Directly Bridging Indoles to 3,3′-Bisindolylmethanes by Using Carboxylic Acids and Hydrosilanes under Mild Conditions

Article abstract of DOI:10.1002/asia.201800766

A straightforward Lewis acid-promoted protocol for 3,3′-bisindolylmethanes (BIMs) synthesis by reductive alkylation of indoles at the C3 position with carboxylic acids in the presence of hydrosilane was developed for the first time. Instead of aldehydes, more readily available, stable, and easy-to-handle carboxylic acids have been employed as alternative alkylating agents. As an efficient organocatalyst, B(C₆F₅)₃ enables the reductive alkylation of various substituted indole derivatives with carboxylic acids with up to 98 % yield at room temperature and under neat conditions. This metal-free strategy offers an alternative approach for the direct functionalization of indoles to BIMs with carboxylic acids and such protocol allows selective reduction of carboxylic acid to aldehyde in combination with C?C bond formation.

Full text of DOI:10.1002/asia.201800766

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Accepted Article
Title: Directly Bridging Indoles to 3,3'-Bisindolylmethanes Using
Carboxylic Acids and Hydrosilanes under Mild Conditions
Authors: Liang-Nian He, Chang Qiao, Xiao-Fang Liu, Hong-Chen Fu,
Hao-Peng Yang, and Zhi-Bo Zhang
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10.1002/asia.201800766
Chemistry - An Asian Journal
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Directly Bridging Indoles to 3,3’-Bisindolylmethanes Using
Carboxylic Acids and Hydrosilanes under Mild Conditions
Chang Qiao,[a] Xiao-Fang Liu,[a] Hong-Chen Fu,[a] Hao-Peng Yang,[a] Zhi-Bo Zhang,[a] Liang-Nian
He*[a],[b]
Abstract: A straightforward Lewis acid-promoted protocol for 3,3’-
bisindolylmethanes (BIMs) synthesis via reductive alkylation of
indoles at C3 position with carboxylic acids in the presence of
hydrosilane was developed for the first time. Instead of aldehydes,
more readily available, stable, and facilely handling carboxylic acids
have been employed as alternative alkylating agents. As an efficient
organocatalyst, B(C6F5)3 enables the reductive alkylation of various
substituted indole derivatives with carboxylic acids with up to 98%
yield at room temperature and under neat conditions. This metal-free
strategy offers an alternative approach for the direct functionalization
of indoles to BIMs with carboxylic acids and such protocol allows
selective reduction of carboxylic acid to aldehyde in combination with
C-C bond formation.
bridged BIMs have been successful, being ascribed to the
limited availability of alkylating reagents. In addition, ether is
another alternative alkylating reagent[9] and an excellent
example of visible-light-induced BIMs synthesis with ether has
been very recently reported, though mainly focusing on N-
carboxamide substituted indoles.[10]
Compared with aldehydes, carboxylic acids are more readily
available, stable, and facilely handling. In this context, carboxylic
acids have recently been employed as promising alkylating
agents for the reductive C-N coupling to replace conventional
aldehyde used in the reductive amination.[11] Therefore, we
speculated that carboxylic acid could also act as alkylating agent
to run reductive C-C bond coupling. To the best of our
knowledge, direct synthesis of BIM from indole with carboxylic
acid has not been explored and only a related example for the
cobalt-catalyzed alkylation of indole with carboxylic acid was
described in which BIM was only identified as a byproduct (yield
< 5%).[12] Notably, as a typical carboxylic acid, formic acid can
be prepared from CO2 through catalytic hydrogenation.[13] In this
perspective, reductive alkylation using formic acid as C1 synthon
can be considered as indirect utilization of CO2, thus providing
an alternative synthetic method and promising protocol for CO2
utilization.[11e]
Introduction
Alkylated indole scaffold has been found widely in bioactive
natural products and therapeutic drug molecules.[1] Therefore,
the synthesis of readily functionalized indole derivatives turns
out to be important. Among these strategies for derivatization of
indoles, alkylation at indole C3 position has successfully
performed with Friedel-Crafts type reaction,[2] allylic alkylation,[3]
or reductive alkylation.[4] As a typical product of the indole
alkylation at C3 position, 3,3’-bisindolylmethanes (BIMs) present
various important biological and pharmacological activities, such
as anti-inflammatory, antibacterial, analgesic and anticancer
properties.[5] Due to the relevant pharmacological properties of
BIMs, the development of alternative methodologies for the
synthesis of BIMs-based molecules continues to be highly
interesting in pharmaceutical discovery, organic synthesis and
catalysis. [6]
The traditional method for directly preparing BIMs depends on
the Friedel-Crafts reaction between indole and aldehyde or
ketone in the presence of Bronsted acid or Lewis acid.[6] Despite
being a practical transformation, the use of carbonyl compounds
especially aldehydes limits its applicability as aldehydes are
often air sensitive or require complicated synthetic process. To
replace sensitive aldehyde, several alternative strategies for
direct BIMs synthesis have been developed which employ
alcohol (restricting to benzyl alcohols and methanol) or tertiary
amine (acting as methylene donor in the presence of oxidants)[8]
as alkylating agent. However, only benzyl- and methylene-
Scheme 1. Direct BIMs synthesis from indoles using a) carbonyl compounds
or b) carboxylic acids as alkylating reagents.
