AlCl3 mediated unexpected migration of sulfonyl groups: Regioselective synthesis of 7-sulfonyl indoles of potential pharmacological interest

Article abstract of 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.

Full text of DOI:10.1039/c2cc35757g

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COMMUNICATION
AlCl3 mediated unexpected migration of sulfonyl groups: regioselective
synthesis of 7-sulfonyl indoles of potential pharmacological interestw
Bagineni Prasad,a Raju Adepu,a Sandhya Sandra,a D. Rambabu,a G. Rama Krishna,b
C. Malla Reddy,b Girdhar Singh Deora,a Parimal Misraa and 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.
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, 3a was 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).
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 bacteria Mycobacterium
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
for N-alkyl/aryl/heteroarylsulfonyl indoles in the presence of AlCl3
leading 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
Scheme 1 Synthesis of 7-sulfonyl indoles via regioselective migration
of the sulfonyl group.
a Institute of Life Sciences, University of Hyderabad Campus,
Gachibowli, Hyderabad 500 046, India.
E-mail: manojitpal@rediffmail.com; Tel: +91 40 6657 1500
b Department of Chemical Sciences, Indian Institute of Science
Education and Research, Kolkata, West Bengal 741252, India
w Electronic supplementary information (ESI) available: Experimental
procedures, spectral data for all new compounds, results of docking
study. CCDC 859365. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2cc35757g
Scheme 2 Synthesis of 2-tert-butyl-N-sulfonyl indole (3).
c
10434 Chem. Commun., 2012, 48, 10434–10436
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Table 2 AlCl3 mediated synthesis of 3-acyl-7-sulfonyl indoles (5)a
Entry Indole (3) 4; R2 = Product (5) Timeb/h Yieldc (%)
1
2
3
4
5
6
7
8
3a
3a
3b
3b
3c
3c
3e
3e
3i
3i
3j
3l
3n
3o
3p
3r
4a; Me
4b; Et
4a
4b
4a
4b
4a
4b
4a
4b
4a
4a
4a
4a
4a
4a
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
6.0
6.5
7.0
6.5
6.5
7.5
6.5
7.0
7.5
8.0
7.5
8.0
8.0
8.0
7.5
8.0
70
67
68
65
66
65
60
58
58
55
56
52
55
58
55
54
9
Fig. 1 ORTEP representation of compound 5a (thermal ellipsoids
10
11
12
13
14
15
16
are drawn at the 50% probability level).
Table 1 Effect of conditions on the reaction of 3a with 4aa
a
Reactions were carried out using 3 (1.75 mmol), 4 (5.25 mmol) and
b
AlCl3 (3.5 mmol), in dry DCM (5.0 mL). After adding 3. Isolated
c
yield.
Equiv. of Equiv. of
4a
Entry AlCl3
Solvent
Timeb/h Yieldc (%)
1
2
3
4
5
6
7
1.0
1.5
1.5
2.0
2.0
2.0
2.0
1.5
2.0
3.0
3.0
3.0
3.0
3.0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
6
6
6
6
8
6
6
28d
41d
49d
70
68
44d
32d
Scheme 3 Effect of the electron withdrawing group at C-5 of an
ClCH2CH2Cl
indole ring.
a
Reactions were carried out using 3a (1 equiv.), 4a and AlCl3 in a
b
solvent (5.0 mL). After adding 3a. Isolated yield. Unreacted 3a
c
d
was recovered.
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).
Scheme 4 Preparation and acetylation of the 2-(n-butyl)indole
derivative.
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 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
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.
c
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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.
Scheme 5 AlCl3 mediated migration of the N-sulfonyl group leading
to 7-sulfonyl indoles.
BP and RA thank CSIR, for Research Fellowships. The
authors thank Prof. J. Iqbal and DBT (Grant BT/01/COE/07/
02) for support.
Scheme 6 Cross over experiment between 3b and 3i.
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, New
York, 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 and
M. 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 and
M. 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.
Scheme 7 Proposed mechanism for the AlCl3 mediated migration of
the sulfonyl group.
4 (a) For migration of the sulfonyl group from an aliphatic nitrogen to
an aliphatic carbon in the presence/absence of Cs2CO3 under thermal
conditions, 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 of
the three products during photodesulfonylation of N-sulfonyl indoles,
see: X. Hong, J. M. M. Oneto, S. France and A. Padwa, Tetrahedron
Lett., 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, see
ref. 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 and
P. T. Reddy, J. Bacteriol., 2006, 188, 8638; (b) S. Sasso, C.
Ramakrishnan, M. Gamper, D. Hilvert and P. Kast, FEBS J.,
2005, 272, 375.
Fig. 2 Docking of compound 5a at the active site of CM.
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
c
10436 Chem. Commun., 2012, 48, 10434–10436
This journal is The Royal Society of Chemistry 2012