Elsevier

Tetrahedron: Asymmetry

Volume 15, Issue 10, 24 May 2004, Pages 1667-1672
Tetrahedron: Asymmetry

Highly regioselective N-alkylation of nonracemic Betti base: a novel one-pot synthesis of chiral N-methyl-N-alkyl Betti bases

https://doi.org/10.1016/j.tetasy.2004.04.006Get rights and content

Abstract

A novel one-pot preparation of chiral N-methyl-N-alkyl Betti bases has been developed involving a highly regioselective N-alkylation of (S)-(+)-Betti base. The strategy involved formation-cleavage of the oxazine ring and N-methylation with BtCH2OH under neutral conditions.

Introduction

Many unnatural homochiral amino-phenol compounds have been reported as excellent ligands in metal ion catalyzed asymmetric reactions in current asymmetric synthesis.1 The ligands, which have the structure of N,N-dialkyl Betti base 1 (Chart 1) are gaining increasing importance.2 Among them, the derivatives of chiral N-methyl-N-alkyl Betti base 2 have induced satisfactory reactivities and stereoselectivities in their catalyzed asymmetric reactions. The replacement of the N-methyl group in N-methyl-N-alkyl Betti base 2 by a large-sized N-alkyl group did not bring any additional satisfactory results, but made the synthetic procedure more difficult.[2](g), [2](h)

Because the aliphatic amine moiety of Betti base 3 has a relatively lower nucleophilic reactivity when compared to its phenoxyl group moiety, the N-alkylation of Betti base 3 seriously lacks for regioselectivity by using routine methods.[1](f), [2](a), [3] Therefore, no derivatives of chiral N,N-dialkyl Betti base 1 in the literature were prepared from nonracemic Betti base 3. The chiral N-methyl-N-alkyl Betti base 2 was prepared mainly by the Mannich condensation of a chiral amine with benzaldehyde and 2-naphthol to yield a N-alkyl Betti base 4 followed by a N-methylation.[2](e), [2](g), [2](h), [2](j) Since few of the N-alkyl Betti bases 4[2](h), [2](g), [2](i) prepared by the Mannich condensation had satisfactory diastereopurity, the diversity of the N-alkyl group in the N-methyl-N-alkyl Betti base 2 is quite limited. Herein, we report a highly regioselective N-alkylation of (S)-(+)-Betti base (S)-3, by which a series of enantiopure N-methyl-N-alkyl Betti base 2 was prepared in a convenient one-pot synthesis.

Section snippets

Results and discussions

Recently, we achieved the synthesis of enantiopure 1-[α-(1-azacycloalkyl)benzyl]-2-naphthols by direct N-alkylation of the (S)-Betti bases (S)-3, in which a strategy that involved the formation-cleavage of an oxazine ring, was employed.[3], [4] Following this strategy, N-methyl-N-alkyl Betti base 2 could be prepared by condensation of (S)-(+)-Betti base (S)-3 with aldehyde 5 to yield 2-(R)-4-phenyl-naphtho[1,2-e][1,3]oxazine 6 as an intermediate followed by simultaneous N-methylation and

Conclusion

In summary, a novel preparation of chiral N-methyl-N-alkyl Betti base 2 has been developed by highly regioselective N-alkylation of (S)-(+)-Betti base (S)-3. 2-(R)-4-phenyl-naphtho[1,2-e][1,3]oxazine 6, obtained by condensation of (S)-(+)-Betti base (S)-3 and aldehyde 5, was N-methylated with BtCH2OH under essentially neutral conditions to yield 2-(R)-N-benzotriazolylmethyl-4-phenyl-naphtho[1,2-e][1,3]oxazine 7. Chiral N-methyl-N-alkyl Betti base 2 was then obtained by simultaneously cleaving

General considerations

All melting points were determined on a Yanaco melting point apparatus and are uncorrected. IR spectra were recorded on a Nicolet FT-IR 5DX spectrometer as KBr pellets. The 1H NMR spectra were recorded on a Bruker ACF-300 spectrometer in CDCl3 with TMS as internal reference. The J values are given in Hz. MS spectra were obtained on a VG-ZAB-HS mass spectrometer with 70 eV. The elemental analyses were performed on a Perkin–Elmer 240C instrument. Optical rotations were determined on a Perkin–Elmer

Acknowledgements

We are grateful to the National Natural Science Foundation of China for financial support.

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