On the other hand, the boron-based Lewis acid as a catalyst
has been widely employed in various reactions.[11c, 14] Notably,
boron can selectively catalyze the reduction of carboxylic acid
to aldehyde,[15] as well as Friedel-Crafts alkylation of indole with
aldehyde to BIM.[16] Inspired by these precedents, it is
envisioned that the Lewis acid catalyst might mediate reductive
alkylation of indole with carboxylic acid to obtain BIM through
stringing both selective reduction of carboxylic acid and C-C
coupling together. Herein we showed that Lewis acid B(C6F5)3
can promote the formation of BIM using indole and carboxylic
acid in the presence of triethylsilane under room temperature
and neat conditions. This organocatalysis can extend to a wide
[a]
[b]
C. Qiao, X.-F. Liu, H.-C. Fu, H.-P. Yang, Z.-B. Zhang, Prof. L. N. He
State Key Laboratory and Institute of Elemento-Organic Chemistry,
College of Chemistry, Nankai University
Tianjin 300071, China
E-mail: heln@nankai.edu.cn
Prof. L. N. He Department Collaborative Innovation Center of
Chemical Science and Engineering (Tianjin)
Tianjin 300071, China
Supporting information for this article is given via a link at the end of
the document.
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10.1002/asia.201800766
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scope of indoles and carboxylic acids, generating BIMs in good
to excellent yields. The work presented here provides the first
general and straightforward catalytic protocol for preparing BIMs
using carboxylic acids as alkylating reagents.
also proved to be a viable substrate, although 2-substitution
seemed to have a detrimental effect (entry 13 vs. 1). Notably,
“free” indole could deliver the desired BIM in good yield with the
N site untouched (entry 14); and both fluoro and methoxyl
substituent suppressed the reaction (entries 15 and 16). The
functionalized indoles bearing a removable N-protecting group
e.g. Boc or Ts. were inactive (entries 17, 18) probably because
the electron-withdrawing group weakens the nucleophilicity of
Results and Discussion
indoles, thus suppressing the coupling reaction.
Table 1. Catalyst screening and condition optimization for reductive alkylation
of 1-methylindole using formic acid[a]
Our research started with the reductive alkylation of 1-
methylindole 1a with formic acid as shown in Table 1. Inspired
by precedent boron-catalyzed reactions vide supra, several
boron-based Lewis acid catalysts were initially tested with
Et3SiH as reductant and CH3CN as solvent at room temperature.
Triethylborane and boronic acids were inactive (entries 1-3,
table 1). Delightedly, Lewis acid with large steric hindrance i.e.
B(C6F5)3 showed nice activity for this reductive alkylation, and
desired
alkylated
product
i.e.
bis(1-methyl-1H-indol-3-
yl)methane 1c was successfully obtained (entry 4). In addition,
the common metal-based Lewis acids failed in promoting this
reaction (entries 5-7). The unique catalytic activity of B(C6F5)3
may be attributed to its ability to form an frustrated Lewis pair
with carboxyl group to activate the hydrosilane,11c which derives
from both Lewis acid center i.e. electrophilic borane and large
steric hindrance of B(C6F5)3. Subsequently, various hydrosilanes
were investigated for the reductive alkylation of 1a with formic
acid (entries 4 and 8-12). PMHS, Ph3SiH and PhSiH3 were
found to be inactive (entries 8-10). (EtO)3SiH, Ph2SiH2 showed
poor reactivity (entries 11-12), and Et3SiH with moderate
reactivity gave the best result among hydrosilanes in this study
(entry 4). The suitable reactivity of hydrosilanes seems to play
an important role in the reductive alkylation reaction.
Hydrosilanes with poor reactivity failed to reduce formic acid,
while hydrosilanes with strong one may result in over-reduction
to alcohols.[15] Furthermore, the amount of formic acid and
hydrosilane were investigated in detail, and the optimal amount
of formic acid and Et3SiH compared to 1a were 2 and 4.5
equivalents, respectively (entries 4 and 13-15). Polar solvent
acetonitrile was a more suitable solvent (entry 4) compared with
ethers and arenes (entries 16-19). This solvent effect may be
attributed to the stability of the intermediate in polar solvent. It is
notable that nearly quantitative yield of 1c could be obtained
under neat condition (entry 20), which may be because HCOOH
provides a relatively polar environment for the reaction.
With the optimal reaction conditions in hand, we investigated
the scope of this novel catalytic protocol using formic acid and
various indoles (Table 2). Various N-substituted indoles were
successfully methylated in good to excellent yields (entries 1-7).
Even N-dodecyl- and N-benzylindoles were still viable
substrates (entries 3-4). Remarkably, excellent functional-group
tolerance was observed. for the three-membered ring, alkenyl
and hydroxyl groups (entries 5-7). Indoles with the substituent
on the phenyl ring were further investigated and the electronic
effect has significant effect on the reaction outcome (entries 8-
12). 6-chloro- and 6-bromo-N-methylindoles were methylenated
smoothly in high yields (entries 9-10). By comparison, the
substituted indoles with strong electron-withdrawing (6-F) and
donating groups (6-Me, 6-MeO) gave the desired BIMs with
lower yields (entries 8, 11 and 12). Besides, 2-substituted indole
Entry
1[b]
2
Catalyst
Et3B
Hydrosilane
Et3SiH
Et3SiH
Et3SiH
Et3SiH
Et3SiH
Et3SiH
Et3SiH
PMHS
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
benzene
THF
1c Yield (%)
trace
trace
-
A
3
B
4
B(C6F5)3
Co(OAc)2
Cu(OAc)2
Zn(OAc)2
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
82[c]
-
5
6
-
7
-
8
-
9
Ph3SiH
PhSiH3
(EtO)3SiH
Ph2SiH2
Et3SiH
Et3SiH
Et3SiH
Et3SiH
Et3SiH
Et3SiH
Et3SiH
Et3SiH
trace
-
10
11
12
13[d]
14[e]
15[f]
16
17
18
19
20
7
9
29
56
43
25
45
45
66
92[c]
toluene
Et2O
-
[a] Reaction conditions: 1a (0.5 mmol, 65.6 mg), catalyst (0.01 mmol, 2 mol%),
HCOOH (46.0 mg, 1.0 mmol), hydrosilane (Si-H 2.25 mmol), 4 h, rt, 1 mL
CH3CN as solvent. Yields are determined by 1H NMR using 1,1,2,2-
tetrachloroethane as an internal standard. [b] Et3B in a THF solution (1.0
mol•L-1). [c] Isolated yield. [d] HCOOH (0.5 mmol), Et3SiH (2.25 mmol). [e]
HCOOH (1.5 mmol), Et3SiH (2.25 mmol). [f] HCOOH (1.0 mmol), Et3SiH (3.0
mmol).
