Lewis acid catalyzed rapid synthesis of 5-hydroxy-benzo[g]indole scaffolds by a modified Nenitzescu reaction

Article abstract of DOI:10.1016/j.tetlet.2010.07.129

A fast solvent-less synthesis of 5-hydroxy-benzo[g]indole scaffolds is accomplished from Lewis acid-catalyzed one-pot reaction of naphthoquinone, ω-morpholinoacetophenone, and urea under microwave irradiation. The key step in the synthesis is the Michael addition followed by in situ aza cyclization reaction using urea as an environmentally benign source of ammonia.

Full text of DOI:10.1016/j.tetlet.2010.07.129

Tetrahedron Letters 51 (2010) 5160–5163
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Lewis acid catalyzed rapid synthesis of 5-hydroxy-benzo[g]indole scaffolds
by a modified Nenitzescu reaction
*
Moyurima Borthakur, Shyamalee Gogoi, Junali Gogoi, Romesh C. Boruah
Medicinal Chemistry Division, North East Institute of Science and Technology (CSIR), Jorhat 785 006, Assam, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A fast solvent-less synthesis of 5-hydroxy-benzo[g]indole scaffolds is accomplished from Lewis acid-cat-
Received 31 May 2010
Revised 14 July 2010
Accepted 22 July 2010
Available online 29 July 2010
alyzed one-pot reaction of naphthoquinone,
x-morpholinoacetophenone, and urea under microwave
irradiation. The key step in the synthesis is the Michael addition followed by in situ aza cyclization reac-
tion using urea as an environmentally benign source of ammonia.
Ó 2010 Elsevier Ltd. All rights reserved.
Nitrogen-containing heterocyclic compounds are well known to
occupy a diverse array of favorable biological and pharmacological
properties.1 The indole ring system, in particular, is a crucial struc-
ture in drug discovery and is the basic component for many well-
known medicinally active compounds.2 The indole heterocyclic
system is available in several naturally occurring alkaloids that
exhibits medicinal and biological activity.3,4 It is a common build-
ing block for many complex molecular constructions and hence are
of significant importance in the development of both natural-prod-
ucts chemistry and pharmaceuticals. Medicinal chemists repeat-
edly turn to indole-based compounds as a target pharmacophore
for the development of therapeutic agents.5 A large number of
indole analogs have been examined for their properties as antiox-
idants and radical scavengers against 2,20-azino-bis-(3-ethylbenz-
thiazoline-6-sulfonic acid) (ABTS) radical cation.6 Polycyclic
indoles including benzo- or pyrido-fused carbazoles are of particu-
lar interest, because of their potential demand in the development
of antitumour agents.7
The great diversity of the biologically active indoles has
prompted much attention to focus on the synthesis and function-
alization of indoles.8–12 Recently, 5-hydroxyindoles have shown
properties as novel 5-lipoxygenase (5-LO) inhibitors13 and annela-
tion of a [g]benzene ring to an indole moiety increased their activ-
ities to more than 10-fold higher potency than the parental
5-hydroxyindoles.14 The Nenitzescu reaction, comprising Michael
addition of enaminoester or enaminoketones with 1,4-quinones,
has proven to be a key strategy for 5-hydroxy-benzo[g]indoles.
However, this methodology has the discrepancy of multi-step reac-
tions and the use of acid sensitive enamines with low to moder-
ately yielding process.15
tute a specially attractive synthetic strategy for rapid and efficient
library generation, enhanced reaction rates, cleaner products, and
manipulative simplicity.17 Recently we have demonstrated solid-
phase synthesis of aza heterocycles using urea as an efficient
source of ammonia under microwave irradiation.18,19 We pre-
sumed that the same strategy could be applied to prepare 5-hydro-
xy-benzo[g]indole by a modified Nenitzescu reaction.
