An efficient, general synthesis of 2-substituted 3,6-dihydropyrrolo[3,2-e] indoles involving one-pot Sonogashira coupling and cyclisation

Article abstract of DOI:10.1007/s00706-012-0859-5

A number of 2-substituted 3,6-dihydropyrrolo[3,2-e]indoles were synthesised efficiently by the reaction of 4-iodo-1-(phenylsulfonyl)-5-(trifluoroacetamido) indole with terminal acetylenes in the presence of a palladium(0) catalyst and a copper(I) co-catal

Full text of DOI:10.1007/s00706-012-0859-5

Monatsh Chem (2013) 144:717–724
DOI 10.1007/s00706-012-0859-5
ORIGINAL PAPER
An efficient, general synthesis of 2-substituted
3,6-dihydropyrrolo[3,2-e]indoles involving one-pot
Sonogashira coupling and cyclisation
•
Moumita Rakshit Taraknath Kundu
•
•
Gandhi K. Kar Manas Chakrabarty
Received: 28 June 2012 / Accepted: 29 August 2012 / Published online: 18 October 2012
Ó Springer-Verlag 2012
Abstract A number of 2-substituted 3,6-dihydropyrrolo-
[3,2-e]indoles were synthesised efficiently by the reaction
of 4-iodo-1-(phenylsulfonyl)-5-(trifluoroacetamido)indole
with terminal acetylenes in the presence of a palladium(0)
catalyst and a copper(I) co-catalyst. The reaction involved
one-pot Sonogashira coupling/heteroannulation, the first
one of its kind in the synthesis of the title compounds. The
required amido-iodoindole was prepared smoothly from
5-nitroindole by successive N-protection, reduction of the
nitroarene, iodination of the resulting aminoarene and
N-trifluoroacetylation.
[1–8]. Our attention was recently drawn to a relatively small
group of compounds, viz. pyrroloindoles whose chemistry,
including synthesis, has been reviewed [9]. Of the various
isomericpyrroloindolenuclei, the3,6-dihydropyrrolo[3,2-e]-
indole nucleus became the focus of efforts because it is
present in a number of bioactive natural products, viz. the
antitumour antibiotics CC-1065 [10–12], duocarmycin A
[13–15], duocarmycin B2 [16], duocarmycin C [14] (identi-
fied as pyrindamycin A [17]), duocarmycins D and S [15],
duocarmycin SA [15, 18, 19], gilvusmycin [20], yatakemycin
(also antifungal) [21–23] and the cAMP phosphodiesterase
inhibitors PDE-I (1) and PDE-II (2) [24, 25] (Fig. 1).
The synthesis and biological studies (antitumour, mainly
DNA alkylation) of these compounds have been under-
taken successfully by various groups. Several syntheses of
the parent nucleus with or without substitution at one or
both the pyrrole nuclei have also been reported using
mostly Fischer mono- and bis-indolisations besides Bis-
chler cyclisation [26–32]. But in nearly all these cases, the
substrates had to be prepared from commercially available
starting materials in several steps, a mixture of linear
and angular regioisomers was always formed, the final 3,6-
dihydropyrrolo[3,2-e]indoles were isolated in very poor to
low yields and, more importantly, none of these methods
was a general synthesis of substituted pyrroloindoles. Thus,
there existed a need for the development of a short, effi-
cient and general synthesis of only one type of substituted
regioisomers, which should be free of the aforementioned
shortcomings.
Keywords 3,6-Dihydropyrrolo[3,2-e]indoles Á
One-pot synthesis Á Palladium(0) catalyst Á
Sonogashira coupling Á Cyclisation
Introduction
Condensed heterocycles continue to be an important arena
for drug development. We have been working on the syn-
thesis of condensed heterocycles for the last few decades
M. Rakshit Á G. K. Kar (&)
Department of Chemistry and Biochemistry,
Presidency University (formerly Presidency College),
86/1, College Street, Kolkata 700073, India
e-mail: gandhikar41@yahoo.co.in
Our overall strategy was to construct the pyrrole ring on
the benzenoid ring of the indole nucleus following
protocols available for the synthesis of the indole ring by a
two-step process, viz. Sonogashira coupling [33–35] of
o-iodoanilines with terminal alkynes, followed by cycli-
sation of the resulting o-alkynylanilines.
M. Chakrabarty
Department of Chemistry, Bose Institute, 93/1,
A.P.C. Road, Kolkata 700009, India
T. Kundu
Department of Chemistry, NIT Sikkim, Ravangla,
South Sikkim 737139, India
123

718
M. Rakshit et al.
synthetic strategy, therefore, involved 4-iodo-1-(phenyl-
sulfonyl)-5-(trifluoroacetamido)indole (3) as the substrate
(Scheme 1).