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Table 2. Reductive alkylation of various indoles with formic acid.[a]
combining reductive coupling and reduction of alkenyl group in
acrylic acid (entry 3). Importantly, the reaction with 2,2,2-
trifluoroacetic acid afforded the trifluoromethyl-containing BIM
which is a useful building block in the pharmaceutical industry in
moderate yield (entry 5). For the coupling of 1-methylindole with
2-phenylacetic acid or hydrocinnamic acid, the corresponding
BIM products were obtained in excellent yields (entries 6-7),
while para-fluoro substituent seemed to have a detrimental
effect on the yield (entry 6 vs. 8). Notably, sulfur-containing
carboxylic acid is amenable substrate (entry 9). However,
aromatic benzoic acids gave low to moderate yields (entries 10-
12), being ascribed to the undesired over-reduction of carboxylic
acid leading to the alcohol formation (see Supporting
Information).
Table 3. Reductive coupling of 1-methylindole with various carboxylic acids.[a]
[a] Reaction conditions: substrate (0.5 mmol), B(C6F5)3 (5.1 mg, 2 mol%),
HCOOH (46.0 mg, 1.0 mmol), Et3SiH (261.6 mg, 2.25 mmol), 4 h, rt, neat.
Yields are determined by 1H NMR using 1,1,2,2-tetrachloroethane as an
internal standard. [b] Isolated yields are given in parentheses. [c] De-
benzylation of 4c was unsuccessful.
[a] Reactions were performed with 1a (0.5 mmol, 65.6 mg), B(C6F5)3 (5.1 mg,
2 mol%), RCOOH (1.0 mmol) and Et3SiH (261.6 mg, 2.25 mmol), 4 h, rt, neat.
Yields are determined by 1H NMR using 1,1,2,2-tetrachloroethane as an
internal standard. [b] Isolated yields are given in parentheses.
Furthermore, the coupling of two different indoles to access
unsymmetrical BIM 1e was successfully realized, though with a
mediocre 21% yield as shown in Scheme 2.
Several control experiments were conducted to gain further
understanding about the reaction mechanism (Scheme 3). Since
it has shown that Lewis acid B(C6F5)3 could efficiently catalyze
the hydrosilylation of carboxylic acid to produce aldehyde
equivalent i.e. disilyl acetal under similar condition,[15]
phenylacetaldehyde was tested as possible intermediate for the
coupling reaction in this study. As a result, nearly quantitative
yield of desired BIM was obtained (eqn. 1). When the reaction
was conducted in the presence of phenylacetic acid, that is, an
acidic condition identical to standard reaction condition, the BIM
product was also attained with 82% yield even without the
catalyst (eqn. 2). Those observations suggested a feasible
pathway involving Lewis acid-mediated reduction of the
carboxylic acid to the aldehyde and subsequent Friedel-Crafts
reaction between indole and aldehyde. In addition, carboxylic
acid not only acts as a reactant, but also promotes the Friedel-
Crafts reaction between indole and aldehyde.[17]
Scheme 2. Reductive coupling of two different indoles to access
unsymmetrical BIMs.
After evaluating the scope of indole, we also studied the
scope of carboxylic acids to explore the generality of this novel
method as shown in Table 3. Aliphatic carboxylic acids afforded
the corresponding BIMs in moderate to good yields (entries 1–5).
It is interesting that the reaction using acrylic acid gave 4d 1-
methyl-3-(1-(1-methyl-1H-indol-3-yl)butyl)-1H-indole,
product
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Conclusions
In conclusion, a general and straightforward synthesis of BIMs
via the Lewis acid B(C6F5)3–promoted reductive coupling of two
indoles at C3 position with carboxylic acid as alkylating reagent
and hydrosilane as reductant is presented in this work. This
novel protocol complements the previously described BIMs
synthesis through Friedel-Crafts reaction between indole and
carbonyl compound. Advantageously, the use of carboxylic acid
expands the potential molecular diversity introduced in the
indole scaffold, due to the readily availability, stability, and easy-
handling of this class of compounds. Such Lewis acid catalysis
ingeniously realizes selective reduction of carboxylic acid
coupled with C-C bond construction and may make contributions
to enlarging the scope of accessible products direct from
carboxylic acids by generating not only new C−C but also C−O
and C−N bonds.
Scheme 3. Control experiments to explore possible intermediate.
On the basis of the above results in this study and previous
reports,[15, 18] a plausible mechanism for the present B(C6F5)3-
catalyzed reductive coupling between indole and carboxylic acid
was proposed, and the pathway was depicted in Scheme 4. At
first, the carboxylic acid reacts with triethylsilane to afford the
silyl ester I coupled with release of gaseous hydrogen. On the
other hand, the hydrosilane is activated by Lewis acid B(C6F5)3
through reversible coordination to the Si-H bond generating the
adduct II. Subsequent transfer of Et3Si+ of II to the carboxyl
oxygen of I delivers the ion pair III. Further hydride transfer from
Experimental Section
General Information
-
HB(C6F5)3 to the carbonyl carbon forms the disilyl acetal IV or
The starting materials were commercially available and were used
without further purification. Solvents were dried and degassed by
standard methods before use. The products were isolated by column
chromatography on silica gel (200-300 mesh) using petroleum ether and
ethyl acetate mixtures. 1H NMR and 13C NMR spectra were recorded on
a Bruker AV400 spectrometer at ambient temperature. All chemical shifts
are reported relative to tetramethylsilane (0.0 ppm for 1H NMR in CDCl3)
and d-solvent peaks (77.16 ppm for 13C NMR, CDCl3), respectively. 1H
NMR peaks are labeled as singlet (s), doublet (d), triplet (t), and multiplet
(m). The coupling constants J are reported in Hertz (Hz). Mass spectra
were recorded on a Shimadzu GCMS-QP2010 equipped with a RTX-
5MS capillary column at an ionization voltage of 70 eV. The data are
given as mass units per charge (m/z). High resolution mass spectrometry
was conducted using a Varian 7.0 T FTICR-MS by ESI technique.
aldehyde under acidic condition and regenerates the catalyst, i.e.