In continuation of our interests, herein, we report a fast solvent-
less Lewis acid-catalyzed one-pot synthesis of 5-hydroxy-benzo-
[g]indole scaffolds from reaction of
x-morpholinoacetophenone
and naphthoquinone using urea as an environmentally benign
source of ammonia under microwave irradiation (Scheme 1). In
a typical reaction, a finely ground mixture of naphthoquinone 1,
x
-morpholino-40-methylacetophenone 2a, urea, and BF3ꢀOEt2
was irradiated under microwave in an open vessel in a Prolabo
Synthwave 402 microwave reactor at 140 °C for 5 min at atmo-
spheric pressure to afford 2-(p-tolyl)-3-morpholino-5-hydroxy-
benzo[g]indole 3a in 80% yield (Table 1, entry 1). The product 3a
was characterized by comparison of physical and spectral data.20
Similarly, 1 reacted with
x-substituted acetophenone 2b–d in
the presence of urea and BF3ꢀOEt2 to yield 2-(p-chlorophenyl)-3-
morpholino-5-hydroxy-benzo[g]indole (3b), 2-phenyl-3-morpho-
lino-5-hydroxy-benzo[g]indole (3c), and 2-(40-nitrophenyl)-3-mor-
pholino-5-hydroxy-benzo[g]indole (3d), respectively, in 50–75%
yields (entries 2–4).
In order to investigate the role of Lewis acid, we carried micro-
wave-mediated reaction of 1, 2a, and urea using other Lewis acids
O
HO
R'
R
O
O
The utility of unconventional microwave energy in synthetic
organic chemistry is increasingly recognized in recent years.16
Microwave-mediated multicomponent reactions (MCRs) consti-
BF3OEt2
R'
+
+
N
H
R
MW, 5 min
NH2
H2N
O
2a-l
1
3a
* Corresponding author. Tel.: +91 376 2372948; fax: +91 376 2370011.
E-mail address: rc_boruah@yahoo.co.in (R.C. Boruah).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.129

M. Borthakur et al. / Tetrahedron Letters 51 (2010) 5160–5163
5161
Table 1
Synthesis of 5-hydroxybenzo[g]indoles 3a–la
O
O
HO
R'
R
O
BF3OEt2
MW
O
+
+
R'
NH2
N
H
H2N
R
2a-l
1
3a-l
Entry
1
Substrate
Product
Time
5
Yieldb
O
O
O
N
N
HO
2a
80
75
73
50
88
77
75
54
82
76
74
52
(p) H3C-C6H4
3a
N
H
C6H4-CH3(p)
O
O
N
O
N
HO
HO
2b
2
3
5
7
(p) Cl-C6H4
3b
3c
N
H
C6H4-Cl(p)
O
O
N
O
N
2c
C6H5
N
H
C6H5
O
O
N
O
N
HO
HO
HO
HO
HO
HO
2d
2e
4
10
5
(p) O3N-C6H4
3d
N
H
C6H4-NO2(p)
O
N
N
5
(p) H3C-C6H4
3e
3f
N
H
C6H4-CH3(p)
O
N
N
2f
6
6
(p) Cl-C6H4
N
H
C6H4-Cl(p)
O
N
N
2g
7
6
C6H5
3g
3h
N
H
C6H5
O
O
N
N
2h
2i
8
10
6
(p) O3N-C6H4
(p) H3C-C6H4
N
H
C6H4-NO2(p)
N
N
9
3i
N
H
C6H4-CH3(p)
O
N
N
HO
HO
HO
2j
10
11
12
7
3j
(p) Cl-C6H4
N
H
C6H4-Cl(p)
O
N
N
2k
7
C6H5
3k
N
H
C6H5
O
N
N
2l
10
(p) O3N-C6H4
3l
N
H
C6H4-NO2(p)
a
Conditions: 1 (1 mmol), 2 (1.6 mmol), urea (5.0 mmol), BF3ꢀOEt2 (cat).
b
Isolated yields.

