DDQ-mediated oxidative cross-coupling between propargylic sp3 and indoles sp2 carbons

Article abstract of DOI:10.1016/j.tetlet.2009.08.075

DDQ-catalyzed oxidative cross-coupling reaction between indoles and propargyl compounds is reported for the first time. The reaction involves direct carbon-carbon bond formation between sp² carbons of indoles and sp³ carbons of propa

Full text of DOI:10.1016/j.tetlet.2009.08.075

Tetrahedron Letters 50 (2009) 6154–6158
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Tetrahedron Letters
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DDQ-mediated oxidative cross-coupling between propargylic sp3 and indoles
sp2 carbons
a,
G. L. V. Damu b, J. Jon Paul Selvam a, C. Venkata Rao b, , Y. Venkateswarlu
*
*
a Natural Products Laboratory, Organic Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Department of Chemistry, Sri Venkateswara University, Tirupathi 517 507, India
a r t i c l e i n f o
a b s t r a c t
Article history:
DDQ-catalyzed oxidative cross-coupling reaction between indoles and propargyl compounds is reported
for the first time. The reaction involves direct carbon–carbon bond formation between sp2 carbons of
indoles and sp3 carbons of propargylates to yield the corresponding propargyl indoles in good yields with
high selectivity.
Received 20 July 2009
Revised 19 August 2009
Accepted 22 August 2009
Available online 26 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Indoles
Propargyl indole
1,3-Diarylpropyne
DDQ
Nitromethane
1. Introduction
no report has been cited in the literature on the oxidative cross-
coupling of indoles and 1,3-diarylpropynes. To verify the reaction,
Allylation1 and propargylation2 of indoles have attracted much
attention in the synthesis of substituted indole alkaloids since fac-
ile transformations of the double and triple bonds in the products
to the other functional groups, which can provide pharmaceutical
intermediates and various important heterocycles. Indole moiety
is a most common structural motif found in plenty of natural prod-
ucts and other biologically active compounds with numerous bio-
logical activities.3 Consequently, the synthesis and reactions on
indole and its derivatives have received great attention in organic
synthesis.4–6 There are numerous examples cited in the literature
for the synthesis of propargylic indoles derived from propargylic
alcohols using various Lewis acid and Brønsted acid catalysts.7
Recently, Weiliang Bao and co-workers reported a novel oxida-
tive cross-coupling propargylation of 1,3-dicarbonyl compounds
using DDQ as the oxidant in nitromethane.8 In continuation of
our interest for developing various useful synthetic methods for
drug-like molecules and pharmaceutical intermediates9 we stud-
ied the synthesis of propargyl indoles from indoles and 1,3-diaryl-
propynes in the presence of DDQ.
we initiated our studies with simple indole 1a and 1,3-diary-
lpropyne 2a using DDQ as the oxidant in nitromethane as a solvent
medium. The reaction was completed in 2.5 h at room temperature
and afforded 3a in 78% yield with good regioselectivity at position
3 on indole (Scheme 1) and without any side products leaving
starting materials. Furthermore, in order to optimize the condi-
tions, the reaction was carried out with various oxidants namely,
Cu(OTf)2 and FeCl3Á6H2O as well as in different solvent systems
which includes nitromethane, toluene, dichloromethane, dimeth-
ylsulfoxide, tetrahydrofuran and N,N-dimethylformamide. After
several trials, nitromethane has been found to be the most effective
solvent for the reaction, in terms of reaction time and yield (Table
1). It has been noticed that DDQ is essential for the reaction to take
place. Lewis acids like metal triflates and other inorganic salts are
found to be not useful for the reaction.
Having established the reaction conditions, we further explored
the generality and efficiency of the DDQ-mediated oxidative cross-
coupling reaction between various heterocycles representing the
substituted indoles (Table 2), pyrrole (Table 2, entry g), furan (Ta-
ble 2, entry h), etc., and with various 1,3-diarylpropyne com-
pounds. In general the reaction proceeded smoothly on simple
indoles (Table 2, entries a, f, j, and l) and the presence of elec-
tron-donating groups on indoles such as Me and Br (Table 2, en-
tries b, d, and m) also afforded the corresponding propargyl
indoles with good yields and selectivity in short times. In cases
of indoles having electron-withdrawing groups such as COOMe,
The reaction involves oxidative cross-coupling between indoles
and 1,3-diarylpropynes in the presence of DDQ as an oxidant in
nitromethane solvent (Scheme 1). To the best of our knowledge,
* Corresponding authors. Tel.: +91 40 27193167; fax: +91 40 27160512.
E-mail addresses: luchem@iict.res.in, luchem@yahoo.com, padalu@gmail.com (Y.
Venkateswarlu).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.075