HO2C
HN
1: R = CONH2
2: R = COCH3
Accordingly, the required precursor 3 was prepared effi-
ciently, following standard protocols, from commercially
available 5-nitroindole by successive N-phenylsulfonyla-
tion, reduction of the N-protected nitroarene to the
corresponding arylamine, regioselective iodination at C-4,
and trifluoroacetylation of the resulting 5-amino-4-iodo-1-
(phenylsulfonyl)indole (Scheme 2).
N
R
MeO
OH
Fig. 1 Pyrrolo[3,2-e]indoles as cAMP phosphodiesterase inhibitors
A perusal of the literature, including a review on the
application of Sonogashira coupling in the synthesis of
heterocycles [36], revealed that a number of one-pot, two-
step procedures for the synthesis of 2-substituted indoles
have been recently developed from N-H/alkyl/acyl
o-iodoanilines and terminal acetylenes by tandem Sono-
gashira coupling/5-endo-dig cyclisation [37–44]. These
tandem reactions were brought about by using a Pd(0)
catalyst (e.g. Pd/C-PPh3, Pd(OAc)2, Pd-zeolite, (PPh3)2
PdCl2), CuI as the co-catalyst and a base (e.g. Et3N,
Et2NH, NH2CH2CH2OH, NaOH, Cs2CO3) as the cyclising
agent in a solvent (usually DMF) at ambient temperature,
under reflux or under microwave or ultrasound irradiation.
We applied a similar methodology for our purpose. As a
result, we have now been able to develop the first one-pot, two-
step synthesis of 2-substituted 3,6-dihydropyrrolo[3,2-e]-
indoles involving a Sonogashira coupling/5-endo-dig cycli-
sation route. The details of our work are briefly presented in
this report.
Initially, we tried the alkynylation of 3 with phenyl-
acetylene (4a, Ar = Ph). Although several palladium
catalysts, co-catalysts, bases and solvents have been widely
used in Sonogashira reactions with varying degrees of
success [50–52], we employed Pd(PPh3)4 and PdCl2(PPh3)2
(10 mol% each) as catalysts because these two compounds
continue to be by far the most frequently used catalysts in
copper-mediated (CuI, 5 mol% in our case) practical So-
nogashira applications [53]. We also used piperidine
(excess) and triethylamine (2, 5 and 10 equiv.) as the base
and, in most cases, DMF as the solvent. The reactions were
carried out (at room temperature or at 110 °C) in argon
atmosphere in order to block homocoupling of the terminal
alkynes through a copper-mediated Hay/Glaser reaction
[54–57]. The outcome of our trial experiments, not detailed
in the ‘‘Experimental’’, is presented in Table 1.
A critical analysis of the results is as follows. When
piperidine was used as the base without the presence of a
co-catalyst, only the alkynylindole 5a was obtained, irre-
spective of the nature of the palladium catalyst and the
temperature (entries 1–3). In subsequent experiments,
5 mol% of cuprous iodide was used as the co-catalyst.
Whereas the use of 2 equiv. of triethylamine also furnished
only 5a (entry 4), the use of 5 equiv. of this base led to the
formation of both 5a and the corresponding cyclised
product 6a with increasing yields of the cyclised product
with increasing periods of heating (5a 59 %, 6a 4 % after
3 h; 5a 51 %, 6a 13 % after 6 h) (entries 5, 6). The optimal
conditions were found to be 10 equiv. of triethylamine and
heating for a period of 6 h when only the cyclised product
6a was isolated in 65 % yield (entry 8). The structures of
both 5a and 6a were ascertained by analysing their spec-
Results and discussion
The crucial step of our synthetic strategy was the palla-
dium(0)-catalysed Sonogashira coupling of N(1)-protected
5-amino-4-haloindoles with terminal alkynes, followed by
cyclisation of the resulting 4-alkynyl-5-aminoindoles.
Since aryl iodides commonly show higher reactivity than
aryl bromides, a 5-amino-4-iodoindole was chosen as the
target. Also, the amine must be protected by an electron-
withdrawing group to promote subsequent cyclisation, and
the best results had earlier been reported in this regard in
other classes of heteroarenes using carbamates and,
more usefully, trifluoroacetamides [45–49]. Our modified
1
troscopic data (IR, H and 13C NMR).
Scheme 1
R
R
HN
I
F3COCHN
F3COCHN
R
C CH
cyclisation
Pd (0)
N
N
N
SO2Ph
SO2Ph
R'
3
5
6 (R' = SO2Ph)
7 (R' = H)
deprotection
123

An efficient, general synthesis of 2-substituted 3,6-dihydropyrrolo[3,2-e]indoles
719
Scheme 2
I
I
H2N
O2N
H2N
F3COCHN
i, ii
iv
iii
N
N
N
N
H
SO2Ph
SO2Ph
SO2Ph
3
-
Reagents and conditions: (i) PhSO2Cl, NaOH, n-Bu4N+HSO4 (cat.), CH2Cl2, rt, 4 h;
95%; (ii) NH2NH2·H2O (98%), 10% Pd-C, MeOH, reflux, 6 h; 89%; (iii) N-
Iodosuccinimide, CH2Cl2, -5 °C, 1.5 h; 70%; (iv) (CF3CO)2O, Et3N, CH2Cl2, 0 °C, 2 h;
91%.
