Br?nsted acid catalyzed synthesis of unsymmetrical arylbis(3-indolyl)-methanes synthesis of unsymmetrical arylbis(3-indolyl) methanes

Article abstract of DOI:10.1055/s-0028-1088109

Unsymmetrical arylbis(3-indolyl)methanes have been synthesized via a Br?nsted acid catalyzed Friedel-Crafts alkylation of a-(3-indolyl) benzylamines with N-methylindole. With 5 mol% of the catalyst, the reaction proceeds smoothly under mild conditions, af

Full text of DOI:10.1055/s-0028-1088109

LETTER
1111
Brønsted Acid Catalyzed Synthesis of Unsymmetrical Arylbis(3-indolyl)-
methanes
Synthesis of
U
nsym
i
metric
n
al Arylbis(3
g
-indolyl)met
-hanes Li He, Feng-Lai Sun, Xiao-Jian Zheng, Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, P. R. of China
Fax +86(21)54925087; E-mail: slyou@mail.sioc.ac.cn
Received 29 December 2008
triarylmethanes7 and the challenge for the synthesis of un-
symmetrical triarylmethanes, we envisaged that the syn-
thesis of unsymmetrical triarylmethanes might be realized
through the Brønsted acid catalyzed Friedel–Crafts alkyl-
Abstract: Unsymmetrical arylbis(3-indolyl)methanes have been
synthesized via a Brønsted acid catalyzed Friedel–Crafts alkylation
of a-(3-indolyl)benzylamines with N-methylindole. With 5 mol%
of the catalyst, the reaction proceeds smoothly under mild condi-
tions, affording the unsymmetrical triarylmethanes in excellent ation of a-(3-indolyl)benzylamine with another electron-
yields (up to 98%).
rich arene (Scheme 1, equation 2). In this paper, we report
a Friedel–Crafts-type reaction of a-(3-indolyl)benzyl-
amine with N-methylindole, and the unsymmetrical aryl-
bis(3-indolyl)methanes could be obtained in up to 98%
yield.
Key words: Brønsted acids, Friedel–Crafts reaction, indole, un-
symmetrical triarylmethane
The synthesis of triarylmethanes has attracted enormous
attention from synthetic community due to their versatile
applications such as biologically active compounds, pro-
tecting groups in organic synthesis, and important dyes.1
Unsymmetrical arylbis(3-indolyl)methanes in particular
have attracted considerable synthetic interests. There have
been many reports recently on the synthesis of arylbis(3-
indolyl)methanes.2 However, most of the current efforts
have been made towards the synthesis of symmetrical
arylbis(3-indolyl)methanes,3 the synthesis of unsymmet-
rical triarylmethanes remains challenging and less ex-
plored.4
We first examined the reaction between a-(3-indolyl)ben-
zylamine with N-methylindole catalyzed by a readily
available achiral Brønsted acid 1, developed originally by
Terada and coworkers.8 With 5 mol% of 1 as catalyst, var-
ious solvents were examined for their effectiveness
(Table 1). Both dichloromethane and diethyl ether could
be used for the reaction except that a longer reaction time
(24 h) was needed in the latter case. The reaction in THF
was slow and gave products in lower yields. Toluene was
found to be the optimal solvent, and the reaction proceed-
ed to completion within 1 hour at room temperature, af-
fording the desired product 4a in 94% yield.9,10 The
reaction also worked with H3PO4, TFA, and TsOH·H2O,
but in lower yields (entries 5–7, Table 1).
During our recent study on the chiral phosphoric acid
catalyzed Friedel–Crafts reaction of indole, we observed
that a side reaction occurred to afford arylbis(3-in-
dolyl)methane byproducts (Scheme 1, equation 1).5,6 Giv-
en the great importance of the indole-containing
In the presence of 5 mol% of 1, the reaction of various
a-(3-indolyl)benzylamine derivatives with N-methylin-
dole were evaluated to examine the generality of the reac-
R
TsHN
Ts
*
(1)
Ar
Ar
N
chiral phosphoric acid
R
+
+
NH
N
H
Ar
R
N
R
H
N
H
byproduct
Ar1
TsHN
Ar2
Ar1
Brønsted acid
Ar2H
(2)
+
R
R
N
H
N
H
Scheme 1 Synthesis of unsymmetrical triarylmethanes inspired by a side reaction
SYNLETT 2009, No. 7, pp 1111–1114
x
x.
x
x.
2
0
0
9
Advanced online publication: 26.03.2009
DOI: 10.1055/s-0028-1088109; Art ID: W19808ST
© Georg Thieme Verlag Stuttgart · New York