B(C6F5)3. Finally, successive nucleophilic attack of indole
towards IV/aldehyde and V, respectively affords the desired
product BIM catalyzed by Lewis acid. In the catalytic route,
B(C6F5)3 activates triethylsilane via interaction between Lewis
acid center i.e. electrophilic borane and hydride of triethylsilane,
thus achieving reduction of carboxylic acid. On the other hand,
B(C6F5)3 can promote the Friedel-Crafts coupling between indole
and aldehyde efficiently. In a word, Lewis acid B(C6F5)3
elaborately combines both reduction and C-C coupling together.
General Procedure A for N-Alkyl Indoles Synthesis
To a solution of indole (5 mmol) in DMSO (20 mL) was added KOH (10.0
mmol) and alkyl bromide (10.0 mmol). The reaction mixture was stirred
and monitored by TLC. Upon completion, the reaction mixture was
quenched by water (20 mL) and extracted by ethyl acetate (3×30 mL).
Combined organic phase was dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was then purified by chromatography
on silica gel with eluent of petroleum ether/ethyl acetate.
General Procedure B for N-Methyl Indoles Synthesis
To a solution of substituted indole (5 mmol) in DMSO (20 mL) was added
KOH (10.0 mmol) and iodomethane (10.0 mmol). The reaction mixture
was stirred and monitored by TLC. Upon completion, the reaction mixture
was quenched by water (20 mL) and extracted by ethyl acetate (3×30
mL). Combined organic phase was dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was then purified by chromatography
on silica gel with eluent of petroleum ether/ethyl acetate.
Bridging Indole with Formic Acid
Scheme 4. Possible reaction mechanism for the B(C6F5)3-catalyzed reductive
coupling of indole to BIM with carboxylic acid.
A 10 mL round bottom flask was charged with B(C6F5)3 (0.01 mmol, 5.1
mg), Et3SiH (2.25 mmol, 261.6 mg) and HCOOH (1.0 mmol, 38 μL)
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successively. A bubble gas generation was observed when HCOOH was
added. N-alkylindole (0.5 mmol) were introduced subsequently. The
reaction mixture was stirred for 4 h at room temperature. After completion,
42.0 mg 1,1,2,2-tetrachroroethane were added as an internal standard,
and then a sample was taken to determine the yield through 1H NMR. To
acquire the pure products, the mixture was purified by silica gel column
chromatography (petroleum ether/ethyl acetate mixtures) to give the
corresponding 3,3’-bisindolylmethane. All reactions were performed at
least twice to ensure reproducibility.
128.4, 127.6, 126.8, 126.6, 121.7, 119.6, 119.0, 115.0, 109.7, 77.5, 77.2,
76.8, 50.00, 21.4. HRMS (ESI): C31H26N2Na+ for [M + Na]+ calculated
449.1988, found 449.1990.
Bis(1-cyclopropylmethyl-1H-indol-3-yl)methane (5c) Oil, 1H NMR (400
MHz, CDCl3) δ 7.62 (d, J = 7.8 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 7.19 (t,
J = 7.6 Hz, 2H), 7.07 (t, J = 7.4 Hz, 2H), 6.95 (s, 2H), 4.25 (s, 2H), 3.90
(d, J = 6.5 Hz, 4H), 1.22 (dd, J = 14.5, 8.2 Hz, 2H), 0.55 (d, J = 7.2 Hz,
4H), 0.30 (d, J = 4.0 Hz, 4H). 13C NMR (101 MHz, CDCl3) δ 136.7, 128.2,
126.0, 121.4, 119.6, 118.6, 114. 3, 109.4, 50.5, 21.3, 11.5, 4.1. GC-MS
(EI, 70eV) m/z (%) 354.2100 (100.00), 299.1551 (63.62), 353.2022
(50.87), 257.1084 (26.47), 355.2137 (25.85), 130.0656 (25.40), 245.1083
(20.31).
Bridging Indole with Carboxylic Acid
A 10 mL round bottom flask was charged with B(C6F5)3 (0.01 mmol, 5.1
mg), Et3SiH (2.25 mmol, 261.6 mg) and RCOOH (1.0 mmol) successively.
A bubble gas generation might be observed when RCOOH was added.
N-methylindole (0.5 mmol, 62 μL) were introduced subsequently. The
reaction mixture was stirred for 4 h at room temperature. Follow-up
processes were similar to those of bridging indole with formic acid vide
supra. All reactions were performed at least twice to ensure
reproducibility.
Bis(1-allyl-1H-indol-3-yl)methane (6c)[19] Milky oil, 1H NMR (400 MHz,
CDCl3) δ 7.61 (d, J = 7.9 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 7.19 (dd, J =
11.2, 4.0 Hz, 2H), 7.12-7.03 (m, 2H), 6.84 (s, 2H), 5.95 (ddt, J = 17.0,
10.4, 5.3 Hz, 2H), 5.15 (dd, J = 10.2, 1.3 Hz, 2H), 5.06 (dd, J = 17.1, 1.4
Hz, 2H), 4.65 (dt, J = 5.3, 1.5 Hz, 4H), 4.23 (s, 2H). 13C NMR (101 MHz,
CDCl3) δ 136.7, 133.9, 128.3, 126.2, 121.6, 119.6, 118.9, 117.1, 114.7,
109.6, 48.8, 21.2. HRMS (ESI): C23H22N2Na+ for [M + Na]+ calculated
349.1675, found 349.1678.
