Elsevier

Tetrahedron

Volume 59, Issue 26, 23 June 2003, Pages 4767-4774
Tetrahedron

Application of directed metalation in synthesis. Part 4: Expedient synthesis of substituted benzo[b]thiophene and naphthothiophene

https://doi.org/10.1016/S0040-4020(03)00710-5Get rights and content

Abstract

A short, simple and inexpensive synthesis of several diversely substituted benzo[b]thiophenes and one naphthothiophene is described. The method involves introduction of methylsulfanyl group ortho- to the amide function of readily available N,N-diethylamides of aryl carboxylic acid by directed metalation. Thioindoxyls, obtained in high yields through side-chain deprotonation and cyclisation in one pot, are reduced to benzo[b]thiophene or napthothiophene.

Introduction

We have recently reported2 a short and expedient route to various methoxybenzo[b]thiophenes. The method consisting of sequential directed ortho-lithiation, side chain deprotonation, cyclisation using tertiary amide function as internal electrophile3 and borohydride reduction compares favourably with earlier reported4., 5. synthesis of these compounds. Since the publication of our results,2 a paper6 appeared describing the synthesis of the key intermediate used by us, by a procedure which is essentially a modification of our method. The only difference is in the use of ester instead of amide as the internal electrophile. Importance of benzo[b]thiophene can be appreciated from the numerous reports in the literature7 since the chemistry4., 5. and the biological activities of these compounds were reviewed. Thus benzo[b]thiophene derivatives have exhibited7 biological activities e.g. anti-inflammatory, analgesic, antiexudative, antipsychotic and enzyme inhibiting properties. Benzo[b]thiophene and naphtho[2,1-b]thiophene based diphosphanes have been developed7 as C1-symmetric ligands for homogeneous stereoselective catalysis. Diaryl substituted benzo[b]thiophenes have been developed7 as novel photochromic materials. Substituted benzo[b]thiophenes and partially hydrogenated benzo[b]thiophenes have been used as building blocks in the synthesis2., 8. of polycondensed systems which include sulfur analogues1., 9. of bioactive natural products. Expedient access to substituted benzo[b]thiophenes, preferably avoiding as much possible use of expensive and environmentally offensive thiols, is thus important. Some time ago we developed a multistep synthesis10 of substituted benzo[b]thiophenes that did not use thiols as starting materials.

We report here the further application of the method2 developed by us in the synthesis of other substituted benzo[b]thiophenes and naphthothiophene establishing the generality of this procedure.

Section snippets

Results and discussion

The starting materials used in the synthesis (Scheme 1) were easily available N,N-diethylamides (1) of arylcarboxylic acids. Methoxy benzamides were synthesized from commercially available hydroxybenzoic acids. Under standard directed metalation condition11 (sec-BuLi/TMEDA/THF/−78°C in argon atmosphere), deprotonation takes place in the ortho-position of the tertiary amide function. Deprotonation took place exclusively in the ortho-position of the tertiary amide, when the molecule also

Conclusion

The procedure described above provides an expedient access to diversely substituted benzo[b]thiophenes and its simplicity constitutes a significant improvement over earlier methods. Thioindoxyls which are key intermediates in the present synthesis of benzo[b]thiophenes are obtained from much simpler and readily available starting materials than were needed earlier.4 The method also compares favorably with a short and expedient synthesis17 of benzo[b]thiophene which is elegant but uses thiols as

General

Commercially available solvents were distilled prior to use. Light petroleum ether (bp 60–80°C) was used for column chromatography. Anhydrous sodium sulfate was used as drying agent. THF, n-hexane, cyclohexane were dried by the usual sodium-benzophenone-ketyl method. 1H NMR spectra (300 MHz) and 13C, DEPT (75.5 MHz) were recorded in CDCl3 solution on Bruker DPX-300 spectrometer. Chemical shift (δ) are expressed in ppm using tetramethylsilane as internal standard. Coupling constant (J) values

Acknowledgements

Thanks are due to the Council of Scientific and Industrial Research (New Delhi) for financial assistance (Project No. 01(1573)/99/EMR-II) and for providing S. K. with a Senior Fellowship.

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