Synthesis of nitroaryl derivatives of glycine via oxidative nucleophilic substitution of hydrogen in nitroarenes

Mieczysław Mąkosza,Daniel Sulikowski,Mikołaj Chromiński,Jacques Royer

doi:10.3998/ark.5550190.0012.608

Abstract

Carbanion of ethyl N-(1,3-dithiolan-2-ylidene)glycinate adds to activated nitroarenes mostly in para position to the nitro group. Subsequent oxidation of the resulting σ adducts with DDQ gave respective α-nitroarylated glycine derivatives in moderate yields. The reaction of esters of chiral alcohols such as (-)-menthol or (-)-8-phenylmenthol proceeds with a moderate or high diastereoselectivity leading to enantiomerically enriched nitroarylglycines.

Highlights

Synthesis of unnatural amino acids is of substantial interest since they are valuable intermediates in the construction of pharmaceutically important products such as peptidomimetics, enzyme inhibitors, etc.[1,2] Of particular interest are arylglycines because they are components of many pharmaceuticals e.g. Plavix3a, Cefprosil3b or Vancomycin,3c etc. there are numerous methods of synthesis of arylglycines[4], those that contain the nitro group in orto or para position are not much known
In a few earlier papers we reported synthesis of some α-nitroaryl-α-amino acids via oxidative nucleophilic substitution of hydrogen (ONSH) in nitroarenes with carbanions of protected esters of amino acids
In this paper we report an application of this methodology for synthesis of C-nitroarylglycines

Summary

Introduction

Synthesis of unnatural amino acids is of substantial interest since they are valuable intermediates in the construction of pharmaceutically important products such as peptidomimetics, enzyme inhibitors, etc.[1,2] Of particular interest are arylglycines because they are components of many pharmaceuticals e.g. Plavix3a, Cefprosil3b or Vancomycin,3c etc. There are numerous methods of synthesis of arylglycines[4], those that contain the nitro group in orto or para position are not much known Synthesis of such nitroarylated glycines are reported via the Strecker reaction,[5] and the base-induced Smiles rearrangement of Nnitrophenylsulfonyl amino acids.[6]. External oxidant.[7] Since the addition is a reversible process and the nucleophiles (carbanions) are sensitive to oxidation, the ONSH proceeds satisfactorily only when the addition equilibrium is shifted to the adduct due to high nucleophilicity of carbanions and high electrophilicity of nitroarenes Following this methodology, we have synthesized the α-nitroaryl derivatives of alanine,8a proline,8b serine8a,8c, threonine8c and phosphoglycine.8d. In this paper we report an application of this methodology for synthesis of C-nitroarylglycines

Results and Discussion

DCC DMAP THF rt

Experimental Section