G. L. V. Damu et al. / Tetrahedron Letters 50 (2009) 6154–6158
6155
DDQ
+
Ph
N
H
CH3NO2, 2.5h, RT
Ph
78%
N
H
1a
2a
3a
Scheme 1. Reaction of indole and 1,3-diarylpropyne.
Table 1
NO2 and CN (Table 2: entries c, e, n, o and p), the coupling reaction
time has increased and the yield has reduced considerably. The
propargylation reaction on carbazole and N-methyl indole (Table
2, entries f and q) has proceeded well with good yields. Further-
more, it has been noticed that an electron-withdrawing group in
arylpropyne made the coupling reaction sluggish; for example,
the reaction of 1-fluoro-4-(3-phenyl-prop-2-ynyl)-benzene with
indole was found to be sluggish with low yield (Table 2, entry k).
On the other hand an electron-donating group (OMe) in aryl-
propyne made the coupling reaction very efficient (Table 2, entries
j and l). Also, no coupling product is noticed between indoles and
Optimization of reaction conditions
Entry
Solvent
Oxidant
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
Toluene
THF
DMSO
DCM
CH3NO2
DMF
CH3NO2
CH3NO2
DDQ
DDQ
DDQ
DDQ
DDQ
DDQ
Cu(OTf)2
FeCl3Á6H2O
12
12
12
12
2–12
12
24
10
10
17
35
78
21
Trace
No reaction
24
Table 2
Oxidative cross-coupling reaction of propargylic sp3 CH and indole sp2 CH bonds
Entry
Substrate 1
Substrate 2
Producta
3
Time (h)
Yieldb (%)
Ph
Ph
Ph
a
2.5
787d
Ph
Ph
Ph
Ph
Ph
N
H
N
H
Ph
Br
Ph
Ph
Ph
Ph
Ph
Br
b
4
677e
347e
777d
297e
N
H
N
H
Ph
O2N
Ph
O2N
c
12
N
H
N
H
Ph
Ph
Me
d
2
N
H
Me
N
H
Ph
MeO2C
Ph
MeO2C
e
12
N
H
N
H
(continued on next page)

6156
G. L. V. Damu et al. / Tetrahedron Letters 50 (2009) 6154–6158
Table 2 (continued)
Entry
Substrate 1
Substrate 2
Producta
3
Time (h)
Yieldb (%)
Ph
Ph
Ph
f
3.5
807e
Ph
N
H
N
H
Ph
N
H
Ph
g
2.5
787e
N
H
Ph
Ph
Ph
O
Ph
Ph
h
3
767e,7g
Ph
O
Ph
Ph
Ph
Ph
i
3.5
687e
Ph
N
Ph
H
N
H
MeO
MeO
j
2
6
4
84
Ph
N
H
Ph
N
H
F
F
k
337c
Ph
N
H
Ph
N
H
MeO
MeO
l
797c
SiMe3
N
H
SiMe3
N
H

