Silica Gel Mediated Friedel–Crafts Alkylation of 3-Indolylmethanols with Indoles: Synthesis of Unsymmetrical Bis(3-indolyl)methanes

Article abstract of DOI:10.1002/ejoc.201700088

An efficient and expedient approach for the synthesis of unsymmetrical bis(3-indolyl)methanes by employing a silica gel mediated Friedel–Crafts alkylation of 3-indolylmethanols with various indoles is described. The synthetic utility of this transformatio

Full text of DOI:10.1002/ejoc.201700088

A Journal of
Accepted Article
Title: Silica gel-mediated Friedel-Crafts alkylation of 3-indolylmethanols
with indoles: synthesis of unsymmetrical 3,3′-bis-indolylmethanes
Authors: Weidong Rao, Yongzhen ZOU, Cuili Chen, Xianxiao Chen,
and Xiaoxiang Zhang
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700088
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700088
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10.1002/ejoc.201700088
European Journal of Organic Chemistry
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Silica Gel-Mediated Friedel–Crafts Alkylation of 3-Indolylmethanols
with Indoles: Synthesis of Unsymmetrical 3,3′-Bis-indolylmethanes
Yongzhen Zou,[a] Cuili Chen,[a] Xianxiao Chen,[a] Xiaoxiang Zhang,*[a] and Weidong Rao*[a]
Abstract: An efficient and expedient approach for the synthesis of
unsymmetrical 3,3′-Bis-indolylmethanes via silica gel-mediated
Friedel–Crafts alkylation of 3-indolylmethanols with diverse indoles is
described. The synthetic utility of this transformation was
demonstrated by reusing silica gel up to 10 times without apparent
respectively (Scheme 1, Lg = NHTs, p-TolSO2H).
Recently, Lewis and Brønsted acid-catalyzed reactions of
alcohols as pro-electrophiles have emerged as efficient and
expedient synthetic strategies for C-C and C-X bond formation.[8-
13]
Among them, Friedel–Crafts alkylation reactions that make
loss of reactivity
.
use of alcohol pro-electrophiles with indoles continues to be
actively pursued.
[11-13]
For example, Ji and co-workers[12] who
reported an efficient synthetic protocol for the preparation of
unsymmetrical 3,3’-bisindolylmethanes from 3-indolylmethanols
with indoles using CAN as catalyst under ultrasonic
Introduction
irradiation(Scheme 1, Lg
=
OH). More recently, Xiao
The indole scaffold is an important and versatile structural motif
that is frequently encountered in numerous biologically active
natural products, pharmaceuticals as well as functional
materials.[1-7] Among these indole derivatives, 3,3′-bis-
indolylalkanes are important class of bioactive metabolite of
terrestrial marine origin and ubiquitously found in many natural
products.[2] Therefore, the development of efficient construction
of 3,3′-bis-indolylalkanes has been actively pursued.[3-7, 12-13] As
an example, a majority of studies show that symmetrical 3,3′-bis-
indolylalkanes can readily be synthesized by condensation
reactions of carbonyl compounds with indoles in the presence of
Lewis or Brønsted acids.[3] Although significant effort has been
made towards the synthesis of symmetrical 3,3′-bis-
indolylalkanes, the synthesis of unsymmetrical 3,3′-bis-
indolylalkanes is sparse and remains challenging. For this
reason, the development of new and efficient methods for the
preparation of unsymmetrical 3,3′-bis-indolylalkanes has and
continues to receive significant synthetic interest.[4-7,13-14] In this
respect, Vallee disclosed the first example of synthesizing
demonstrated that Ji’s reported transformation could be
achieved in fluorinated alcohol[13b] or water[13a] under catalyst-
free conditions. Although the advences of those reported
methodologies, many of them were suffered from the formation
of large amounts of by-product or harsh conditions. Hence,
developing synthetic approaches to prepare this class of
unsymmetrical 3,3’-bis-indolylmethanes that make use of readily
available precursors, mild reaction conditions, simple operation
and environmentally friendly catalysts are desirable. To the best
of our knowledge, synthesis of unsymmetrical 3,3’-bis-
indolylmethanes using a recyclable catalyst via Friedel–Crafts
alkylation under mild conditions is not known.
Silica gel has proven versatile in mediating a wide variety of
organic transformations to various synthetically valuable
products[14-16]. The use of silica gel in mediating organic
transformations is advantageous because silica gel is readily
available, inexpensive, non-toxic and can be reused. The use of
silica gel as a promoter features an environmentally benign,
operational simplicity and highly desirable process. Herein, we
disclose the details of silica gel-mediated Friedel–Crafts
alkylation of 3-indolylmethanols with indoles, which leads to an
efficient and environmentally benign manner for the preparation
of unsymmetrical 3,3’-bis-indolylalkane derivatives (Scheme 1).