5162
M. Borthakur et al. / Tetrahedron Letters 51 (2010) 5160–5163
Table 2
To study the influence of aza heterocyclic ring of 2 in benzo-
Effect of Lewis acid on benzo[g]indole 3a formationa
[g]indole formation, we attempted a three-component reaction of
N-phenacylpyridinium salt, 1, and urea using BF3ꢀOEt2 under
microwave conditions. As expected, no product formation of 3a
could be observed even on prolonged microwave heating
(30 min), rather, subsequent work-up of the reaction mixture led
to recovery of the starting material with some decomposed prod-
ucts. The failure of the formation of benzo[g]indole could be rea-
soned to the electropositive or low basicity of the pyridinium
ring, which hinders the generation of the nucleophilic site essential
for Michael attack.
Entry
Lewis acid
Reaction time (min)
Yield %
1
2
3
4
5
6
BF3ꢀOEt2
TiCl4
AlCl3
ZnCl2
InCl3
Nil
5
8
10
10
8
80
62
48
45
52
0
15
a
Reactions were carried under microwave.
On the basis of the results obtained, a plausible mechanism for
the formation of 2-(p-tolyl)-3-morpholino-5-hydroxy-benzo[g]in-
dole 3a is shown in Scheme 2.19 The key step of the mechanism
involves Lewis acid-catalyzed Michael addition and aza cyclization
reaction. Under microwave condition, BF3ꢀOEt2-catalyzed the tau-
tomerism of 2a to its enol form and facilitated the Michael addition
with 1 to afford 1,4-dicarbonyl intermediate A. Under microwave
heating, urea released ammonia21 and reacted with A to facilitate
a diimine intermediate that equilibrated to 1,4-diamino intermedi-
ate B. Intramolecular cyclocondensation of B under the reaction
conditions afforded 3a with concomitant loss of ammonia. The
BF3ꢀOEt2-catalyzed condensation of 1 and 2a in the absence of urea
to intermediate A, followed by its independent reaction with urea
to afford 3a rendered further support to our proposed mechanism.
However, our attempt to prepare 5-hydroxy-indole derivative from
the reaction of benzoquinone and 2a under identical conditions
failed, rather we obtained some insoluble compound which was
difficult to characterize.
such as TiCl4, AlCl3, ZnCl2, SmCl2, and InCl3 under similar reaction
conditions (Table 2). It was observed that in comparison to
BF3ꢀOEt2 catalyzed reaction, all the other Lewis acids afforded poor
results (entries 2–5). The reaction did not proceed in the absence of
the Lewis acid (entry 6).
With the optimized conditions in hand, we planned to explore
the scope and limitations of our methodology. The reaction of naph-
thoquinone 1 with
x-pyrrolidinoacetophenone (2e–h) and, x-pip-
eridinoacetophenone (2i–l) under identical conditions afforded
corresponding 2-aryl-3-pyrrolidino-5-hydroxy-benzo[g]indoles
(3e–h, Table 1, entries 5–8) and 2-aryl-3-piperidino-5-hydroxy-
benzo[g]indoles (3i–l, Table 1, entries 9–12) in 52–88% yields. It
was observed that electron releasing substrates 2a, 2e, and 2i facil-
itated the enhancement of product yields (entry 1, 5, and 9), whereas
the electron deficient 2d, 2h, and 2l decreased the yield of the prod-
ucts (entries 4, 8, and 12).
The reaction failed to proceed when thiourea was employed in
place of urea under microwave irradiation indicating that urea has
played the unique role as a source of ammonia for the azacycliza-
tion reaction. On the other hand, the thermal reaction of 1, 2a, and
urea under refluxing xylene for 24 h accomplished poor yield of the
product 3a (18%). The increase of reaction time beyond 24 h did
not improve the yield of 3a. Our attempt to use ammonium acetate
as an alternate source of ammonia did not afford 3a. The failure of
the reaction could be attributed to the complete release of ammo-
nia much below the required reaction temperature. The reaction of
1 with 2a in the absence of urea afforded 1,4-diketo intermediate A
as the sole product and an independent reaction of A with urea un-
der microwave irradiation yielded 3a in 92% yield.
