10434 Chem. Commun., 2012, 48, 10434–10436 This journal is c The Royal Society of Chemistry 2012

Cite this: Chem. Commun., 2012, 48, 10434–10436

AlCl3 mediated unexpected migration of sulfonyl groups: regioselective

synthesis of 7-sulfonyl indoles of potential pharmacological interestw

Bagineni Prasad,aRaju Adepu,

aSandhya Sandra,

aD. Rambabu,

aG. Rama Krishna,

b

C. Malla Reddy,bGirdhar Singh Deora,

aParimal Misra

aand Manojit Pal*

a

Received 8th August 2012, Accepted 5th September 2012

DOI: 10.1039/c2cc35757g

A conceptually new and straightforward introduction of sulfonyl

groups at the C-7 position of an indole ring has been achieved via

AlCl3 mediated unexpected regioselective sulfonyl group migration for

N-alkyl/aryl/heteroarylsulfonyl indoles affording potential inhibitors

of Mycobacterium tuberculosis H37Rv chorismate mutase.

The discovery of new and efficient reactions leading to the

novel and diversity based carbocyclic/heterocyclic structures is

of enormous importance. The indole framework being an

integral part of many bioactive molecules1 is considered as

one of the privileged structures in drug discovery. The devel-

opment of new synthetic methods for indoles therefore has

immense impact and value.

Due to its absence in animals but not in bacteriaMycobacterium

tuberculosis H37Rv chorismate mutase (CM) is considered as a

promising target for the identification of new and potential

antitubercular agents.2 However, only few small molecules are

known as inhibitors of CM.3 In pursuance of our research on the

identification of indole based inhibitors3a of CM we required new

routes to access our target indole derivatives. Accordingly, we

unexpectedly observed a regioselective sulfonyl group migration

forN-alkyl/aryl/heteroarylsulfonyl indoles in the presence of AlCl3leading to functionalized new indoles in which the nitrogen atom

was unprotected and the sulfonyl group shifted to C-7 of an indole

ring (Scheme 1). The migration of the sulfonyl group4 was found

to be highly selective and allowed the straightforward introduction

of sulfonyl groups at C-7 of an indole ring. To the best of

our knowledge no effective route was known earlier leading

to 7-sulfonyl indoles4c of potential medicinal value. Herein,

we report our preliminary results on the synthesis, crystal

structure analysis and in vitro pharmacological evaluation of

7-sulfonyl indoles against CM.

The key starting material i.e. indole 3 required for our study was

prepared in high yields via a Pd/C-mediated coupling–cyclization

reaction5 (Scheme 2). We then examined the acylation of indole 3a

under Friedel–Crafts conditions using MeCOCl (4a)–AlCl3. To

our surprise the reaction proceeded well affording 3-acetyl-7-

sulfonyl indole (5a) as a result of unusual migration of the sulfonyl

group along with acetylation. Compound 5a was characterized by

spectral (NMR, IR and MS) data and its molecular structure was

confirmed unambiguously by a single crystal X-ray diffraction

study (Fig. 1).6 This prompted us to investigate the reaction

further under various conditions (Table 1). Initially, 3awas treated

with 1.0 and 1.5 equiv. of AlCl3 and 4a, respectively, in dry

dichloromethane (DCM) for 6 h when 5a was isolated in low

yield (entry 1, Table 1). Systematic increase in equivalent of both

AlCl3 and 4a increased the yield of 5a (entries 2–4, Table 1).

Scheme 1 Synthesis of 7-sulfonyl indoles via regioselective migration

of the sulfonyl group.

Scheme 2 Synthesis of 2-tert-butyl-N-sulfonyl indole (3).

a Institute of Life Sciences, University of Hyderabad Campus,Gachibowli, Hyderabad 500 046, India.E-mail: manojitpal@rediffmail.com; Tel: +91 40 6657 1500

bDepartment of Chemical Sciences, Indian Institute of ScienceEducation and Research, Kolkata, West Bengal 741252, India

w Electronic supplementary information (ESI) available: Experimentalprocedures, spectral data for all new compounds, results of dockingstudy. CCDC 859365. For ESI and crystallographic data in CIF orother electronic format see DOI: 10.1039/c2cc35757g

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This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 10434–10436 10435

However, increase in the reaction time did not improve the

product yield (entry 5, Table 1) and the use of other solvents such

as CHCl3 and 1,2-dichloroethane was found to be less effective

(entries 6 and 7, Table 1). Thus a combination of AlCl3 (2 equiv.)

and 4a (3 equiv.) in dry DCM was found to be optimum for the

preparation of 5a (entry 4, Table 1).