unsymmetrical
3,3’-bisindolylmethanes
with
benzylhydroxylamine as the leaving group (Scheme 1).[4]
Following this seminal work, there has only been a small handful
of studies of demonstrating the preparation of unsymmetrical
3,3′-bis-indolylalkanes. Bhuyan and co-workers reported
unsymmetrical 3,3’-bis-indolylmethanes could be synthesized
under the catalyst-free conditions. However, under such
conditions, N,N-dimethylbarbituric acid was inevitably formed as
the by-product (Scheme 1, Lg = N,N-dimethylbarbituric acid).[5]
Other similar examples were reported by You[6] and Petrini[7] that
the preparation of unsymmetrical 3,3’-bis-indolylmethanes were
achieved through the Friedel–Crafts alkylation of 3-
indolylbenzylamines and 3-indolylarylsulfones with indoles in the
presence of Brønsted acid. In these examples, tosylamide and
p-toluenesulfinic acid were generated as the by-product,
[a]
Jiangsu Key Lab of Biomass-based Green Fuels and Chemicals,
College of Chemical Engineering, Nanjing Forestry University,
Nanjing 210037, P. R. China
E-mail: weidong@njfu.edu.cn (W.R); zhangxiaoxiang@njfu.edu.cn
(X.Z)
Scheme 1. General strategies for the synthesis of unsymmetrical 3,3’-bis-
indolylalkanes
http://hg.njfu.edu.cn/newsshow.php?cid=25&id=2058
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201700088
European Journal of Organic Chemistry
FULL PAPER
Supplied by Sigma-Aldrich (230-400 mesh). [d] Supplied by Jiangyou silicone
Co., Ltd., Yantai, Shangdong province (200-300 mesh).
Results and Discussion
Initially, we chose to examine Friedel–Crafts alkylation of (1H-
indol-3-yl)(phenyl)methanol 1a with 2-phenyl-1H-indole 2a as
the model substrates to establish the reaction conditions (Table
1). This revealed that treating 1a (0.2 mmol) with the 2a (0.22
mmol) with silica gel (1 gram, source: Sigma-Aldrich, particle
size: 230-400 Mesh) in toluene under ambient conditions at
room temperature for 2 h gave 3a in 99% yield (entry 1).
Encouraged by this preliminary result, we next examined the
silica gel with varying particle size from different suppliers. To
our delight, the same yield of 99% was found on repeating the
reaction with silica gel from different suppliers (source: Jiangyou
silicone, particle size: 200-300 Mesh) (entry 2). In our hands,
similar product yields of 94-97% along with increased reaction
times were observed on changing the solvent from toluene to
CH2Cl2, MeCN, EA-PE (v:v=1:20) (entries 3, 5-6). Longer
reaction time of 9 hours and markedly lower product yield of
64% were observed when the reaction was repeated in ethanol
(entry 7). However, switching the solvent to THF was found to
result in no reaction observed on the basis of TLC and 1H NMR
analysis (entry 4). On the contrary, further studies showed that
excellent product yield of 99% was achieved even in the
presence of reduced amount of silica gel (240 mg and 60 mg,
entry 8, 9 respectively). Control experiment in the absence of
silica gel was carried out for 24h and both starting materials
were recovered in near quantitative yields, evidencing that acidic
silica gel is the active species(entry 10).
To examined the recyclability of silica gel in Friedel–Crafts
alkylation of 1a with 2a, the reactions were carried out on 0.2
mmol scale with silica gel 1 gram as the promoter. The used
silica gel was recovered by simple filtration, washed with ethyl
acetate and dried under vacumm. To our delight, the silica gel
could be reused at least nine times in the reactions. It is
observed that all the reactions proceeded smoothly to afford 3a
in excellent yield under the same above-mentioned conditions
without any apparent loss of reactivity (Table 2).
Table 2. Recyclable silica gel for Friedel–Crafts alkylation of 1a with 2-
phenylindole 2a[a]
Run
1
2
3
4
5
6
7
8
9
10
93
Yield(%)[b]
99
97
94
96
96
98
95
92
95
[a] All reactions were performed with 0.2 mmol of 1a and 0.22 mmol 2a in
toluene (4 mL) at room temperature with silica gel (1gram, source: Sigma-
Aldrich, particle size: 230-400 Mesh). [b] Isolated yield.
To define the scope of the present procedure, we next sought to
assess its generality for a series of sterically and electronically
3-indolylmethanols 1 with indoles 2 (Table 3). Overall, the
reaction conditions were found to be general and a diverse set
of unsymmetrical 3,3’-bisindolylmethanes 3a-y containing a
variety of substitution patterns were afforded in good to excellent
yields (61–99%). Reactions of (1H-indol-3-yl)(phenyl)methanol
1a with C-2 substituted indoles or C-2 substituted N-methyl
indoles gave unsymmetrical 3,3’-bis-indolylmethanes 3a-e in
excellent yield of 92-99%. Having pendant of electron-
withdrawing groups at C-5 position of indoles furnished the
adduct 3f-g in 87-95% yield. When 2-phenyl-3-indolylmethanol
1b was used to react with both N-methylindole and 2-
phenylindole under the optimized reaction conditions, the
reactions were found to proceed efficiently to afford 3h-3i in
good yield (71-77%). The present procedure was also shown to
proceed well for 3-indolylmethanols which containing a variety of
substituents of different electronic properties on the aryl group
with N-methylindole giving 3j-3r in 82-98% yield. Similarly, the
Friedel–Crafts alkylation of 3-indolylmethanol containing 1-
naphthyl or 2-naphthyl group were also shown to be well-
tolerated and furnished 3s and 3t in 95% and 89% yield,
respectively. Notably, slightly lower yields of 3,3’-bis-
indolylmethanes 3v-w were obtained for the reactions of 3-
indolylmethanols which contain phenylacetylene moiety on the
aryl group. In contrast, the presence of acetylene instead of
phenylacetylene as the substituent on the aryl group of 3-
indolylmethanols furnished 3u in good yield of 86%. The
tolerance of an acetylene moiety under the reactions conditions
provides potential for further functional groups transformations.
