Synthesis of bisindolylmethane, bispyrrolylmethane, and indolylpyrrolylmethane derivatives via reductive heteroarylation

Article abstract of DOI:10.1016/j.tet.2021.132338

An efficient and general reductive heteroarylation approach toward the synthesis of bisindolylmethane, bispyrrolylmethane, and indolylpyrrolylmethane derivatives has been developed. Thus, treatment of acylpyrrole or acylindole derivatives with indoles or pyrroles in the presence of a combination of sodium borohydride and acetic acid resulted in the formation of the title compounds in moderate to excellent isolated yields.

Full text of DOI:10.1016/j.tet.2021.132338

Tetrahedron 94 (2021) 132338
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of bisindolylmethane, bispyrrolylmethane, and
indolylpyrrolylmethane derivatives via reductive heteroarylation
Hang Zhou, Zhuo Huang, He Huang, Chuanjun Song*, Junbiao Chang**
College of Chemistry, Green Catalysis Center, Zhengzhou University, Zhengzhou, 450001, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and general reductive heteroarylation approach toward the synthesis of bisindolylmethane,
bispyrrolylmethane, and indolylpyrrolylmethane derivatives has been developed. Thus, treatment of
acylpyrrole or acylindole derivatives with indoles or pyrroles in the presence of a combination of sodium
borohydride and acetic acid resulted in the formation of the title compounds in moderate to excellent
isolated yields.
Received 6 May 2021
Received in revised form
6 July 2021
Accepted 6 July 2021
Available online 9 July 2021
© 2021 Elsevier Ltd. All rights reserved.
Keywords:
Reductive heteroarylation
Bisindolylmethane
Bispyrrolylmethane
Indolylpyrrolylmethane
1. Introduction
Alternatively, indole-3-carbinols can be prepared via reduction of
3-acylindoles with lithium aluminium hydride or Grignard addition
The 3,30-bisindolylmethanes (3,30-BIMs) and analogues consti-
tute an important class of alkaloids widely distributed in nature
(Fig. 1) [1,2]. These natural products exhibit a range of important
biological activities including anti-cancer [3], anti-oxidant [4], anti-
inflammatory [5], anti-angiogenic [6], and anti-neurodegenerative
[7] activities. BIM itself is a major metabolite of indole-3-carbinol
found in cruciferous vegetables such as broccoli and cauliflower,
and has recently been identified as a nonlipid-like GPR84 agonist
[8]. Due to the observed biological activities of BIMs and analogues,
a number of methods have been developed for their synthesis. The
condensation of indoles with aldehydes or ketones catalyzed by
Lewis acids is the most proven approach to access symmetrical
BIMs (Scheme 1) [9]. However, there still lacks an efficient and
general method to date toward the synthesis of unsymmetrical
BIMs. The initially formed alcohol product from the reaction of one
indole molecule and one aldehyde or ketone molecule react rapidly
with a second indole molecule to generate the symmetrical BIM
under the reaction conditions. Therefore, attempted isolation of the
alcohol intermediate is successful only in rare cases [10].
to indole-3-carbaldehydes [11]. However, syntheses of unsym-
metrical BIMs from these molecules are mostly limited to aryl-
substituted derivatives [12]. Occasionally, unsymmetrical BIMs
can be prepared from condensation of indoles with 3-
hydroxyaminoalkylindoles [13], 3-dimehylaminomethylindoles
[14], 3-methylthiomethylindoles [15], and 3-vinylindoles [16] in
the presence of transition metal or Lewis acid catalyst. The majority
of these methods suffered from drawbacks such as limited sub-
strate scope, use of expensive catalyst, and/or multiple reaction
steps to access the required substrates.
Direct reduction of unprotected indole-3-carbonyl compounds
with lithium aluminium hydride to 3-methylylindole has been re-
ported in the literature [17]. The carbonyl group is first reduced to
the corresponding alcohol, further reduction of which via 3-
methyleneindole intermediate generated the target molecule. We
therefore envisioned that if a suitable indole molecule capable of
capturing the 3-methyleneindole intermediate is introduced to the
reaction system, we can then develop an efficient and general
synthetic route toward BIMs. Obviously, this will require judicious
choice of reducing agent and reaction conditions to facilitate the
formation but avoid competitive reduction of the 3-
methyleneindole intermediate. Herein, we report a combination
of sodium borohydride and acetic acid mediated reductive heter-
oarylation approach for the synthesis of bisindolylmethanes, bis-
pyrrolylmethanes [18], as well as indolylpyrrolylmethanes under
* Corresponding author.
** Corresponding author.
E-mail addresses: chjsong@zzu.edu.cn (C. Song), changjunbiao@zzu.edu.cn
(J. Chang).
https://doi.org/10.1016/j.tet.2021.132338
0040-4020/© 2021 Elsevier Ltd. All rights reserved.

H. Zhou, Z. Huang, H. Huang et al.
Tetrahedron 94 (2021) 132338
studying the syntheses of a variety of indolylpyrrolylmethane,
bisindolylmethane, and bispyrrolylmethane derivatives via reduc-
tive heteroarylation and the results were collected in Table 2.
Synthesis of indolylpyrrolylmethane derivatives was inspected
first. Under the conditions, reaction of indole-3-carbaldehydes with
pyrroles proceeded as expected to yield indolylpyrrolylmethane
3a-c in good to excellent isolated yields. It was found that LiBH4
was a superior reductant to NaBH4 when 3-ketoindoles were used
as substrates. Under the joint effect of LiBH4 and AcOH, 3d and 3e
could be isolated in 74% and 71% yields, respectively. When 3-
trifluoroacetylindoles were used as substrates, the corresponding
trifluoromethylcarbinols resulting from reduction of the keto group
were the only products obtained. Fortunately, the desired indo-
lylpyrrolylmethanes 3f and 3g could be isolated in 74% and 65%
yields, respectively, when a combination of LiBH4 and TFA was
applied. Besides, indol-2-yl-pyrrol-2-ylmethane 3h could also be
obtained, albeit in moderate yield. Next, we turned our attention to
the synthesis of bisindolylmethanes. Starting from N-benzyl-
indole-3-carbaldehyde and substituted indoles, substituted indole-
3-carbaldehydes and indole, as well as substituted indole-3-
carbaldehydes and substituted indoles, a variety of unsymmetri-
cal bisindolylmethanes 3i-q were produced in moderate to good
isolated yields. Under the reaction conditions, the four natural
symmetrical bisindolylmethanes 3r-u could also be obtained
eventlessly. Finally, the synthesis of bispyrrolylmethanes was
explored. While 3w was obtained in moderate yield under the
optimized reaction conditions, synthesis of mono N-protected de-
rivatives 3v and 3y were best carried out using LiBH4 as reductant,
and 3x would require TFA as acid.
Fig. 1. Representative examples of naturally occurring 3,30-BIMs and analogues.
Scheme 1. Synthesis of symmetrical BIMs.
mild reaction conditions (Scheme 2).
To explore further the applicability of the method, we first
subjected a mixture of pyrrole 2a and an excess of indole-3-
carbaldehyde 1a to the reaction conditions. The reaction provided
bisindolylmethylpyrrole 7 in 38% isolated yield resulting from
double reductive heteroarylation (Scheme 3). Second, Vilsmeier-
Haack formylation of 3w provided pyrrolylmethyl-pyrrole-2-
carbaldehyde 8. Treatment of 8 with NaBH4 and AcOH in reflux-
ing DCM for 6 h gave hexahydroporphyrin 9 in 16% isolated yield.