Table 1 Optimisation studies
Ph
Ph
1
I
3
HN
F3COCHN
F3COCHN
+
Ph C CH
+
6
N
N
N
SO2Ph
SO2Ph
SO2Ph
3
4a
5a
6a
Entry
Pd catalyst
Base (equiv.)
Solvent
Temp./°C
Time/h
Yield/%
5a
6a
1
2
3
4
5
6
7
8
Pd(PPh3)4
Piperidine
Piperidine
Piperidine
Et3N (2)
–
r.t.
6
4
4
4
3
6
3
6
50
50
60
65
59
51
20
–
–
Pd(PPh3)4
–
100
100
110
110
110
110
110
–
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
–
–
DMF
DMF
DMF
DMF
DMF
–
Et3N (5)
4
Et3N (5)
13
39
65
Et3N (10)
Et3N (10)
All reactions were carried out in argon atmosphere using 10 mol% of Pd catalyst. In entries 4–8, 5 mol% of CuI was additionally used
Since the outcome of the reaction presented in entry 8
unveiled a novel synthetic route to 2-substituted 3,6-dihy-
dropyrrolo[3,2-e]indoles, we next explored the generality
of this procedure. Accordingly, 3 was treated with a
number of terminal acetylenes bearing a p-tolyl group (4b),
alkyl groups (4c–4e), alkyl groups attached to an electron-
withdrawing group (4f, 4g), a methoxycarbonyl group (4h)
and a trimethylsilyl group (4i) using the conditions
employed in entry 8 of Table 1 (Scheme 3). All the reac-
tions were complete in 3–9 h. The results are presented in
Table 2.
As expected, all the products were identified spectro-
scopically as the novel 6-phenylsulfonyl derivatives of the
corresponding cyclised products (6a–6f, 6h), i.e. the cor-
responding 2-substituted 3,6-dihydropyrrolo[3,2-e]indoles,
except for those arising from 4g and 4i. The product from
propargyl propionate (4g) was identified as 3,6-dihydro-2-
(hydroxymethyl)pyrrolo[3,2-e]indole (6g), suggesting that
either the initially formed, unisolated coupling product (5g)
or the corresponding cyclised product underwent hydroly-
sis during the reaction. The product from TMS-acetylene
(4i), on the other hand, underwent hydrosilylation either
before or after the cyclisation, furnishing 6i as the only
isolated product. Noticeably, except for these two cases
Scheme 3
123

720
M. Rakshit et al.
Table 2 One-pot synthesis of N(6)-protected 2-substituted 3,6-dihydropyrrolo[3,2-e]indoles 6a–6i (Scheme 3)
Entry
Alkyne
Product
Time/h
Yield/%
M.p./°C
1
2
3
4
5
6
7
8
9
4a, R = C6H5
6a, R = C6H5
6
5
4
4
4
4
9
3
3
65
65
64
60
58
66
35
45
80
200–202
204–206
98–100
80–82
4b, R = 4-MeC6H4
4c, R = n-C4H9
4d, R = n-C5H11
4e, R = n-C6H13
4f, R = (CH2)3CN
4g, R = n-C3H7CO2CH2
4h, R = COOMe
4i, R = TMS
6b, R = 4-MeC6H4
6c, R = n-C4H9
6d, R = n-C5H11
6e, R = n-C6H13
6f, R = (CH2)3CN
6g, R = CH2OH
6h, R = COOMe
6i, R = H
60–62
160–162
166–168
151–153
108–110
Conditions: 3 (0.5 mmol), CuI (5 mol%), PdCl2(PPh3)2 (10 mol%), alkynes 4a–4i (1.5 equiv), Et3N (10 equiv), 5 cm3 DMF, 110 °C, 3–9 h
and for methyl propiolate (4h), the yields of the pyrro-
loindoles ranged from 58–66 %. Whereas TMS-acetylene
(4i) led to a higher yield (80 %) of the desilylated pyrro-
loindole (6i), propargyl propionate (4g) and methyl
propiolate (4h) furnished 6g and 6h in inexplicably lower
yields, viz. 35 and 45 %, respectively. In the last two cases,
no other product was found (TLC monitoring) to be
formed.
Experimental
All reactions were carried out using oven-dried glassware.