To test the generality of the present method other indoles were

reacted with acetyl and propionyl chloride under optimized

conditions (Table 2). Indoles 3 containing N-alkyl (entries 1–8,

Table 2), aryl (entries 9–12, Table 2) and heteroaryl (entries

13–16, Table 2) sulfonyl groups were employed to give 5. The

sulfonyl group migration occurred smoothly in the presence of

an electron donating group e.g. F, Cl, Br or Me at C-5. An

electron withdrawing or deactivating group e.g. –NO2 or –COMe

at C-5 however afforded the corresponding 3-acetyl indole (6)

along with 3-sulfonyl indole (7) as a minor product (Scheme 3).

The N–S bond cleavage seemed to be aided by the bulky tert-

butyl group at C-2 resulting in the migration of the N-sulfonyl

group. This was supported by the fact that acetylation of

2-(n-butyl)-5-chloro-1-(methylsulfonyl)-1H-indole (3s) under

the optimized conditions afforded the normal acylation product

(Scheme 4) without migration of the N-sulfonyl group to the

other position. Additionally, the observation that a number of

indoles e.g. 3a–b, 3i, 3n–p and 3r underwent smooth N–S bond

cleavage in the absence of acyl chloride leading to the C-7

sulfonyl substituted indoles (9) indicated the key role played by

AlCl3 in this transformation (Scheme 5).

To understand the mode of migration of the sulfonyl group

a cross over experiment was performed using a 1 : 1 mixture of

3b and 3i under the optimized conditions. The isolation of

cross over products i.e. 5a and 5k (Scheme 6) clearly suggested

a non-concerted process for the observed sulfonyl group

migration.7 Thus, the reaction seemed to proceed (Scheme 7)

via AlCl3-assisted activation of the indolyl double bond followed

by N–S bond cleavage to give E-1 which underwent sufonylation

at C-7 to give E-3 via E-2. In addition to its steric bulk that

perhaps aided the departure of the N-sulfonyl group the t-Bu

group facilitated the C-7 sulfonylation via stabilizing the

carbocation E-2. The reaction follows a similar pathway in

the presence of an acyl chloride when C-3 acylation facilitated

the migration of the N-sulfonyl group to C-7.

Fig. 1 ORTEP representation of compound 5a (thermal ellipsoids

are drawn at the 50% probability level).

Table 1 Effect of conditions on the reaction of 3a with 4aa

EntryEquiv. ofAlCl3

Equiv. of4a Solvent Timeb/h Yieldc (%)

1 1.0 1.5 CH2Cl2 6 28d

2 1.5 2.0 CH2Cl2 6 41d

3 1.5 3.0 CH2Cl2 6 49d

4 2.0 3.0 CH2Cl2 6 705 2.0 3.0 CH2Cl2 8 686 2.0 3.0 CHCl3 6 44d

7 2.0 3.0 ClCH2CH2Cl 6 32d

a Reactions were carried out using 3a (1 equiv.), 4a and AlCl3 in a

solvent (5.0 mL). b After adding 3a. c Isolated yield. d Unreacted 3a

was recovered.

Table 2 AlCl3 mediated synthesis of 3-acyl-7-sulfonyl indoles (5)a

Entry Indole (3) 4; R2 = Product (5) Timeb/h Yieldc (%)

1 3a 4a; Me 5a 6.0 702 3a 4b; Et 5b 6.5 673 3b 4a 5c 7.0 684 3b 4b 5d 6.5 655 3c 4a 5e 6.5 666 3c 4b 5f 7.5 657 3e 4a 5g 6.5 608 3e 4b 5h 7.0 589 3i 4a 5i 7.5 5810 3i 4b 5j 8.0 5511 3j 4a 5k 7.5 5612 3l 4a 5l 8.0 5213 3n 4a 5m 8.0 5514 3o 4a 5n 8.0 5815 3p 4a 5o 7.5 5516 3r 4a 5p 8.0 54

a Reactions were carried out using 3 (1.75 mmol), 4 (5.25 mmol) and

AlCl3 (3.5 mmol), in dry DCM (5.0 mL). b After adding 3. c Isolated

yield.

Scheme 3 Effect of the electron withdrawing group at C-5 of an

indole ring.

Scheme 4 Preparation and acetylation of the 2-(n-butyl)indole

derivative.

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10436 Chem. Commun., 2012, 48, 10434–10436 This journal is c The Royal Society of Chemistry 2012

Some of the compounds synthesized were tested for their

inhibitory potential against CM in vitro.8 The assay involved

determination of the activity of enzyme CM which catalyzes

the conversion of chorismate to prephenate. A known inhibitor of

CM i.e. 4-(3,5-dimethoxyphenethylamino)-3-nitro-5-sulfamoylben-

zoic acid3a was used as a reference compound (IC50 o 10 mM).

Compounds 5c, 5e, 5m, 5o and 5p showed 22–30% inhibition

whereas 5a showed 45% inhibition of CM when tested at 30 mM.