To gain deep insight into the reaction mechanism, we carried
out the following control experiments (Scheme 4). First, no reaction
occurred when a mixture of 1a and 2a was treated with AcOH
which ruled out an alkylation-reduction sequence. Second, in the
absence of AcOH, NaBH4 alone could not reduce 1a in DCM. This, in
combination with the result of entry 9 in Table 1, implied that the
reductant might be sodium monocetoxyborohydride or sodium
diacetoxyborohydride. Third, under the reaction conditions, indole-
3-carbinol 4a could react with pyrrole to generate 3a in 47% iso-
lated yield. Based on the results obtained, a plausible mechanism is
depicted in Scheme 5. Reduction of 1 provided alcohol 4, which is
converted into 3-methyleneindole intermediate B and captured by
2 to provide 3.
2. Results and discussion
With N-benzylindole-3-carbaldehyde 1a and pyrrole 2a as
substrates, the results for the optimization of reaction conditions
were shown in Table 1. No desired indolylpyrrolylmethane 3a was
obtained when the mixture of 1a and 2a was treated with LiAlH4
(Entry 1) or NaBH4 (Entry 2) in refluxing THF. Instead, indole-3-
carbinol 4a was isolated in 80% and 85% yields, respectively.
Delightfully, 3a was isolated in 39% yield when a combination of
NaBH4 and AcOH was applied (Entry 3). No reaction occurred in the
presence of LiAlH4 and AcOH (Entry 4). The solvent was then
explored (Entries 5e8). With DCM as solvent under reflux, 3a could
be isolated in 90% yield (Entry 5). Other reductants such as NaB-
H(OAc)3, NaBH3CN, LiBH4 were tested (Entries 9e11). Among these,
only LiBH4 could provide 3a in a comparable but slightly lower
isolated yield (Entry 11 vs 5). Exploration of the effect of other
€
Bronsted and Lewis acid indicated that NaBH4 and AcOH remained
the best combination (Entries 12e17 vs 5). Varying the amount of
NaBH4 or AcOH (Entries 18e20), as well as lowering the reaction
temperature (Entries 21, 22) could not give a better result.
With the optimized conditions in hand, we embarked on
Scheme 2. Comparation of literature and present work.
2

H. Zhou, Z. Huang, H. Huang et al.
Tetrahedron 94 (2021) 132338
Table 1
Optimization of the reaction Conditions.
Entry
Solvent
Reductant (eq)
Acid (eq)
Temp
Yielda
3a
Yielda
4a
Yielda
5a
Yielda
6a
1
2
3
4
5
6
7
8
THF
THF
THF
THF
DCM
DCE
DCE
LiAlH4 (1.5)
NaBH4 (1.5)
NaBH4 (1.5)
LiAlH4 (1.5)
NaBH4 (1.5)
NaBH4 (1.5)
NaBH4 (1.5)
NaBH4 (1.5)
NaBH(OAc)3 (1.5)
NaBH3CN (1.5)
LiBH4 (1.5)
NaBH4 (1.5)
NaBH4 (1.5)
NaBH4 (1.5)
NaBH4 (1.5)
NaBH4 (1.5)
NaBH4 (1.5)
NaBH4 (2.0)
NaBH4 (1.5)
NaBH4 (1.5)
NaBH4 (1.5)
NaBH4 (1.5)
e
reflux
reflux
reflux
reflux
reflux
50 ꢀC
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
25 ꢀC
0%
0%
39%
0%
80%
85%
54%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
13%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
0%
10%
0%
0%
0%
0%
0%
0%
0%
0%
0%
e
AcOH (5)
AcOH (5)
AcOH (5)
AcOH (5)
AcOH (5)
AcOH (5)
AcOH (5)
AcOH (5)
AcOH (5)
TFA (5)
HCO2H (5)
Me2CHCO2H (5)
Me3CCO2H (5)
AlCl3 (5)
FeCl3 (5)
AcOH (5)
AcOH (6)
AcOH (4)
AcOH (5)
AcOH (5)
b
90%
82%
82%
78%
0%
66%
85%
0%
13%
82%
77%
0%
THF/DCMc
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
9b
10
11
12b
13
14
15
16b
17b
18
19
20
21
22
0%
86%
88%
76%
77%
45%
0
ꢀC
a
Isolate yield.
No reaction.
v/v ¼ 4:1.
b
c
3. Conclusions
combined organic extracts were washed successively with brine
(20 mL) and water (20 mL), then dried over anhydrous Na2SO4 and
evaporated in vacuo. The residue was purified by flash chroma-
tography, eluting at 20% ethyl acetate in petroleum ether to yield
the product 8 (0.27 g, 45%) as a pale yellow solid. 1H NMR (400 MHz,
In summary, we have developed a novel reductive hetero-
arylation approach toward the synthesis of bisindolylmethane,
bispyrrolylmethane, and indolylpyrrolylmethane derivatives under
mild reaction conditions. The substrate scope is wide and the
strategy is well adapted to the synthesis of nitrogen-containing
poly-heterocyclic systems.
CDCl3)
d 10.75 (s, 1H), 9.34 (s, 1H), 8.99 (s, 1H), 6.97e6.95 (m, 1H),
6.71e6.69 (m, 1H), 6.18e6.17 (m, 1H), 6.13 (q, J ¼ 2.8 Hz, 1H),
6.06e6.04 (m, 1H), 4.04, (s, 2H) ppm; 13C NMR (100 MHz, CDCl3)
d
178.8, 141.8, 132.2, 127.3, 124.3, 117.7, 110.5, 106.8, 26.7 ppm.
General Procedure I for the synthesis of compounds 3a-3c,
4. Experimental section
3i-3u, 3w, 7 and 9. In a 25 mL oven dried round-bottom flask, were
added aldehyde 1 (0.5 mmol, 1.0 equiv), pyrrole/indole 2 (1.5 mmol,
3.0 equiv), CH2Cl2 (10.0 mL), AcOH (2.5 mmol, 5.0 equiv) and NaBH4
(0.75 mmol, 1.5 equiv). The reaction mixture was heated to reflux
and monitored by TLC until the reaction was complete. The reaction
was cooled to room temperature and quenched with saturated
sodium bicarbonate (10 mL). The mixture was extracted with
CH2Cl2 (3 ꢁ 10 mL). The combined organic layers were dried over
anhydrous Na2SO4 and evaporated under vacuum. The residue was
purified by column chromatography.
General Procedure II for the synthesis of compounds 3d-3h,
3v, 3x and 3y. In a 25 mL oven dried round-bottom flask, were
added aldehyde/ketone 1 (0.5 mmol, 1.0 equiv), pyrrole/indole 2
(1.5 mmol, 3.0 equiv), CH2Cl2 (10.0 mL) and LiBH4 (2 mol/L in THF;
0.75 mmol, 1.5 equiv). The resulting mixture was heated to reflux
until 1 was fully consumed (monitored by TLC). AcOH was added
slowly via a syringe. After addition, the reaction mixture was stirred
at reflux until the reaction was complete (monitored by TLC) and
then cooled to room temperature. The reaction was quenched with
saturated sodium bicarbonate (10 mL) and extracted with CH2Cl2
(3 ꢁ 10 mL). The combined organic layers were dried over
4.1. General information
Melting points were determined on a hot-stage apparatus and
were uncorrected. Infrared spectra were obtained using an FT-IR
spectrometer. 1H and 13C NMR spectra were obtained on a
400 MHz spectrometer. Mass spectra were recorded on a Q-TOF
micro spectrometer. Flash column chromatography was performed
over silica gel 200e300 mesh.