Commercial grade reagents were used without further puri-
fication. Solvents were dried prior to use following standard
literature procedures. Petroleum ether (PE) refers to the
fraction boiling in the range 60–80 °C. DMF was dried,
˚
distilled and stored over molecular sieves (4 A). Tetra-
The N-deprotection of the products 6 was not expected
to pose any problem. Yet, in order to verify this notion,
each of 6a, 6c and 6i, chosen arbitrarily, was separately
refluxed in methanol solution with magnesium and
ammonium chloride [58–60] to afford the corresponding
N-deprotected 3,6-dihydropyrrolo[3,2-e]indoles 7a, 7c and
kis(triphenylphosphine)palladium(0), bis(triphenylphos-
phine)palladium(II) dichloride, N-iodosuccinimide and all
alkynes were purchased from Sigma-Aldrich (USA). Tri-
fluoroacetic anhydride was purchased from Alfa Aesar
(Lancaster). Melting points were recorded in open capillar-
ies. Infrared spectra were obtained as thin films on KBr
pellets using a Shimadzu Fourier transform (FT–IR) 8300
spectrophotometer. 1H (500 MHz) and 13C (125 MHz, PND
and DEPT-135) NMR spectra were recorded on a Bruker
AVANCE III 500 MHz NMR spectrometer using tetra-
methylsilane as the internal standard. HR-MS spectra were
taken using a TRACE GC ULTRA POLARIS Q mass
spectrometer. Precoated silica gel 60 F254 TLC sheets
(Merck) were used for thin-layer chromatography (TLC). All
new compounds were also subjected to elemental analysis
(C, H, N) in a Perkin Elmer 2400 Series II Analyser, and the
results were in good agreement ( 0.3 %) with the calculated
values. Purification by column chromatography (CC) was
done using 100–200 mesh silica gel (Merck). Anhydrous
sodium sulfate was used for drying solutions. 1-(Phenylsul-
fonyl)indol-5-amine was prepared from 5-nitroindole,
procured commercially, on 10 mmol scale, following a
procedure [61] reported earlier from this laboratory.
1
7i in 64, 55 and 67 % yields, respectively. The H NMR
data of both 7a [26] and 7i [31] agreed well with those
reported earlier for them. Pertinently, compound 7a had
earlier been prepared from acetophenone and (1-acetyl-5-
indolinyl)hydrazine in four steps in an overall yield of
0.4 % [26], which is clearly of no synthetic significance.
Conclusion
We have developed an expedient synthesis of 2-substituted
3,6-dihydropyrrolo[3,2-e]indoles from 4-iodo-1-(phenylsul-
fonyl)-5-(trifluoroacetamido)indole and terminal acetylenes
involving one-pot Sonogashira coupling/heteroannulation as
the key step. The indolic substrate was efficiently prepared
from 5-nitroindole in a four-step procedure. Noticeably, the
use of trimethylsilylacetylene furnished the 2-unsubstituted
3,6-dihydropyrroloindole directly. To our knowledge, the
present synthesis constitutes the first one-pot Sonogashira
coupling/heteroannulation route to 2-substituted 3,6-dihydro-
pyrrolo[3,2-e]indoles. This general synthesis of only one type
of regioisomeric pyrroloindole is short yet efficient and devoid
of the difficulties encountered in earlier routes to this class of
condensed heterocycles.
4-Iodo-1-(phenylsulfonyl)indol-5-amine (C14H11IN2O2S)
N-Iodosuccinimide (2.70 g, 12 mmol) was added in por-
tions to a solution of 2.72 g 1-(phenylsulfonyl)indol-5-
amine (10 mmol) in 50 cm3 dry CH2Cl2 at -5 °C, and the
solution was stirred until the reaction was complete (1.5 h).
The mixture was poured into 10 % aqueous Na2S2O3
solution, and the organic layer was separated, washed with
123

An efficient, general synthesis of 2-substituted 3,6-dihydropyrrolo[3,2-e]indoles
721
water, dried, filtered and the solvent removed under
vacuum. A dark coloured residue was obtained, which
was purified by CC using EtOAc/PE (1:9) as the eluent to
furnish the product as a yellow solid. Yield: 2.78 g (70 %);
m.p.: 138–140 °C; IR (KBr): vꢀ = 3,428, 3,325, 1,447,
1,370, 1,168, 1,137 cm-1; 1H NMR (CDCl3): d = 4.04 (br
s, 2H), 6.49 (dd, J = 3.5 Hz, 0.5 Hz, 1H), 6.73 (d,
J = 8.5 Hz, 1H), 7.41 (tt, J = 7.5 Hz, 1.5 Hz, 2H), 7.51
(tt, J = 7.5 Hz, 1.5 Hz, 1H), 7.52 (d, J = 3.5 Hz, 1H),
7.76 (dd, J = 9.0 Hz, 1.0 Hz, 1H), 7.82 (dd, J = 8.5 Hz,
1.0 Hz, 2H) ppm; 13C NMR (CDCl3): d = 75.7, 127.7,
136.4, 138.5, 143.9 (all Ar–C), 113.0, 113.4, 114.8, 127.0,
127.3, 129.6, 134.2 (all Ar–CH) ppm; HR-MS: calcd for
C14H11IN2O2S 397.9586 (M?), found 397.9584.
