Electrochemical Synthesis of Bisindolylmethanes from Indoles and Ethers

Article abstract of DOI:10.1021/acs.orglett.8b00968

An electrochemical bisindolylation of ethers was developed. Carried out under ambient conditions and in the absence of any chemical oxidants, this reaction exhibits a broad substrate scope and good functional group compatibility.

Full text of DOI:10.1021/acs.orglett.8b00968

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Electrochemical Synthesis of Bisindolylmethanes from Indoles and
Ethers
Ke-Si Du and Jing-Mei Huang*
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South
China University of Technology, Guangzhou, Guangdong 510640, China
S
* Supporting Information
ABSTRACT: An electrochemical bisindolylation of ethers
was developed. Carried out under ambient conditions and in
the absence of any chemical oxidants, this reaction exhibits a
broad substrate scope and good functional group compati-
bility.
3,3′-Bis(indolyl)methanes (BIMs) are present in a large variety
of natural products, and their derivatives exhibit diverse
biological activitites.1 BIM derivatives have also been used in
materials chemistry.2 As a consequence, various methods for
the preparation of BIMs have been developed over the past few
decades. Synthesis of bis(indolyl)alkane derivatives has been
effected through the reaction of indoles with aldehydes,3
ketones,3 olefin derivatives,4 alkynes/allenes,5 amines,6 and
amides7 as the alkyl sources. In 2009, Li’s group8 developed a
new method for the synthesis of BIMs from ethers promoted
by a DTBP/FeCl2 system (Figure 1). Very recently, an efficient
photochemical alkylation of indoles with ethers has been
achieved by Loh’s group (Figure 1).9 Although these protocols
serve as powerful methods for the synthesis of BIMs, they suffer
from one or more disadvantages, such as utilization of an
external chemical oxidant, elevated temperature, use of an
expensive catalyst, and a stoichiometric amount of a single-
electron-transfer reagent. Therefore, environmentally friendly
methods for the synthesis of BIMs using inexpensive and
readily available reagents are still highly desirable.
The electroorganic synthesis is considered to be an
environmentally friendly methodology since dangerous and
toxic redox reagents can be replaced by an electrical current or
generated in situ in the course of electrolysis. Over the past
decade, organic electrochemistry has experienced a renaissance
in the field of organic synthesis.10 In continuation of our
interest in the application of electrochemical methods to
organic synthesis,11 herein, we report an efficient synthesis of
BIMs from indoles and ethers through an electrochemical
method with the catalysis of LaCl3 (Figure 1).
We began our study by optimizing the electrolysis conditions
for the synthesis of BIMs from N-methylindole 1a and THF 2a.
The reaction was conducted at a constant current in an
undivided cell equipped with a Pt wire anode and a Pt foil
cathode. 1a and 2a reacted efficiently in the presence of 10 mol
% LaCl3 to afford the desired product 3a in 92% yield at 5 mA
(Table 1, entry 1). The electrolysis at higher or lower current
density blunted the product formation (Table 1, entries 2−3).
No reaction took place without electricity (Table 1, entry 4).
Other La3+ salts, for instance, La(NO3)3·6H2O, La(OAc)3 and
La(OTf)3, were shown to be inferior to LaCl3 in terms of yields
(Table 1, entries 5−8). The influence of the electrolyte was also
studied. When other electrolytes, such as NaClO4, NH4ClO4,
and NaBF4, were used instead of LiClO4, the yields of the
desired products decreased (Table 1, entries 9−11). A reaction
Received: March 26, 2018
Figure 1. Synthesis of BIMs by ethers and indoles.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00968
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a b
,
Table 1. Optimization of Reaction Conditions
Scheme 1. Substrate Scope
b
entry
variation from the standard conditions
yield (%)
1
none
92
2
3 mA instead of 5 mA
8 mA instead of 5 mA
no electric current
37
3
56
4
0
5
in the absence of LaCl3
La(NO3)3·6H2O instead of LaCl3
La(OAc)3 instead of LaCl3
La(OTf)3 instead of LaCl3
NaClO4 instead of LiClO4
NaBF4 instead of LiClO4
NH4ClO4 instead of LiClO4
under N2
47
6
60
7
25
8
67
9
22
10
11
12
13
trace
trace
89
under O2
73
a
Unless otherwise noted, the mixture of 1a (0.8 mmol), LaCl3 (0.08
mmol) in solvent (THF/MeCN = 2:1, v/v, 5 mL) with 0.2 M LiClO4
as supporting electrolyte was electrolyzed at constant current (5 mA)
in an undivided cell at room temperature for 6.5 h, anode: Pt wire
(diameter: 0.5 mm, height: 1.5 cm), cathode: Pt foil (1.0 × 1.5 cm2).