Preparation of 5-((1H-pyrrol-2-yl)methyl)-1H-pyrrole-2-
carbaldehyde (8). [19] DMF (1.9 mL) was added to a dry round-
bottom flask and cooled to 0 ꢀC. POCl3 (0.46 g, 3.01 mmol) was
added dropwise and stirred for 10 min to yield the Vilsmeier re-
agent. In another dry round-bottom flask, dipyrromethane 3w
(0.50 g, 3.42 mmol) was dissolved in DMF (7.5 mL) under nitrogen
and cooled to 0 ꢀC. To the reaction mixture, the freshly prepared
Vilsmeier reagent was added dropwise and stirred at 0 ꢀC for 2 h. A
biphasic solution of ethyl acetate (50 mL) and saturated sodium
bicarbonate solution (50 mL) was added and stirred at room tem-
perature for 4 h. Ethyl acetate was separated and the aqueous layer
was extracted three times with ethyl acetate (3 ꢁ 20 mL). The
3

H. Zhou, Z. Huang, H. Huang et al.
Tetrahedron 94 (2021) 132338
Table 2
Substrate Scope.
anhydrous Na2SO4 and evaporated under vacuum. The residue was
purified by column chromatography.
3-((1H-Pyrrol-2-yl)methyl)-1-benzyl-1H-indole (3a). The title
compound was prepared according to the general procedure I by
stirring a mixture of 1-benzyl-1H-indole-3-carbaldehyde (118 mg,
0.5 mmol), 1H-pyrrole (101 mg, 1.5 mmol), CH2Cl2 (10 mL), AcOH
(150 mg, 2.5 mmol) and NaBH4 (29 mg, 0.75 mmol) at reflux for 4 h.
The crude product was purified by column chromatography on
silica gel (petroleum ether/ethyl acetate ¼ 15:1) to afford 3a
(129 mg, 90% yield) as a yellow oil; 1H NMR (400 MHz, CDCl3)
d 7.82
(s, 1H), 7.49 (d, J ¼ 8.0 Hz, 1H), 7.29e7.23 (m, 4H), 7.18e7.14 (m, 1H),
7.10e7.04 (m, 3H), 6.90 (s,1H), 6.56e6.54 (m,1H), 6.13 (q, J ¼ 2.8 Hz,
Scheme 3. Synthesis of bisindolylmethylpyrrole 7 and hexahydroporphyrin 9.
4

H. Zhou, Z. Huang, H. Huang et al.
Tetrahedron 94 (2021) 132338
6.92e6.90 (m, 2H), 6.74 (s, 1H), 6.64e6.63 (m, 1H), 6.14e6.12 (m,
1H), 6.01 (s,1H), 5.20 (s, 2H), 4.98 (s, 2H), 3.95 (s, 2H) ppm; 13C NMR
(100 MHz, CDCl3)
d 138.5, 137.8, 136.8, 131.7, 128.7, 128.6, 127.9,
127.5, 127.3, 126.7, 126.51, 126.49, 121.8, 121.4, 119.3, 119.1, 113.3,
109.6, 107.9, 107.0, 50.4, 49.9, 22.9 ppm; IR (neat): nmax ¼ 3024,
1604, 1451, 1350, 1175, 1072 cmꢂ1; HRMS (ESI-TOF) m/z: [M þ H]þ
C27H25N2 377.2012; found: 377.2010.
3-(1-(1H-Pyrrol-2-yl)ethyl)-1-benzyl-1H-indole (3d). The title
compound was prepared according to the general procedure II by
stirring
a mixture of 1-(1-benzyl-1H-indol-3-yl)ethan-1-one
(125 mg, 0.5 mmol), 1H-pyrrole (101 mg, 1.5 mmol), CH2Cl2
(10 mL) and LiBH4 (2 mol/L in THF; 0.38 mL, 0.75 mmol) at reflux for
5 h, then AcOH (150 mg, 2.5 mmol) was added and refluxed for a
further 2 h. The crude product was purified by column chroma-
tography on silica gel (petroleum ether/ethyl acetate ¼ 15:1) to
afford 3d (110 mg, 74% yield) as a yellow oil; 1H NMR (400 MHz,
CDCl3)
d
7.82 (s, 1H), 7.45 (d, J ¼ 7.6 Hz, 1H), 7.31e7.24 (m, 4H),
Scheme 4. Control experiments.
7.17e7.10 (m, 3H), 7.06e7.02 (m, 1H), 6.92 (s, 1H), 6.55 (q, J ¼ 2.4 Hz,
1H), 6.16 (q, J ¼ 2.8 Hz, 1H), 6.12e6.11 (m, 1H), 5.24 (s, 2H), 4.41 (q,
J ¼ 7.2 Hz, 1H), 1.70 (d, J ¼ 7.2 Hz, 3H) ppm; 13C NMR (100 MHz,
CDCl3)
d 137.6, 137.0, 136.6, 128.8, 127.7, 127.3, 126.9, 125.6, 122.0,
119.7, 119.3, 119.2, 116.2, 109.9, 108.0, 104.2, 50.1, 29.9, 21.4 ppm; IR
(neat): nmax ¼ 3432, 1465, 1243, 1027 cmꢂ1; HRMS (ESI-TOF) m/z:
[M þ H]þ C21H21N2 301.1699; found: 301.1698.
1-Benzyl-3-(phenyl(1H-pyrrol-2-yl)methyl)-1H-indole (3e).
The title compound was prepared according to the general pro-
cedure II by stirring a mixture of (1-benzyl-1H-indol-3-yl)(phenyl)
methanone (156 mg, 0.5 mmol), 1H-pyrrole (101 mg, 1.5 mmol),
CH2Cl2 (10 mL) and LiBH4 (2 mol/L in THF; 0.38 mL, 0.75 mmol) at
reflux for 1 h, then AcOH (150 mg, 2.5 mmol) was added and
refluxed for a further 1 h. The crude product was purified by col-
umn chromatography on silica gel (petroleum ether/ethyl
acetate ¼ 15:1) to afford 3e (113 mg, 71% yield) as a yellow oil; 1H
Scheme 5. Proposed reaction mechanism.
NMR (400 MHz, CDCl3) d 7.91 (s, 1H), 7.32e7.19 (m, 11H, overlapped
1H), 6.04 (s, 1H), 5.21 (s, 2H), 4.09 (s, 2H) ppm; 13C NMR (100 MHz,
with the peak of chloroform), 7.15e7.11 (m, 1H), 7.08e7.06 (m, 2H),
7.02e6.98 (m, 1H), 6.75 (s, 1H), 6.66e6.64 (m, 1H), 6.15 (q,
CDCl3)
d 137.6, 136.9, 131.1, 128.9, 128.1, 127.7, 126.9, 126.6, 122.1,
119.4, 119.3, 116.4, 113.0, 109.8, 108.3, 105.6, 50.0, 23.8 ppm; IR
(neat): nmax ¼ 3420, 1610, 1465, 1263, 1024 cmꢂ1; HRMS (ESI-TOF)
m/z: [M þ H]þ C20H19N2 287.1543; found: 287.1545.