General procedure for the synthesis of compounds
6a–6i
A mixture of 3 (0.5 mmol), alkyne 4 (0.75 mmol),
Pd(PPh3)2Cl2 (10 mol%), CuI (5 mol%), Et3N (5 mmol)
and 5 cm3 DMF was stirred at 110 °C for 3–9 h in an argon
atmosphere. It was then cooled to rt, filtered through a bed
of Celite and the Celite bed was washed with CH2Cl2
(3 9 15 cm3). The combined organic extract was washed
with brine and then water, dried and the solvent distilled
off. Purification of the residue by CC and elution with
EtOAc/PE afforded 6a–6i in 35–80 % yields.
3,6-Dihydro-2-phenyl-6-(phenylsulfonyl)pyrrolo[3,2-e]-
indole (6a, C22H16N2O2S)
Yellow solid; yield: 121 mg (65%); m.p.: 200–202 °C; IR
(KBr): vꢀ = 3,432, 1,359, 1,182, 1,141, 1,124 cm-1 1H
;
N-[4-Iodo-1-(phenylsulfonyl)indol-5-yl]trifluoroacetamide
(3, C16H10F3IN2O3S)
NMR (DMSO-d6): d = 7.15 (dd, J = 3.5 Hz, 0.5 Hz, 1H),
7.20 (d, J = 1.5 Hz, 1H), 7.37 (tt, J = 7.5 Hz, 1.0 Hz,
1H), 7.47 (d, J = 9.0 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H),
7.62 (t, J = 7.5 Hz, 2H), 7.71 (tt, J = 7.5 Hz, 1.0 Hz, 1H),
7.82 (d, J = 9.0 Hz, 1H), 7.83 (d, J = 3.5 Hz, 1H), 7.91
(dd, J = 8.5 Hz, 1.0 Hz, 2H), 8.00 (dd, J = 9.0 Hz,
1.0 Hz, 2H), 11.81 (s, 1H) ppm; 13C NMR (DMSO-d6):
d = 97.9, 108.1, 109.1, 109.7, 125.3, 126.0, 126.9, 127.8,
129.4, 130.1, 134.7 (all Ar–CH), 121.6, 123.0, 129.2,
132.6, 134.0, 137.8, 138.1 (all Ar–C) ppm; HR-MS: calcd
for C22H16N2O2S 372.0932 (M?), found 372.0928.
Et3N (2 cm3) and 1.95 cm3 (CF3CO)2O were successively
added to a solution of 3.98 g 4-iodo-1-(phenylsulfonyl)
indol-5-amine (10 mmol) in 50 cm3 dry CH2Cl2 at 0 °C,
and the solution was stirred until the reaction was complete
(2 h). The reaction mixture was poured into water, the
organic layer separated and the aqueous layer extracted
with CH2Cl2 (3 9 25 cm3). The combined organic extract
was washed with water, dried and the solvent removed.
The residue was crystallised from CH2Cl2/PE to furnish 3
as a light brown solid. Yield: 4.5 g (91%); m.p.:
218–220 °C; IR (KBr): vꢀ = 3,355, 1,716, 1,376, 1,170,
1,135 cm-1; 1H NMR (CDCl3): d = 6.67 (dd, J = 3.5 Hz,
0.5 Hz, 1H), 7.50 (tt, J = 7.5 Hz, 1.5 Hz, 2H), 7.51 (d,
J = 9.0 Hz, 1H), 7.61 (tt, J = 7.5 Hz, 1.5 Hz, 1H), 7.70
(d, J = 3.5 Hz, 1H), 7.89 (dd, J = 8.5 Hz, 1.0 Hz, 2H),
7.98 (d, J = 9.0 Hz, 1H), 10.01 (br s, 1H) ppm; 13C NMR
(CDCl3): d = 84.7, 132.3, 132.9, 136.3, 137.9 (all Ar-C),
113.1, 114.1, 122.8, 127.0, 127.9, 129.9, 134.7 (all Ar-CH)
ppm; HR-MS: calcd for C16H10F3IN2O3S 493.9409 (M?),
found 493.9412.