General Procedure for Control Experiments
Bis(1-(ethan-1-ol)-1H-indol-3-yl)methane (7c) Yellow oil, 1H NMR (400
MHz, CDCl3) δ 7.61 (d, J = 7.9 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 7.19 (dd,
J = 11.2, 4.0 Hz, 2H), 7.08 (t, J = 7.4 Hz, 2H), 6.88 (s, 2H), 4.20 (s, 2H),
4.13 (t, J = 5.2 Hz, 4H), 3.81 (t, J = 5.3 Hz, 4H), 1.71 (s, 2H). 13C NMR
(101 MHz, CDCl3) 13C NMR (101 MHz, CDCl3) δ 136.8, 128.3, 126.5,
121.8, 119.6, 119.1, 114.9, 109.5, 62.1, 48.6, 21.1. HRMS (ESI):
C21H22N2O2Na+ for [M + Na]+ calculated 357.1573, found 357.1575.
(1) To a solution of B(C6F5)3 (0.01 mmol, 5.1 mg), phenylacetaldehyde (1
mmol, 120.2 mg) in 1 mL CH3CN and N-methylindole (0.5 mmol, 62 μL)
were introduced subsequently. (2) To a solution of phenylacetaldehyde
(1 mmol, 120.2 mg) and phenylacetic acid (1.0 mmol, 136.2 mg) in 1 mL
CH3CN and N-methylindole (0.5 mmol, 62 μL) were introduced
subsequently. The reaction mixture was stirred for
4 h at room
temperature. After completion, 42.0 mg 1,1,2,2-tetrachroroethane were
added as an internal standard, and then a sample was taken to
determine the yield through 1H NMR. All reactions were performed at
least twice to ensure reproducibility.
Bis(1-methyl-6-fluoro-1H-indol-3-yl)methane (8c) Yellow solid, mp 111
- 112 oC. 1H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 8.6, 5.4 Hz, 2H),
6.93 (dd, J = 9.9, 2.2 Hz, 2H), 6.87-6.77 (m, 2H), 6.73 (s, 2H), 4.13 (s,
2H), 3.61 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 160.1 (d, J = 237.2 Hz),
137.3 (d, J = 12.0 Hz), 127.3 (d, J = 3.6 Hz), 124.5 (s), 120.1 (d, J = 10.1
Hz), 114.5 (s), 107.4 (d, J = 24.5 Hz), 95.6 (d, J = 26.1 Hz), 32.8 (s), 21.1
(s). HRMS (ESI): C19H16F2N2K+ for [M + K]+ calculated 349.0913, found
349.0915.
Bis(1-methyl-1H-indol-3-yl)methane (1c)[19] White solid (63.0 mg, 92%),
mp 118 - 119 oC. 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 7.9 Hz, 2H),
7.29 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 7.2 Hz, 2H), 7.09 (t, J = 7.4 Hz, 2H),
6.79 (s, 2H), 4.22 (s, 2H), 3.70 (s, 6H). 13C NMR (101 MHz, CDCl3) δ
137.3, 128.1, 127.1, 121.5, 119.4, 118.7, 114.5, 109.2, 32.7, 21.1. HRMS
(ESI): C19H18N2Na+ for [M + Na]+ calculated 297.1362, found 297.1368.
Bis(1-methyl-6-chloro-1H-indol-3-yl)methane (9c) White solid, mp 125
- 126 oC. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.4 Hz, 2H), 7.26 (d, J
= 1.7 Hz, 2H), 7.02 (dd, J = 8.4, 1.8 Hz, 2H), 6.74 (s, 2H), 4.12 (s, 2H),
3.64 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 137.6, 127.7, 126.5, 120.2,
119.4, 114.4, 109.3, 32.7, 20.9. HRMS (ESI): C19H16Cl2N2K+ for [M + K]+
calculated 381.0322, found 381.0325.
Bis(1-ethyl-1H-indol-3-yl)methane (2c)[19] Colorless liquid, 1H NMR
(400 MHz, CDCl3) δ 7.62 (d, J = 7.9 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H),
7.23-7.17 (m, 2H), 7.11-7.03 (m, 2H), 6.86 (s, 2H), 4.23 (s, 2H), 4.09 (q,
J = 7.3 Hz, 4H), 1.40 (t, J = 7.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ
136.2, 128.2, 125.4, 121.3, 119.5, 118.6, 114.4, 109.3, 40.8, 21.2, 15.6.
HRMS (ESI): C21H22N2Na+ for [M + Na]+ calculated 325.1675, found
325.1680 HRMS (ESI): C21H22N2K+ for [M + K]+ calculated 341.1415,
found 341.1409.
Bis(1-methyl-6-bromo-1H-indol-3-yl)methane (10c) White solid, mp
158 - 159 oC. 1H NMR (400 MHz, CDCl3) δ 7.41 (dd, J = 9.4, 4.9 Hz, 4H),
7.15 (dd, J = 8.4, 1.6 Hz, 2H), 6.72 (s, 2H), 4.12 (s, 2H), 3.64 (s, 6H). 13C
NMR (101 MHz, CDCl3) δ 138.1, 127.6, 126.8, 122.0, 120.6, 115.4,
114.4, 112.4, 32.8, 20.9. HRMS (ESI): C19H16Br2N2K+ for [M + K]+
calculated 468.9312, found 468.9315.