G. L. V. Damu et al. / Tetrahedron Letters 50 (2009) 6154–6158
6157
Table 2 (continued)
Entry Substrate 1
Substrate 2
Producta
3
Time (h)
Yieldb (%)
Ph
Br
Ph
Br
m
4
727g
457e
317g
357e
817d
N
H
N
H
Ph
NC
Ph
Ph
Ph
NC
n
o
p
q
12
12
12
4
N
H
N
H
Ph
O2N
O2N
N
H
N
H
Ph
MeO2C
MeO2C
N
H
N
H
Ph
Ph
Ph
N
Ph
N
Me
Me
Products characterized by 1H NMR, 13C NMR, IR, MASS spectrometry.
Isolated yield after silica gel column chromatography.
a
b
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2. Conclusion
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In conclusion, the present method has potential use for direct
carbon–carbon bond formation between arylpropargylic com-
pounds and with a variety of heterocycles such as indole, furan,
pyrrole and carbazoles with regioselectivity, good yields and in
short reaction times. Due to its efficiency, simplicity and mild reac-
tion conditions, this will add as an attractive procedure to the
existing armory for the preparation of propargyl indoles.
Acknowledgements
The authors (G.L.V.D. and J.J.P.S.) are thankful to CSIR, New Del-
hi, India, for award of fellowships and to the Director IICT for his
encouragement.
References and notes
1. (a) Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314–6315; (b)
Bandini, M.; Melloni, A.; Piccinelli, F.; Sinisi, R.; Tommasi, S.; Umani-Ronchi, A.
J. Am. Chem. Soc. 2006, 128, 1424–1425; (c) Yadav, J. S.; Reddy, B. V. S.; Basak, A.

6158
G. L. V. Damu et al. / Tetrahedron Letters 50 (2009) 6154–6158
(g) Zhan, Z.-P.; Yu, J.-L.; Liu, H.-J.; Cui, Y.-Y.; Yang, R.-F.; Yang, W.-Z.; Li, J.-P. J. Org.
added DDQ (0.248 g, 1.1 mmol). The resulting mixture was stirred at room
temperature for 2.5 h. After completion of the reaction as noticed by TLC, water
was added and extracted into ethyl acetate. The organic layer was dried over
anhydrous Na2SO4 and concentrated under reduced pressure to get crude
product, which was purified on silica gel column chromatography using
hexane and ethyl acetate (8:2) as eluent to give product 3a (0.239 g,
0.78 mmol) in 78% yield.
Chem. 2006, 71, 8298–8301; (h) Yadav, J. S.; Subba Reddy, B. V.; Raghavenrda Rao,
K. V.; Narayana Kumar, G. G. K. S. Tetrahedron Lett. 2007, 48, 5573–5576; (i) Jana,
U.; Maiti, S.; Biswas, S. Tetrahedron Lett. 2007, 48, 7160–7163.
8. Cheng, D.; Bao, W. J. Org. Chem. 2008, 73, 6881–6883.
9. (a) Jon Paul Selvam, J.; Suresh, V.; Rajesh, K.; Chanti Babu, D.; Suryakiran, N.;
Venkateswarlu, Y. Tetrahedron Lett. 2008, 49, 3463–3465; (b) Suryakiran, N.;
Rajesh, K.; Prabhakar, P.; Jon Paul Selvam, J.; Venkateswarlu, Y. Catal. Commun.
2007, 8, 1635–1640; (c) Suryakiran, N.; Prabhakar, P.; Srikanth Reddy, T.;
Chinni Mahesh, K.; Rajesh, K.; Venkateswarlu, Y. Tetrahedron Lett. 2007, 48,
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Compound 3j: 3-(1-(4-methoxyphenyl)-3-phenylprop-2-ynyl)-1H-indole:
Yellow liquid; IR (KBr):
m
3416, 3056, 2923, 2853, 1601, 1503, 1453, 1222,
1156, 1093, 846, 746, 692 cmÀ1
.
1H NMR (300 MHz, CDCl3): d 3.72 (s, 3H), 5. 08
(s, 1H), 6.65–6.79 (m, 4H), 6.89–6.93 (m, 3H), 7.03–7.30 (m, 6H), 7.37 (d,
J = 7.5 Hz, 1H), 7.77 (br s, 1H). 13C NMR (75 MHz, CDCl3,): d 158.2, 136.4, 133.1,
132.3, 130.0, 128.5, 128.4, 127.4, 122.9, 122.7, 120.2, 118.9, 114.2, 112.1, 111.1,
86.8, 80.9, 55.8, 32.4 ppm. MS (EI, 70 eV): m/z 338 [M+H+].
10. General experimental procedure: To a stirred solution of indole 1a (0.117 g,
1 mmol) and 1,3-diaryl propyne 2a (0.211 g, 1.1 mmol) in MeNO2 (5 mL) was