Three-component reaction involving metal-free heteroannulation of N-Boc-3-amido indole, aryl aldehydes, and aromatic alkynes under microwave conditions: Synthesis of highly diversified δ-carbolines

Article abstract of DOI:10.1016/j.tetlet.2010.09.054

An efficient synthesis toward highly diversified δ-carbolines via one-pot multicomponent reaction using N-Boc-3-amido indoles, aryl aldehydes, and aromatic terminal alkynes under microwave conditions has been described.

Full text of DOI:10.1016/j.tetlet.2010.09.054

Tetrahedron Letters 51 (2010) 6022–6024
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Three-component reaction involving metal-free heteroannulation
of N-Boc-3-amido indole, aryl aldehydes, and aromatic alkynes under
microwave conditions: synthesis of highly diversified d-carbolines q
Sudhir K. Sharma a, Anil K. Mandadapu a, Mohammad Saifuddin a, Sahaj Gupta a, Piyush K. Agarwal a,
Ashok K. Mandwal a, Harsh M. Gauniyal b, Bijoy Kundu a,
⇑
a Medicinal and Process Chemistry Division, Central Drug Research Institute, CSIR, Lucknow 226 001, India
b Sophisticated Analytical Instrument Facility, Central Drug Research Institute, CSIR, Lucknow 226 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis toward highly diversified d-carbolines via one-pot multicomponent reaction using
N-Boc-3-amido indoles, aryl aldehydes, and aromatic terminal alkynes under microwave conditions has
been described.
Received 16 August 2010
Revised 7 September 2010
Accepted 10 September 2010
Available online 19 September 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
d-Carboline
Alkyne
N-Boc-3-amido indoles
Multicomponent reaction
Cyclization
Search for one-pot multicomponent reactions (MCRs)1 that allow
multi-bond formation in a single step to furnish products compris-
ing portions of all the components has become one of the major chal-
lenges for the organic chemists. Over the years several important
multicomponent reactions, such as, Biginelli,2 Passerini,3 Ugi,4 and
Mannich-type5 have been extensively used for rapid transforma-
tions of mixtures of relatively simple 3 or 4 starting materials into
the complex heterocyclic structures for pharmaceutical develop-
ment. As part of our continuing effort on the development of new
routes for the synthesis of indole-based natural products6 as well
as polyheterocycles7, we embarked with a search for MCR involving
amino functionalized indoles as one of the components. In recent
years MCRs with alkynes as one of the components8 have, although,
received much attention and achieved great progress, indoles, in
general, despite being a privileged9 pharmaceutical template have
remained relatively under explored.10 We envisaged that owing to
the activated nature of the indole ring, thus being prone to electro-
philic attack, and use of either 2 or 3-amino substituted indoles as
one of the components in a MCR with an aldehyde and a terminal
aromatic alkyne as other components may facilitate heteroannula-
tion via 6-endo cyclization either at C-3 or C-2 nucleophilic carbon
of the indole. In the first instance, due to relatively poor stability
and limited synthetic accessibility of the 2-amino indoles,11 we pro-
ceeded to explore MCR with 3-amino indoles and report our findings
in this letter. The methodology allows direct access to the synthesis
of highly substituted d-carbolines.
We commenced our studies by assessing the compatibility of
N-protected 3-amidoindoles to MCR due to the poor shelf life of
free amines.12 We argued that protecting amino function with an
acid/heat13 labile protecting group such as Boc, may allow the
resulting N-Boc-3-amido indole derivative amicable to MCR by
allowing the generation of free amine in situ which in turn would
immediately get trapped in the presence of aldehydes to form
Schiff base. Initial attempts to carry out MCR involving N-Boc-3-
R1
NHBoc
+
N
O
(i)
+
X
R1
N
X
R2
N
R
4-6
R2
R
1a X = C; R = H
1b X = C; R = CH3
1c X = N; R = H
2
3
q
CDRI Communication No. 7955.
⇑
Corresponding author. Tel.: +91 522 2612411 18; fax: +91 522 2623405.
E-mail address: bijoy_kundu@yahoo.com (B. Kundu).