3,6-Dihydro-2-(4-methylphenyl)-6-(phenylsulfonyl)pyrrolo-
[3,2-e]indole (6b, C23H18N2O2S)
White solid; yield: 126 mg (65%); m.p.: 204–206 °C; IR
(KBr): vꢀ = 3,449, 3,399, 1,364, 1,178, 1,136 cm-1 1H
;
NMR (CDCl3): d = 2.40 (s, 3H), 6.91 (d, J = 2.5 Hz, 2H),
7.22 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 9.0 Hz, 1H), 7.36
(t, J = 8.0 Hz, 2H), 7.45 (t, J = 7.5 Hz, 1H), 7.53 (d,
J = 8.0 Hz, 2H), 7.59 (d, J = 3.5 Hz, 1H), 7.85
(d, J = 8.5 Hz, 3H), 8.44 (s, 1H) ppm; 13C NMR (CDCl3):
d = 21.25 (CH3), 97.8, 108.2, 108.5, 125.0, 125.4, 126.6,
128.4, 129.1, 129.4, 129.7, 133.5 (all Ar–CH), 121.8,
123.1, 129.3, 129.8, 133.1, 137.6, 138.4 (all Ar–C) ppm;
HR-MS: calcd for C23H18N2O2S 386.1089 (M?), found
386.1085.
N-[4-(Phenylethynyl)-1-(phenylsulfonyl)indol-5-yl]-
trifluoroacetamide (5a, C24H15F3N2O3S)
White solid; yield: 120 mg (51%); m.p.: 194–196 °C; IR
(KBr): vꢀ = 3,382, 2,174, 1,724, 1,368, 1,347, 1,155,
1
1,140 cm-1; H NMR (CDCl3): d = 6.88 (d, J = 3.5 Hz,
2-Butyl-3,6-dihydro-6-(phenylsulfonyl)pyrrolo[3,2-e]-
indole (6c, C20H20N2O2S)
1H), 7.38–7.43 (m, 3H), 7.47 (t, J = 7.5 Hz, 2H),
7.51–7.60 (m, 3H), 7.67 (d, J = 3.5 Hz, 1H), 7.88 (dd,
J = 8.0 Hz, 1.5 Hz, 2H), 8.03 (d, J = 9.0 Hz, 1H), 8.31
(d, J = 9.5 Hz, 1H), 8.80 (br s, 1H) ppm; 13C NMR
(CDCl3): d = 80.9, 101.4, 106.3, 114.8, 121.7, 128.4,
132.1, 132.2, 138.0, 154.4, 154.7 (all Ar–C), 108.6, 114.7,
117.0, 126.9, 127.0, 128.8, 129.60, 129.63, 131.6, 134.3
(all Ar–CH) ppm; HR-MS: calcd for C24H15F3N2O3S
468.0755 (M?), found 468.0760.
Light brown solid; yield: 113 mg (64%); m.p.: 98–100 °C;
1
IR (KBr): vꢀ = 3,400, 1,364, 1,185, 1,166, 1,139 cm-1; H
NMR (CDCl3): d = 0.93 (t, J = 7.5 Hz, 3H), 1.39 (m,
2H), 1.68 (m, 2H), 2.75 (t, J = 7.5 Hz, 2H), 6.39 (d,
J = 2.0 Hz, 1H), 6.86 (dd, J = 4.0 Hz, 0.5 Hz, 1H), 7.23
(d, J = 9.0 Hz, 1H), 7.34 (tt, J = 7.5 Hz, 1.5 Hz, 2H),
7.43 (tt, J = 7.5 Hz, 1.0 Hz, 1H), 7.57 (d, J = 4.0 Hz,
1H), 7.78 (dd, J = 9.0 Hz, 0.5 Hz, 1H), 7.84 (dd,
123

722
M. Rakshit et al.
J = 8.5 Hz, 1.5 Hz, 2H), 8.03 (br s, 1H) ppm; 13C NMR
(CDCl3): d = 14.2 (CH3), 22.7, 28.4, 31.8 (all CH2), 98.4,
107.6, 108.6, 108.7, 125.5, 127.0, 129.4, 133.8 (all
Ar–CH), 121.1, 123.1, 130.0, 132.4, 138.8, 140.4 (all
Ar–C) ppm; HR-MS: calcd for C20H20N2O2S 352.1245
(M?), found 352.1240.
3,6-Dihydro-6-(phenylsulfonyl)pyrrolo[3,2-e]indole-2-
methanol (6g, C17H14N2O3S)
White solid; yield: 57 mg (35 %); m.p.: 166–168 °C; IR
(KBr): vꢀ = 3,362, 3,213, 1,349, 1,165, 1,143 cm-1 1H
;
NMR (DMSO-d6): d = 2.50 (br, 1H), 2.86 (d, J = 7.0 Hz,
1H), 2.95 (d, J = 7.0 Hz, 1H), 6.64 (d, J = 3.5 Hz, 1H),
7.43 (q, J = 7.0 Hz, 2H), 7.52 (br, 1H), 7.53 (d,
J = 7.0 Hz, 1H), 7.55 (d, J = 3.5 Hz, 1H), 7.83
(t, J = 7.0 Hz, 2H), 7.93 (t, J = 7.5 Hz, 1H), 7.98 (d,
J = 7.0 Hz, 1H), 10.32 (br s, 1H) ppm; 13C NMR (DMSO-
d6): d = 109.5, 113.6, 113.9, 118.5, 126.6, 127.2, 129.3,
133.9 (all Ar–CH), 131.0, 132.2, 132.3, 137.8, 155.0, 155.5
(all Ar–C) ppm; HR-MS: calcd for C17H14N2O3S 326.0725
(M?), found 326.0721.