J ¼ 2.8 Hz, 1H), 5.92e5.90 (m, 1H), 5.70 (s, 1H), 5.24 (s, 2H) ppm; 13
C
NMR (100 MHz, CDCl3)
d 143.3, 137.6, 137.0, 133.9, 128.8, 128.6,
128.5, 127.60, 127.58, 127.5, 126.60, 126.55, 122.0, 119.9, 119.4, 117.7,
116.6, 109.8, 108.2, 107.0, 50.1, 42.2 ppm; IR (neat): nmax ¼ 3420,
1464, 1241, 1043 cmꢂ1; HRMS (ESI-TOF) m/z: [M þ H]þ C26H23N2
363.1856; found: 363.1854.
3-((1H-Pyrrol-2-yl)methyl)-1-benzyl-6-chloro-1H-indole
(3b). The title compound was prepared according to the general
procedure I by stirring a mixture of 1-benzyl-6-chloro-1H-indole-
3-carbaldehyde (135 mg, 0.5 mmol),1H-pyrrole (101 mg,1.5 mmol),
CH2Cl2 (10 mL), AcOH (150 mg, 2.5 mmol) and NaBH4 (29 mg,
0.75 mmol) at reflux for 6 h. The crude product was purified by
column chromatography on silica gel (petroleum ether/ethyl
acetate ¼ 15:1) to afford 3b (143 mg, 89% yield) as a yellow oil; 1H
1-Benzyl-3-(2,2,2-trifluoro-1-(1H-pyrrol-2-yl)ethyl)-1H-
indole (3f). The title compound was prepared according to the
general procedure II by stirring a mixture of 1-(1-benzyl-1H-indol-
3-yl)-2,2,2-trifluoroethan-1-one (152 mg, 0.5 mmol), 1H-pyrrole
(101 mg, 1.5 mmol), CH2Cl2 (10 mL) and LiBH4 (2 mol/L in THF;
0.38 mL, 0.75 mmol) at reflux for 1 h, then TFA (285 mg, 2.5 mmol)
was added and refluxed for a further 12 h. The crude product was
purified by column chromatography on silica gel (petroleum ether/
ethyl acetate ¼ 15:1) to afford 3f (130 mg, 74% yield) as a yellow oil;
NMR (400 MHz, CDCl3)
d
7.85 (s, 1H), 7.37 (d, J ¼ 8.4 Hz, 1H),
7.32e7.26 (m, 3H), 7.24 (d, J ¼ 1.6 Hz, 1H), 7.10e7.07 (m, 2H), 7.02
(dd, J ¼ 8.4, 2.0 Hz, 1H), 6.91 (s, 1H), 6.61e6.59 (m, 1H), 6.13, (q,
J ¼ 2.8 Hz, 1H), 6.03e6.02 (m, 1H), 5.18 (s, 2H), 4.07 (s, 2H) ppm; 13
C
NMR (100 MHz, CDCl3) d 137.3, 137.0, 130.6, 128.9, 128.1, 127.8, 127.1,
1H NMR (400 MHz, CDCl3)
d
8.04 (s, 1H), 7.43 (d, J ¼ 8.0 Hz, 1H),
126.8, 126.6, 120.2, 120.1, 116.5, 113.3, 109.7, 108.4, 105.8, 50.0,
7.32e7.27 (m, 4H), 7.21e7.16 (m, 2H), 7.11e7.07 (m, 3H), 6.66 (m,
1H), 6.29 (s, 1H), 6.19e6.18 (m, 1H), 5.29 (s, 2H), 5.07 (q, J ¼ 9.2 Hz,
23.8 ppm; IR (neat): nmax ¼ 3429, 1606, 1466, 1024 cmꢂ1; HRMS
35
(ESI-TOF) m/z: [M þ H]þ C20
H ClN2 321.1153 found: 321.1154.
11
1H) ppm; 13C NMR (100 MHz, CDCl3)
d 137.0, 136.6, 128.9, 127.9,
1-Benzyl-3-((1-benzyl-1H-pyrrol-2-yl)methyl)-1H-indole
127.8, 127.3, 126.8, 126.2 (q, JC-F ¼ 278.6 Hz), 124.5 (q, JC-F ¼ 1.7 Hz),
122.5, 120.1, 119.4, 118.0, 110.1, 108.8, 108.7 (q, JC-F ¼ 1.1 Hz), 107.3 (q,
JC-F ¼ 1.7 Hz), 50.3, 41.4 (q, JC-F ¼ 29.9 Hz) ppm; IR (neat):
nmax ¼ 3431, 1466, 1248, 1150, 1093 cmꢂ1; HRMS (ESI-TOF) m/z:
[M þ H]þ C21H18F3N2 355.1417; found: 355.1418.
(3c). The title compound was prepared according to the general
procedure
I by stirring a mixture of 1-benzyl-1H-indole-3-
carbaldehyde (118 mg, 0.5 mmol), 1-benzyl-1H-pyrrole (236 mg,
1.5 mmol), CH2Cl2 (10 mL), AcOH (150 mg, 2.5 mmol) and NaBH4
(29 mg, 0.75 mmol) at reflux for 4 h. The crude product was purified
by column chromatography on silica gel (petroleum ether/ethyl
acetate ¼ 99:1) to afford 3c (119 mg, 64% yield) as a light yellow
3-(2,2,2-Trifluoro-1-(1H-pyrrol-2-yl)ethyl)-1H-indole
(3g).
The title compound was prepared according to the general pro-
cedure II by stirring a mixture of 2,2,2-trifluoro-1-(1H-indol-3-yl)
ethan-1-one (107 mg, 0.5 mmol), 1H-pyrrole (101 mg, 1.5 mmol),
CH2Cl2 (10 mL) and LiBH4 (2 mol/L in THF; 0.38 mL, 0.75 mmol) at
solid: mp 40e42 ꢀC; 1H NMR (400 MHz, CDCl3)
1H), 7.27e7.20 (m, 7H), 7.16e7.12 (m, 1H), 7.07e7.04 (m, 3H),
d
7.46 (d, J ¼ 8.0 Hz,
5