b
Yield determined by 1H NMR with nitrobenzene as the internal
standard
was carried out under nitrogen producing a comparable yield
(89%, Table 1, entry 12). However, the yield decreased to 73%
under an oxygen atmosphere (Table 1, entry 13). In addition,
more Lewis acids (Table S1) and solvent systems (Table S2)
were suveyed and it was found that LaCl3 displayed the highest
catalytic effeciency and THF/MeCN (2:1, v/v) was superior to
other solvents.
With the optimized conditions in hand, we then examined
the substrate scope (Scheme 1). First, the reactivity of N-
methylindoles with substituents on the benzene ring was
studied. In general, both electron-donating and -withdrawing
groups were tolerated in this reaction. Substrates with methyl
or methoxyl groups provided the desired products in good
yields (3b, 85%; 3c, 73%); N-methylindoles bearing electron-
withdrawing groups, such as CN, COOMe, and NO2, could
also be transformed to the corresponding products in moderate
to excellent yields (3g, 90%; 3h, 76%; 3i, 66%). Notably, halide
substituents remained intact in the reaction (3d, 73%; 3e, 75%;
3f, 63%), which provide the opportunity for further
derivatization. Next, the C-2 substituted N-methylindoles,
with increased steric hindrance, were explored, and it was
found that these substrates were compatible with this
transformation (3l, 71%; 3m, 57%). The influence of the N-
substitution of indoles was then probed. Replacing the N-
methyl group with n-butyl, -benzyl, and -phenyl had little
influence on the reaction, and the corresponding indoles
worked smoothly in this process to furnish the desired products
in good yields (3n, 85%; 3o, 88%; 3p, 87%). Replacement of
the N-methyl group of indoles with electron-withdrawing
groups, such as N,N-dimethylcarbamoyl and N-tosyl, led to
attenuated efficiency (3q, 29%; 3r, 0%). To our delight, N-H
indoles could be transformed to the desired products (3s, 51%;
3t, 56%; 3u, 54%) successfully, albeit with moderate yields.
Finally, we turned our attention to the scope of
corresponding ether sources. When 2-methyltetrahydrofuran
a
Unless otherwise noted, the reaction were carried out at room
temperature under air using 1 (0.8 mmol), 10 mol % LaCl3, 0.2 M
LiClO4, THF/MeCN (2:1, v/v, 5 mL) in an undivided cell for 6.5 h.
Anode: Pt wire (diameter: 0.5 mm, height: 1.5 cm), cathode: Pt foil
b
(1.0 × 1.5 cm2). Yield determined by 1H NMR with nitrobenzene as
c
the internal standard. 2-Methyl tetrahydrofuran; reaction time: 2 h.
d
e
f
1,4-Dioxane. Diethyl ether/MeCN = 5:2. Isochroman/MeCN =
4:1; reaction time: 2 h.
was employed instead of THF, the homologous product 3v was
isolated in 58% yield. 1,4-Dioxane and diethyl ether could also
participate in the reaction to afford the desired products in
moderate yields (3w, 61%; 3x, 55%). When isochroman was
B
DOI: 10.1021/acs.orglett.8b00968
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Organic Letters
Letter
used as the ether source, two products were detected (3y, 59%;
3z, 13%).
