CuI-catalyzed highly regioselective C[sbnd]H functionalization of indoles using indole-3-tosylhydrazones as carbene precursor: An efficient synthesis of 3,3-bis(indolyl)methane derivatives

Article abstract of DOI:10.1016/j.tetlet.2019.151162

Herein, we have developed a novel approach for synthesizing symmetrical and unsymmetrical 3,3-bis(indolyl)methane derivatives via CuI-catalyzed C[sbnd]H functionalization of indole using indole-3-tosylhydrazones as carbene precursor. This procedure works well with different substitutions such as NO₂, Br, CH₃ and OMe on indole or indole-3-tosylhydrazones and features high regioselectivity for C-3 functionalization over the C-1 and N-1 positions. Further, we have also revealed the feasibility of this protocol in a one-pot fashion starting from indole-3-carboxyaldehyde.

Full text of DOI:10.1016/j.tetlet.2019.151162

Tetrahedron Letters xxx (xxxx) xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
CuI-catalyzed highly regioselective CAH functionalization of indoles
using indole-3-tosylhydrazones as carbene precursor: An efficient
synthesis of 3,3-bis(indolyl)methane derivatives
Priya Kamboj a, Sunil Dutt a, Sourav Chakroborty b, Vikas Tyagi a,
⇑
a School of Chemistry and Biochemistry, Thapar Institute of Engineering and Technology, Patiala 147004, Punjab, India
b Institute of Science and Supramolecular Engineering, CNRS, 7006 UMR University of Strasbourg, 8 rue Gaspard Monge, 67000 Strasbourg, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein, we have developed a novel approach for synthesizing symmetrical and unsymmetrical 3,3-bis
(indolyl)methane derivatives via CuI-catalyzed CAH functionalization of indole using indole-3-tosylhy-
drazones as carbene precursor. This procedure works well with different substitutions such as NO2, Br,
CH3 and OMe on indole or indole-3-tosylhydrazones and features high regioselectivity for C-3 function-
alization over the C-1 and N-1 positions. Further, we have also revealed the feasibility of this protocol in a
one-pot fashion starting from indole-3-carboxyaldehyde.
Received 19 July 2019
Revised 11 September 2019
Accepted 16 September 2019
Available online xxxx
Keywords:
Bis indoles
Ó 2019 Elsevier Ltd. All rights reserved.
N-tosylhydrazone
Copper-catalyst
Regioselective
Carbene insertion
Introduction
However, the synthesis of 3,3-bis(indolyl)methane having methy-
lene bridge is quite challenging and only a few methods were
Bis-indoles belong to a structurally fascinating and imperative
class of heterocycles as they are broadly found in a number of
pharmacologically and biologically important natural as well as
synthetic compounds (Fig. 1) [1]. Moreover, 3,3-bis(indolyl)
methanes (BIM) derivatives possesses two indole units linked by
a methylene bridge exhibited remarkable biological activities such
as anti-inflammatory, antihyperglycemic, antiviral, antibacterial,
anticancer etc [2]. Therefore, the effective preparation of 3,3-bis
(indolyl)methane derivatives have attracted great attention in
the chemical community over the past years [3].
In general, the 3,3-bis(indolyl)methane can be prepared by
reaction of indoles with various aromatic or aliphatic aldehydes
or ketones in the presence of Lewis acids or Bronsted acids [4].
These traditional methods have a number of disadvantages e.g.,
longer reaction time, requirement of more than stoichiometric
amount of reagents and tedious aqueous work-up. The deactiva-
tion of Lewis acids or sometimes possible decomposition by nitro-
gen containing reactants may also create problems.
reported [1g]. In this context, Deb and his co-workers have been
reported a microwave assisted Ru(III)/TBHP-mediated reaction of
indoles with tetramethylurea to prepare bis(indolyl)methanes
(Scheme 1a) [6]. Afterwards, Loh et. al. has been reported the syn-
thesis of 3,3-bis(indolyl)methanes catalyzed by Mg-Al mixed oxi-
des supported iridium catalyst (Scheme 1b) [7]. But, these
methods also have certain drawbacks such as only applicable to
produce symmetrical bis(indolyl)methanes consisting methylene
bridge efficiently. So, an efficient method is highly desirable to pre-
pare both symmetrical and unsymmetrical 3,3-bis(indolyl)
methane derivatives.
On the other hand, the functionalization of indole ring using
transition-metal catalysts and substituted diazo compounds as
carbene precursor have widely been explored [8]. For example,
Zhou et al. used copper and palladium based complexes to catalyze
the selective CAH functionalization of indoles with diazo com-
pounds [9]. Very recently, Fasan’s group reported a biocatalytic
strategy for enabling the direct C3-functionalization of unpro-
tected indoles [10]. The CuI-catalyzed 3-alkylation of indoles using
N-tosylhydrazones as carbene precursor was reported by Yang’s
group [11]. Despite the usefulness of carbene insertion in CAH
functionalization of indole, it suffers from competing reactions at
C-2 and N-1 positions of the indole ring [12]. In order to develop
an efficient method for the synthesis of 3,3-bis(indolyl)methanes
In this regard, numerous alternative methods have been devel-
oped to overcome aforementioned limitations to some extent [5].
⇑
Corresponding author.
E-mail address: vikas.tyagi@thapar.edu (V. Tyagi).
https://doi.org/10.1016/j.tetlet.2019.151162
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: P. Kamboj, S. Dutt, S. Chakroborty et al., CuI-catalyzed highly regioselective CAH functionalization of indoles using indole-3-
tosylhydrazones as carbene precursor: An efficient synthesis of 3,3-bis(indolyl)methane derivatives, Tetrahedron Letters, https://doi.org/10.1016/j.
tetlet.2019.151162