1112
Q.-L. He et al.
LETTER
MeO
Ph
TsHN
OMe
OMe
Ph
1 (5 mol%)
+
toluene, r.t., 1 h
(1)
MeO
N
H
MeO
OMe
N
H
2a
4p
61% yield
TsHN
Ph
Ph
1 (5 mol%)
N
+
(2)
Me
toluene, r.t., 24 h
N
H
N
N
H
5
4a
Me
80% yield
Scheme 2 Examination of the substrate scope
tion. The results are summarized in Table 2. For the elimination of amine moiety to afford the intermediate I.
substituents on the aryl group of 2, electron-donating Intermediate I reacts with N-methylindole via a Friedel–
groups (2b,c) accelerated the reaction, whereas reactions Crafts-type reaction to afford the unsymmetrical triaryl-
with electron-withdrawing groups (2d–g) were relatively methane 4a. This reaction mechanism hypothesis was
slow. Fortunately, excellent yields were obtained in both supported by the fact that no reaction occurred with N-di-
cases (83–97% yield, entries 1–7, Table 2). Substituents arylmethyltosylamide and the reaction of 5 was much
at the different positions of indole (2h–n) with different slower.
electronic properties did not show any notable effects on
In summary, we have developed a facile synthesis of un-
the reaction rate. In all cases, moderate to excellent yields
symmetrical arylbis(3-indolyl)methanes through the
were obtained (66–98% yield, entries 8–14, Table 2). In-
Brønsted acid catalyzed Friedel–Crafts alkylation of a-(3-
indolyl)benzylamines with N-methylindole. This repre-
sents an interesting example that a useful method was de-
veloped by the inspiration of a side reaction. Ongoing
terestingly, excellent yield (88%) was obtained even in
the case of 2-methyl substituted indole 2o (entry 15,
Table 2).
In addition to N-methylindole, the current catalytic system efforts in our laboratory include the development of an
also worked for 1,3,5-trimethoxybenzene, providing the asymmetric version of the current reaction, and the enantio-
unsymmetrical triarylmethane 4p in 61% yield selective synthesis of unsymmetrical triarylmethanes will
(Scheme 2, equation 1). It should be pointed out that no be reported in due course.
reaction occurred when a-(3-indolyl)benzylamine 2a was
replaced by the simple N-diarylmethyltosylamide. How-
ever, the reaction between 5 and indole in the presence of
5 mol% 1 still proceeded to afford 4a in 80% yield in a
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
much longer reaction time (24 h; Scheme 2, equation 2).
Acknowledgment
Mechanistically, we proposed the following catalytic
cycle as listed in Scheme 3. With the assistance by Brøn-
sted acid (X–H), a-(3-indolyl)benzylamine 2a undergoes
We thank the National Natural Science Foundation of China,
National Basic Research Program of China (973 Program
NuH
X
H
TsHN
TsHN
Ph
Ph
Ph
– TsNH2
X
H
– X–
+ NuH
N+
N
H
N
H
H
I
2a
Ph
NuH = N-methylindole
– H+
N
Me
N
4a
H
Scheme 3 The Brønsted acid catalyzed Friedel–Crafts alkylation of 2a with N-methylindole
Synlett 2009, No. 7, 1111–1114 © Thieme Stuttgart · New York