Bis(1-dodecyl-1H-indol-3-yl)methane (3c) Colorless oil, 1H NMR (400
MHz, CDCl3) δ 7.60 (d, J = 7.9 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 7.21-
7.14 (m, 2H), 7.10-7.00 (m, 2H), 6.82 (s, 2H), 4.22 (s, 2H), 4.00 (t, J = 7.2
Hz, 4H), 1.82-1.70 (m, 4H), 1.25 (d, J = 12.9 Hz, 36H), 0.88 (t, J = 6.9 Hz,
6H). 13C NMR (101 MHz, CDCl3) δ 136.5, 128.2, 126.2, 121.3, 119.5,
118.5, 114.2, 109.4, 46.3, 32.1, 30.5, 29.8, 29.8, 29.7, 29.7, 29.5, 29.4,
27.2, 22.8, 21.3, 14.3. HRMS (ESI): C41H62N2K+ for [M + K]+ calculated
605.4805, found 605.4808. HRMS (ESI): C41H62N2Na+ for [M + Na]+
calculated 621.4545, found 621.4547.
Bis(1-methyl-6-methyl-1H-indol-3-yl)methane (11c) White solid, mp
110 - 111 oC. 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J = 8.0 Hz, 2H), 7.07
(s, 2H), 6.91 (dd, J = 8.0, 0.7 Hz, 2H), 6.69 (s, 2H), 4.16 (s, 2H), 3.64 (s,
6H), 2.49 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 137.7, 131.3, 126.5,
126.0, 120.4, 119.1, 114.4, 109.2, 32.6, 22.0, 21.1. HRMS (ESI):
C21H22N2Na+ for [M + Na]+ calculated 325.1675, found 325.1678.
Bis(1-benzyl-1H-indol-3-yl)methane (4c)[19] White solid, mp 109 - 110
oC. 1H NMR (400 MHz, CDCl3) 7.62 (d, J = 7.8 Hz, 2H), 7.30 – 7.19 (m,
8H), 7.15 (t, J = 7.6 Hz, 2H), 7.11 – 7.03 (m, 6H), 6.91 (s, 2H), 5.23 (s,
4H), 4.26 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 138.0, 137.0, 128.8,
Bis(1-methyl-6-methoxyl-1H-indol-3-yl)methane (12c) White solid, mp
107 - 109 oC. 1H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 7.9, 1.3 Hz, 2H),
6.77-6.71 (m, 4H), 6.66 (s, 2H), 4.13 (s, 2H), 3.86 (s, 6H), 3.62 (s, 6H).
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13C NMR (101 MHz, CDCl3) δ 156.4, 137.9, 125.9, 122.5, 120.1, 114.5,
108.5, 92.9, 55.8, 32.7, 21.2. HRMS (ESI): C21H22N2O2Na+ for [M + Na]+
calculated 357.1573, found 357.1577.
0.85 (t, J = 6.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 137.4, 127.7,
126.3, 121.3, 119.9, 119.4, 118.5, 109.2, 36.6, 34.0, 32.8, 32.1, 29.9,
29.4, 28.6, 22.8, 14.3. HRMS (ESI): C26H32N2Na+ for [M + Na]+ calculated
395.2458, found 395.2462.
Bis(1,2-dimethyl-1H-indol-3-yl)methane (13c)[19] White solid, mp 161 -
1
164 oC. H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 7.9 Hz, 2H), 7.20 (d, J
1,1-Bis(1-methyl-1H-indol-3-yl)-2,2,2-trifluoroethane (6d)[23] White
solid, mp 119 - 121 oC 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.9 Hz,
2H), 7.27 (d, J = 8.2 Hz, 2H), 7.21 (t, J = 7.5 Hz, 2H), 7.12-7.01 (m, 4H),
5.28 (q, J = 9.3 Hz, 1H), 3.69 (s, 6H). 13C NMR (101 MHz, CDCl3) δ
137.0 (s), 128.3 (s), 127.5 (s), 122.0 (s), 119.5 (s), 119.3 (s), 109.5 (s),
109.2 (s), 39.1 (q, J = 29.9 Hz), 32.9 (s) HRMS (ESI): C20H17F3N2Na+ for
[M + Na]+ calculated 365.1236, found 365.1238.
= 8.1 Hz, 2H), 7.13-7.04 (m, 2H), 7.00-6.91 (m, 2H), 4.14 (s, 2H), 3.62 (s,
6H), 2.36 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 136.6, 132.8, 128.2,
120.3, 118.6, 118.5, 110.5, 108.4, 29.5, 20.1, 10.6. HRMS (ESI):
C21H22N2Na+ for [M + Na]+ calculated 325.1675, found 325.1678.
Bis(1H-indol-3-yl)methane (14c)[20] White solid (33.2 mg, 54%), mp 167
- 169 oC. 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 2H), 7.62 (d, J = 7.9 Hz,
2H), 7.34 (d, J = 8.1 Hz, 2H), 7.18 (t, J = 7.5 Hz, 2H), 7.09 (t, J = 7.4 Hz,
2H), 6.91 (s, 2H), 4.23 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 136.6,
127.9, 122.4, 122.0, 119.3, 119.3, 115.8, 111.20, 21.3. HRMS (ESI):
C17H14N2Na+ for [M + Na]+ calculated 269.1049, found 269.1050.
1,1-Bis(1-methyl-1H-indol-3-yl)-2-phenylethane (7d)[24] White solid
(62,8 mg, 69%), mp 146 - 149 oC 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J
= 7.9 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 7.19-7.09 (m, 7H), 7.02 (t, J = 7.4
Hz, 2H), 6.78 (s, 2H), 4.78 (t, J = 7.4 Hz, 1H), 3.66 (s, 6H), 3.51 (d, J =
7.4 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 141.5, 137.4, 129.1, 128.1,
127.5, 126.8, 125.8, 121.4, 119.9, 118.6, 118.3, 109.2, 42.3, 36.1, 32.7.
HRMS (ESI): C26H24N2Na+ for [M + Na]+ calculated 387.1832, found
387.1835. HRMS (ESI): C26H24N2K+ for [M + K]+ calculated 403.1571,
found 403.1576.
