Facile three-component domino reactions in the regioselective synthesis and antimycobacterial evaluation of novel indolizines and pyrrolo[2,1-a] isoquinolines

Article abstract of DOI:10.1016/j.tetlet.2010.09.128

The domino reactions of pyridine/isoquinoline, bromoacetonitrile/ethyl bromoacetate and a series of β-nitrostyrenes in the presence of triethylamine afforded novel tri-/disubstituted indolizines and pyrrolo[2,1-a]isoquinolines regioselectively, presumably via substitution-dipole generation-1,3-dipolar cycloaddition-elimination and/or aromatisation sequence. In vitro screening of all the seventeen compounds synthesized against Mycobacterium tuberculosis H37Rv discloses that ethyl 2-(4-fluorophenyl) pyrrolo[2,1-a]isoquinoline-3-carboxylate displays maximum potency with minimum inhibitory concentration (MIC) of 1.0 μM, being 7.6 and 4.7 times more potent than the standard first line TB drugs, ethambutol and ciprofloxacin, respectively.

Full text of DOI:10.1016/j.tetlet.2010.09.128

Tetrahedron Letters 51 (2010) 6439–6443
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile three-component domino reactions in the regioselective synthesis and
antimycobacterial evaluation of novel indolizines and
pyrrolo[2,1-a]isoquinolines
Sivasubramanian Muthusaravanan a, Subbu Perumal a, , Perumal Yogeeswari b, Dharmarajan Sriram b
⇑
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625 021, India
b Medicinal Chemistry & Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science—Pilani, Hyderabad Campus, Jawahar Nagar,
Hyderabad 500 078, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 July 2010
Revised 27 September 2010
Accepted 29 September 2010
Available online 7 October 2010
The domino reactions of pyridine/isoquinoline, bromoacetonitrile/ethyl bromoacetate and a series of
b-nitrostyrenes in the presence of triethylamine afforded novel tri-/disubstituted indolizines and pyrrolo
[2,1-a]isoquinolines regioselectively, presumably via substitution-dipole generation-1,3-dipolar cycload-
dition-elimination and/or aromatisation sequence. In vitro screening of all the seventeen compounds
synthesized against Mycobacterium tuberculosis H37Rv discloses that ethyl 2-(4-fluorophenyl)pyrrolo
[2,1-a]isoquinoline-3-carboxylate displays maximum potency with minimum inhibitory concentration
Keywords:
(MIC) of 1.0
lM, being 7.6 and 4.7 times more potent than the standard first line TB drugs, ethambutol
1,3-Dipolar cycloaddition
Pyridinium ylides
Indolizines
and ciprofloxacin, respectively.
Ó 2010 Elsevier Ltd. All rights reserved.
Pyrrolo[2,1-a]isoquinolines
Domino
Three-component
Antimycobacterial
Mycobacterium tuberculosis
Indolizine, being isomeric to indole, constitutes the core struc-
ture of many naturally occurring alkaloids, viz. (ꢀ)-slaframine,1
(ꢀ)-dendroprimine,2 indolizidine 167B3 and coniceine.4 They are
important as potential central nervous system depressants,5 cal-
cium entry blockers,6 cardiovascular7 and antimycobacterial
agents,8 spectral sensitizers9 and novel dyes.10 They are also used
for the treatment of angina pectoris11 and as testosterone 5R-reduc-
tase inhibitors,12 besides serving as key intermediates for the syn-
thesis of cycloazines.13 Consequently, the synthesis of indolizines,
especially the biologically active ones,14 continues to attract the
attention15 of organic chemists. Typical syntheses of indolizine have
been well documented in the literature16 among which, the
1,3-dipolar cycloaddition reaction of pyridinium N-ylide generated
in situ from a pyridinium salt in the presence of a base with an elec-
tron-deficient alkene/alkyne is one versatile methodology.17
gent enable a rapid and elegant access to molecules of high levels
of diversity and complexity in high yields relative to multi-step
reactions and hence are increasingly preferred. This study stems
as a part of our research programme embarked on the construction
of novel heterocycles employing tandem/domino multi-component
reactions19 and/or to screen them for antimycobacterial activities.20
In the present investigation, the domino reactions of a mixture of
pyridine 3 or isoquinoline 4, bromoacetonitrile 2a or ethyl bromo-
acetate 2b and b-nitrostyrenes 1 (Scheme 1) in a 1:1.2:1 molar ratio
in the presence of triethylamine were performed in acetonitrile at
room temperature for 3–5 h.21 The reaction afforded 1-nitro-2-aryl-
3-indolizine carbonitriles 5, ethyl 2-aryl-1-nitroindolizine-3-car-
boxylates 6, 1-nitro-2-arylpyrrolo[2,1-a]isoquinoline-3-carbonitrile
7 and ethyl 2-arylpyrrolo[2,1-a]isoquinoline-3-carboxylates 8
(Scheme 1) from the respective reactants in moderate to good yields
(44–80%) of the product (Table 1). All these reactions are regioselec-
tive affording only 5–8, whilst their regioisomers 50–80 were not
obtained even in traces (Scheme 2).