Scheme 3. Control Experiments
To gain an understanding of the reaction mechanism, more
studies were conducted. Only a trace amount of product 3a was
observed when the reaction was carried out in the presence of
butylated hydroxytoluene (BHT) or 1,1-diphen-ylethylene
(Scheme 2a). It suggested that the reaction might go through
Scheme 2. Radical Experiments
a radical mechanism. Hence, radical-trapping experiments were
further explored. As shown in Scheme 2b, when an excess
amount of triethyl phosphite was added to the reaction mixture,
the indole-phosphorylation product 5a was obtained in 71%
yield, implying the involvement of indole radicals during the
reaction.12 Furthermore, the cyclic voltammetry (CV) studies
showed an oxidative peak of 1a at 1.46 V vs SCE and an
oxidative peak of THF at 1.78 V vs SCE, which suggested the
possibility of the anodic oxidation of 1a to produce indole
radicals (Figure 2).
utilized, the high current density on the anode could promote
the oxidation of THF to produce alkyoxycarbienium ion, as the
concentration of THF was very high in the reaction system.15
Second, 2,3-dihydrofuran 6 was found to be an unproductive
reaction partner, which revealed that 6 was not involved in this
reaction (Scheme 3c).8,16 As a trace of monoindolylated THF 7
could be detected in the mixture of the standard reaction, 7 was
then prepared and subjected to the standard conditions, and 3a
was obtained in 97% yield which suggested the intermediacy of
7 in the present process (Scheme 3d). Finally, the effects of
LaCl3 and electricity on the transformation of 7 to 3a were
studied. It was found that LaCl3 worked as a Lewis acid to
catalyze the reaction of 7 with the second N-methylindole
(Scheme 3d, 3e, and 3f). However, the electricity was not
necessary for this step (Scheme 3d and 3f).
On the basis of the above results and the literature
reports,8,9,12,13,17 a tentative mechanism was proposed, as
shown in Scheme 4. First, the N-methylindole radical cation b
was formed by the anode oxidant through single electron
transfer. Then radical cation b reacted with 2a to give the THF
radical c, which was trapped by 1a to generate the
monoindolylated product 7 (path A). 7 might also be obtained
through the reaction of 1a with the alkoxycarbenium ion e,
which was produced by the anodic oxidation of THF (path B).
Subsequently, Friedel−Craft alkylation of 7 afforded the cross-
coupling product 3a. Meanwhile, cathodic reduction of proton-
hydrogen led to the formation of hydrogen gas.
Figure 2. Cyclic voltammogram of 0.2 M LiClO4 solution in THF/
MeCN (2:1, v/v) at room temperature: (a) none, (b) MeCN instead
of THF/MeCN (2:1, v/v), (c) 1a (0.008 M). The voltammogram was
obtained with a Pt wire as an auxiliary electrode and a saturated
calomel electrode (SCE) as a reference electrode. The scan rate was
0.1 V/s on a platinum disk electrode (d = 2 mm).
To gain more insight into the reaction, diverse control
reactions were undertaken (Scheme 3). First, the “cation pool
method” was performed.10b,13 THF was electrolyzed for 4.5 h,14
followed by the addition of 1a in the absence of current. After
the resulting mixture stirred for 1 h, the stepwise reactions gave
3a in a yield of 55% (Scheme 3a). This result showed that the
alkyoxycarbienium ion might have been generated during the
reaction.13 Moreover, when the Pt wire was replaced by the Pt
foil (1.0 × 1.5 cm2) as an anode, the yield decreased to 79%
(Scheme 3b). It indicated that when a Pt wire anode was
In summary, an electrochemical synthesis of BIMs from a
broad range of indoles and ethers has been developed. Carried
C
DOI: 10.1021/acs.orglett.8b00968
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00968.
Experimental procedures and spectroscopic data (PDF)
(10) For recent representative reviews and articles, see: (a) Sperry, J.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chehjm@scut.edu.cn.
ORCID
2521. (d) Waldvogel, S. R.; Mohle, S. Angew. Chem., Int. Ed. 2015, 54,
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6398−6399. (e) Yan, M.; Kawamata, Y.; Baran, P. S. Chem. Rev. 2017,
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Chem. Rev. DOI: 10.1021/acs.chemrev.7b00271. (i) Yoshida, J-i.;
Shimizu, A.; Hayashi, R. Chem. Rev. DOI: 10.1021/acs.chem-
rev.7b00475. (j) Tang, S.; Liu, Y.; Lei, A. Chem. 2018, 4, 27−45.
(k) Moeller, K. D. Chem. Rev. DOI: 10.1021/acs.chemrev.7b00656.
(l) Fu, N.; Sauer, G. S.; Lin, S. J. Am. Chem. Soc. 2017, 139, 15548−
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Jing-Mei Huang: 0000-0003-2861-3856
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Grant Nos. 21672074 and 21372089) for financial
support.
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