The docking of 5a at the active site of CM (Fig. 2, see ESIw)indicated a perfect H-bond bridge between the carbonyl oxygen of

5a and Glutamine-76 as well as Arginine-72 residue of the protein.

Overall, since tuberculosis is a leading cause of death worldwide

hence the present class of compounds is of further interest.

In conclusion, a novel methodology has been developed via

an AlCl3 mediated unexpected sulfonyl group migration for

N-sulfonyl indoles leading to new 7-sulfonyl indoles as potential

inhibitors of CM. This represents a regioselective, straightforward

and easy introduction of sulfonyl groups at C-7 of an indole ring.

A representative compound, the molecular structure of which was

confirmed unambiguously by a single crystal X-ray diffraction

study, showed inhibition and interactions with CM both in in vitro

and in silico studies.

BP and RA thank CSIR, for Research Fellowships. The

authors thank Prof. J. Iqbal and DBT (Grant BT/01/COE/07/

02) for support.

Notes and references

1 For in depth reviews, see: (a) G. R. Humphrey and J. T. Kuethe,Chem. Rev., 2006, 106, 2875; (b) S. Cacchi and G. Fabrizi, Chem.Rev., 2005, 105, 2873; (c) G. W. Gribble, in Comprehensive Hetero-cyclic Chemistry II, ed. A. R. Katrizky, C. W. Rees and E. F. V.Scriven, Pergamon, Oxford, 1996, vol. 2, p. 20.

2 E. Haslam, Shikimic Acid: Metabolism and Metabolites, Wiley, NewYork, 1993.

3 For selected references, see: (a) H. Agarwal, A. Kumar, N. C. Bal,M. I. Siddiqi and A. Arora, Bioorg. Med. Chem. Lett., 2007, 17, 3053;(b) A. Nakhi, B. Prasad, R. M. Rao, U. Reddy, S. Sandra,R. Kapavarapu, D. Rambabu, G. R. Krishna, C. M. Reddy,R. Kishore, P. Misra, J. Iqbal and M. Pal, MedChemComm, 2011,2, 1006; (c) K. S. Kumar, D. Rambabu, S. Sandra, R. Kapavarapu,G. R. Krishna, M. V. B. Rao, K. Chatti, C. M. Reddy, P. Misra andM. Pal,Bioorg.Med. Chem., 2012, 20, 1711; (d) K. S. Kumar, R. Adepu,S. Sandra, D. Rambabu, G. R. Krishna, C. M. Reddy, P. Misra andM. Pal, Bioorg. Med. Chem. Lett., 2012, 22, 1146; (e) T. R. Reddy,L. S. Reddy, G. R. Reddy, K. Yarbagi, Y. Lingappa, D. Rambabu,G. R. Krishna, C. M. Reddy, K. S. Kumar and M. Pal, Green Chem.,2012, 14, 1870.

4 (a) For migration of the sulfonyl group from an aliphatic nitrogen toan aliphatic carbon in the presence/absence of Cs2CO3 under thermalconditions, see: X. Xin, D. Wang, X. Li and B. Wan, Angew. Chem.,Int. Ed., 2012, 57, 1693(b) I. Nakamura, U. Yamagishi, D. Song,S. Konta and Y. Yamamoto, Angew. Chem., Int. Ed., 2007, 46, 2284;(c) The 7-sulfonylated indole was isolated in 4–11% yield as one ofthe three products during photodesulfonylation ofN-sulfonyl indoles,see: X. Hong, J. M. M. Oneto, S. France and A. Padwa, TetrahedronLett., 2006, 47, 2409.

5 M. Pal, Synlett, 2009, 2896.6 CCDC 859365 (5a).7 Notably, migration of the sulfonyl group during gold- and indium-catalyzed synthesis of 3- and 6-sulfonylindoles from o-alkynyl-N-sulfonylanilines was found to be an intramolecular process, seeref. 4b. We thank one of the reviewers for bringing this to our notice.

8 (a) S. K. Kim, S. K. Reddy, B. C. Nelson, G. B. Vasquez, A. Davis,A. J. Howard, S. Patterson, G. L. Gilliland, J. E. Ladner andP. T. Reddy, J. Bacteriol., 2006, 188, 8638; (b) S. Sasso, C.Ramakrishnan, M. Gamper, D. Hilvert and P. Kast, FEBS J.,2005, 272, 375.

Scheme 5 AlCl3 mediated migration of the N-sulfonyl group leading

to 7-sulfonyl indoles.

Scheme 6 Cross over experiment between 3b and 3i.

Scheme 7 Proposed mechanism for the AlCl3 mediated migration of

the sulfonyl group.

Fig. 2 Docking of compound 5a at the active site of CM.

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