Convenient synthesis of bis(indolyl)alkanes and bis(pyrrolyl)alkanes by Cu(OTf)2-catalyzed addition of indole and pyrrole to acetylenic sulfone

Article abstract of DOI:10.1016/j.tetlet.2009.12.093

Sulfonyl-containing bis(indolyl)alkanes and bis(pyrrolyl)alkanes were synthesized conveniently by Cu(OTf)₂-catalyzed double Michael addition of indole and pyrrole to acetylenic sulfone.

Full text of DOI:10.1016/j.tetlet.2009.12.093

Tetrahedron Letters 51 (2010) 1213–1215
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Tetrahedron Letters
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Convenient synthesis of bis(indolyl)alkanes and bis(pyrrolyl)alkanes
by Cu(OTf)2-catalyzed addition of indole and pyrrole to acetylenic sulfone
*
Mei-Hua Xie , Fa-Dong Xie, Gao-Feng Lin, Jin-Hua Zhang
Key Laboratory of Functional Molecular Solids (Ministry of Education), Anhui Key Laboratory of Molecular Based Materials, College of Chemistry and Materials Science,
Anhui Normal University, Wuhu, Anhui 241000, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Sulfonyl-containing bis(indolyl)alkanes and bis(pyrrolyl)alkanes were synthesized conveniently by
Cu(OTf)2-catalyzed double Michael addition of indole and pyrrole to acetylenic sulfone.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 21 September 2009
Revised 10 December 2009
Accepted 18 December 2009
Available online 24 December 2009
Keywords:
Cu(OTf)2
Michael addition
Bis(indolyl)alkanes
Bis(pyrrolyl)alkanes
Indole derivatives are found abundantly in nature and are well
known to possess various biological activities, which are used in
antioxidatives and pharmaceuticals.1 Bis(indolyl)alkanes are pres-
ent in many biologically active natural products and are known to
have applications in research areas such as pharmaceuticals and
materials science.2 Consequently, there is an increasing interest
in the synthesis of compounds containing bis(indolyl)alkanes moi-
ety due to their importance and a number of synthetic methods for
the synthesis of bis(indolyl)alkanes have been described in the lit-
erature. However, the procedures described in the literature to ac-
cess bis(indolyl)alkanes are mainly focused on the condensation of
indole with carbonyl compounds in the presence of a protic acid or
a Lewis acid.3 Syntheses of bis(indolyl)alkanes by the reaction of
indoles with alkynes are very rare and these methods suffered
from disadvantages such as only terminal alkynes can be used or
the use of expensive transition metal (e.g., Au, Pd, or Pt) catalysts
is necessary.4
Michael additions have attracted much attention as one of the
most important carbon–carbon bond-forming reactions in organic
synthesis for the reason that Michael additions are atom-efficient
procedures and thus are inherently green transformations.5 Various
Lewis acids such as metal halides or metal triflates are used to pro-
mote Michael addition reaction.6 Acetylenic sulfones are very
attractive Michael acceptors since the sulfonyl moiety is a strong
electron-withdrawing group and can be readily transformed into
different substituents by alkylation, by desulfonylation reaction,
and by Julia olefination.7 Therefore, the chemistry of sulfones has
been extensively studied and exploited in the organic synthesis
for the past several decades. However, to the best of our knowledge,
synthesis of bis(indolyl)alkanes or bis(pyrrolyl)alkanes from acety-
lenic sulfone has not been reported. Recently, we have reported the
regio- and stereoselective synthesis of polysubstituted vinyl sulf-
ones by Michael addition of organozinc reagent to acetylenic sul-
fone.8 During our ongoing investigations on the application of
acetylenic sulfone in organic synthesis, we have found that sulfo-
nyl-containing bis(indolyl)alkanes or bis(pyrrolyl)alkanes can be
obtained conveniently from the reaction of indole or pyrrole with
acetylenic sulfone. Herein, we wish to report the synthesis of sulfo-
nyl-containing bis(indolyl)alkanes and bis(pyrrolyl)alkanes by
Cu(OTf)2-catalyzed double Michael addition of indole or pyrrole
to acetylenic sulfone.