Table 1. Optimization of the reaction conditions[a]
Entry
Catalyst
Solvent
Time
(h)
Yield[b]
(%)
1
2
3
4
5
6
7
8
9
10
silica gel I (1 g) [c]
silica gel II (1g) [d]
silica gel I (1 g)
silica gel I (1 g)
silica gel I (1 g)
silica gel I (1 g)
silica gel I (1 g)
silica gel I (240 mg)
silica gel I (60 mg)
none
Toluene
Toluene
CH2Cl2
2
99
2
99
6
97
THF
24
8
N.R.
96
EA-PE(1:20)
CH3CN
EtOH
16
9
94
64
Toluene
Toluene
Toluene
2
99
2
99
24
N.R.
[a] Unless stated otherwise, all reactions were performed with 0.2 mmol of 1a
and 0.22 mmol 2a in solvent (4 mL) at room temperature. [b] Isolated yield. [c]
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10.1002/ejoc.201700088
European Journal of Organic Chemistry
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Interestingly, under the heating conditions, reaction of N-benzyl-
3-indolylmethanol with N-methylindole was also found to be
effective, giving 3x in nearly quantitatively yield. Additionally,
substrate with a alkyl moiety such as 1-(1-benzyl-1H-indol-3-
yl)pentan-1-ol, was found to proceed well and provide 3y in 91%
yield.
phenyl-1H-indole 2a (6.6 mmol) in toluene with reduced amount
of silica gel (1 gram) under the conditions as described in
Scheme 2 was successfully scaled, affording 3a in excellent
yield (93%).
Table 3. Friedel–Crafts alkylation of 3-indolylmethanols with diverse indoles
mediated by silica gel[a]
Scheme 2. Gram-scale Friedel–Crafts alkylation of 1a with 2-pehenylindole 2a
mediated by silica gel.
Conclusions
In summary, we have demonstrated an efficient and expedient
approach for the synthesis of unsymmetrical 3,3’-bis-
indolylmethanes via silica gel-mediated Friedel–Crafts alkylation
of 3-indolylmethanols with indoles. The transformation exhibits
good tolerance for structurally diverse set of 3-indolymethanols
and indoles. Moreover, the operationally simplicity and mild
reaction conditions of this protocol would provide potential for
scale-up strategy for the preparation of unsymmetrical 3,3’-bis-
indolylmethanes, which was demonstrated by gram-scale
synthesis of one example in excellent yield. Added to this, the
synthetic utility of this transformation was demonstrated by
reusing silica gel for nine further consecutive transformations
without any apparent decrease of reactivity. Further studies on
the synthetic applications of the present methodology are
currently underway in our laboratory.
Experimental Section
General Materials and Methods
Unless specified, all reagents and solvents were purchased from
commercial sources and used as received. Analytical thin layer
chromatography (TLC) was performed using Merck 60 F254 pre-coated
silica gel plate. The products were purified by flash column
chromatography on silica gel (200–300 mesh) eluted with a gradient of
petroleum ether and ethyl acetate. 1H and 13C NMR spectra were
recorded with Bruker AVQ-400 spectrometer. Chemical shifts (ppm) were
recorded in CDCl3 with tetramethylsilane (TMS) as the internal reference
standard. Multiplicities are given as: s (singlet), brs (broad singlet), d
(doublet), t (triplet), dd (doublet of doublets), td (triplet of doublets), dt
(doublet of triplet) or m (multiplets). The number of protons (n) for a given
resonance is indicated by nH and coupling constants are reported as a J
value in Hz. Infrared spectra were recorded on NICOLET 6700 FTIR
Spectrometer. High resolution mass spectra (HRMS) were obtained
using LTQ Orbitrap and reported in units of mass to charge (m/z).
[a] Unless stated otherwise, all reactions were performed with 0.2 mmol of 1
(0.2 mmol) and 2 (0.22 mmol) in toluene (4 mL) at room temperature with
silica gel (60 mg, source: Sigma-Aldrich, particle size: 230-400 Mesh ) for 2 h.
Values in parenthesis denote isolated product yields [b] The reaction was
carried out at 80 oC for 2h. [c] The reaction was carried out with 1-(1-benzyl-
1H-indol-3-yl)pentan-1-ol (0.24 mmol) and 5-bromo-indole (0.2 mmol) in
toluene (4 mL) at room temperature for 15 h.
General procedure for silica gel-mediated Friedel–Crafts alkylation
of 3-Indolylmethanols with Indoles: To a solution of 3-indolylmethanols
1 (0.2 mmol), indoles 2 (0.22 mmol) in toluene (4 mL) was added silica
gel (60 mg). The mixture was stirred at room temperature and monitored
by TLC analysis. Upon completion, the reaction mixture was filtered and
washed with ethyl acetate, the solvent was removed under reduced
pressure and purified by flash chromatography on silica gel (eluent:
Under the established conditions, we were pleased to find that
this transformation could be readily scaled up. Reaction starting
with (1H-indol-3-yl)(phenyl)methanol 1a (6 mmol, 1.34g) and 2-
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10.1002/ejoc.201700088
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petroleum ether: ethyl acetate = 30:1 to 10:1) to give the desired product
3.
1H), 7.56-7.54 (m, 2H), 7.46-7.33 (m, 8H), 7.28-7.17 (m, 6H), 7.04-7.00
(m, 1H), 6.98-6.93 (m, 1H), 6.77 (s, 1H), 6.11 (s, 1H), 3.71 (s, 3H); 13C
NMR (100 MHz, CDCl3): δ = 144.2, 137.3, 136.3, 134.9, 133.0, 128.9,
128.8, 128.7, 128.5, 128.0, 127.9, 127.8, 125.8, 121.9, 121.5, 121.4,
120.0, 119.5, 118.8, 117.4, 115.8, 110.8, 109.1, 39.3, 32.7.