H. Zhou, Z. Huang, H. Huang et al.
Tetrahedron 94 (2021) 132338
reflux for 1 h, then TFA (285 mg, 2.5 mmol) was added and refluxed
for a further 12 h. The crude product was purified by column
chromatography on silica gel (petroleum ether/ethyl acetate ¼ 4:1)
to afford 3g (85 mg, 65% yield) as a yellow oil; 1H NMR (400 MHz,
carbaldehyde (118 mg, 0.5 mmol), 6-bromo-1H-indole (294 mg,
1.5 mmol), CH2Cl2 (10 mL), AcOH (150 mg, 2.5 mmol) and NaBH4
(29 mg, 0.75 mmol) at reflux for 6 h. The crude product was purified
by column chromatography on silica gel (petroleum ether/ethyl
acetate ¼ 10:1) to afford 3k (120 mg, 58% yield) as a light yellow
CDCl3)
d
8.16 (s, 1H), 8.03 (s, 1H), 7.42 (d, J ¼ 8.0 Hz, 1H), 7.37 (d,
J ¼ 8.4 Hz, 1H), 7.24e7.20 (m, 2H), 7.12e7.08 (m, 1H), 6.67e6.65 (m,
solid: mp 144e145 ꢀC; 1H NMR (400 MHz, DMSO)
d 10.97 (s, 1H),
1H), 6.30 (s, 1H), 6.19 (q, J ¼ 2.8 Hz, 1H), 5.07 (q, J ¼ 9.2 Hz, 1H) ppm;
7.55e7.53 (m, 2H), 7.46 (d, J ¼ 8.4 Hz, 1H), 7.38 (d, J ¼ 8.0 Hz, 1H),
7.29e7.22 (m, 5H), 7.16e7.14 (m, 2H), 7.08e7.04 (m, 2H), 6.97e6.94
(m, 1H), 5.34 (s, 2H), 4.15 (s, 2H) ppm; 13C NMR (100 MHz, DMSO)
13C NMR (100 MHz, CDCl3)
d
136.0, 126.5, 126.2 (q, JC-F ¼ 278.3 Hz),
124.5 (q, JC-F ¼ 1.8 Hz), 123.7 (q, JC-F ¼ 1.6 Hz), 122.8, 120.3, 119.1,
118.0, 111.4, 108.8,108.7 (q, JC-F ¼ 1.2 Hz),108.4 (q, JC-F ¼ 1.9 Hz), 41.4
(q, JC-F ¼ 29.9 Hz) ppm; IR (neat): nmax ¼ 3401, 1458, 1251, 1157,
1102 cmꢂ1; HRMS (ESI-TOF) m/z: [M þ H]þ C14H12F3N2 265.0947;
found: 265.0944.
d
139.0, 137.8, 136.7, 128.9, 128.2, 127.7, 127.3, 127.2, 126.6, 124.4,
121.6, 121.4, 120.9, 119.5, 118.9, 114.7, 114.4, 114.3, 114.1, 110.5, 49.3,
29.2 ppm; IR (neat): nmax ¼ 3418, 1607, 1463, 1327, 1092 cmꢂ1
;
79
HRMS (ESI-TOF) m/z: [M þ H]þ C24
H BrN2 415.08045; found:
20
2-((1H-Pyrrol-2-yl)methyl)-1-benzyl-1H-indole (3h). The title
compound was prepared according to the general procedure II by
stirring a mixture of 1-benzyl-1H-indole-2-carbaldehyde (118 mg,
0.5 mmol), 1H-pyrrole (101 mg, 1.5 mmol), CH2Cl2 (10 mL) and
LiBH4 (2 mol/L in THF; 0.38 mL, 0.75 mmol) at reflux for 1 h, then
TFA (285 mg, 2.5 mmol) was added and refluxed for a further 10 h.
The crude product was purified by column chromatography on
silica gel (petroleum ether/ethyl acetate ¼ 10:1) to afford 3h
(58 mg, 41% yield) as a yellow oil; 1H NMR (400 MHz, DMSO)
415.0803.
3-((1-Benzyl-1H-indol-3-yl)methyl)-1H-indole-5-
carbonitrile (3l). The title compound was prepared according to
the general procedure I by stirring a mixture of 1-benzyl-1H-
indole-3-carbaldehyde (118 mg, 0.5 mmol), 1H-indole-5-
carbonitrile (213 mg, 1.5 mmol), CH2Cl2 (10 mL), AcOH (150 mg,
2.5 mmol) and NaBH4 (29 mg, 0.75 mmol) at reflux for 4 h. The
crude product was purified by column chromatography on silica gel
(petroleum ether/ethyl acetate ¼ 10:1) to afford 3l (93 mg, 54%
yield) as a light yellow solid: mp 164e165 ꢀC; 1H NMR (400 MHz,
d
10.68 (s, 1H), 7.48e7.46 (m, 1H), 7.31e7.19 (m, 4H), 7.03e6.94 (m,
4H), 6.64e6.62 (m, 1H), 6.23 (d, J ¼ 0.8 Hz, 1H), 5.93 (q, J ¼ 2.8 Hz,
DMSO)
d
11.39 (s, 1H), 8.03e8.02 (m, 1H), 7.53 (dt, J ¼ 8.0, 0.8 Hz,
1H), 5.80e5.79 (m, 1H), 5.38 (s, 2H), 4.01 (s, 2H) ppm; 13C NMR
1H), 7.49 (dd, J ¼ 8.4, 0.8 Hz, 1H), 7.44 (d, J ¼ 2.4 Hz, 1H), 7.42 (s, 1H),
7.39e7.38 (m, 1H), 7.37e7.36 (m, 1H), 7.31e7.27 (m, 2H), 7.24e7.16
(m, 3H), 7.06e7.02 (m, 1H), 6.96e6.92 (m, 1H), 5.36 (s, 2H), 4.19 (s,
(100 MHz, DMSO)
d 139.9, 138.8, 137.4, 129.0, 128.02, 127.96, 127.5,
126.7, 121.0, 120.1, 119.6, 117.3, 110.2, 107.9, 106.3, 100.9, 46.3,
25.8 ppm; IR (neat): nmax ¼ 3245, 1603, 1461, 1314, 1025 cmꢂ1
;
2H) ppm; 13C NMR (100 MHz, DMSO)
d 139.0, 138.6, 136.7, 128.9,
HRMS (ESI-TOF) m/z: [M
þ
H]þ C20H19N2 287.1543; found:
128.1, 127.7, 127.40, 127.38, 127.3, 126.0, 124.9, 124.0, 121.6, 121.4,
119.5, 118.9, 115.7, 114.0, 113.1, 110.5, 100.5, 49.3, 21.1 ppm; IR (neat):
nmax ¼ 3352, 2217, 1614, 1467, 1355, 1175 cmꢂ1; HRMS (ESI-TOF) m/
z: [M þ H]þ C25H20N3 362.1652; found: 362.1654.
287.1544.
3-((1H-Indol-3-yl)methyl)-1-benzyl-1H-indole (3i). The title
compound was prepared according to the general procedure I by
stirring a mixture of 1-benzyl-1H-indole-3-carbaldehyde (118 mg,
0.5 mmol), 1H-indole (176 mg, 1.5 mmol), CH2Cl2 (10 mL), AcOH
(150 mg, 2.5 mmol) and NaBH4 (29 mg, 0.75 mmol) at reflux for 5 h.
