Elsevier

Tetrahedron: Asymmetry

Volume 17, Issue 22, 27 November 2006, Pages 3135-3143
Tetrahedron: Asymmetry

Aziridin-2-yl methanols as organocatalysts in Diels–Alder reactions and Friedel–Crafts alkylations of N-methyl-pyrrole and N-methyl-indole

https://doi.org/10.1016/j.tetasy.2006.11.028Get rights and content

Abstract

A series of enantiomerically pure aziridin-2-yl methanols have been synthesized from aziridine-2-carboxylic esters and have been tested as organocatalysts in Diels–Alder reactions and Friedel–Crafts alkylations of N-methyl-pyrrole and N-methyl-indole using α,β-unsaturated aldehydes. Moderate to good ee’s have been obtained. The coupling of N-methyl-pyrrole with crotonaldehyde and cinnamaldehyde using (2S,3S)-3-methylazirin-2-yl(diphenyl)methanol-TFA salt as the catalyst gave the best results (ee 75%).

Introduction

Functionalized aziridines are highly valuable three-membered ring systems in modern synthetic chemistry, because of their widely recognized versatility as synthetic building blocks and their use in functional group transformations.1 In synthetic transformations, their utility is mostly associated with stereo- and regio-controlled ring-opening reactions of the highly strained three-membered ring.2 Moreover, chiral aziridines can serve as a source of chirality in stereocontrolled reactions and have been employed both as ligands and chiral auxiliaries in asymmetric synthesis.2(d), 3 Aziridine-2-carbinols of type 1 have been used in the preparation of oxazaborolidines, which are mediating reagents in the enantioselective reduction of ketones.4 It has been demonstrated that the N-trityl derivative5 and a number of N-alkylated derivatives6 of 1 are effective catalysts in the enantioselective addition of diethylzinc to aromatic and aliphatic aldehydes. N-Trityl-azirin-2-yl-(diphenyl)methanol 5a turned out to be superior in this respect.5, 7 Aziridine alcohols have also been screened as chirality transfer reagents in the enantioselective addition of dialkylzincs to N-(diphenylphosphinoyl) imines.8 Very recently, the acetate salt of 1 was tested in an intramolecular formal aza [3+3] cycloaddition reaction as an organocatalyst.9 Although the aziridine salt was efficient in promoting the reaction, a very poor ee was obtained.

In recent years there has been an increasing awareness that small organic molecules, in addition to metal complexes and biocatalysts, can serve as highly selective and efficient catalysts.10 In particular, the use of chiral amines as organocatalysts has received considerable attention in enantioselective synthesis. Typical reactive intermediates are iminium ions formed by the reversible reaction of the amine catalyst with a carbonyl substrate. A pioneering example of iminium catalysis is MacMillan’s enantioselective Diels–Alder reactions of α,β-unsaturated aldehydes11 or ketones12 using the chiral imidazolidinone catalyst of type 2. This type of catalysis has been further extended to other reactions of α,β-unsaturated aldehydes, such as [3+2] cycloaddition with nitrones,13 Friedel–Crafts alkylation with pyrroles,14 indoles15 and benzenes,16 and the Mukaiyama–Michael reaction17 achieving high yields and enantioselectivities.

The efficiency of chiral imidazolidinone as chiral catalysts, prompted us to investigate the possibility of using the three-membered ring aziridin-2-yl methanols 1 as organocatalysts. An intriguing additional question is whether the aziridinium ions, which will be the true chirality transferring species, will be sufficiently stable under these catalytic processes.

Section snippets

Preparation of aziridine-2-carbinols 1

We prepared a series of compounds 1 with the aim of exploring their use as organocatalysts. Various approaches18 for the preparation of optically active aziridine-2-carboxylic esters 3a and 3b, that are the precursors of the aziridine-2-carbinols 1, have been described. We selected N-tritylmethylesters of l-serine and l-threonine as starting materials from which the compounds 3a and 3b could be prepared,4, 19 by a convenient multigram ‘one-pot procedure’ using methansulfonyl chloride and

Conclusion

A series of aziridine carbinol catalysts 1 was prepared with the aim of investigating their capacity to asymmetrically catalyze Diels–Alder reactions and Friedel–Crafts alkylations of N-methyl-pyrrole and N-methyl-indole using α,β-unsaturated aldehydes. The Diels–Alder reaction took place with moderate ee’s ranging from 10% to 66% with catalyst 1a-HClO4 giving the best results. The asymmetric alkylation of N-methyl-pyrrole with (E)-crotonaldehyde 7b as well as with (E)-cinnamaldehyde 7a,

General methods

Unless stated otherwise, all reagents were obtained from commercial suppliers and used without further purification. Column chromatography was carried out with 70–230 mesh silica gel. Light petroleum ether refers to the fraction with a boiling range of 40–60 °C. Melting points are uncorrected. 1H and 13C NMR spectra were recorded at 400 and 100 MHz, respectively, in CDCl3 as solvent. Chemical shifts are reported on the δ scale and measured in parts per million relative to residual CHCl3 (δ = 7.26 

Acknowledgments

We acknowledge financial support by the University of Bologna (ex 60% mpi) and by the National Project ‘Stereoselezione in Sintesi Organica. Metodologie ed Applicazioni’ 2005.

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