3-((1H-indol-3-yl)(phenyl)methyl)-2-phenyl-1H-indole (3a)[13]
: White
solid (77 mg, 97% yield); 1H NMR (400 MHz, CDCl3): δ = 7.84 (s, 1H),
7.68 (s, 1H), 7.49-7.47 (m, 2H), 7.41-7.17 (m, 14H), 7.03 (td, J = 7.9, 0.9
Hz, 1H), 6.96 (td, J = 7.8, 1.1 Hz, 1H), 6.70 (dd, J = 2.3, 0.9 Hz, 1H), 6.07
(s, 1H); 13C NMR (100 MHz, CDCl3): δ = 144.0, 136.5, 136.3, 135.0,
133.0, 128.9, 128.8, 128.6, 128.0, 127.9, 127.4, 125.9, 124.2, 121.9,
121.5, 119.9, 119.5, 119.3, 119.0, 115.6, 111.1, 110.9, 39.3.
1-methyl-2-phenyl-3-(phenyl(2-phenyl-1H-indol-3-yl)methyl)-1H-
indole (3i)[13]: White solid (69 mg, 71% yield); 1H NMR (400 MHz, CDCl3):
δ = 7.90 (s, 1H), 7.42-7.21 (m, 12H), 7.17-7.12 (m, 6H), 7.00-6.94 (m,
4H), 6.89-6.85 (m, 1H), 6.04 (s, 1H), 3.52 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 145.0, 139.1, 137.2, 136.0, 135.2, 133.0, 132.0, 130.4, 129.3,
129.0, 128.3, 128.3, 128.2, 127.8, 127.7, 127.6, 127.4, 126.0, 121.9,
121.6, 121.4, 121.0, 119.4, 119.2, 115.7, 115.2, 110.6, 109.2, 40.2, 30.8.
3-((1H-indol-3-yl)(phenyl)methyl)-2-methyl-1H-indole (3b)[6b]
: White
solid (62 mg, 92% yield); 1H NMR (400 MHz, CDCl3) δ = 7.88 (s, 1H),
7.73 (s, 1H), 7.38-7.18 (m, 10H), 7.09 (t, J = 7.6 Hz, 1H), 7.01 (t, J = 7.5
Hz, 1H), 6.94 (t, J = 7.5 Hz, 1H), 6.68 (s, 1H), 5.95 (s, 1H), 2.25 (s, 3H);
13C NMR (100 MHz, CDCl3): δ = 144.0, 136.7, 135.2, 131.5, 128.8, 128.6,
128.1, 127.5, 125.9, 123.7, 121.9, 120.7, 119.9, 119.4, 119.3, 119.0,
114.0, 111.0, 110.0, 39.4, 12.3.
3-((1H-indol-3-yl)(p-tolyl)methyl)-1-methyl-1H-indole (3j)[5,13]
: White
solid (67 mg, 71% yield); 1H NMR (400 MHz, CDCl3): δ = 7.79 (s, 1H),
7.48 (dd, J = 7.9, 3.7 Hz, 2H), 7.37-7.21 (m, 6H), 7.16 (d, J = 7.9 Hz, 2H),
7.10-7.05 (m, 2H), 6.68-6.67 (m, 1H), 6.58 (s, 1H), 5.93 (s, 1H), 3.70 (s,
3H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 141.3, 137.5, 136.7,
135.5, 129.0, 128.6, 128.3, 127.6, 127.2, 123.6, 121.9, 121.5, 120.1,
120.0, 119.2, 118.7, 118.4, 111.1, 109.2, 39.8, 32.7, 21.2.
3-((1H-indol-3-yl)(phenyl)methyl)-1-methyl-1H-indole (3c) [6b,13]: White
solid (65 mg, 97% yield); 1H NMR (400 MHz, CDCl3): δ = 7.85 (s, 1H),
7.46 (dd, J = 7.9, 2.8 Hz, 2H), 7.44-7.40 (m, 2H), 7.37-7.33 (m, 4H), 7.30-
7.21 (m, 3H), 7.07 (tdd, J = 7.0, 2.3, 1.0 Hz, 2H), 6.67 (dd, J = 2.3, 0.8 Hz,
1H), 6.57 (d, J = 0.6 Hz, 1H), 5.96 (s, 1H), 3.70 (s, 3H); 13C NMR (100
MHz, CDCl3): δ = 144.3, 137.5, 136.7, 128.8, 128.3, 128.3, 127.5, 127.1,
126.1, 123.7, 121.9, 121.5, 120.1, 120.0, 119.8, 119.2, 118.7, 118.2,
111.1, 109.2, 40.2, 32.7.