The crude product was purified by column chromatography on
silica gel (petroleum ether/ethyl acetate ¼ 10:1) to afford 3i
3-((1H-Indol-3-yl)methyl)-5-bromo-1H-indole (3m). [14b]
The title compound was prepared according to the general pro-
cedure
I
by stirring
a
mixture of 5-bromo-1H-indole-3-
carbaldehyde (112 mg, 0.5 mmol), 1H-indole (176 mg, 1.5 mmol),
CH2Cl2 (10 mL), AcOH (150 mg, 2.5 mmol) and NaBH4 (29 mg,
0.75 mmol) at reflux for 7 h. The crude product was purified by
column chromatography on silica gel (petroleum ether/ethyl
acetate ¼ 4:1) to afford 3m (125 mg, 77% yield) as a yellow solid:
(120 mg, 72% yield) as a yellow oil; 1H NMR (400 MHz, CDCl3)
d 7.64
(s, 1H), 7.60 (t, J ¼ 6.4 Hz, 2H), 7.25e7.11 (m, 7H), 7.08e7.00 (m, 4H),
6.83 (s, 1H), 6.80e6.79 (m, 1H), 5.14 (s, 2H), 4.21 (s, 2H) ppm; 13C
NMR (100 MHz, CDCl3)
d
138.0, 136.9, 136.5, 128.8, 128.3, 127.6,
mp 153e154 ꢀC; 1H NMR (400 MHz, DMSO)
d 10.98 (s, 1H), 10.76 (s,
127.5, 126.7, 126.6, 122.3, 121.9, 121.7, 119.6, 119.3, 119.2, 119.0, 115.7,
114.8,111.2,109.8, 49.9, 21.3 ppm; IR (neat): nmax ¼ 3412,1612,1453,
1332, 1010 cmꢂ1; HRMS (ESI-TOF) m/z: [M þ Na]þ C24H20N2Na
359.1519; found: 359.1520.
1H), 7.66 (s, 1H), 7.50 (d, J ¼ 7.6 Hz, 1H), 7.33e7.28 (m, 2H), 7.23 (s,
1H), 7.17e7.12 (m, 2H), 7.03 (t, J ¼ 7.2 Hz, 1H), 6.91 (t, J ¼ 7.2 Hz, 1H),
4.11 (s, 2H) ppm; 13C NMR (100 MHz, DMSO)
d 136.9, 135.5, 129.5,
127.5, 125.0, 123.6, 123.3, 121.4, 121.3, 119.1, 118.5, 114.5, 114.2, 113.8,
1-Benzyl-3-((6-methoxy-1H-indol-3-yl)methyl)-1H-indole
(3j). The title compound was prepared according to the general
111.8, 111.2, 21.2 ppm; IR (neat): nmax ¼ 3461, 3389, 1453,
1083 cmꢂ1; HRMS (ESI-TOF) m/z: [M þ Na]þ C17
H BrN2Na
13
79
procedure
I
by stirring
a
mixture of 1-benzyl-1H-indole-3-
347.0154; found: 347.0155.
carbaldehyde (118 mg, 0.5 mmol), 6-methoxy-1H-indole (220 mg,
1.5 mmol), CH2Cl2 (10 mL), AcOH (150 mg, 2.5 mmol) and NaBH4
(29 mg, 0.75 mmol) at reflux for 4 h. The crude product was purified
by column chromatography on silica gel (petroleum ether/ethyl
acetate ¼ 10:1) to afford 3j (100 mg, 55% yield) as a yellow oil; 1H
3-((1H-Indol-3-yl)methyl)-1H-indole-5-carbonitrile (3n). The
title compound was prepared according to the general procedure I
by stirring a mixture of 3-formyl-1H-indole-5-carbonitrile (85 mg,
0.5 mmol), 1H-indole (176 mg, 1.5 mmol), CH2Cl2 (10 mL), AcOH
(150 mg, 2.5 mmol) and NaBH4 (29 mg, 0.75 mmol) at reflux for
10 h. The crude product was purified by column chromatography
on silica gel (petroleum ether/ethyl acetate ¼ 4:1) to afford 3n
(115 mg, 85% yield) as a yellow solid: mp 195e196 ꢀC; 1H NMR
NMR (400 MHz, CDCl3)
d
7.73 (s, 1H), 7.62 (d, J ¼ 7.6 Hz, 1H), 7.46 (d,
J ¼ 8.8 Hz, 1H), 7.26e7.22 (m, 4H), 7.15 (td, J ¼ 8.0, 1.2 Hz, 1H),
7.09e7.05 (m, 3H), 6.89 (s, 1H), 6.82e6.81 (m, 2H), 6.75 (dd, J ¼ 8.8,
2.4 Hz, 1H), 5.22 (s, 2H), 4.20 (s, 2H), 3.83 (s, 3H) ppm; 13C NMR
(400 MHz, DMSO)
d 11.37 (s, 1H), 10.79 (s, 1H), 8.06 (s, 1H),
(100 MHz, CDCl3)
d
156.4, 137.9, 137.2, 136.8, 128.7, 128.3, 127.5,
7.53e7.48 (m, 2H), 7.39e7.37 (m, 2H), 7.32 (d, J ¼ 8.0 Hz, 1H),
126.7, 126.5, 122.0, 121.7, 121.0, 119.9, 119.5, 118.9, 115.7, 114.8, 109.7,
109.1, 94.6, 55.7, 49.9, 21.3 ppm; IR (neat): nmax ¼ 3388, 1626, 1462,
1159, 1026 cmꢂ1; HRMS (ESI-TOF) m/z: [M þ H]þ C25H23N2O
367.1805; found: 367.1802.
1-Benzyl-3-((6-bromo-1H-indol-3-yl)methyl)-1H-indole
(3k). The title compound was prepared according to the general
7.26e7.25 (m,1H), 7.04, (t, J ¼ 7.2 Hz,1H), 6.92 (t, J ¼ 7.2 Hz,1H), 4.17
(s, 2H) ppm; 13C NMR (100 MHz, DMSO)
d 138.5, 136.9, 127.5, 127.4,
125.9, 124.9, 124.0, 123.4, 121.4, 121.3, 119.1, 118.6, 116.1, 114.0, 113.1,
111.8, 100.5, 21.0 ppm; IR (neat): nmax ¼ 3389, 2221, 1614, 1426,
1222, 1096 cmꢂ1; HRMS (ESI-TOF) m/z: [M þ H]þ C18H14N3
272.1182; found: 272.1184.
procedure
I
by stirring
a
mixture of 1-benzyl-1H-indole-3-
6-Chloro-3-((5-methyl-1H-indol-3-yl)methyl)-1H-indole
6

H. Zhou, Z. Huang, H. Huang et al.
Tetrahedron 94 (2021) 132338
(3o). The title compound was prepared according to the general
(150 mg, 2.5 mmol) and NaBH4 (29 mg, 0.75 mmol) at reflux for 7 h.
The crude product was purified by column chromatography on
silica gel (petroleum ether/ethyl acetate ¼ 4:1) to afford 3s (90 mg,
66% yield) as a light yellow solid: mp 115e117 ꢀC; 1H NMR
procedure
I by stirring a mixture of 6-chloro-1H-indole-3-
carbaldehyde (90 mg, 0.5 mmol), 5-methyl-1H-indole (197 mg,
1.5 mmol), CH2Cl2 (10 mL), AcOH (150 mg, 2.5 mmol) and NaBH4
(29 mg, 0.75 mmol) at reflux for 6 h. The crude product was purified
by column chromatography on silica gel (petroleum ether/ethyl
acetate ¼ 4:1) to afford 3o (85 mg, 80% yield) as a light yellow solid:
(400 MHz, DMSO)
J ¼ 8.0 Hz, 2H), 7.03 (d, J ¼ 2.4 Hz, 2H), 6.86 (dd, J ¼ 8.0, 1.6 Hz, 2H),
4.05 (s, 2H), 2.33 (s, 6H) ppm; 13C NMR (100 MHz, DMSO)
135.2,
d 10.59 (s, 2H), 7.30e7.29 (m, 2H), 7.20 (d,
d
mp 116e117 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.50e7.79 (m, 2H), 7.49
127.9, 126.8,123.3, 122.8, 118.7, 114.1, 111.5, 21.8, 21.4 ppm; IR (neat):
nmax ¼ 3417, 3353, 1457, 1418, 1220, 1087 cmꢂ1; HRMS (ESI-TOF) m/
z: [M þ Na]þ C19H18N2Na 297.1362; found: 297.1361.