3,6-Dihydro-2-pentyl-6-(phenylsulfonyl)pyrrolo[3,2-e]-
indole (6d, C21H22N2O2S)
Light brown solid; yield: 110 mg (60%); m.p.: 80–82 °C;
1
IR (KBr): vꢀ = 3,406, 1,363, 1,185, 1,139 cm-1; H NMR
(CDCl3): d = 0.87 (t, J = 7.0 Hz, 3H), 1.34 (m, 4H), 1.69
(quintet, J = 7.5 Hz, 2H), 2.74 (t, J = 7.5 Hz, 2H), 6.38
(s, 1H), 6.85 (d, J = 3.5 Hz, 1H), 7.23 (d, J = 8.5 Hz,
1H), 7.34 (t, J = 7.5 Hz, 2H), 7.43 (t, J = 7.5 Hz, 1H),
7.56 (d, J = 3.5 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.83
(d, J = 7.5 Hz, 2H), 8.01 (br s, 1H), ppm; 13C NMR
(CDCl3): d = 14.0 (CH3), 22.3, 28.3, 29.1, 31.5 (all CH2),
98.0, 107.3, 108.2, 108.3, 125.2, 126.6, 129.0, 133.5 (all
Ar–CH), 121.2, 122.8, 129.7, 132.0, 138.5, 140.1 (all
Ar–C) ppm; HR-MS: calcd for C21H22N2O2S 366.1402
(M?), found 366.1408.
Methyl 3,6-dihydro-6-(phenylsulfonyl)pyrrolo[3,2-e]-
indole-2-carboxylate (6h, C18H14N2O4S)
White solid; yield: 80 mg (45 %); m.p.: 151–153 °C; IR
(KBr): vꢀ = 3,366, 1,718, 1,370, 1,189, 1,164 cm-1 1H
;
NMR (DMSO-d6): d = 3.86 (s, 3H), 7.15 (d, J = 3.5 Hz,
1H), 7.42 (d, J = 2.0 Hz, 1H), 7.42 (d, J = 9.0 Hz, 1H),
7.54 (t, J = 7.5 Hz, 2H), 7.63 (t, J = 7.5 Hz, 1H), 7.80 (d,
J = 3.5 Hz, 1H), 7.91 (d, J = 9.0 Hz, 1H), 7.93 (d,
J = 7.5 Hz, 2H), 12.14 (s, 1H) ppm; 13C NMR (DMSO-
d6): d = 52.6 (CO2CH3), 107.3, 109.5, 111.0, 112.1, 126.9,
127.3, 130.6, 135.3 (all Ar–CH), 120.4, 124.4, 129.5, 130.8,
135.1, 138.1 (all Ar-C), 162.0 (CO2Me) ppm; HR-MS:
calcd for C18H14N2O4S 354.0674 (M?), found 354.0678.
2-Hexyl-3,6-dihydro-6-(phenylsulfonyl)pyrrolo[3,2-e]-
indole (6e, C22H24N2O2S)
Light brown solid; yield: 110 mg (58%); m.p.: 60–62 °C;
1
IR (KBr): vꢀ = 3,460, 1,618, 1,399, 1,363, 1,140 cm-1; H
NMR (CDCl3): d = 0.89 (t, J = 7.0 Hz, 3H), 1.32 (m,
4H), 1.71 (m, 2H), 1.38 (m, 2H), 2.76 (t, J = 7.5 Hz, 2H),
6.40 (s, 1H), 6.88 (d, J = 3.5 Hz, 1H), 7.25 (d, J = 8.5 Hz,
1H), 7.36 (t, J = 7.5 Hz, 2H), 7.45 (t, J = 7.5 Hz, 1H),
7.58 (d, J = 3.5 Hz, 1H), 7.80 (d, J = 9.0 Hz, 1H), 7.85
(d, J = 7.5 Hz, 2H), 8.05 (br s, 1H) ppm; 13C NMR
(CDCl3): d = 14.2 (CH3), 22.7, 28.5, 29.1, 29.5, 31.7 (all
CH2), 98.1, 107.4, 108.4, 125.3, 126.7, 129.1, 133.6 (all
Ar–CH), 121.3, 122.9, 129.8, 132.2, 138.6, 140.2 (all
Ar–C) ppm; HR-MS: calcd for C22H24N2O2S 380.1558
(M?), found 380.1561.
