Elsevier

Tetrahedron

Volume 71, Issue 4, 28 January 2015, Pages 700-708
Tetrahedron

Hypervalent iodine-mediated synthesis of benzoxazoles and benzimidazoles via an oxidative rearrangement

https://doi.org/10.1016/j.tet.2014.11.066Get rights and content

Abstract

A Beckmann-type rearrangement of o-hydroxy and o-aminoaryl N–H ketimines has been developed to prepare benzoxazoles and N-Ts benzimidazoles, respectively. The ketimine derivatives were easily prepared by condensation of ammonia with the corresponding ketones and (diacetoxyiodo)benzene was found to act as an efficient oxidant to trigger the [1,2]-aryl migration towards the formation of the desired heterocycles. Depending on the substitution pattern, the results revealed another mechanistic pathway through which benzisoxazoles or 1H-indazoles could be formed. The Beckmann-type rearrangement strategy was applied to the synthesis of benzimidazole-containing biorelevant targets such as chlormidazole and clemizole.

Introduction

With the preparation of the first organic hypervalent iodine species, iodobenzene dichloride (PhICl2) in 1886, C. Willgerodt paved the way to what has recently evolved as a thriving field of chemistry.1 Hypervalent iodine compounds have been developed as oxidants but they can be used as electrophilic reagents as well. These properties, combined with a non-toxic profile and an ease of handling, make hypervalent iodine reagents attractive alternatives to toxic transition metals in a wide range of organic transformations.2 A profusion of publications that ensued from the discovery of (diacetoxyiodo)benzene (DAIB),3 2-iodoxybenzoic acid (IBX)4 or Dess-Martin periodinane (DMP)5 relied on the oxidation of various functional groups (i.e., alcohols, amine, thiols)6 and applications in total synthesis of natural products.7 Besides such reactivities, breakthroughs in this area have been driven by the implementation of new synthetic methodologies.8 The electrophilic nature of the iodine atom in hypervalent iodine species associated with the leaving group ability of iodophenyl moiety have been harnessed by several research groups in synthetically interesting new directions. Within this context, oxidative rearrangement processes have been described in literature.9 Despite great advances in this field, hypervalent iodine-mediated Beckmann rearrangement remains an unexplored territory to prepare benzoxazoles and benzimidazoles. These heterocycles are common structural units in many marketed pharmaceuticals and drug candidates.10, 11 For instance, Tafamidis is a drug marketed for the treatment of transthyretin-associated familial amyloid polyneuropathy, which is a progressive neurodegenerative disease, while Flunoxaprofen was investigated as a non-steroidal anti-inflammatory drug (Fig. 1). The benzimidazole scaffold is found in Esomeprazole and Bendamustine, which are respectively used in the treatment of gastroesophageal reflux disease and lymphocytic leukemia and lymphomas. Additionally, benzoxazoles and benzimidazoles are found in natural products,12 polymers,13 and various functional materials.14

The most common synthetic strategies towards the preparation of benzoxazole and benzimidazole structures lie in the condensation of o-aminophenols or o-phenylenediamines with an aldehyde or carboxylic acid derivatives (Scheme 1, route a)15 and the intramolecular condensation of anilide or amidine derivatives under oxidative conditions (Scheme 1, route b).16 Another strategy, which has received less attention by the academic community employs o-hydroxy or o-aminoaryl N–H ketimine derivatives (Scheme 1, route c). In the presence of various additives, these substrates undergo a Beckmann-type rearrangement to produce the corresponding benzoxazole or benzimidazole units.17 Strong acids or harsh reaction conditions are often used to promote such rearrangements, while to the best of our knowledge, hypervalent iodine reagents have never been used to trigger the Beckmann-type rearrangement towards the formation of benzoxazole and benzimidazole motifs.

Built upon the interesting features of hypervalent iodine reagents, we surmised that a hypervalent iodine-mediated Beckmann-type rearrangement could be the centerpiece of a strategy devoted to the synthesis of heterocyclic architectures from readily available substrates (Scheme 2). We describe herein a PhI(OAc)2-mediated synthesis of benzoxazoles and benzimidazoles from the corresponding imines and the application of the methodology to the synthesis of biologically relevant targets.

Section snippets

Results and discussion

We first investigated the reaction of bromo imine 1a, readily prepared from the corresponding acetophenone derivative,17c in the presence of PhI(OAc)2, in order to get the best reaction conditions (Table 1). The transformation of 1a into the benzoxazole 2a was performed at room temperature for 30 min as a model reaction. Our initial investigation concentrated on the study of the effect of the amount of PhI(OAc)2 on the yield (entries 1–5). The best result was obtained by performing the reaction

Conclusion

In summary, we have reported a PhI(OAc)2-mediated Beckmann-type rearrangement towards the preparation of functionalized benzoxazoles and N-Ts benzimidazoles. This strategy was applied to a range of o-hydroxy and o-aminoaryl N–H ketimines easily prepared by condensation of the corresponding ketones with ammonia. The results outlined herein demonstrate the importance of the substitution pattern at the aromatic ring on the mechanistic pathway. Depending on the substituents, the [1,2]-migration of

General

1H NMR (200, 300 or 500 MHz) and 13C (75 or 125 MHz) spectra were recorded with 200, 300 or 500 MHz spectrometers in chloroform-d or DMSO-d6 with the residual peak solvent or tetramethylsilane as an internal standard. Chemical shifts (δ) are given in parts per million and coupling constants are given as absolute values expressed in Hertz. Electrospray ionization (ESI) mass spectra were collected using a Q-TOF instrument. Samples (solubilized in ACN at 1 mg/mL and then diluted by 1000) were

Acknowledgements

The authors thank CNRS, University of Versailles-St-Quentin-en-Yvelines and the National Natural Science Foundation of China (No. 21350110501 and No. 21372265) for financial support. We also warmly acknowledge the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry, the Natural Science Foundation Project of CQ CSTC (No. cstc2013jcyjA0217), and the Fundamental Research Funds for the Central Universities (Nos. CQDXWL-2013-Z012 and CDJZR-14225502).

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