2
P. Kamboj et al. / Tetrahedron Letters xxx (xxxx) xxx
Fig. 1. Representative structures of biologically active 3,3-bis(indolyl)methane containing natural or synthetic compounds.
Scheme 1. Methods for the synthesis 3,3-bis(indolyl)methane consisting methylene bridge.
having methylene bridge, herein, we have designed a copper cat-
alyzed regioselective CAH functionalization of indole using
indole-3-tosylhydrazone as carbene precursor (Scheme 1c).
increase the yield of model reaction (entry 4–9, Table 1) and
Cs2CO3 was found the most effective one (entry 5, Table 1). Also,
2.0 equiv. of Cs2CO3 was essential to obtain maximum conversion
(entry 10–11, Table 1). Interestingly, replacement of CuI with CuBr,
CuCl, CuSO4 and Cu(OAc)2 provided (3a) either in inferior yield or
only in trace amount (entry 12–15, Table 1).
Results and discussion
Next, the use of different solvents in the combination of CuI as
catalyst and Cs2CO3 as base, did not showed any improvement in
the yield of (3a) (entry 16–21, Table 1). It was also observed that
there was no product formation in the absence of either CuI or base
(entry 22–23, Table 1). Further optimization revealed that 10 mol%
of CuI was essential to get the maximum conversion in this reac-
tion (entry 24–25, Table 1).
After having the optimal reaction conditions (entry 5, Table 1)
for the synthesis of bisindoles (3a), the effect of different substitu-
tions on indole (1) and tosylhydrazone (2) was tested and all the
results were summarized in Table 2. Initially, we have tested the
scope of substitution for the synthesis of symmetrical bisindoles
We have started our investigation by considering the reaction of
indole (1a) with tosylhydrazone (2a) as a model reaction for the
optimization of the reaction conditions and all the results were
summarized in Table 1. First, we have tested CuI as catalyst with
K2CO3 as a base in 1,4-dioxane and obtained the product (3a) in
49% yield, whereas only trace amount of product (3a) was observed
in the presence of Pd(OAc)2 (entry 1–2, Table 1). When, we
replaced K2CO3 with KOtBu as a base in the presence of Pd(OAc)2
as catalyst, there was no improvement in the formation of (3a)
(entry 3, Table 1). Next, we screened various bases such as NaOH,
Cs2CO3, KOtBu, LiOtBu, DBU and Et3N with CuI as catalyst to
Please cite this article as: P. Kamboj, S. Dutt, S. Chakroborty et al., CuI-catalyzed highly regioselective CAH functionalization of indoles using indole-3-
tosylhydrazones as carbene precursor: An efficient synthesis of 3,3-bis(indolyl)methane derivatives, Tetrahedron Letters, https://doi.org/10.1016/j.
tetlet.2019.151162