3,6-Dihydro-3-(phenylsulfonyl)pyrrolo[3,2-e]indole
(6i, C16H12N2O2S)
White solid; yield: 119 mg (80 %); m.p.: 108–110 °C; IR
(KBr): vꢀ = 3,378, 1,612, 1,365, 1,185, 1,135 cm-1 1H
;
NMR (CDCl3): d = 6.69 (t, J = 2.0 Hz, 1H), 6.91 (d,
J = 3.5 Hz, 1H), 7.21 (t, J = 2.5 Hz, 1H), 7.32
(d, J = 9.0 Hz, 1H), 7.35 (t, J = 7.5 Hz, 2H), 7.43 (t,
J = 7.5 Hz, 1H), 7.60 (d, J = 3.5 Hz, 1H), 7.84 (d,
J = 7.5 Hz, 2H), 7.87 (d, J = 9.0 Hz, 1H), 8.47 (s, 1H)
ppm; 13C NMR (CDCl3): d = 101.3, 108.6, 108.8, 109.3,
124.4, 125.7, 127.0, 129.5, 133.9 (all Ar-CH), 120.7, 123.7,
130.0, 132.7, 138.8 (all Ar–C) ppm; HR-MS: calcd for
C16H12N2O2S 296.0619 (M?), found 296.0622.
4-[3,6-Dihydro-6-(phenylsulfonyl)pyrrolo[3,2-e]indol-
2-yl]butanenitrile (6f, C20H17N3O2S)
White solid; yield: 120 mg (66%); m.p.: 160–162 °C; IR
(KBr): vꢀ = 3,325, 2,256, 1,382, 1,361, 1,185, 1,159,
;
1,133 cm-1 1H NMR (DMSO-d6): d = 2.00 (quintet,
General procedure for N-deprotection of 6a, 6c, and 6i
J = 7.5 Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H), 2.92
(t, J = 7.5 Hz, 2H), 7.42 (d, J = 9.0 Hz, 1H), 7.60 (dd,
J = 3.5 Hz, 0.5 Hz, 1H), 7.61 (t, J = 8.0 Hz, 2H), 7.71 (tt,
J = 7.5 Hz, 1.0 Hz, 1H), 7.81 (dd, J = 9.0 Hz, 0.5 Hz,
1H), 7.88 (d, J = 3.5 Hz, 1H), 7.98 (dd, J = 8.5 Hz,
1.0 Hz, 2H), 11.83 (br s, 1H) ppm; 13C NMR (DMSO-d6):
d = 16.3, 25.2, 27.3 (all CH2), 106.5, 107.8, 109.9, 126.0,
126.9, 130.1, 134.8 (all CH), 120.7, 121.7, 122.6, 129.5,
133.1, 137.6, 139.5 (all Ar–C) ppm; HR-MS: calcd for
C20H17N3O2S 363.1041 (M?), found 363.1048.
A stirred mixture of compound 6a/6c/6i (0.134 mmol), Mg
turnings (2.68 mmol) and NH4Cl (0.60 mmol) in 3 cm3 dry
MeOH was refluxed until the substrate was fully consumed
(8–10 h) and then filtered hot. The filtrate was concentrated
to a small volume, diluted with 20 cm3 water and extracted
with CH2Cl2 (3 9 15 cm3). The combined organic extract
was washed with water, dried and the solvent distilled off.
The residue was purified by CC using EtOAc/PE as eluent
to furnish pure 7a/7c/7i.
123

An efficient, general synthesis of 2-substituted 3,6-dihydropyrrolo[3,2-e]indoles
723
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3,6-Dihydro-2-phenylpyrrolo[3,2-e]indole (7a)
Light brown solid; yield: 20 mg (64 %); m.p.: 138–140 °C
(140–141 °C [26]).
2-Butyl-3,6-dihydropyrrolo[3,2-e]indole (7c, C14H16N2)
Light brown gum; yield: 16 mg (58 %); 1H NMR (CDCl3):
d = 0.96 (t, J = 7.5 Hz, 3H), 1.44 (m, 2H), 1.74 (quintet,
J = 7.5 Hz, 2H), 2.81 (t, J = 7.5 Hz, 2H), 6.48 (s, 1H),
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(M?), found 212.1319.
3,6-Dihydropyrrolo[3,2-e]indole (7i)
White solid; yield: 18 mg (67 %); m.p.: 90–92 °C
(89–92 °C [31]).
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Acknowledgments Professor M. Chakrabarty, Emeritus Scientist,
thanks the Director of Bose Institute for laboratory facilities and the
Council of Scientific and Industrial Research (CSIR), Govt. of India,
for financial assistance (Sanction no. 21(824)/10/EMR-II, dated
23.12.2010). Professor G. K. Kar and Mrs. M. Rakshit are thankful to
the CSIR, Govt. of India, for providing CSIR-NET fellowship to
M. Rakshit. All the authors are thankful to Mr. B. Majumdar and
Mr. S. R. Maji, both of Bose Institute, for recording NMR and GC
HR-MS spectra, respectively.
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