Firstly, the Michael addition of indole to (1-phenyl-2-tosyl)eth-
yne (1a) was investigated. Catalysts and reaction solvents were
screened. It was found that no reaction happened when indole 2a
(3 equiv) and acetylenic sulfone 1a (1 equiv) was stirred in CH2Cl2
at room temperature. In the presence of 10 mol % Cu(OTf)2, the reac-
tion completed in 10 h and bis(indolyl)alkane 3a was obtained in
Ph CH2SO2Tol
Cu(OTf)2
Ph
SO2Tol
+
CH2Cl2, r.t.
N
H
N
N
H
H
2a
1a
3a
* Corresponding author. Tel.: +86 553 3869310; fax: +86 553 3883517.
E-mail address: xiemh@mail.ahnu.edu.cn (M.-H. Xie).
Scheme 1. Cu(OTf)2-catalyzed reaction of 1a and 2a.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.093

1214
M.-H. Xie et al. / Tetrahedron Letters 51 (2010) 1213–1215
52% yield (Scheme 1). The use of 10 mol % FeCl3 gave the expected
product 3a only in 8% yield along with a recovery of 1a. Other Lewis
acid catalysts, such as CeCl3Á7H2O, ZnCl2, Cu(acac)2, and Cu(OAc)2,
could not catalyze the reaction. The yield of 3a was increased to
68% when 20 mol % Cu(OTf)2 was used. Further increasing the
amount of catalyst has no apparent effect on the yield. Among the
various solvents such as ether, acetonitrile, ethanol, and tetrahydro-
furan tested, CH2Cl2 was found to be the most effective for this reac-
tion. Therefore, we used 20 mol % Cu(OTf)2 as catalyst in CH2Cl2 at
room temperature as the standard reaction conditions in the subse-
quent studies.
The scope and generality of this reaction was investigated under
the optimized reaction conditions. The results are complied in
Table 1.9 Table 1 shows that several substituted indoles can react
with acetylenic sulfones to give the corresponding bis(indo-
lyl)alkanes 3 in moderate to good yield. Indoles can be unsubstituted
indole (Table 1, entries 1, 6 and 11), N-ethyl (Table 1, entries 2 and
7), N-benzyl (Table 1, entries 3 and 8), 5-bromo (Table 1, entries 4
and 9), or 5-methoxyl-indoles (Table 1, entries 5 and 10). Acetylenic
sulfone can be phenyl- or n-pentyl-substituted acetylenic sulfone.
However, only mono-adduct 4a was obtained in 52% yield and
no expected bis(indolyl)alkane was observed when 2-methylindol
reacted with (1-phenyl-2-tosyl)ethyne 1a under standard reaction
conditions (Scheme 2). This is probably because of the steric hin-
derance of the methyl in 2-position which inhibits the second Mi-
chael addition. 2-Phenyl and N-tosyl indole are inert under the
same reaction conditions. This may be attributed to the large steric
effect of phenyl and the electron-withdrawing effect of tosyl,
respectively.
Ph
H
Cu(OTf)2
+
Ph
SO2Tol
SO2Tol
CH2Cl2, r.t.
CH3
N
H
CH3
4a
N
H
Scheme 2. Cu(OTf)2-catalyzed reaction of 1a and 2-methylindole.
H
+
N
SO2Tol
H
H
N
R1
CuLn
6
SO2Tol
N
H
2
R1
H
4
CuLn
2
R1
SO2Tol
CuLn
5
R1 CH2SO2Tol
R1
SO2Tol
N
N
H
H
1
3
Scheme 3. Plausible mechanism.
A plausible catalytic mechanism that explains the formation of
product 3 is shown in Scheme 3. The first step of the catalytic cycle
is the coordination of Cu(II) catalyst to the triple bond of alkyne 1
to form intermediate 5. Addition of indole to the b-position of
acetylenic sulfone generates vinylcopper intermediate 6. Proton
release followed by protonation of 6 affords indolylalkene 4. The
second Michael addition of indole to the formed 4 leading to
bis(indolyl)alkane 3 is considered to proceed in the same way.
The indolylalkene 4 as an intermediate of the reaction can be sup-
ported by the mono-adduct 4a, which was obtained by the reaction
of 2-methylindol with 1a.