Scheme 1. Reagents and optimal conditions: (i) 30%, TFA in CH3CN 90 °C, lW, 1.5 h.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.054

S. K. Sharma et al. / Tetrahedron Letters 51 (2010) 6022–6024
6023
Table 1
Optimization of reaction conditions for the conversion of 1a–4a
Entry
Reaction conditions
Temp (°C)
Time (h)
Yield of 4a
1
2
3
4
5
6
7
8
9
10% CuI/10% Yb(OTf)3 in CH3CN
10% CuI/10% Yb(OTf)3 in CH3CN
CH3CN
10% CuI/10% TFA/Yb(OTf)3 in CH3CN
10% CuI/10% TFA in CH3CN
10% CuI/30% TFA in CH3CN
10% TFA in CH3CN
30% TFA in CH3CN
30% TFA in CH3CN
30% TFA in CH3CN
90
16
0
0
0
28
35
48
50
62
73
—
68
0
54
34
0
130/
130/
l
l
W
W
1.5
1.5
1.5
1.5
1.5
1.5
16
1.5
0.5
1.0
1.5
1.5
1.5
24
90
90
90
90
90
90/
l
W
rt
10
90/
90/
90/
90/
l
l
l
l
W
W
W
W
11
12
13
14
15
30% TFA in H2O
30% TFA in toluene
p-TsOH in CH3CN
10% FeCl3 in toluene
10% FeCl3/30% TFA in toluene
110
110
24
47
amido indoles14 (1a), phenylacetylene, and 4-chlorobenzaldehyde
(Scheme 1) utilizing a reaction condition similar to those used
for MCR involving aryl amine, terminal aromatic alkyne, and aryl
aldehyde by Nagarajan and co-workers (10% CuI/10% Yb(OTf)3 in
acetonitrile under reflux at 80 °C),15 failed to furnish any adducts
or products through additions/annulations. Since TLC of the crude
product exhibited the presence of protected N-Boc-3-amido in-
doles under this condition, further reaction in microwave condi-
tions at 130 °C, to facilitate the deprotection of the Boc group at
elevated temperatures13 still failed to yield the desired product de-
spite complete disappearance of N-Boc-3-amido indoles. Indeed, it
was unclear as to whether free 3-aminoindole was liberated in situ
from N-Boc-3-amido indoles or the latter underwent degradation
at elevated temperature. This led us to carry out a series of reac-
tions both under metal-free as well as under acidic conditions by
applying either conventional or microwave heating. In general,
heating the reaction mixture in the absence of acidic conditions
failed to produce any annulated product.
reported prefer Pd-catalyzed intramolecular arylation24 reactions.
To the best of our knowledge, MCR for the synthesis of d-carbolines
has not yet been reported and this led us to investigate the scope
and limitation of our three component reaction for the synthesis
of d-carbolines.
The N-Boc-3-amido indole 1a was treated with a range of aryl
aldehydes and aromatic alkynes using the optimized conditions
to synthesize small array d-carbolines 4a–g. In the subsequent
studies 1-methyl-N-Boc-3-amido indole 1b was subjected to MCR
furnishing d-carbolines 5a–d in 68–75% yield. Next, we applied
our methodology to yet another indole derivative. N-Boc-3-ami-
do-7-azaindole25 1c and treated it with a series of aldehydes and
aryl alkynes to furnish d-carbolines based on 6a–n. The crude prod-
ucts were purified by column chromatography and characterized
using NMR and mass. Yields and structure of compounds are sum-
marized in Table 2 and as evident in most cases of aryl aldehydes
Table 2
Synthesis of d-carbolines 4–6
A careful examination of the reaction products under 10% TFA in
CH3CN revealed the presence of the unreacted N-Boc-3-amido in-
doles thereby furnishing d-carboline in low yield. This prompted
us to increase the concentration of TFA from 10% to 30%, which
then afforded the desired d-carbolines in 62% yield (Table 1; entry
8) after heating for 16 h. To further improve the yield and reduce
the reaction timings, the reaction was carried out under micro-
wave conditions at 90 °C and we were pleased to obtain the desired
product 4a16 in 73% isolated yield (Table 1; entry 9). Conducting
the reaction in the presence of FeCl3 or replacing TFA with p-TsOH
or solvents (toluene, water) offered no improvements in the yield.
Similarly, attempt to allow Schiff base formation at room temper-
ature followed by heating in microwave had no influence on the
yield of d-carbolines.
The 5H-pyrido[3,2-b]indoles are useful building blocks as well
as important skeletons of biologically active alkaloids such as, cry-
ptolepine,17 quindoline,18 and glycozoline.19 The roots of these
species are used for the treatment of malaria and other infectious
and noninfectious diseases such as antimuscarinic, antibacterial,
antiviral, antiplasmodial,20 and antihyperglycemic.21 Thus, due to
their various and important biological activities, a MCR reaction
would be a new entry to the synthesis of highly diversified
d-carbolines.