The biological importance of indolizines prompted the synthesis
of the hitherto unreported substituted indolizines and pyrrolo[2,1-
a]isoquinolines 5–8 (Scheme 1) employing domino reactions, to
screen them for antimycobacterial activities and to report the re-
sults in this Letter. Incidentally, domino reactions18 being conver-
The reaction performed in the presence of different bases, viz.
Et3N, DBU, DMAP, piperidine and K2CO3 (Table 2) clearly shows
that Et3N is the most efficient base for these domino reactions
and that the reaction affords a maximum yield of the product when
a molar equivalent of Et3N was employed.
⇑
Corresponding author. Tel./fax: +91 452 2459845.
E-mail address: subbu.perum@gmail.com (S. Perumal).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.128

6440
S. Muthusaravanan et al. / Tetrahedron Letters 51 (2010) 6439–6443
X = CN
NO2
N
NO2
N
or
NC
NC
NO2
Ar
Br
X
Ar
Ar
7
5
2a: X=CN,
2b:
1
X= COOEt
CH3CN, TEA
rt, 3-5 h
or
N
X = COOEt
NO2
N
or
N
3
N
4
EtOOC
Ar
EtOOC
Ar
8
6
Scheme 1. Synthesis of indolizines and pyrrolo[2,1-a]isoquinolines 5–8.
Table 1
Synthesis and antimycobacterial activities of indolizines and pyrrolo[2,1-a]-isoquinolines 5–8 against MTB
Entry
Compd.
Ar
X
Reaction time (h)
Yield (%)a
MIC (lM)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
5a
5b
5c
5d
5e
5f
6a
6b
7a
7b
7c
7d
8a
8b
8c
8d
8e
8f
2,4,6-(MeO)3C6H2
4-MeOC6H4
4-MeC6H4
4-PriC6H4
4-ClC6H4
4-FC6H4
4-ClC6H4
2,4-Cl2C6H3
4-MeOC6H4
4-MeC6H4
4-ClC6H4
CN
CN
CN
CN
CN
CN
COOEt
COOEt
CN
CN
CN
CN
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
3
5
3
5
4
4
3
3
5
3
4
4
3
4
3
3
4
3
44
52
54
51
57
53
58
54
53
60
71
58
62
68
65
80
62
77
>85
85
45.1
40.9
21.0
5.5
9.1
NTb
36.4
9.6
9.0
2.3
16.0
16.7
17.3
7.8
4-FC6H4
4-MeOC6H4
4-MeC6H4
C6H5
4-PriC6H4
4-ClC6H4
17
18
3.9
1.0
4-FC6H4
Rifampicin
Isoniazid
Ciprofloxazin
Ethambutol
0.1
0.4
4.7
7.6
a
Isolated yield after purification by column chromatography.
Not tested.
b
The structure of the indolizines and arylpyrrolo[2,1-a]isoquino-
studies of single crystals of two representative cases, 5b and 8d
(vide Supplementary data).24
lines 5–8 was established from 1H, 13C and 2D NMR spectroscopic
data. The chemical shifts of 5c, a representative example, were
assigned on the basis of straightforward considerations including
HMBCs and H,H-COSY correlations, substituent induced chemical
shifts and signal multiplicities of 1H NMR signals (Fig. 1). A compar-
ison of the chemical shifts of 5c with those of a model compound,
ethyl 2-iodo-1-nitroindolizine-3-carboxylate,22 shows that the
chemical shifts and vicinal J values of H-6, H-7 and H-8 of both
the compounds differ little supporting the position of the nitro
function in 5c and hence the regiochemistry of the reaction. The
chemical shift of H-5 of 5c and that of model compound alone dif-
fer significantly ascribable to the van der Waals deshielding of H-5
by the ester function in the latter.23 The IR spectrum of 5c had the
frequencies expected for the nitrile and nitro groups at 2214 cmꢀ1
(CN) and 1500 and 1367 cmꢀ1 (NO2). The structures deduced from
NMR spectra were further confirmed by the X-ray crystallographic
A plausible mechanism for the formation of 5–8 is depicted in
Scheme 2. Presumably, a domino sequence of reactions involving
substitution, generation of 1,3-dipole and cycloaddition of pyridi-
nium ylides to b-nitrostyrenes 1 afford 10, which undergo sponta-
neous elimination and/or aromatisation to furnish 5–8 (Scheme 2).