Bis(pyrrolyl)alkanes derivatives are among the most important
fundamental constituents of biologically and physiologically active
molecules, such as porphyrins and related macrocycles, hemoglo-
bins, and vitamin B12. Bis(pyrrolyl)alkanes derivatives have been
synthesized using a variety of procedures and most of them based
on the direct condensation of carbonyl reagents with pyrrole.4a,10
These processes are often plagued by the inaccessibility of func-
tionalized carbonyl and the formation of undesired side products
such as azafulvenes and N-confused dipyrromethanes. Encouraged
by the experimental results of the double Michael addition of in-
dole to acetylenic sulfone, we further investigated the reaction of
pyrrole with acetylenic sulfone in the similar reaction conditions,
hoping to synthesize sulfonyl-containing pyrrole derivatives. The
experimental results show that the double Michael addition of pyr-
role to acetylenic sulfone proceeded smoothly to give the corre-
sponding bis(pyrrolyl)alkane 7 in moderate to good yields.11 The
results are summarized in Table 2. Acetylenic sulfone can be differ-
ently substituted acetylenic sulfone. However, no desired product
was obtained in the case of N-methyl pyrrole or N-tosyl pyrrole.
The molecular structure of compound 7a was confirmed by X-ray
diffraction analysis (Fig. 1).12
Table 1
Cu(OTf)2-catalyzed Michael addition of indole to acetylenic sulfone
CH2SO2Ar
R1
R3
R3
R3
Cu(OTf)2 (20 mol%)
CH2Cl2, r.t.
R1
SO2Ar
+
N
R2
N
R2
N
R2
2
1
3
Entry
R1
Ar
R2
R3
Yielda (%)
1
2
3
4
5
6
7
8
9
C6H5
C6H5
C6H5
C6H5
C6H5
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
C6H5
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-CH3C6H4
p-ClC6H4
H
H
H
H
Br
CH3O
H
H
H
Br
3a 68
3b 72
3c 80
3d 60
3e 62
3f 55
3g 65
3h 74
3i 48
3j 52
3k 62
CH3CH2
C6H5CH2
H
H
H
CH3CH2
C6H5CH2
H
H
H
10
11
CH3O
H
a
Isolated yield based on 1.

M.-H. Xie et al. / Tetrahedron Letters 51 (2010) 1213–1215
1215
Table 2
Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73–103; (e) Bandini, M.; Melloni,
A.; Tommasi, S.; Umani-Ronchi, A. Synlett 2005, 1199–1222; (f) Patil, S.;
Buolamwini, J. K. Curr. Org. Synth. 2006, 3, 477–498.
Cu(OTf)2-catalyzed Michael addition of pyrrole to acetylenic sulfone
R1 CH2SO2Ar
2. (a) Kam, T. S. In Pelletier, S. W., Ed.; Alkaloids, Chemical and Biological
Perspectives; Pergamon: Amsterdam, 1999; Vol. 4, p 429; (b) Bifulco, G.; Bruno,
I.; Riccio, R.; Lavayre, J.; Bourdy, G. J. Nat. Prod. 1995, 58, 1254–1260; (c)
Chakrabarty, M.; Basak, R.; Harigaya, Y. Heterocycles 2001, 55, 2431–2447; (d)
Hong, C.; Firestone, G. L.; Bjeldanes, L. F. Biochem. Pharmacol. 2002, 63, 1085–
1097; (e) Benabadji, S. H.; Wen, R.; Zheng, J.; Dong, X.; Yuan, S. Acta Pharmacol.
Sin. 2004, 25, 666–672.
HN
Cu(OTf)2 (20 mol%)
CH2Cl2, r.t.
NH
R1
SO2Ar
+
N
H
1
7
Entry
R1
Ar
Yielda (%)
3. For some of the most recent examples, see: (a) Silveira, C. C.; Mendes, S. R.;
Líbero, F. M.; Lenardão, E. J.; Perin, G. Tetrahedron Lett. 2009, 50, 6060–6063; (b)
Seyedi, N.; Saidi, K.; Khabazzadeh, H. Synth. Commun. 2009, 39, 1864–1870; (c)
Liao, B. S.; Chen, J. T.; Liu, S. T. Synthesis 2007, 3125–3128; (d) Deb, M. L.;
Bhuyan, P. J. Tetrahedron Lett. 2006, 47, 1441–1443; (e) Chakrabarty, M.;
Mukherji, A.; Karmakar, S.; Arima, S.; Harigaya, Y. Heterocycles 2006, 68, 331–
338; (f) Nair, V.; Vidya, N.; Abhilash, K. G. Tetrahedron Lett. 2006, 47, 2871–
2873; (g) Gibbs, T. J. K.; Tomkinson, N. C. O. Org. Biomol. Chem. 2005, 3, 4043–
4045.