Entry Amine R1
R2
Product Yield (%)
1
2
3
4
5
6
1a
1a
1a
1a
1a
1a
4-Cl–C6H4
4-Br–C6H4
4-C2H5O–C6H4
4-CH3–C6H4
4-OH–C6H4
3,4-Di-OCH3–
C6H4
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4a
4b
4c
4d
4e
4f
73
64
71
52
66
70
7
8
9
1a
1b
1b
4-Cl–C6H4
4-Cl–C6H4
4-Cl–C6H4
4-CH3–C6H4
4-CH3–C6H4
4-t-C(CH3)3–
C6H4
4-CH3–C6H4
4-t-C(CH3)3–
C6H4
C6H5
C6H5
C6H5
C6H5
4g
5a
5b
71
75
70
10
11
1b
1b
4-Br–C6H4
4-Br–C6H4
5c
5d
68
72
12
13
14
15
16
17
18
1c
1c
1c
1c
1c
1c
1c
4-Cl–C6H4
4-Br–C6H4
4-F–C6H4
4-C2H5O–C6H4
3,4-Di-Cl–C6H4
4-CH3–C6H4
3,4-Di-OCH3–
C6H4
6a
6b
6c
6d
6e
6f
67
69
62
68
59
64
66
C6H5
C6H5
C6H5
6g
19
20
21
22
23
1c
1c
1c
1c
1c
4-OH–C6H4
4-Cl–C6H4
4-C2H5O–C6H4
4-N(CH3)2–C6H4
3,4-Di-OCH3–
C6H3
C6H5
6h
6i
6j
6k
6l
63
58
67
71
68
4-OCH3–C6H4
4-CH3–C6H4
4-CH3–C6H4
4-CH3–C6H4
A careful survey of the literature revealed few reports22 dealing
with the synthesis of d-carbolines. Papamical et al.22a have
described the synthesis of less diverse d-carbolines via the reaction
of 3-acylaminoindoles and 1,3-dicarbonyl compounds. Recently
Jeanty et al.23 reported the synthesis of natural glycozoline d-carb-
oline using Aza-Fischer indole cyclization; whereas other methods
24
25
1c
1c
4-Cl–C6H4
4-t-C(CH3)3–
C6H4
4-t-C(CH3)3–
C6H4
6m
6n
69
62
4-OH–C6H4

6024
S. K. Sharma et al. / Tetrahedron Letters 51 (2010) 6022–6024
S.; Gribble, G. W. Tetrahedron Lett. 2007, 48, 1003–1005; (d) Witulski, B.;
Alayrac, C.; Tevzadze-Saeftel, L. Angew. Chem., Int. Ed. 2003, 42, 4257–4260.
12. (a) Roy, S.; Gribble, G. W. Tetrahedron Lett. 2008, 49, 1531–1533; (b) Robinson,
M. M.; Robinson, B. L.; Butler, F. P. J. Am. Chem. Soc. 1958, 81, 743–747.
and aromatic alkynes, the three-component reaction proceeded
smoothly under the optimized condition and the corresponding
products were obtained in moderate to good yields (52–75%).
The electronic effect appeared to have negligible effect on the reac-
tion since either electron withdrawing or the electron donating
groups on the different aromatic rings offered products with min-
imal variation in yields. Similarly, introduction of methyl group at
N-1 in the indole ring had no effect on the yields of annulated prod-
ucts. An attempt to employ aliphatic aldehydes or alkynes failed to
furnish title compounds that indicates limitations of our MCR
strategy.
In summary, we have developed an efficient method for the
synthesis of highly substituted d-carboline derivatives under metal
catalyst-free conditions. In general the strategy involves one-pot
multicomponent synthesis of highly diversified d-carbolines by
irradiating a mixture of N-Boc-3-amido indoles, aromatic terminal
alkynes, and aryl aldehydes under acidic conditions.