Bis(6-fluoro-1H-indol-3-yl)methane (15c)[21] White solid, mp 165 - 167
oC. 1H NMR (400 MHz, CDCl3) δ 7.87 (s, 2H), 7.47 (dd, J = 8.6, 5.4 Hz,
2H), 7.01 (dd, J = 9.7, 1.9 Hz, 2H), 6.94-6.73 (m, 4H), 4.17 (s, 2H). 13C
NMR (101 MHz, CDCl3) δ 160.1 (d, J = 237.3 Hz), 136.5 (d, J = 12.4 Hz),
124.2 (s), 122.5 (d, J = 3.5 Hz), 120.0 (d, J = 10.1 Hz), 115.7 (s), 108.1
(d, J = 24.4 Hz), 97.5 (d,
J
= 26.0 Hz), 21.4 (s). HRMS (ESI):
1,1-Bis(1-methyl-1H-indol-3-yl)-3-phenylpropane (8d) Yellow oil, 1H
NMR (400 MHz, CDCl3) δ 7.55 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 7.8 Hz,
4H), 7.20-7.13 (m, 5H), 7.05-6.98 (m, 2H), 6.84 (s, 2H), 4.48 (t, J = 7.4
Hz, 1H), 3.65 (s, 6H), 2.74-2.67 (m, 2H), 2.58-2.47 (m, 2H). 13C NMR
(101 MHz, CDCl3) δ 142.8, 137.4, 128.7, 128.4, 127.6, 126.4, 125.7,
121.4, 119.8, 118.8, 118.6, 109.2, 38.0, 34.6, 33.4, 32.7. HRMS (ESI):
C27H26N2Na+ for [M + Na]+ calculated 401.1988, found 401.1990.
C17H14F2N2K+ for [M + K]+ calculated 321.0600, found 321.0602.
Bis(6-methoxyl-1H-indol-3-yl)methane (16c)[21] Brown solid, mp 175 -
176 oC. 1H NMR (400 MHz, DMSO) δ 10.51 (s, 2H), 7.34 (d, J = 8.6 Hz,
2H), 6.97 (d, J = 1.8 Hz, 2H), 6.81 (d, J = 2.1 Hz, 2H), 6.56 (dd, J = 8.6,
2.2 Hz, 2H), 4.02 (s, 2H), 3.72 (s, 6H). 13C NMR (101 MHz, DMSO) δ
155.3, 137.0, 121.7, 121.3, 119.2, 114.2, 108.2, 94.4, 55.1, 21.1. HRMS
(ESI): C19H18N2O2K+ for [M + K]+ calculated 345.1000, found 345.1008.
1,1-Bis(1-methyl-1H-indol-3-yl)-p-fluorophenylethane (9d)[25] Yellow
oil, 1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 7.9 Hz, 2H), 7.25 (d, J = 8.2
Hz, 2H), 7.17 (t, J = 7.7 Hz, 2H), 7.05-6.97 (m, 4H), 6.80 (t, J = 8.8 Hz,
(1-(Ethan-1-ol)-1H-indol-3-yl)(1-dodecyl-1H-indol-3-yl)methylene (1e)
Oil, 1H NMR (400 MHz, CDCl3) 1H NMR (400 MHz, CDCl3) δ 7.60 (dd, J
= 14.1, 7.9 Hz, 2H), 7.34 – 7.29 (m, 2H), 7.22 – 7.16 (m, 2H), 7.10 – 7.03
(m, 2H), 6.86 (d, J = 7.9 Hz, 2H), 4.22 (s, 2H), 4.16 (t, J = 5.2 Hz, 2H),
4.01 (t, J = 7.1 Hz, 2H), 3.87 (t, J = 5.1 Hz, 2H), 1.81 – 1.78 – 1.75 (m,
2H), 1.47 (s, 1H), 1.27 - 1.24 (m, 18H), 0.88 (t, J = 6.5 Hz, 4H). 13C NMR
(101 MHz, CDCl3) δ 136.9, 136.6, 128.5, 128.2, 126.5, 126.1, 121.8,
121.4, 119.7, 119.5, 119.1, 118.6, 115.3, 114.0, 109.5, 109.4, 62.3, 48.7,
46.4, 32.1, 30.5, 29.9, 29.8, 29.7, 29.7, 29.5, 29.4, 27.2, 22.8, 21.2, 14.3.
HRMS (ESI): C31H42N2ONa+ for [M + Na]+ calculated 481.3189, found
481.3192.
2H), 4.70 (t, J = 7.4 Hz, 1H), 3.65 (s, 6H), 3.47 (d, J = 7.4 Hz, 2H). 13
C
NMR (101 MHz, CDCl3) δ 161.3 (d, J = 243.0 Hz), 137.4 (s), 137.1 (d, J =
3.1 Hz), 130.4 (d, J = 7.8 Hz), 127.4 (s), 126.8 (s), 121.5 (s), 119.8 (s),
118.7 (s), 118.0 (s), 114.8 (d, J = 21.0 Hz), 109.3 (s), 41.5 (s), 36.5 (s),
32.8 (s). HRMS (ESI): C26H23FN2Na+ for [M + Na]+ calculated 405.1737,
found 405.1742.
1,1-Bis(1-methyl-1H-indol-3-yl)-2-thienylethane (10d) White solid, mp
157 - 158 oC 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 7.9 Hz, 2H), 7.26
(d, J = 8.2 Hz, 2H), 7.20 (dd, J = 12.3, 5.0 Hz, 2H), 7.04 (t, J = 7.2 Hz,
2H), 6.99 (dd, J = 5.1, 0.8 Hz, 1H), 6.83 (s, 2H), 6.79 (dd, J = 5.0, 3.5 Hz,
1H), 6.70 (d, J = 2.8 Hz, 1H), 4.81 (t, J = 7.3 Hz, 1H), 3.79 – 3.60 (m, 8H).