The regioselectivity observed in the formation of 5–8 is ascribable
to the preference of the anionic centre of the dipole to react with
the electron-deficient
a-carbon of the b-nitrostyrenes during the
cycloaddition reaction. Probably, the enhanced steric interaction
in the intermediate 10b with the isoquinoline sub-structure trig-
gers the elimination of HNO2 and the concomitant aromatisation
affording 8 (Scheme 2).
In previous synthetic methods, indolizines and pyrrolo[2,1-a]
isoquinolines were obtained by multi-step protocols from the reac-
tions of pyridinium/isoquinolinium yide, prepared in a separate

S. Muthusaravanan et al. / Tetrahedron Letters 51 (2010) 6439–6443
6441
Br
X
Et3N
a:
X=CN,
N
+
N
b: X= COOEt
N
2
X
X
aromatization
X = CN
or
NO2
N
NO2
N
NO2
N
NC
Ar
NC
NC
Ar
Ar
5
7
10a
N
NO2
X
H
Ar
aromatization
X = COOEt
or
NO2
N
NO2
N
N
with or without
elimination of
HNO2
EtOOC
EtOOC
Ar
Ar
EtOOC
Ar
6
8
10b
N
Ar
NO2
Ar
NO2
N
Ar
N
EtOOC
NC
EtOOC
8'
5' or 7'
6'
(Regioisomeric products 5' to 8' not formed)
Scheme 2. Plausible mechanism for the formation of indolizines and pyrrolo-[2,1-a]isoquinolines 5–8.
Table 2
Influence of base on the formation of 5c
The indolizines and pyrrolo[2,1-a]isoquinolines synthesized in
the present work were screened for their in vitro antimycobac-
terial activity against M. tuberculosis H37Rv (MTB) by agar dilu-
tion method32 for the determination of minimum inhibitory
concentration (MIC) in triplicate and these MIC values along
with those of the standard drugs are presented in Table 1.
Among all the compounds screened, three compounds, viz. 7d,
Entry
Base
Mol %
Reaction time (h)
Yield of 5c (%)a
1
2
3
4
5
6
7
8
Et3N
Et3N
Et3N
Et3N
DMAP
DBU
Piperidine
K2CO3
25
50
75
100
100
100
100
100
14
14
14
3
5
5
10
45
51
72
65
55
8e and 8f with MIC values of 2.3, 3.9 and 1.0
emerged more potent than the standard drug ethambutol (MIC:
7.6 M). Ethyl 2-(4-fluorophenyl)pyrrolo[2,1-a]isoquinoline-3-
lM, respectively,
b
15
10
—
—
b
l
carboxylate (8f) displayed maximum activity, being 7.6 and 4.7
times more potent than ethambutol and ciprofloxacin, respectively.
However, all the compounds are less active against MTB than
a
Isolated yield after purification by column chromatography.
Product not obtained.
b
step, with electron-deficient alkenes which proceed via cycloaddi-
tion-elimination/oxidation sequence.22,25–30 Only one three-com-
ponent domino approach has been reported in the literature, viz.
the drugs, isoniazid (MIC: 0.4 lM) and rifampicin (MIC: 0.1 lM),
It is to be noted that, in general, both indolizine series 6 bearing
ester and nitro groups and pyrrolo[2,1-a]isoquinoline series 8,
respectively, with ester function in the pyrrole sub-structure
led to enhanced activity than series 5 and 7 with nitrile and
nitro functions (Table 1).