1
2
3
4
5
6
C6H5
C6H5
n-C5H11
p-CH3C6H4
p-CH3OC6H4
C6H5
p-CH3C6H4
C6H5
p-CH3C6H4
C6H5
C6H5
p-ClC6H4
7a 78
7b 80
7c 58
7d 75
7e 68
7f 78
a
Isolated yield based on 1.
4. (a) Kitamura, T. Eur. J. Org. Chem. 2009, 1111–1125; (b) Barluenga, J.;
Fernández, A.; Rodríguez, F.; Fañanás, F. J. J. Organomet. Chem. 2009, 694,
546–550; (c) Ferrer, C.; Amijs, C. H. M.; Echavarren, A. M. Chem. Eur. J. 2007, 13,
1358–1373; (d) Yadav, J. S.; Reddy, B. V. S.; Padmavani, B.; Gupta, M. K.
Tetrahedron Lett. 2004, 45, 7577–7579.
5. (a) Ko, K.; Nakano, K.; Watanabe, S.; Ichikawa, Y.; Kotsuki, H. Tetrahedron Lett.
2009, 50, 4025–4029; (b) Tan, B.; Zeng, X. F.; Lu, Y. P.; Chua, P. J.; Zhong, G. F.
Org. Lett. 2009, 11, 1927–1930; (c) Jia, Y. X.; Zhu, S. F.; Yang, Y.; Zhou, Q. L. J. Org.
Chem. 2006, 71, 75–80; (d) Lu, S. F.; Du, D. M.; Xu, J. X. Org. Lett. 2006, 8, 2115–
2118; (e) Trost, B. M. Acc. Chem. Res. 2002, 35, 695–705.
6. (a) Schätz, A.; Rasappan, R.; Hager, M.; Gissibl, A.; Reiser, O. Chem. Eur. J. 2008,
14, 7259–7265; (b) Huang, Z. H.; Zou, J. P.; Jiang, W. Q. Tetrahedron Lett. 2006,
47, 7965–7968; (c) Ma, S. M.; Yu, S. C. Org. Lett. 2005, 7, 5063–5065; (d) Bartoli,
G.; Bosco, M.; Foglia, G.; Giuliani, A.; Marcantoni, E.; Sambri, L. Synthesis 2004,
895–900.
7. For reviews, see: (a) Back, T. G. Tetrahedron 2001, 57, 5263–5301; (b) Nájera, C.;
Yus, M. Tetrahedron 1999, 55, 10547–10658.
8. (a) Xie, M. H.; Wang, J. L.; Zhang, W.; Wang, S. W. J. Organomet. Chem. 2009, 694,
2258–2262; (b) Xie, M. H.; Gu, X. X.; Wang, J. L.; Zhang, J. H.; Lin, G. F.; Wang, S.
W. Appl. Organomet. Chem. 2009, 23, 258–266; (c) Xie, M. H.; Wang, J. L.; Gu, X.
X.; Sun, Y.; Wang, S. W. Org. Lett. 2006, 8, 431–434.
Figure 1. The molecular structure of compound 7a.
9. General procedure for the synthesis of compound 3a: Cu(OTf)2 22 mg (0.06 mmol)
was added to a solution of indole (2a) 105 mg (0.9 mmol) and (1-phenyl-2-
tosyl)ethyne (1a) 77 mg (0.3 mmol) in CH2Cl2 (4 mL). The reaction mixture was
stirred at room temperature. After the reaction was complete (monitored by
TLC), the mixture was quenched with a saturated NH4Cl solution and was
extracted with CH2Cl2 (3 Â 10.0 mL). The organic layer was combined and dried
over MgSO4. After filtration and removal of solvent in vacuo, the crude product
was purified with flash chromatography (silica gel, petroleum ether–ethyl
acetate 5:1 as eluent) to afford product 3-(1-(1H-indol-3-yl)-1-phenyl-2-
tosylethyl)-1H-indole 3a. White solid, mp 167–168 °C. 1H NMR (300 MHz,
CDCl3): d 8.07 (s, 2H), 7.45 (d, J = 7.3 Hz, 2H), 7.31–7.14 (m, 8H), 7.02–6.95 (m,
6H), 6.73–6.69 (m, 3H), 4.77 (s, 2H), 2.20 (s, 3H). 13C NMR (75 MHz, DMSO): d
144.5, 142.8, 137.8, 135.7, 128.8, 128.3, 128.0, 127.9, 127.6, 126.6, 126.5, 123.3,
123.1, 116.8, 114.1, 111.3, 64.7, 46.8, 21.4. IR (KBr): v (cmÀ1) 3398, 1492, 1282,
1138, 1080. HRMS (EI) calcd for C31H26N2O2S (M+): 490.1715, found 490.1718.