13C NMR (101 MHz, CDCl3) δ 144.1, 137.4, 127.5, 126.9, 126.4, 125.2,
123.2, 121.5, 119.7, 118.7, 117.9, 109.3, 36.7, 36.6, 32.8. HRMS (ESI):
C24H22N2SNa+ for [M + Na]+ calculated 393.1396, found 393.1399.
1,1-Bis(1-methyl-1H-indol-3-yl)ethane (2d)[20] Oil, 1H NMR (400 MHz,
CDCl3) δ 7.58 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 7.23-7.15 (m,
2H), 7.09-6.98 (m, 2H), 6.78 (s, 2H), 4.67 (q, J = 7.1 Hz, 1H), 3.71 (s, 6H),
1.78 (d, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 137.4, 127.4,
126.1, 121.4, 120.5, 112.0, 118.5, 109.2, 32.8, 28.1, 22.3. HRMS (ESI):
C20H20N2Na+ for [M + Na]+ calculated 311.1519, found 311.1522.
Bis(1-methyl-1H-indol-3-yl) methylbenzene (11d)[20] White solid (29.3
mg, 34%), mp 201 - 203 oC 1H NMR (400 MHz, CDCl3) δ 7.35 (dd, J =
15.6, 7.7 Hz, 4H), 7.26 (t, J = 7.4 Hz, 4H), 7.18 (t, J = 8.0 Hz, 3H), 6.98 (t,
J = 7.4 Hz, 2H), 6.51 (s, 2H), 5.87 (s, 1H), 3.63 (s, 6H). 13C NMR (101
MHz, CDCl3) δ 144.6, 137.5, 128.8, 128.4, 128.3, 127.6, 126.1, 121.5,
120.2, 118.8, 118.4, 109.2, 40.2, 32.8. HRMS (ESI): C25H22N2Na+ for [M
+ Na]+ calculated 373.1675, found 373.1678.
1,1-Bis(1-methyl-1H-indol-3-yl)propane (3d(4d))[22] Milky oil, 1H NMR
(400 MHz, CDCl3) δ 7.61 (d, J = 7.9 Hz, 2H), 7.28 (s, 2H), 7.21-7.15 (m,
2H), 7.06-7.00 (m, 2H), 6.84 (s, 2H), 4.36 (t, J = 7.4 Hz, 1H), 3.71 (s, 6H),
2.22 (p, J = 7.3 Hz, 2H), 1.00 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 137.4, 127.7, 126.4, 121.4, 119.9, 119.1, 118.5, 109.2, 35.9,
32.8, 29.4, 13.3. HRMS (ESI): C21H22N2Na+ for [M + Na]+ calculated
325.1675, found 325.1678.
Bis(1-methyl-1H-indol-3-yl)-p-chlorophenylmethane (12d)[26] White
solid, mp 206 oC 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 7.9 Hz, 2H),
7.29 (d, J = 8.2 Hz, 2H), 7.27 – 7.18 (m, 6H), 7.06 – 6.96 (m, 2H), 6.50 (s,
2H), 5.85 (s, 1H), 3.68 (s, 6H). 13C NMR (101 MHz, CDCl3) δ 143.1,
137.6, 131.8, 130.2, 128.5, 128.4, 127.4, 121.7, 120.0, 118.9, 117.9,
109.3, 39.6, 32.8.
1,1-Bis(1-methyl-1H-indol-3-yl)octane (5d) Yellow oil, 1H NMR (400
MHz, CDCl3) δ 7.61 (d, J = 7.9 Hz, 2H), 7.25 (d, J = 8.1 Hz, 2H), 7.17 (t,
J = 7.6 Hz, 2H), 7.03 (t, J = 7.4 Hz, 2H), 6.83 (s, 2H), 4.45 (t, J = 7.4 Hz,
1H), 3.70 (s, 6H), 2.18 (dd, J = 14.6, 7.3 Hz, 2H), 1.30-1.20 (m, 10H),
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Bis(1-methyl-1H-indol-3-yl)-p-bromophenylmethane (13d)[20] White
solid, mp 216 - 217 oC. 1H NMR (400 MHz, CDCl3) δ 7.39 -7.21 (m, 10H),
7.01 (d, J = 6.9 Hz, 2H), 6.50 (s, 2H), 5.83 (s, 1H), 3.67 (s, 6H). 13C NMR
(101 MHz, CDCl3) δ 143.7, 137.5, 131.4, 130.6, 128.4, 127.4, 121.7,
120.0, 119.9, 118.9, 117.7, 109.3, 39.7, 32.8.
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This work was financially supported by the National Program on
Key Research Project (2016YFA0602900), National Natural
Science Foundation of China (21472103, 21672119, 21421001),
the Natural Science Foundation of Tianjin (16JCZDJC39900)
and the Ph.D. Candidate Research Innovation Fund of the
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Conflict of interest
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10.1002/asia.201800766
Chemistry - An Asian Journal
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COMMUNICATION
An efficient Lewis acid B(C6F5)3-
promoted straightforward reductive
alkylation of indoles at C3 position with
readily available and stable carboxylic
acids and hydrosilane was developed
for 3,3’-bisindolylmethanes (BIMs)
synthesis under greener conditions.
This metal-free strategy offers an
Chang Qiao,[a] Xiao-Fang Liu,[a]
Hong-Chen Fu,[a]
Hao-Peng Yang,[a] Zhi-Bo Zhang,[a]
Liang-Nian He*[a],[b]
Page No. – Page No.
alternative
functionalization of indoles to BIMs
with carboxylic acids.
approach
for
direct
Directly Bridging Indoles to 3,3’-
Bisindolylmethanes Using Carboxylic
Acids and Hydrosilanes under Mild
Conditions
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