3-((4-fluorophenyl)(1H-indol-3-yl)methyl)-1-methyl-1H-indole
(3k):
White solid (63 mg, 89% yield); m.p. 198-200 oC; 1H NMR (400 MHz,
CDCl3): δ = 7.81 (s, 1H), 7.47 (dd, J = 7.9, 3.3 Hz, 2H), 7.40-7.36 (m, 4H),
7.32-7.25 (m, 2H), 7.16-7.02 (m, 4H), 6.65 (d, J = 1.6 Hz, 1H), 6.58 (s,
1H), 5.96 (s, 1H), 3.72 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 161.5(d,
JC-F = 242.0 Hz, 1C), 140.0 (d, JC-F = 3.0 Hz, 1C), 137.5, 136.8, 130.2 (d,
JC-F = 7.8 Hz, 1C), 128.3, 127.4, 127.0, 123.7, 122.1, 121.7, 120.1, 119.9,
119.7, 119.4, 118.9, 118.1, 115.1(d, JC-F = 21.0 Hz, 1C), 111.2, 109.3,
39.5, 32.7; IR (KBr) v: 3379, 2933, 1603, 1217, 743 cm-1; HRMS (ESI)
calcd. for C24H20FN2(M++H): 355.1611, found: 355.1623.
3-((1H-indol-3-yl)(phenyl)methyl)-1,2-dimethyl-1H-indole
(3d)[13a]
:
1
White solid (69 mg, 98% yield); H NMR (400 MHz, CDCl3): δ = 7.86 (s,
1H), 7.40-7.13 (m, 11H), 7.03 (t, J = 7.6 Hz, 1H), 6.94 (t, J = 7.4 Hz, 1H),
6.69 (s, 1H), 6.00 (s, 1H), 3.70 (s, 3H), 2.35 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 144.3, 136.8, 136.7, 133.3, 128.8, 128.1, 127.6, 127.5, 125.8,
123.8, 121.9, 120.3, 119.9, 119.5, 119.3, 119.2, 118.6, 113.4, 111.0,
108.5, 39.7, 29.5, 10.7.
3-((4-chlorophenyl)(1H-indol-3-yl)methyl)-1-methyl-1H-indole
(3l):
White solid (71 mg, 96% yield); m.p. 214-216 oC; 1H NMR (400 MHz,
CDCl3): δ = 7.83 (s, 1H), 7.44 (dd, J = 7.8, 3.7 Hz, 2H), 7.38-7.23 (m, 8H),
7.09 (td, J = 7.3, 3.4 Hz, 2H), 6.65 (s, 1H), 6.56 (s, 1H), 5.93 (s, 1H), 3.71
(s, 3H); 13C NMR (100 MHz, CDCl3): δ = 142.8, 137.5, 136.7, 131.8,
130.1, 128.4, 128.3, 127.3, 126.9, 123.7, 122.1, 121.7, 120.0, 119.9,
119.4, 119.3, 118.8, 117.6, 111.1, 109.3, 39.6, 32.7; IR (KBr) v: 3380,
2927, 1632, 743 cm-1; HRMS (ESI) calcd. for C24H19N235ClNa (M++Na):
393.1134, found: 393.1125.
3-((1H-indol-3-yl)(phenyl)methyl)-1-methyl-2-phenyl-1H-indole
(3e)[13a]: White solid (80 mg, 97% yield); 1H NMR (400 MHz, CDCl3): δ =
7.88 (s, 1H), 7.45-7.14 (m, 16H), 6.98-6.94 (m, 2H), 6.85 (s, 1H), 5.79 (s,
1H), 3.66 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 144.4, 138.1, 137.6,
136.5, 132.0, 130.8, 128.7, 128.4, 128.2, 128.0, 127.4, 127.2, 125.7,
123.9, 121.8, 121.3, 121.2, 120.0, 119.4, 119.1, 119.1, 115.5, 110.9,
109.3, 39.8, 31.0.
3-((4-bromophenyl)(1H-indol-3-yl)methyl)-1-methyl-1H-indole (3m)[5]
:
1
White solid (77 mg, 93% yield); H NMR (400 MHz, CDCl3): δ = 7.93 (s,
1H), 7.44-7.38 (m, 5H), 7.33 (d, J = 8.2 Hz, 1H), 7.29-7.20 (m, 4H), 7.07-
7.02 (m, 2H), 6.68 (d, J = 1.6 Hz, 1H), 6.53 (s, 1H), 5.88 (s, 1H), 3.71 (s,
3H); 13C NMR (100 MHz, CDCl3): δ = 143.3, 137.5, 136.7, 131.3, 130.5,
128.3, 127.3, 126.9, 123.6, 122.1, 121.6, 119.9, 119.9, 119.9, 119.4,
119.3, 118.8, 117.5, 111.1, 109.2, 39.7, 32.7.
3-((1H-indol-3-yl)(phenyl)methyl)-5-chloro-1H-indole (3f): Colorless
solid (68 mg, 95% yield); m.p. 139-141 oC; 1H NMR (400 MHz, CDCl3): δ
= 7.76 (s, 1H), 7.72 (s, 1H), 7.45-7.16 (m, 10H), 7.09-7.04 (m, 1H), 6.64-
6.56 (m, 2H), 5.88 (s, 1H); 13C NMR (100 MHz, CDCl3): δ = 143.7, 136.8,
135.0, 128.7, 128.4, 128.2, 127.0, 126.4, 125.1, 125.0, 123.7, 122.3,
122.1, 119.9, 119.4, 119.3, 1193, 112.2, 111.3, 40.1; IR (KBr) v: 3423,
2930, 1631, 741 cm-1; HRMS (ESI) calcd. for C23H18N2Cl (M++H):
357.1159, found: 357.1164.
