A convenient synthesis of 2-substituted indoles by the reaction of 2-(chloromethyl)phenyl isocyanides with organolithiums
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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2011, Tetrahedron LettersRecent application of isocyanides in synthesis of heterocycles
2011, TetrahedronCitation 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.