(d, J ¼ 8.4 Hz, 1H), 7.37e7.36 (m, 1H), 7.30e7.29 (m, 1H), 7.23 (d,
J ¼ 8.4 Hz, 1H), 7.05e7.00 (m, 2H), 6.88e6.85 (m, 2H), 4.16 (t,
J ¼ 1.2 Hz, 2H), 2.42 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3)
d
136.8,
Bis(5-bromo-1H-indol-3-yl)methane. (3t). [20] The title com-
pound was prepared according to the general procedure I by stir-
ring a mixture of 5-bromo-1H-indole-3-carbaldehyde (112 mg,
0.5 mmol), 5-bromo-1H-indole (294 mg, 1.5 mmol), CH2Cl2 (10 mL),
AcOH (150 mg, 2.5 mmol) and NaBH4 (29 mg, 0.75 mmol) at reflux
for 10 h. The crude product was purified by column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate ¼ 4:1) to afford 3t
(136 mg, 67% yield) as a light yellow solid: mp 175e176 ꢀC; 1H NMR
134.8, 128.5, 127.8, 127.7, 126.2, 123.6, 122.9, 122.4, 120.1, 119.9,
118.8, 116.0, 114.8, 111.0, 110.8, 21.6, 21.1 ppm; IR (neat): nmax ¼ 3417,
1618, 1453, 1218, 1088 cmꢂ1; HRMS (ESI-TOF) m/z: [M þ H]þ
35
C18
H ClN2 295.0997; found: 295.0994.
16
3-((6-Chloro-1H-indol-3-yl)methyl)-1H-indole-5-
carbonitrile (3p). The title compound was prepared according to
the general procedure I by stirring a mixture of 6-chloro-1H-indole-
3-carbaldehyde (90 mg, 0.5 mmol), 1H-indole-5-carbonitrile
(214 mg, 1.5 mmol), CH2Cl2 (10 mL), AcOH (150 mg, 2.5 mmol)
and NaBH4 (29 mg, 0.75 mmol) at reflux for 10 h. The crude product
was purified by column chromatography on silica gel (petroleum
ether/ethyl acetate ¼ 3:1) to afford 3p (65 mg, 43% yield) as a light
(400 MHz, DMSO)
J ¼ 8.8 Hz, 2H), 7.27 (d, J ¼ 2.0 Hz, 2H), 7.16e7.13 (dd, J ¼ 8.8, 2.0 Hz,
2H), 4.10 (s, 2H) ppm; 13C NMR (100 MHz, DMSO)
135.5, 129.4,
d
11.00 (s, 2H), 7.66 (d, J ¼ 1.6 Hz, 2H), 7.31 (d,
d
125.1, 123.7, 121.4, 114.1, 113.9, 111.2, 21.0 ppm; IR (neat):
nmax ¼ 3433, 1449, 1215, 1092 cmꢂ1; HRMS (ESI-TOF) m/z:
[M ꢂ C6H8BrN þ H]þ C9H779BrN 207.9756; found: 207.9755.
yellow solid: mp 160e161 ꢀC; 1H NMR (400 MHz, DMSO)
d 11.39 (s,
1H), 10.95 (s, 1H), 8.05 (s, 1H), 7.52e7.48 (m, 2H), 7.40e7.37 (m, 3H),
Bis(6-chloro-1H-indol-3-yl)methane (3u). The title compound
was prepared according to the general procedure I by stirring a
mixture of 6-chloro -1H-indole-3-carbaldehyde (90 mg, 0.5 mmol),
6-chloro-1H-indole (227 mg, 1.5 mmol), CH2Cl2 (10 mL), AcOH
(150 mg, 2.5 mmol) and NaBH4 (29 mg, 0.75 mmol) at reflux for
10 h. The crude product was purified by column chromatography
on silica gel (petroleum ether/ethyl acetate ¼ 4:1) to afford 3u
(111 mg, 71% yield) as a light yellow solid: mp 187e188 ꢀC; 1H NMR
7.31e7.30 (m, 1H), 6.94 (dd, J ¼ 8.4, 2.0 Hz, 1H), 4.17 (s, 2H) ppm; 13
C
NMR (100 MHz, DMSO)
d 138.5, 137.2, 127.4, 126.3, 126.1, 126.0,
124.8, 124.6, 124.0, 121.4, 120.4, 118.9, 115.8, 114.4, 113.1, 111.4, 100.6,
20.9 ppm; IR (neat): nmax ¼ 3413, 2218, 1615, 1453, 1221, 1089 cmꢂ1
;
35
HRMS (ESI-TOF) m/z: [M þ H]þ C18
H ClN3 306.0793; found:
13
306.0795.
6-Chloro-3-((6-methoxy-1H-indol-3-yl)methyl)-1H-indole
(3q). The title compound was prepared according to the general
procedure by stirring mixture of 6-chloro-1H-indole-3-
(400 MHz, DMSO)
J ¼ 1.6 Hz, 2H), 7.20 (d, J ¼ 2.0 Hz, 2H), 6.93 (dd, J ¼ 8.4, 2.0 Hz, 2H),
4.11 (s, 2H) ppm; 13C NMR (100 MHz, DMSO)
137.2, 126.3, 126.0,
d
10.92 (s, 2H), 7.49 (d, J ¼ 8.4 Hz, 2H), 7.36 (d,
I
a
carbaldehyde (90 mg, 0.5 mmol), 6-methoxy-1H-indole (221 mg,
1.5 mmol), CH2Cl2 (10 mL), AcOH (150 mg, 2.5 mmol) and NaBH4
(29 mg, 0.75 mmol) at reflux for 10 h. The crude product was pu-
rified by column chromatography on silica gel (petroleum ether/
ethyl acetate ¼ 4:1) to afford 3q (105 mg, 68% yield) as a light
d
124.4, 120.4, 118.9, 114.7, 111.4, 21.1 ppm; IR (neat): nmax ¼ 3435,
1610, 1449, 1331, 1228, 1088 cmꢂ1; HRMS (ESI-TOF) m/z: [M þ Na]þ
35
C17
H Cl2N2Na 337.0270; found: 337.0267.