13. Wasserman, H. H.; Berger, G. D.; Cho, K. R. Tetrahedron Lett. 1982, 23, 465–468.
14. To
a stirred solution of 3-nitro indole (1 mmol) in methanol was added
saturated solution of ammonium chloride solution (4 mL). Zn dust was added
to the reaction mixture (10 mmol) portion wise over 15 min while maintaining
the temperature at 0 °C. After 10 min, (Boc)2O (1.2 mmol) was added and the
reaction mixture was allowed to warm to room temperature. After completion
of the reaction, the reaction mixture was filtered through Celite, the methanol
was distilled off under vacuo and the aqueous residue was extracted with DCM
(3 ꢀ 15 mL) .The combined organic phases were dried over anhydrous Na2SO4
and concentrated. The crude product was purified by column chromatography
to afford 1a–c.
tert-Butyl 1H-pyrrolo[2,3-b]pyridin-3-ylcarbamate (1c): Yield = 0.857 g (60%),
light yellow solid, mp 184–186 °C, Rf = 0.42 (2:8 EtOAc/hexane) IR (KBr) mmax
3340, 2955, 1685, 1588, 1462, 1366, 1162 cmꢁ1 1H NMR (200 MHz, CDCl3)
;
d = 9.80 (1H, s, NH), 8.31 (1H, dd, J = 4.8, 1.4 Hz ArH), 7.90–7.86 (1H, m, ArH),
7.55 (1H, s, CONH), 7.11–7.05 (1H, m, ArH), 6.49 (1H, s, ArH), 1.51 (9H, s,
3 ꢀ CH3); 13C NMR (100 MHz, CDCl3) d = 146.5, 143.3, 126.2, 115.5, 114.5,
113.8, 80.6, 28.5 ppm. Mass (ES+) m/z 234.2 (M++1). Anal. Calcd for
C
12H15N3O2: C, 61.79; H, 6.48; N, 18.01. Found: C, 61.75; H, 6.49; N, 18.04.
15. Gaddam, V.; Ramesh, S.; Nagarajan, R. Tetrahedron 2010, 66, 4218–4222.
16. A mixture of N-Boc-3-amido indoles 1a–c (1.0 mmol), aldehydes 2 (1.0 mmol),
and alkynes 3 (1.5 mmol) was treated with 30% solution of trifluoroacetic acid
in MeCN (5 mL), placed in a 10 mL microwave vial containing a stirring bar. The
reaction mixture was heated at 90 °C for 1.5 h in microwave (Biotage). The
reaction mixture was cooled to ambient temperature, washed with aq NaHCO3
(20 mL), and extracted with DCM (2 ꢀ 30 mL). The combined organic layer was
dried over anhydrous Na2SO4 and the solvent was removed in vacuo. The crude
product was purified on a silica gel column using ethyl acetate/hexane (v/v
1:4) as eluent to afford 4a–g, 5a–d, and 6a–n.
Acknowledgment
S.K.S., A.K.M., M.S., S.G., and P.K.A. are thankful to CSIR, New
Delhi, India for fellowships.
References and notes
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25. 2-(4-Chlorophenyl)-4-phenyl-5H-pyrido[20,30:4,5]pyrrolo[2,3-b]pyridine
Yield = 0.204 g (67%), light brown solid, mp >250 °C, Rf = 0.48 (2:8 EtOAc/
hexane). IR (KBr) mmax 3071, 2375, 1599, 1462, 1366, 1162 cmꢁ1 1H NMR
(6a):
;
(400 MHz, DMSO-d6) d = 12.12 (1H, s, NH), 8.67–8.58 (2H, m, ArH), 8.31
(2H, d, J = 8.4 Hz, ArH), 8.05 (1H, s, ArH), 7.91 (2H, d, J = 7.0 Hz, ArH),
7.63–7.55 (5H, m, ArH), 7.35 (1H, t, J = 5.8 Hz, ArH); 13C NMR (100 MHz,
CDCl3) d = 153.5, 148.7, 140.3, 138.3, 135.8, 133.1, 133.0, 129.6, 129.2,
129.0, 128.9, 128.7, 128.4, 117.8, 116.4, 114.6 ppm. Mass (ES+) m/z 356.1
(M++1). Anal. Calcd for C22H14ClN3: C, 74.26; H, 3.97; N, 11.81. Found: C,
74.22; H, 3.98; N, 11.84.
10. For review see: Sapi, J.; Laronze, J. Y. Arkivoc 2004, 208–222. and references
cited therein.
11. (a) Hino, T.; Nakagawa, M.; Hashizume, T.; Yamaji, N.; Miwa, Y. Tetrahedron
Lett. 1970, 11, 2205–2208; (b) Nakagawa, M.; Yamaguchi, H.; Hino, T.
Tetrahedron Lett. 1970, 11, 4035–4038. and references cited therein; (c) Roy,