electrophilic trapping sequence provides a stereocontrolled route to trisubstituted aziridines. Using (R)-N-tert-butylsulfonyl-2-phenylaziridine, the r,r-disubstituted aziridines can be produced as single enantiomers (er >98:2), indicating that the intermediate organolithium is configurationally stable. Efficient aziridine ring-opening reactions leading to 1,2-diamines and 1,4-diamines are also reported.

BH 3 -Promoted Stereoselective β-Lithiation of N -Alkyl-2-phenylaziridines

The Journal of Organic Chemistry, 2011

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.

Synthesis and lithiation of oxazolinylaziridines: The N-substituent effect

Tetrahedron, 2005

The preparation of N-substituted oxazolinylaziridines and their deprotonation to afford the corresponding aziridinyllithiums is described. The chemical and configurational stability of the lithiated species depends on the N-substituent on the aziridine ring. The trapping with carbonyl compounds of (R*,S*) configurated oxazolinylaziridines is an interesting route for the preparation of functionalised a,b-aziridino-g-lactones. q

(Heteroarylchloromethyl)lithiums as Darzens Reagents: Synthesis of Heteroarylaziridines

Journal of Organic Chemistry, 1995

Like oxiranes, aziridines are highly strained compounds.' The ring strain makes them susceptible to ringopening reactions that dominate their chemistry and give them the ability to act as useful synthetic intermediates for the preparation of a great variety of organic compounds, such as alkaloids,2 amino acids,3 aminosugars: antibiotics: aminophosphonic acids: homoallylic amines,' labeled propynylglycine,s (tosy1amino)carbonyl comp o u n d~,~ and pyrrolidines.1°

Expedient synthesis of substituted (S)-N-(α)-methylbenzylaziridines

We report for the first time that after O-acylation the conjugate addition products of (S)-N-(a-methylbenzyl)hydroxylamine undergo an efficient diastereoselective 3-exo-tet ring-closure reaction affording 2-and 2,3-disubstituted-N-alkylaziridines in good to excellent yields.

On the lithiation of oxazolinylaziridines

Tetrahedron Letters, 2003

Lithiated N-sulfonyloxazolinylaziridines 6a and 7a, generated by deprotonation of the corresponding aziridines 6 and 7 with sec-BuLi/TMEDA at −98°C in THF, were found to be chemically and configurationally stable to be stereospecifically captured by electrophiles, while warming up to rt resulted in the formation of oxazolinylazirine 15. In contrast, lithiation of N-phenyloxazolinylaziridines 8 and 9 led to oxazolinylenamine 18. Tricyclic aziridines 10 and 11 resulted from an intramolecular addition of the aziridinyllithium 6a to the phenyl ring of the benzenesulfonyl group.

Expedient synthesis of substituted (S)-N-(?-methylbenzyl)aziridines

Chemical Communications, 2006

We report for the first time that after O-acylation the conjugate addition products of (S)-N-(a-methylbenzyl)hydroxylamine undergo an efficient diastereoselective 3-exo-tet ring-closure reaction affording 2-and 2,3-disubstituted-N-alkylaziridines in good to excellent yields.

Directed ortho lithiation of N-alkylphenylaziridines

Organic Letters, 2005

The ortho lithiation−trapping sequence of phenylaziridines is described. This methodology, which counts on the ability of the aziridino group to act as a directed metalation group (DMG), provides an easy access to functionalized arylaziridines as well as to phthalans and phthalides. The importance of the aziridine N-substituent in this DoM reaction is stressed as well.

Synthesis of oxazolinyl aziridines

Tetrahedron Letters, 1999

Aziridinyllithiums 4a and 4b, which are stable at low temperature, can be generated by deprotonation of 3a and 3b. Oxazolinyl aziridines 5a-j and 6a-b have been prepared by the reaction of oxazolinyl aziridinyllithiums 4a and 4b with electrophiles. Aziridines 6c and 6d were, instead, synthesized by a Darzens-like reaction from 2-(1-chloroethyl)-2-oxazoline lb.