In conclusion, a facile, regioselective synthesis of novel indoli-
zines and pyrrolo[2,1-a]isoquinolines has been achieved via a
domino sequence of reactions from simple, readily available start-
ing materials in a one-pot operation. These compounds also display
significant antimycobacterial activities.
for the synthesis of indolizines by the reaction of pyridine,
a-
haloketone and alkyne under microwave irradiation.31 Hence, the
present work constitutes the first report on the synthesis of novel
tri-/disubstituted indolizines and pyrrolo[2,1-a]isoquinolines in
high yields of 44–80% (Table 1) by the three component domino
reaction of pyridinium/isoquinolinium ylide, generated in situ
from pyridine/isoquinoline with bromoacetonitrile or ethyl bro-
moacetate, with b-nitrostyrenes at ambient temperature.

6442
S. Muthusaravanan et al. / Tetrahedron Letters 51 (2010) 6439–6443
7.24, td,
8.43, dt,
J = 7, 1 Hz
J = 7, 1 Hz
H
H
7
9.67, d
J = 7 Hz
7.12, td,
J = 7, 1 Hz
6
111.6
NC
7.63, ddd,
J = 9,7,1Hz
H
5
H
H
O
6
N
5
97.4
136.3
134.1
7.52, ddd,
H
J = 9,7,1Hz
EtO C
7
129.2
8
N
129.6
139.9
125.5
H
8
8.60, dt,
J = 9, 1 Hz
8.58, d,
J = 9 Hz
NO2
I
H
H3C
H
7.46, d,
NO2
2.44, s, 3H
21.4
J = 8 Hz
H
7.33, d,
J = 8 Hz
H,H-COSY
HMBC
Figure 1. Selected 2D-correlations and chemical shifts for 5c and for model compound, ethyl 2-iodo-1-nitroindolizine-3-carboxylate.22
17. (a) Prostakov, N. S.; Batibaev, O. B. Russ. Chem. Rev. 1975, 44, 748; (b) Uchida, T.;
Acknowledgements
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Pergamon Press: New York, 1984; Vol. 8, p 443.
S.P. thanks the Department of Science and Technology, New
Delhi, for the award of an Indo-Spanish collaborative major
research project (No. DST/INT/SPAIN/09) and for funds under IRH-
PA programme for the purchase of a high resolution NMR spec-
trometer. S.P. also thanks the University Grants Commission,
New Delhi for the award of a UGC-JRF Fellowship to S.M.
18. Tietze, Lutz F. Chem. Rev. 1996, 96, 115–136; Ho, T.-L. Tandem Organic
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.09.128.
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21. General procedure for the synthesis of indolizines and pyrrolo[2,1-a]isoquinolines:
A
mixture of b-nitrostyrene 1 (1 mmol), pyridine 3 (1 mmol), bromo-
acetonitrile 2 (1.2 mmol) and triethylamine (1 mmol) in acetonitrile (8 ml)
was stirred at room temperature for 3 h. The progress of the reaction was
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solvent was removed and the product was purified by column chromatography
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indolizines and pyrrolo[2,1-a]isoquinolines. Spectroscopic data for representative
indolizines and pyrrolo[2,1-a]isoquinolines are given below.
2-(4-methylphenyl)-1-nitro-3-indolizinecarbonitrile 5c: Isolated as white solid.
Yield 54%. Mp 234–238 °C; IR (KBr) 2214 cmꢀ1 (C„N), 1367, 1500 cmꢀ1 (NO2);
1H NMR (300 MHz, CDCl3) dH 2.44 (s, 3H), 7.24, td (1H, J = 7,1 Hz), 7.33 (d, 2H,
J = 8 Hz), 7.46 (d, 2H, J = 8 Hz) 7.63 (ddd, 1H, J = 9, 7, 1 Hz), 8.43 (dt, 1H, J = 7,
1 Hz), 8.60 (dt, 1H, J = 9, 1 Hz); 13C NMR (75 MHz, CDCl3) dC 21.4, 97.4, 111.6,
116.7, 120.2, 125.5, 125.7, 129.2, 129.6, 130.0, 134.1, 136.3, 139.9. Anal. Calcd
for C16H11N3O2: C, 69.31; H, 4.00; N, 15.15. Found: C, 69.35; H, 3.97; N, 15.12.