In conclusion, we have developed a modified Nenitzescu reaction
for the synthesis of 5-hydroxy-2,3-disubstituted-benzo[g]indoles
using stable
x-substituted-acetophenones with naphthoquinone
and urea under microwave irradiation. The solvent-less one-pot
synthesis is devoid of potentially unstable enamino ketones as well
as hazardous and toxic organic solvents. The reaction is catalyzed by
BF3ꢀOEt2 and failed to work in the absence of urea. The methodology
is advantageous because of solvent-less conditions, one-pot reac-
tion, high yields, and enhancedreaction rates. Ourmethodologypro-
vides a new strategy for the facile incorporation of the nitrogen
heterocycle such as morpholine, pyrrolidine, or piperidine at
the 3-position of indoles. In addition, we could successfully
O
N
O
O
Tolyl(p)
HO
N
MW
1
N
O
Tolyl(p)
BF3.OEt2
Tolyl(p)
O
MW, BF3.OEt2
A
O
OH
2a
Urea
NH3
O
O
O
N
N
HO
N
Tolyl(p)
Tolyl(p)
HO
HO
-NH3
Tolyl(p)
N
H
NH2
NH
NH
NH2
3a
B
Scheme 2. Proposed mechanism for the synthesis of benzo[g]indole (3a).

M. Borthakur et al. / Tetrahedron Letters 51 (2010) 5160–5163
5163
Ganguly, S. N.; Sharma, A. H.; Banik, B. K. Synthesis 2002, 1578; (d) Bagley, M.
C.; Cale, J. W.; Baueer, J. Chem. Commun. 2002, 1682; (e) Bora, U.; Saikia, A.;
Boruah, R. C. Org. Lett. 2003, 5, 435.
demonstrate the utility of urea as an environmentally benign source
of ammonia for indole synthesis. The newly developed methodology
would play an important strategy for the easily inaccessible 5-hy-
droxy-benzo[g]indoles.
18. (a) Barthakur, M. G.; Borthakur, M.; Devi, P.; Saikia, C. J.; Saikia, A.; Bora, U.;
Chetia, A.; Boruah, R. C. Synlett 2007, 223; (b) Borthakur, M.; Boruah, R. C.
Steroids 2008, 73, 637.
19. Borthakur, M.; Dutta, M.; Gogoi, S.; Boruah, R. C. Synlett 2008, 3125.
20. Illustrative experimental procedure: (a) Using urea: To a finely ground mixture of
Acknowledgments
napthoquinone (1, 0.11 g, 1 mmol),
x
-morpholino-40-methylacetophenone
(2a, 0.35 g, 1.60 mmol) and urea (0.30 g, 5.0 mmol) was added a catalytic
amount of BF3ꢀOEt2. The reaction mixture was irradiated in an open vessel of a
Synthwave 402 Prolabo focussed microwave reactor (manufactured by M/s
Prolabo, 54 rue RogerSalengro, Cedex, France) at 140 °C and power at 80%
(maximum output 300 W). On completion of reaction (5 min, vide TLC),
the reaction mixture was cooled and extracted with CH2Cl2 (3 ꢁ 30 ml). The
organic portion was washed with water, dried over anhydrous Na2SO4 and the
solvent was removed to obtain a crude product. Thin layer chromatography
separation using EtOAc/hexane (15:85) as eluant afforded 5-hydroxy-3-
morpholino-2-(p-tolyl)-benzo[g]indole (3a) in 80% yield. This procedure was
followed for the synthesis of all products listed in Table 1. Compound 3a: yield
We acknowledge the Department of Science and Technology for
their financial support and CSIR, New Delhi for the award of SRF (to
M.B.). We are thankful to the Director of NEIST, Jorhat for his keen
interest.