3-((1H-indol-3-yl)(m-tolyl)methyl)-1-methyl-1H-indole (3n): White solid
(68 mg, 97% yield); m.p. 139-140 oC; 1H NMR (400 MHz, CDCl3): δ =
7.76 (s, 1H), 7.49 (dd, J = 7.9, 3.7 Hz, 2H), 7.37 (dd, J = 8.2, 3.6 Hz, 2H),
7.32-7.20 (m, 5H), 7.15-7.05 (m, 3H), 6.67 (dd, J = 2.2, 0.7 Hz, 1H), 6.59
(s, 1H), 5.94 (s, 1H), 3.70 (s, 3H), 2.38 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 144.3, 137.7, 137.5, 136.7, 129.5, 128.3, 128.2, 127.6, 127.2,
127.0, 125.8, 123.7, 121.9, 121.5, 120.1, 120.0, 119.9, 119.3, 118.7,
118.3, 111.1, 109.2, 40.2, 32.7, 21.6; IR (KBr) v: 3409, 2930, 1603, 741
cm-1; HRMS (ESI) calcd. for C25H23N2 (M++H): 351.1861, found:
351.1849.
3-((1H-indol-3-yl)(phenyl)methyl)-5-bromo-1H-indole (3g)[6b]
: White
solid (70 mg, 87% yield); 1H NMR (400 MHz, CDCl3): δ = 7.78 (s, 1H),
7.75 (s, 1H), 7.60 (d, J = 1.4 Hz, 1H), 7.47-7.17 (m, 11H), 7.08 (t, J = 7.5
Hz, 1H), 6.59 (dd, J = 7.2, 1.9 Hz, 2H), 5.87 (s, 1H); 13C NMR (100 MHz,
CDCl3): δ = 143.6, 136.8, 135.3, 128.8, 128.7, 128.4, 127.0, 126.4, 124.9,
124.9, 123.7, 122.3, 122.1, 119.9, 119.4, 119.4, 119.3, 112.7, 112.6,
111.2, 40.1.
1-methyl-3-(phenyl(2-phenyl-1H-indol-3-yl)methyl)-1H-indole (3h)[13]
White solid (64 mg, 77% yield); H NMR (400 MHz, CDCl3): δ = 8.08 (s,
:
1
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10.1002/ejoc.201700088
European Journal of Organic Chemistry
FULL PAPER
3-((3-fluorophenyl)(1H-indol-3-yl)methyl)-1-methyl-1H-indole
(3o):
1459, 1332, 741 cm-1; HRMS (ESI) calcd. for C28H23N2 (M++H): 387.1861,
found: 387.1850.
White solid (62 mg, 87% yield); m.p. 90-92 oC; 1H NMR (400 MHz,
CDCl3): δ = 7.86 (s, 1H), 7.45-7.43 (m, 2H), 7.37 (t, J = 8.2 Hz, 2H), 7.32-
7.20 (m, 4H), 7.10-7.06 (m, 3H), 6.96 (t, J = 8.2 Hz, 1H), 6.69 (d, J = 1.0
Hz, 1H), 6.58 (s, 1H), 5.94 (s, 1H), 3.71 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ = 163.0 (d, JC-F = 243.4 Hz, 1C), 147.1 (d, JC-F = 6.7 Hz, 1C),
137.5, 136.7, 129.7 (d, JC-F = 8.1 Hz, 1C), 128.3, 127.4, 127.0, 124.5 (d,
JC-F = 2.4 Hz, 1C),, 123.6, 122.1, 121.6, 119.9, 119.8, 119.4, 119.2,
118.8, 117.5, 115.6 (d, JC-F = 21.4 Hz, 1C), 113.1 (d, JC-F = 21.1 Hz, 1C),
111.1, 109.2, 40.0, 32.7; IR (KBr) v: 3412, 2926, 1613, 742 cm-1; HRMS
(ESI) calcd. for C24H20N2F (M++H): 355.1611, found: 355.1617.
3-((2-ethynylphenyl)(1H-indol-3-yl)methyl)-2-phenyl-1H-indole (3u):
White solid (73 mg, 86% yield); m.p. 159-161 oC; 1H NMR (400 MHz,
CDCl3): δ = 7.91 (d, J = 12.0 Hz, 1H), 7.73 (d, J = 14.4 Hz, 1H), 7.48-
7.41 (m, 5H), 7.37-7.31 (m, 5H), 7.19-7.11 (m, 5H), 6.98-6.89 (m, 2H),
6.67-6.64 (m, 1H), 6.39 (s, 1H), 2.57 (s, 1H); 13C NMR (100 MHz, CDCl3):
δ =146.6, 136.8, 136.2, 135.6, 133.6, 133.1, 129.2, 128.8, 128.6, 128.4,
128.3, 127.7, 127.0, 126.0, 124.5, 122.2, 121.9, 121.7, 121.1, 120.0,
119.4, 119.2, 118.7, 114.1, 111.0, 110.9, 82.1, 81.6, 38.4; IR (KBr) v:
3412, 3055, 1456, 743 cm-1; HRMS (ESI) calcd. for C31H22N2Na (M++
Na): 445.1681, found: 445.1675.