12
2-((1H-Pyrrol-2-yl)methyl)-1-benzyl-1H-pyrrole (3v). The ti-
tle compound was prepared according to the general procedure II
by stirring mixture of 1-benzyl-1H-pyrrole-2-carbaldehyde
yellow solid: mp 175e177 ꢀC; 1H NMR (400 MHz, DMSO)
d 10.88 (s,
1H), 10.54 (s, 1H), 7.49 (d, J ¼ 8.4 Hz, 1H), 7.35e7.33 (m, 2H), 7.17 (d,
J ¼ 2.4 Hz, 1H), 6.99 (d, J ¼ 2.4 Hz, 1H), 6.92 (dd, J ¼ 8.4, 2.0 Hz, 1H),
6.82 (d, J ¼ 2.0 Hz,1H), 6.57 (dd, J ¼ 8.4, 2.0 Hz,1H), 4.07 (s, 2H), 3.73
a
(93 mg, 0.5 mmol), 1H-pyrrole (101 mg, 1.5 mmol), CH2Cl2
(10 mL) and LiBH4 (2 mol/L in THF; 0.38 mL, 0.75 mmol) at reflux for
1 h, then AcOH (150 mg, 2.5 mmol) was added and refluxed for a
further 2 h. The crude product was purified by column chroma-
tography on silica gel (petroleum ether/ethyl acetate ¼ 10:1) to
afford 3v (90 mg, 76% yield) as a brown solid: mp 40e42 ꢀC; 1H
(s, 3H) ppm; 13C NMR (100 MHz, DMSO)
d 155.8, 137.5, 137.2, 126.4,
126.0, 124.4, 122.0, 121.8, 120.5, 119.6, 118.8, 115.1, 114.3, 111.3, 108.7,
94.9, 55.6, 21.3 ppm; IR (neat): nmax ¼ 3415, 1620, 1453, 1158 cmꢂ1
;
HRMS (ESI-TOF) m/z: [M þ H]þ C18
H ClN2O 311.0946; found:
35
16
311.0944.
NMR (400 MHz, CDCl3) d 7.77 (s, 1H), 7.31e7.22 (m, 3H), 6.92 (d,
Di(1H-indol-3-yl)methane (3r). [20] The title compound was
prepared according to the general procedure I by stirring a mixture
of 1H-indole-3-carbaldehyde (73 mg, 0.5 mmol), 1H-indole
(176 mg, 1.5 mmol), CH2Cl2 (10 mL), AcOH (150 mg, 2.5 mmol) and
NaBH4 (29 mg, 0.75 mmol) at reflux for 5 h. The crude product was
purified by column chromatography on silica gel (petroleum ether/
ethyl acetate ¼ 10:1) to afford 3r (75 mg, 61% yield) as a light yellow
J ¼ 7.2 Hz, 2H), 6.64 (t, J ¼ 2.4 Hz, 1H), 6.61e6.60 (m, 1H), 6.13 (t,
J ¼ 3.2 Hz,1H), 6.10 (q, J ¼ 2.8 Hz, 1H), 6.04e6.03 (m, 1H), 5.95e5.93
(m, 1H), 4.90 (s, 2H), 3.81 (s, 2H) ppm; 13C NMR (100 MHz, CDCl3)
d
138.3, 129.8, 129.0, 128.8, 127.5, 122.1, 116.9, 108.40, 108.36, 107.2,
105.9, 50.4, 25.5 ppm; IR (neat): nmax ¼ 3372, 1561, 1453, 1312,
1022 cmꢂ1; HRMS (ESI-TOF) m/z: [M þ H]þ C16H17N2 237.1386;
found: 237.1384.
solid: mp 166e167 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.86 (s, 2H),
Di(1H-pyrrol-2-yl)methane (3w). [21] The title compound was
prepared according to the general procedure I by stirring a mixture
of 1H-pyrrole-2-carbaldehyde (48 mg, 0.5 mmol), 1H-pyrrole
(101 mg, 1.5 mmol), CH2Cl2 (10 mL), AcOH (150 mg, 2.5 mmol) and
NaBH4 (29 mg, 0.75 mmol) at reflux for 4 h. The crude product was
purified by column chromatography on silica gel (petroleum ether/
ethyl acetate ¼ 10:1) to afford 3w (36 mg, 49% yield) as a light
7.63e7.61 (m, 2H), 7.36e7.34 (m, 2H), 7.21e7.17 (m, 2H), 7.11e7.07
(m, 2H), 6.92e6.91 (m, 2H), 4.24 (s, 2H) ppm; 13C NMR (100 MHz,
CDCl3)
d 136.4, 127.6, 122.2, 121.9, 119.25, 119.19, 115.7, 111.1,
21.2 ppm; IR (neat): nmax ¼ 3391, 1453, 1087, 1006 cmꢂ1; HRMS
(ESI-TOF) m/z: [M þ Na]þ C17H14N2Na 269.1049; found: 269.1047.
Bis(5-methyl-1H-indol-3-yl)methane (3s). The title compound
was prepared according to the general procedure I by stirring a
mixture of 5-methyl-1H-indole-3-carbaldehyde (80 mg, 0.5 mmol),
5-methyl-1H-indole (197 mg, 1.5 mmol), CH2Cl2 (10 mL), AcOH
yellow solid: mp 73e74 ꢀC; 1H NMR (400 MHz, CDCl3)
d
7.59 (s, 2H),
6.58e6.56 (m, 2H), 6.14 (q, J ¼ 2.8 Hz, 2H), 6.03e6.01 (m, 2H), 3.89
(s, 2H) ppm; 13C NMR (100 MHz, CDCl3)
129.2, 117.5, 108.3, 106.6,
d
7

H. Zhou, Z. Huang, H. Huang et al.
Tetrahedron 94 (2021) 132338
26.4 ppm; IR (neat): nmax ¼ 3328, 1561, 1439, 1328, 1181, 1024 cmꢂ1
;
Declaration of competing interest
HRMS (ESI-TOF) m/z: [M ꢂ H2 þ H]þ C9H9N2 145.0760; found:
145.0759.
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
2,2'-(2,2,2-Trifluoroethane-1,1-diyl)bis(1H-pyrrole) (3x). [22]
The title compound was prepared according to the general pro-
cedure II by stirring a mixture of 2,2,2-trifluoro-1-(1H-pyrrol-2-yl)
ethan-1-one (82 mg, 0.5 mmol), 1H-pyrrole (101 mg, 1.5 mmol),
CH2Cl2 (10 mL) and LiBH4 (2 mol/L in THF; 0.38 mL, 0.75 mmol) at
reflux for 1 h, then TFA (285 mg, 2.5 mmol) was added and refluxed
for a further 7 h. The crude product was purified by column chro-
matography on silica gel (petroleum ether/ethyl acetate ¼ 10:1) to
afford 3x (85 mg, 80% yield) as a light yellow solid: mp 65e66 ꢀC;
Acknowledgement
We are grateful to NSFC-Henan (U1804283) and Postgraduate
Education Reform and Quality Improvement Project of Henan
Province (YJS2021KC03) for financial support.
1H NMR (400 MHz, CDCl3)
6.25e6.24 (m, 2H), 6.22e6.20 (m, 2H), 4.83 (q, J ¼ 4.8 Hz, 1H) ppm;
13C NMR (100 MHz, CDCl3)
d 8.08 (s, 2H), 6.76e6.74 (m, 2H),
Appendix A. Supplementary data
d
125.2 (q, JC-F ¼ 278.1 Hz), 122.9 (q, JC-
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2021.132338.
¼ 1.7 Hz), 118.7, 109.1 (q, JC-F ¼ 0.9 Hz), 108.9, 43.3 (q, JC-
F
¼ 30.0 Hz) ppm; IR (neat): nmax ¼ 3365, 1326, 1243, 1160, 1097,
F
1042 cmꢂ1; HRMS (ESI-TOF) m/z: [M ꢂ HF þ H]þ C10H9F2N2
195.0728; found: 195.0916.
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