References and notes
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80%, mp 255 °C (decomp.); Rf = 0.3 (EtOAc/hexane = 15:85); IR (CHCl3) cmꢂ1
:
m
3327, 2942, 1675, 1635, 1594, 1565, 1301, 1242, 1209, 1118, 981, 775, 726; 1
H
2. Gill, C.; Brase, S. J. Comb. Chem. 2009, 11, 175.
NMR (CDCl3, 300 MHz): 10.35 (1H, s, –NH), 8.00–7.22 (9H, m), 6.02 (1H, s, –
OH), 3.86 (4H, m), 3.48 (4H, m), 2.34 (3H, s). 13C NMR (CDCl3, 75 MHz): d 153.7,
140.1, 134.0, 132.7 (2C), 132.2, 129.9, 129.8 (2C), 129.2, 127.2 (2C), 126.7,
126.1, 125.6, 111.8 (2C), 104.7, 66.7 (2C), 49.1 (2C), 21.4. ESI mass m/z = 358
[M+]. 5-Hydroxy-3-morpholino-2-(p-chlorophenyl)-benzo[g]indole 3b: yield 75%,
3. Nachshon-Kedmi, M.; Yannai, S.; Haj, A.; Fares, F. A. Food Chem. Toxicol. 2003,
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mp 262 °C (decomp.); Rf = 0.3 (EtOAc/hexane = 15:85); IR (CHCl3) cmꢂ1
:
m
5. Gribble, G. W., 2nd ed.. In Comprehensive Heterocyclic Chemistry; Pergamon
Press: New York, 1996; Vol. 2, p 211.
3392, 2923, 1676, 1641, 1592, 1566, 1301, 1242, 1209, 1116, 981, 774, 727; 1
H
NMR (CDCl3, 300 MHz): 10.40 (1H, s, –NH), 8.05–7.27 (9H, m), 6.03 (1H, s, –
OH), 3.87 (4H, m), 3.50 (4H, m). 13C NMR (CDCl3, 75 MHz): d 153.7, 144.1,
141.7, 134.0 (2C), 132.7 (2C), 132.2, 131.4, 131.0, 130.5, 129.5, 127.3, 126.8
(2C), 125.6 (2C), 111.9, 66.7 (2C), 49.1 (2C). ESI mass m/z = 378 [M+]. 5-
Hydroxy-3-pyrrolidino-2-(p-chlorophenyl)-benzo[g]indole 3f: yield 77%, mp
6. Herraiz, T.; Galisteo, J. Free Radical Res. 2004, 38, 323.
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248 °C (decomp.); Rf = 0.2 (EtOAc/hexane = 15:85); IR (CHCl3) cmꢂ1
: m 3327,
2924, 1676, 1622, 1593, 1557, 1294, 1265, 1005; 1H NMR (CDCl3, 300 MHz):
10.20 (1H, s, –NH), 8.04–7.30 (9H, m), 6.0 (1H, s, –OH), 2.85 (4H, m), 1.94 (4H,
m). 13C NMR (CDCl3, 75 MHz): d 152.8, 143.6, 140.9, 135.1, 133.5, 131.5 (2C),
130.9, 130.3, 129.2, 128.7, 126.6, 125.3 (2C), 124.8, 123.4 (2C), 118.7, 47.4 (2C),
26.1 (2C). ESI mass m/z = 362 [M+].
(b) Without urea: To a finely ground mixture of napthoquinone (1, 0.055 g,
0.50 mmol) and
x
-morpholino-40-methylacetophenone (2a, 0.18 g, 0.80 mmol)
was added a catalytic amount of BF3ꢀOEt2. The reaction mixture was irradiated
in an open vessel of a Synthwave 402 Prolabo focussed microwave reactor at
140 °C and power at 80% (maximum output 300 W) for 5 min. The reaction
mixture was cooled and extracted with CH2Cl2 (2 ꢁ 20 ml), washed with water,
dried over anhydrous Na2SO4, and the solvent was removed. Thin layer
chromatography separation of the crude product afforded intermediate A in
70% yield, gum; Rf = 0.4 (EtOAc/hexane = 15:85); IR (CHCl3) cmꢂ1
: m 3510,
2940, 1675, 1680, 1648, 1520; 1H NMR (CDCl3, 300 MHz): 7.80–7.10 (8H, m),
6.45 (1H, s, –OH), 5.65 (1H, br s), 3.94 (5H, m), 3.60 (5H, m), 2.41 (3H, s). ESI
mass m/z = 377 [M+].
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