3-((2-fluorophenyl)(1H-indol-3-yl)methyl)-1-methyl-1H-indole(3p):
White solid (66 mg, 93% yield); m.p.187-189 oC; 1H NMR (400 MHz,
CDCl3): δ = 7.89 (s, 1H), 7.45 (dd, J = 7.9, 4.4 Hz, 2H), 7.38 (d, J = 8.2
Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.28-7.20 (m, 4H), 7.14-7.02 (m, 4H),
6.73 (d, J = 1.6 Hz, 1H), 6.60 (s, 1H), 6.28 (s, 1H), 3.71 (s, 3H); 13C NMR
(100 MHz, CDCl3): δ = 160.7 (d, JC-F = 244.6 Hz, 1C), 137.5, 136.7,
131.1(d, JC-F = 14.0 Hz, 1C), 130.4 (d, JC-F = 4.1 Hz, 1C), 128.2, 127.8 (d,
JC-F = 8.2 Hz, 1C), 127.3, 126.9, 123.9 (d, JC-F = 3.5 Hz, 1C), 123.6,
3-((1H-indol-3-yl)(2-(phenylethynyl)phenyl)methyl)-1-methyl-1H-
indole (3v): White solid (58 mg, 66% yield); m.p. 202-204 oC; 1H NMR
(400 MHz, CDCl3): δ = 7.79 (s, 1H), 7.68-7.66 (m, 1H), 7.57-7.51 (m, 2H),
7.36-7.21 (m, 11H), 7.10-7.16 (m, 2H), 6.69-6.68 (m, 1H), 6.62-6.60 (m,
2H), 3.68 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 146.3, 137.5, 136.7,
132.3, 131.6, 128.7, 128.4, 128.4, 128.2, 128.1, 127.7, 127.3, 126.1,
123.7, 123.4, 122.8, 121.9, 121.5, 120.1, 120.0, 119.5, 119.3, 118.7,
117.6, 111.1, 109.1, 94.0, 88.4, 37.9, 32.7; IR (KBr) v: 3413, 3052, 1474,
738 cm-1; HRMS (ESI) calcd. for C32H25N2 (M++ H): 437.2018, found:
437.2030.
122.0, 121.6, 119.9, 119.8, 119.3, 118.8, 118.5, 116.7, 115.3 (d, JC-F
=
22.1 Hz, 1C), 111.1, 109.2, 32.7, 32.5 (d, JC-F = 3.8 Hz, 1C); IR (KBr) v:
3417, 3052, 1483, 741 cm-1; HRMS (ESI) calcd. for C24H20N2F (M++H):
355.1611, found: 355.1606.
3-((2-bromophenyl)(1H-indol-3-yl)methyl)-1-methyl-1H-indole
(3q)[5,13]: White solid (81 mg, 98% yield); 1H NMR (400 MHz, CDCl3): δ =
7.90 (s, 1H), 7.65 (dd, J = 7.9, 1.2 Hz, 1H), 7.44 (t, J = 7.2 Hz, 2H), 7.38
(d, J = 8.1 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.28-7.16 (m, 4H), 7.12 (dd,
J = 7.6, 1.7 Hz, 1H), 7.10-7.03 (m, 2H), 6.65 (d, J = 1.5 Hz, 1H), 6.51 (s,
1H), 6.35 (s, 1H), 3.70 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 144.1,
136.5, 136.3, 135.1, 133.0, 128.9, 128.8, 128.6, 128.5, 128.1, 127.9,
127.4, 125.9, 124.3, 121.9, 121.5, 119.9, 119.4, 119.3, 118.9, 115.6,
111.2, 111.0, 39.3.
3-((1H-indol-3-yl)(2-(phenylethynyl)phenyl)methyl)-1-methyl-2-
phenyl-1H-indole (3w): White solid (65 mg, 63% yield); m.p. 189-191
oC; 1H NMR (400 MHz, CDCl3): δ = 7.79 (s, 1H), 7.55 (dd, J = 7.5, 1.3 Hz,
1H), 7.47 (t, J = 8.3 Hz, 2H), 7.37 (d, J = 8.2 Hz, 1H), 7.29-7.11 (m, 14H),
7.00-6.89 (m, 4H), 6.61 (s, 1H), 6.38 (s, 1H), 3.59 (s, 3H); 13C NMR (100
MHz, CDCl3): δ = 146.4, 138.7, 137.4, 136.7, 132.4, 132.0, 131.5, 130.6,
129.3, 128.1, 128.0, 127.9, 127.8, 127.7, 127.5, 125.9, 123.6, 123.5,
122.8, 121.7, 121.2, 120.6, 120.0, 119.7, 119.2, 119.1, 114.2, 110.8,
109.2, 93.6, 88.4, 38.6, 30.9; IR (KBr) v: 3410, 3054, 1463, 742 cm-1;
HRMS (ESI) calcd. for C38H29N2 (M++ H): 513.2331, found: 513.2338.
3-((2,4-dichlorophenyl)(1H-indol-3-yl)methyl)-1-methyl-1H-indole
(3r)[13]: White solid (66 mg, 82% yield); 1H NMR (400 MHz, CDCl3): δ =
7.88 (s, 1H), 7.50 (d, J = 2.1 Hz, 1H), 7.46-7.34 (m, 4H), 729-7.20 (m,
4H), 7.21 (d, J = 8.5 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.12-7.06 (m, 2H),
1-benzyl-3-((1-methyl-1H-indol-3-yl)(phenyl)methyl)-2-phenyl-1H-
1
indole (3x): Pale-yellow solid (100 mg, 99% yield); m.p. 177-179 oC; H
NMR (400 MHz, CDCl3): δ = 7.45 (d, J = 7.8 Hz, 1H), 7.38-7.10 (m, 18H),
6.99-6.95 (m, 4H), 6.72 (s, 1H), 5.82 (s, 1H), 5.29 (s, 2H), 3.72 (s, 3H);
13C NMR (100 MHz, CDCl3): δ = 146.4, 138.7, 137.4, 136.7, 132.4, 132.0,
131.5, 130.6, 129.3, 128.1, 128.0, 127.9, 127.8, 127.7, 127.5, 125.9,
123.6, 123.5, 122.8, 121.7, 121.2, 120.6, 120.0, 119.7, 119.2, 119.1,
114.2, 110.8, 109.2, 93.6, 88.4, 38.6, 30.9; IR (KBr) v: 3409, 3052, 1463,
744 cm-1; HRMS (ESI) calcd. for C37H31N2 (M++ H): 503.2482, found:
503.2488.