Ethyl 2-(4-chlorophenyl)-1-nitroindolizine-3-carboxylate 6a: Isolated as white
solid. Yield 58%. Mp 175–178 °C; IR (KBr) 1750, 1622 cmꢀ1 (COOEt); 1H NMR
(300 MHz, CDCl3) dH 0.91 (t, 3H, J = 7 Hz), 4.09 (q, 2H, J = 7 Hz), 7.17–7.22 (m,
1H), 7.30 (d, 2H, J = 7 Hz), 7.42 (d, 2H, J = 7 Hz), 7.60–7.70 (m, 1H) 8.62 (dd, 1H,
J = 8, 1 Hz), 9.75 (d, 1H, J = 6 Hz); 13C NMR (75 MHz, CDCl3) dC 13.4, 60.7, 113.3,
116.3, 119.2, 127.8, 128.3, 129.6, 130.4, 131.5, 133.03, 133.8, 134.1, 161.1.
Anal. Calcd. for C17H13ClN2O4: C, 59.23; H, 3.80; N, 8.13. Found C, 59.35; H,
3.88; N, 8.05.
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2-(4-Chlorophenyl)-1-nitropyrrolo[2,1-a]isoquinoline-3-carbonitrile 7c: Isolated
pale yellow solid. Yield 71%. Mp 270–274 °C; 1H NMR (300 MHz, CDCl3) dH 7.09
(d, 1H, J = 7 Hz), 7.45–7.48 (m, 2H), 7.53–7.64 (m, 2H), 7.69–7.72 (m, 1H), 7.77–
7.81 (m, 2H), 8.08 (d, 1H, J = 7 Hz), 8.14 (dd, 1H, J = 8, 2 Hz); 3C NMR (75 MHz,
CDCl3) dC 94.6, 99.9, 113.7, 114.2, 122.4, 123.0, 124.6, 127.4, 127.9, 128.1,
128.4, 129.2, 130.8, 134.2, 134.3, 135.4. Anal. Calcd. for C19H10ClN3O2: C, 65.62;
H, 2.90; N, 12.08. Found C, 65.55; H, 3.01; N, 12.15.
Ethyl 2-phenylpyrrolo[2,1-a]isoquinoline-3-carboxylate 8c: Isolated as white
solid. Yield 65%. Mp 140–144 °C; IR (KBr) 1675, 1606 cmꢀ1 (COOEt); 1H NMR
(300 MHz, CDCl3) dH 1.10 (t, 3H, J = 7 Hz), 4.21 (q, 2H, J = 7 Hz), 7.02 (d, 2H,
J = 7 Hz), 7.34–7.39 (m, 3H), 7.48–7.56 (m, 4H), 7.66–7.69 (m, 1H), 8.12 (d, 1H,
J = 8 Hz), 9.30 (d, 1H, J = 8 Hz); 13C NMR (75 MHz, CDCl3) dC 13.8, 59.8, 103.7,
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112.5, 113.1, 123.1, 124.7, 125.2, 126.8, 127.0, 127.4, 127.5, 128.0, 129.9, 134.1,
136.7, 136.8, 162.0. Anal. Calcd for C21H17NO2: C, 79.98; H, 5.43; N, 4.44. Found
C, 79.90; H, 5.51; N, 4.40.
of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
25. Peng, W.; Zhu, S. J. Chem. Soc., Perkin Trans. 1 2001, 3204–3210.
26. Jian, Z.; Yuefei, Hu; Hongwen, H. Synthesis 1999, 1, 166–170.
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1549.
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32. Biological Screening: All compounds were screened for their in vitro anti-
mycobacterial activity against MTB in Middlebrook 7H1agar medium
supplemented with OADC by agar dilution method similar to that
recommended by the National Committee for Clinical Laboratory Standards
for the determination of MIC in triplicate.
23. It appears that the long range couplings (4JH,H = 1 Hz) of both H-5 and H-8 for
the model compound. ethyl 2-iodo-1-nitroindolizine-3-carboxylate22 have not
been reported in the earlier work probably because of poor resolution but are
essential to explain the observed multiplicities of H-6 and H-8 as found for 5c.
24. Crystallographic data (excluding structure factors) for ethyl 2-(4-isopropyl-
phenyl)pyrrolo(2,1-a)isoquinoline-3-carboxylate 8d and 2-(4-methoxyphenyl)-1-
nitro-3-indolizinecarbonitrile 5b in this Letter have been deposited with the
Cambridge Crystallographic Data Centre as supplementary publication
numbers CCDC 775513 and 775514. Copies of the data can be obtained, free