LETTER
Synthesis of Unsymmetrical Arylbis(3-indolyl)methanes
1113
Table 2 Synthesis of Unsymmetrical Arylbis(3-indolyl)methanesa
Table 1 Optimization of the Reaction Conditions for the Synthesis
of Triarylmethanes
TsHN
Ts
Ar
Ar
N
O
1 (5 mol%)
TsHN
P
N
R
+
Ph
OH
N
Ph
Me
toluene, r.t.
N
H
N
R
Ts
1 (5 mol%)
N
N
+
Me
Me
H
N
2
3
4
N
H
Me
solvent, r.t.
N
H
Time (h) Yield of 4 (%)b
2a
3
4a
Entry
1
2 R
Ar
Ph
Entrya
Solvent
toluene
CH2Cl2
Et2O
Time (h)
1.0
Yield (%)b
2a H
2b H
2c H
2d H
2e H
2f H
2g H
1
4a 94
4b 95
4c 97
4d 97
4e 95
4f 97
4g 83
4h 93
4i 92
4j 74
4k 72
4l 74
4m 98
4n 66
4o 88
1
94
74
74
30
22
67
85
2
4-MeOC6H4
0.1
0.1
2
1.0
3
4-MeC6H4
3
24.0
24.0
24.0
1.0
4
2-BrC6H4
22
4
THF
5c
6c
7c
8
4-BrC6H4
1
16
40
1
5c
6d
7e
toluene
toluene
toluene
4-O2NC6H4
3-O2NC6H4
1.0
2h 5-MeO
2i 5-Me
2j 5-Br
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
a Reaction conditions: 3 (0.3 mmol), 1 (5 mol%), 2 (0.2 mmol) in sol-
vent (4 mL), r.t.
9
1
b Isolated yields.
10
11
12
13
14
15
1
c 5 mol% H3PO4 was used instead of 1.
d 5 mol% TFA was used.
2k 5-F
1
e 5 mol% TsOH·H2O was used.
2l 6-BnO
2m 6-Br
2n 4-Me
2o 2-Me
1
2009CB825300), the Knowledge Innovation Program of the Chine-
se Academy of Sciences, and the Science and Technology Commis-
sion of Shanghai Municipality (07pj14106, 07JC14063) for
generous financial support.
5
1
2
a Reaction conditions: 3 (0.3 mmol), 1 (5 mol%), 2 (0.2 mmol) in tol-
uene (4 mL), r.t.
References and Notes
b Isolated yields.
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Commun. 2008, 38, 1291. (b) Khalafi-Nezhad, A.; Parhami,
A.; Zare, A.; Zare, A. R. M.; Hasaninejad, A.; Panahi, F.
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Baltork, I.; Memarian, H. R.; Khosropour, A. R.; Nikoofar,
K.; Ghanbary, P. J. Heterocycl. Chem. 2008, 45, 377.
(d) Hosseini-Sarvari, M. Synth. Commun. 2008, 38, 832.
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Murthy, C. V. S. R.; Kumar, G. M.; Madan, C. Synthesis
2001, 783. (b) Ramesh, C.; Banerjee, J.; Pal, R.; Das, B.
Adv. Synth. Catal. 2003, 345, 557. (c) Nair, V.; Abhilash,
K. G.; Vidya, N. Org. Lett. 2005, 7, 5857. (d) Podder, S.;
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3100. (e) Wang, Z.; Sun, X.; Wu, J. Tetrahedron 2008, 64,
5013. (f) Sun, S.; Wang, M.; Deng, H.; Liu, Q. Synthesis
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Synlett 2009, No. 7, 1111–1114 © Thieme Stuttgart · New York

1114
Q.-L. He et al.
LETTER
(6) (a) Kang, Q.; Zhao, Z.-A.; You, S.-L. J. Am. Chem. Soc.
2007, 129, 1484. (b) Wang, Y.-Q.; Song, J.; Hong, R.; Li,
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(9) General Procedure for the Synthesis of the
Unsymmetrical Arylbis(3-indolyl)methanes in Table 2
In a dry Schlenk tube, a-(3-indolyl)benzylamine 2 (0.20
mmol; see ref. 6 for the preparation) and phosphorodiamidic
acid 1 (4.8 mg, 0.01 mmol) were dissolved in toluene (4 mL)
under argon. N-Methylindole (39.3 mg, 0.30 mmol) was
added and the solution was stirred at r.t. After the reaction
was complete (monitored by TLC), sat. aq NaHCO3 (3 mL)
was added to quench the reaction. The mixture was extracted
with EtOAc (10 mL). The organic layer was washed by brine
(5 mL), separated, and dried over anhyd Na2SO4. The
solvents were removed under reduced pressure, and the
residue was purified by flash chromatography (EtOAc–PE,
1:8 to 1:5) to afford the product.
(10) 3-[(1-Methyl-1H-indol-3-yl)(phenyl)methyl]-1H-indole
(Table 2, Entry 1)
Prepared according to the general procedure to provide the
title compound as a white solid (94% yield) following silica
gel chromatography (EtOAc–PE, 1:6).
Analytical Data
1H NMR (300 MHz, CDCl3): d = 3.65 (s, 3 H), 5.87 (s, 1 H),
6.49 (s, 1 H), 6.63 (s, 1 H), 6.69–7.02 (m, 2 H), 7.13–7.39
(m, 11 H), 7.82 (s, 1 H). 13C NMR (75 MHz, CDCl3): d =
32.6, 40.1, 109.1, 111.0, 118.0, 118.6, 119.1, 119.7, 119.9,
120.0, 121.4, 121.8, 123.6, 126.0, 127.4, 126.0, 126.9,
127.4, 128.1, 128.2, 128.6, 136.5, 137.3, 144.1. IR (film):
3410, 3053, 2923, 1605, 1456, 1418, 1371, 1329, 1154,
1092, 1011, 740, 703, 580 cm–1. HRMS (EI): m/z calcd for
C24H20N2: 336.1626; found: 336.1628.
Synlett 2009, No. 7, 1111–1114 © Thieme Stuttgart · New York

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