10. (a) Oyamada, J.; Kitamura, T. Tetrahedron 2009, 65, 3842–3847; (b) Singh, K.;
Behal, S.; Hundal, M. S. Tetrahedron 2005, 61, 6614–6622; (c) Sobral, A. J. F. N.;
Rebanda, N. G. C. L.; Silva, M.; Lampreia, S. H.; Silva, M. R.; Beja, A. M.; Paixão, J.
A.; Gonsalves, A. M. R. Tetrahedron Lett. 2003, 44, 3971–3973.
In conclusion, we have developed a novel and straightforward
method to synthesize sulfonyl-containing bis(indolyl)alkanes and
bis(pyrrolyl)alkanes by double Michael addition of indole or pyr-
role to acetylenic sulfone at room temperature in the presence of
both moisture and air. This is a convenient, atom-efficient, and
green method to synthesis the important indole and pyrrole
derivatives. Due to the versatile reactivity of the sulfonyl group,
it is predictable that these compounds are potential precursors of
differently substituted bis(indolyl)alkanes and bis(pyrrolyl)alkanes.
Acknowledgments
The authors are grateful to the National Natural Science Foun-
dation of China (Nos. 20672001 and 20772001) for financial sup-
port of this work. We are also grateful to Professor Jiping Hu,
Yun Wei, and Cuiping Gu for their helpful assistances.
11. General procedure for the synthesis of compound 3-(1-phenyl-1-(1H-pyrrol-3-yl)-
2-tosylethyl)-1H-pyrrole 7a: Compound 7a was prepared by the similar
procedure as described above. White solid, mp 186–187 °C. 1H NMR
(300 MHz, CDCl3): d 8.99 (s, 2H), 7.46 (d, J = 7.3 Hz, 2H), 7.22–7.16 (m, 5H),
6.97 (d, J = 6.9 Hz, 2H), 6.76 (s, 2H), 6.10 (m, 2H), 5.66 (s, 2H), 4.47 (s, 2H), 2.42
(s, 3H). 13C NMR (75 MHz, CDCl3): d 144.4, 142.6, 138.2, 133.9, 129.8, 128.2,
Supplementary data
128.1, 127.5, 127.4, 117.9, 108.6, 107.8, 67.7, 48.4, 21.6. IR (KBr): v (cmÀ1
)
3437, 1454, 1265, 1134, 1083. HRMS (EI) calcd for C23H22N2O2S: 390.1402,
found 390.1406.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.12.093.
12. X-ray data for 7a have been deposited at the Cambridge Crystallographic Data
Centre, deposition number CCDC 736055. Crystal data for 7a: C23H22N2O2S,
MW = 390.49, monoclinic, space group C2/c, a = 41.797(10), b = 9.486(2),
c = 41.828(10) Å;
a
= 90, b = 166.078(4),
= 0.183 mmÀ1, k = 0.71073 Å; F(0 0 0) 1648, 4588
c
= 90°. V = 3990.2(16) Å3, T = 293 K,
References and notes
Z = 8, Dcalcd = 1.300 g cmÀ1
,
l
independent reflections (Rint = 0.0553), 16,398 reflections collected; refinement
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(c) Wang, M. Z.; Wong, M. K.; Che, C. M. Chem. Eur. J. 2008, 14, 8353–8364; (d)
method, full-matrix least-squares on F2; goodness-of-fit on F2 = 1.061; Final R
indices [I > 2r(I)] R1 = 0.0717, wR2 = 0.1611.