A convenient synthesis of 2-substituted indoles by the reaction of 2-(chloromethyl)phenyl isocyanides with organolithiums

doi:10.1016/j.tet.2009.06.127

Tetrahedron

Volume 65, Issue 36, 5 September 2009, Pages 7523-7526

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Abstract

The reaction of 2-(chloromethyl)phenyl isocyanides, readily available by dehydration of the respective N-[2-(chloromethyl)phenyl]formamides, with organolithiums produced 2-substituted indoles in satisfactory yields through addition of organolithiums to the isocyano carbon followed by intramolecular substitution reaction of the resulting imidoyl anion intermediates.

Graphical abstract

Introduction

Indoles are undoubtedly very important heterocycles in organic synthesis. Therefore, development of new and efficient methods for the general preparation of indoles has been the subject of intense research.1, 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), 1(m), 1(n), 1(o), 1(p) In this paper we wish to describe that a new and convenient method for the preparation of 2-substituted indoles, which is based on reactions of 2-(chloromethyl)phenyl isocyanides with organolithiums, has been developed. The utility of ortho-functionalized phenyl isocyanides in heterocycle synthesis is well established.2, 2(a), 3, 4, 4(a), 4(b), 4(c), 5, 5(a), 5(b), 5(c), 5(d), 5(e), 5(f), 5(g), 5(h) In particular, Fukuyama and Tokuyama have elegantly demonstrated the utility of 2-isocyanosrtyrene derivatives in the synthesis of indole derivatives including natural products.2, 2(a) A synthesis of 2,3-disubstituted quinolines through cyclization of 2-alkynylisocyanobenzenes has been reported by Ito and Suginome.³ Ichikawa has reported syntheses of 3-fluoroquinoline derivatives based on reactions utilizing β-difluoro-2-isocyanostyrenes.4, 4(a), 4(b), 4(c) However, there have been few reports on utilization of 2-(chloromethyl)phenyl isocyanides in organic synthesis so far, though 2-(chloromethyl)phenyl isocyanide has been used in the synthesis of 1- and 2-platinum(II)-substituted indole derivatives by Michelin and colleagues.⁶ To the best of our knowledge, the present report is the first example of the practical use of these isocyanide in organic synthesis.

Section snippets

Results and discussion

Our preparation of 2-substituted indoles 3 was conducted as illustrated in Scheme 1. The starting materials of the present synthesis, N-(2-chlorophenyl)formamides 1, were easily prepared by formylation of 2-aminobenzyl alcohols with ethyl or butyl formate followed by chlorination with thionyl chloride. These formamides 1 were converted into 2-(chloromethyl)phenyl isocyanides 2 on treatment with phosphorous oxychloride in the presence of triethylamine in THF.7, 7(a), 7(b) Because these

General

All melting points were obtained on a Laboratory Devices MEL-TEMP II melting apparatus and are uncorrected. IR spectra were determined with a Shimadzu FTIR-8300 spectrophotometer. The ¹H NMR spectra were determined in CDCl₃ using TMS as an internal reference with a JEOL ECP500 FT NMR spectrometer operating at 500 MHz. The ¹³C NMR spectra were determined in CDCl₃ using TMS as an internal reference with a JEOL ECP500 FT NMR spectrometer operating at 125 MHz. Low- and high-resolution MS spectra (EI,

Acknowledgements

We thank Mrs. Miyuki Tanmatsu of this University for her assistance in determining the mass spectra and performing combustion analyses.

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Citation Excerpt :
In the following sections, we wish to update some recent advances in application of isocyanide in the synthesis of heterocycles. The reaction of 2-(chloromethyl)phenyl isocyanides 1, readily available by dehydration of the respective N-[2-(chloromethyl)phenyl]formamides, with organolithiums produced 2-substituted indoles 2 in satisfactory yields through the addition of organolithiums to the isocyano carbon followed by an intramolecular substitution reaction of the resulting imidoyl anion intermediates (Scheme 1).4 The formation of 2-substituted indoles 2 is induced by attack of the organolithium at the isocyano carbon of 2-(chloromethyl)phenyl isocyanides 1 to generate the imidoyl anion intermediate.

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A convenient synthesis of 2-substituted indoles by the reaction of 2-(chloromethyl)phenyl isocyanides with organolithiums

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

General

Acknowledgements

Bull. Chem. Soc. Jpn.

Org. Synth.

Chem. Pharm. Bull.

Chem. Rev.

Heterocycles

Synlett

Eur. J. Org. Chem.

Synlett

Tetrahedron Lett.

Eur. J. Org. Chem.

J. Org. Chem.

Synthesis

Synlett

Org. Biomol. Chem.

J. Am. Chem. Soc.

Synlett

Synth. Commun.

Org. Lett.

Tetrahedron Lett.

Chem. Rec.

Synlett

Org. Lett.

Org. Lett.

Synlett

Synlett

Chem. Lett.

Bull. Chem. Soc. Jpn.

Chem. Lett.

Tetrahedron Lett.

Bull. Chem. Soc. Jpn.

Tetrahedron

Bull. Chem. Soc. Jpn.

Synthesis

Organometallics

J. Med. Chem.

J. Chem. Soc., Perkin Trans. 1