6.64 (dd, J = 2.3, 0.8 Hz, 1H), 6.53 (s, 1H), 6.33 (s, 1H), 3.71 (s, 3H); 13
C
NMR (100 MHz, CDCl3): δ = 140.3, 137.5, 136.7, 134.6, 132.4, 131.2,
129.3, 128.4, 127.3, 127.0, 126.9, 123.8, 122.2, 121.7, 119.9, 119.8,
119.5, 118.9, 118.0, 116.2, 111.2, 109.3, 36.3, 32.8.
3-((1H-indol-3-yl)(naphthalen-1-yl)methyl)-1-methyl-1H-indole (3s):
White solid (73 mg, 95% yield); m.p. 227-229 oC; 1H NMR (400 MHz,
CDCl3): δ = 8.34 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.90- 7.88
(m, 1H), 7.60-7.28 (m, 11H), 7.15 (t, J = 7.1 Hz, 2H), 6.83 (s, 1H), 6.53 (s,
1H), 6.51 (s, 1H), 3.62 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 139.8,
137.5, 136.8, 134.0, 131.9, 129.0, 128.7, 127.5, 127.1, 127.0, 126.2,
125.9, 125.6, 125.3, 124.4, 124.4, 122.0, 121.5, 120.0, 119.9, 119.6,
119.3, 118.7, 117.7, 111.1, 109.2, 35.8, 32.7; IR (KBr) v: 3417, 3052,
1483, 741 cm-1; HRMS (ESI) calcd. for C28H23N2 (M++H): 387.1861,
found: 387.1874.
1-benzyl-3-(1-(5-bromo-1H-indol-3-yl)pentyl)-1H-indole
(3y):
Colorless oil (86 mg, 91% yield); 1H NMR (400 MHz, CDCl3): δ = 7.91 (s,
1H), 7.73 (d, J = 1.6 Hz, 1H), 7.58 (d, J = 7.9 Hz, 1H), 7.36-7.01 (m,
12H); 13C NMR (100 MHz, CDCl3): δ = 137.9, 137.0, 135.3, 128.9, 128.8,
127.7, 127.4, 126.5, 125.7, 124.6, 122.6, 122.3, 121.6, 120.3, 119.8,
119.1, 118.8, 112.5, 112.3, 109.7, 49.9, 35.3, 34.1, 30.5, 22.8, 14.1; IR
(KBr) v: 3411, 3054, 1461 cm-1; HRMS (ESI) calcd. for C28H2879BrN2
(M++ H): 471.1430, found: 471.1441.
3-((1H-indol-3-yl)(naphthalen-2-yl)methyl)-1-methyl-1H-indole(3t):
White solid (69 mg, 89% yield); m.p. 197-199 oC; 1H NMR (400 MHz,
CDCl3): δ = 7.90-7.88 (m, 1H), 7.85-7.83 (m, 2H), 7.79-7.76 (m, 2H), 7.60
(dd, J = 8.5, 1.5 Hz, 1H), 7.52-7.47 (m, 4H), 7.37 (t, J = 7.3 Hz, 2H),
7.32-7.26 (m, 2H), 7.08 (t, J = 7.4 Hz, 2H), 6.66 (d, J = 1.6 Hz, 1H), 6.59
(s, 1H), 6.14 (s, 1H), 3.68 (s, 3H); 13C NMR (100 MHz, CDCl3): δ = 141.9,
137.5, 136.7, 133.7, 132.4, 128.5, 128.0, 127.9, 127.8, 127.7, 127.6,
127.2, 126.8, 125.8, 125.4, 123.9, 122.0, 121.6, 120.2, 120.0, 119.6,
119.4, 118.8, 118.0, 111.1, 109.2, 40.4, 32.7; IR (KBr) v: 3406, 3052,
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (Grant Nos. 21502093, 21302096), the
Natural Science Foundation of Jiangsu Province (Grant Nos.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700088
European Journal of Organic Chemistry
FULL PAPER
[10] For recent representative examples on the use of alcohol pro-
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BK20150871, BK20130962), the Project Fund from the Priority
Academic Program Development of Jiangsu Higher Education
Institutions (PAPD) and Top-notch Academic Programs Project
of Jiangsu Higher Education Institutions (TAPP).
Keywords: 3,3’-Bis-indolylmethane • Friedel–Crafts alkylation •
Silica Gel • Heterogeneous Catalysis • Recyclable
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10.1002/ejoc.201700088
European Journal of Organic Chemistry
FULL PAPER
FULL PAPER
Bis-indolylmethanes synthesis
Y. Zou, C. Chen, X. Chen, X. Zhang*
W.Rao*
Page No. – Page No.
Silica gel-mediated Friedel–Crafts
alkylation of 3-indolylmethanols with
indoles: synthesis of unsymmetrical
3,3′-bis-indolylmethanes
Text for Table of Contents
Unsymmetrical 3,3′-Bis-indolylmethanes can be synthesized from easily accessible 3-indolylmethanols and indoles mediated
by silica gel under mild reaction conditions. The silica gel can be recovered and reused up to 10 times without apparent loss
of its activity.
This article is protected by copyright. All rights reserved.