An efficient and rapid protocol for the synthesis of diversely functionalized bisindolylmethanesby A. Swetha, B. Madhu Babu, H.M. Meshram

Tetrahedron Letters

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Year
2015
DOI
10.1016/j.tetlet.2015.02.032
Subject
Organic Chemistry / Biochemistry / Drug Discovery

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Accepted Manuscript

An efficient and rapid protocol for the synthesis of diversely functionalized bisindolylmethanes

A. Swetha, B. Madhu Babu, H.M. Meshram

PII: S0040-4039(15)00302-0

DOI: http://dx.doi.org/10.1016/j.tetlet.2015.02.032

Reference: TETL 45900

To appear in: Tetrahedron Letters

Received Date: 12 January 2015

Revised Date: 9 February 2015

Accepted Date: 10 February 2015

Please cite this article as: Swetha, A., Madhu Babu, B., Meshram, H.M., An efficient and rapid protocol for the synthesis of diversely functionalized bisindolylmethanes, Tetrahedron Letters (2015), doi: http://dx.doi.org/ 10.1016/j.tetlet.2015.02.032

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An efficient and rapid protocol for the synthesis of diversely functionalized bisindolylmethanes

A. Swetha, B. Madhu Babu and H. M. Meshram*

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Tetrahedron Letters 1

An efficient and rapid protocol for the synthesis of diversely functionalized bisindolylmethanes

A. Swetha, B. Madhu Babu and H. M. Meshram*

Medicinal Chemistry and pharmacology division

Indian Institute of Chemical Technology, Hyderabad – 500 007, India

Tel.: +91-40-27191640, Fax: +91-40-27193275, E-mail address- hmmeshram@yahoo.com

Abstract— An efficient and general protocol is described for the synthesis of bisindolylmethanes by the reaction of indole with aldehydes in the presence of BF3.OEt2. The method is rapid and applicable for aromatic, heteroaromatic and aliphatic aldehydes.

Keywords: Bisindolylmethanes; Friedel–Crafts reaction; BF3.OEt2; Rapid synthesis.

Heteroaryl-substituted triarylmethanes are valuable structural units frequently found in pharmaceuticals and bioactive molecules.1 Particularly, bisindolylmethanes (BIMs) and their derivatives are found in terrestrial and marine metabolites,2 and they are known to possess a wide range of biological and pharmacological activities such as antimicrobial,3 antifungal,4 antibacterial,5 antitumor,6 HIV-1 integrase inhibitor7 and aromatase inhibitor for breast cancer.8 Some of the bisindolylmethane derivatives are used as estrogen metabolism in humans,9 in the treatment of fibromyalgia, chronic fatigue and irritable bowel syndrome.10 In addition to this, diheteroarylmethanes are also used in the food industry,11 where as triheteroarylmethanes find applications in non-linear optics and conducting polymers.12 Due to distinct properties of bisindolylmethanes, there is continuous research interest to develop an efficient and convenient method for the synthesis of bisindolylmethanes in mild condition.

N

H

H

N

OH

OH

HIV-1 integrase inhibitor

N

H

NH

Vibrindole A

N

H

NH

H

N O

Trisindoline

Fig. 1: Representative examples of biologically active bisindolylmethane derivatives.

There are numerous methods for the synthesis of bisindolylmethanes. Most of the common methods involve

Friedel–Crafts reaction of indoles with various carbonyl compounds in the presence of either Lewis acids or protic acids such as molecular iodine,13a,13b metal halides,13c-13g silica sulphuric acid (SSA),14a acetic acid,14b NBS14c and CAN.14d

Metal triflates are also reported to accomplish the reaction.15a15e In addition to this solid acidic catalysts like Amberlyst15,16 montmorillonite clay K-1017a,17b and Zeolites17c,17d are also used for this transformation. Recently, ionic liquids,18 iron(III) dodecyl sulfate,19a Sc(OTf)319b and iron complex19c have been used for the synthesis of bisindolylmethanes.

Though the reported methods are satisfactory, some of the methods suffer from certain drawbacks such as need of expensive catalysts,15a-15c longer reaction time,13e,13f,14b,18b harsh reaction conditions (e.g. high temperatures, pressure vessels),13d cumbersome work-up procedures and poor yield of the desired product.14b In this context the development of an efficient and rapid method for the synthesis of bisindolylmethanes under mild reaction condition is highly desirable.

Recently, the use of BF3.OEt2 for various organic transformations is an area of growing interest.20 To the best of our knowledge, there is no report for the synthesis of bisindolylmethanes using BF3.OEt2 as a catalyst. Hence, as a part of our21 ongoing research in the application of BF3.OEt2, herein we wish to report an operationally simple, rapid and efficient method for the synthesis of bisindolylmethanes using

BF3.OEt2 under mild reaction condition.

N

H

BF3.OEt2 rt, 2 min

HN

NH

OMe

CHO

OMe

Scheme 1: Optimization of the reaction conditions.

Thus the reaction of 3-methoxybenzaldehyde (1a, 1 mmol) with indole (2a, 2 mmol) in the presence of BF3.OEt2 (1 equiv) in DCM at room temperature (Scheme 1) gave bisindolylmethane 3a in high yield. After completion of the reaction, the reaction mixture was directly loaded on column chromatography by avoiding aqueous work up-extraction

Tetrahedron Letters 2 step. The product 3a was confirmed by 1H NMR, 13C NMR,

IR and Mass spectrometry analysis (Table 2, entry 1).

Table 1: Optimization of the reaction conditions.a

Entry Lewis acid (equiv)

Solvent Yieldb (%) 1 3 5 6

TMSCl (2.0)

Toluene

THF

Toluene 38Sc(OTf)3 (2.0)

BF3.OEt2 (1.0)

Time 78 68 2 min 30 min 60 min

BF3.OEt2 (1.0) DCM 2 min 2 BF3.OEt2 (2.0) 962 minDCM 4 DCMBi(OTf)3 (2.0) 815 h

BF3.OEt2 (1.0)10 822 min 7 8 9 3 h 5 h 5 h

Yb(OTf)3 (2.0)

FeCl3 (2.0) DCE

TfOH (2.0)

EtOH 18 39 51 95

MeCN

DCM

BF3.OEt2 (0.5)11 862 minDCM a

All the reactions were conducted with 3-methoxybenzaldehyde 1a (1 equiv), indole 2a (2 equiv) in the presence of BF3.OEt2 in 5 mL solvent at room temperature. b Isolated yield.