P. Kamboj et al. / Tetrahedron Letters xxx (xxxx) xxx
3
Table 1
Optimization of the reaction conditions for the regioselective CAH functionalization of indole.a
entry
catalyst
base
solvent
yield %b
1
2
3
4
5
6
7
8
CuI
K2CO3
K2CO3
KOtBu
NaOH
Cs2CO3
KOtBu
LiOtBu
DBU
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
toluene
49
Pd(OAc)2
Pd(OAc)2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
trace
trace
27
59
42
34
trace
13
9
Et3N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
–
44c
55d
41
CuI
CuBr
CuCl
CuSO4
Cu(OAc)2
CuI
CuI
CuI
CuI
CuI
CuI
–
CuI
CuI
20
trace
trace
51
49
20
DMF
THF
DMSO
DMA
trace
51
CH3CN
26
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
0e
0e
Cs2CO3
Cs2CO3
32f
61g
CuI
a
Reaction conditions: All reactions were performed in a 10 mL sealed tube using indole 1a (1.2 equiv., 0.96 mmol), indole-3-tosylhydrazone (1.0 equiv., 0.64 mmol),
catalyst (10 mol %) and base (2.0 equiv. 1.27 mmol), solvent 2 mL at 110 °C for 15–18 h at conventional heating,
b
isolated yield,
used 1.0 equiv. of base,
used 3.0 equiv. of base
no reaction,
used 5 mol% of catalyst,
used 20 mol% of catalyst.
c
d
e
f
g
(entry 1–4, Table 2) and we obtained good yields of corresponding
symmetrical bisindoles in case of 5-Br, and 2-CH3 substitutions
(entry 2–3, Table 2). In contrast, 5-nitro substitution gave the infe-
rior yield of the product (entry 4, Table 2) and it might be due to
the instability of the product. Next, we have seen the effect of
electron withdrawing and donating group for the synthesis of
unsymmetrical indoles. To our delight, many substitutions
e.g. -CH3, -OCH3, and -Br irrespective of the positions on the phenyl
ring of indole-3-tosylhydrazone were found compatible with good
yields of the resultant products (entry 5–8, Table 2), however, the
yield of corresponding product was slightly higher in the case of
5-OMe substitution (entry 6, Table 2). Further, when we had mild
electron withdrawing group (-Br) on (1) and electron donating
group (-CH3 or -OMe) on (2), reaction gave 58–69% yields (entry
9–11, Table 2). Whereas, 5-Br and 4-Br substitutions on (1) and
(2), respectively, were furnished the corresponding product in
56% yield (entry 12, Table 2). We got the product in 43% yield,
when started the reaction of 5-NO2-indole with indole-3-tosylhy-
drazone containing 5-Br substitution (entry 13, Table 2). Further,
no reaction was observed in the case of 3-Me substitution at
tosylhydrazone (2), which proves the regioselectivity of this
transformation. Besides, we have observed the formation of a com-
plex mixture of indole-3-carboxyaldehyde, sulfone and other
unidentified products in some reactions due to the decomposition
of tosylhydrazones via its self-reaction in the presence of Cs2CO3
and CuI [13], as a result reactions gave moderate yield of the
desired products.
We continued our investigation to find the role of substitution
on the N-1 position of indole as well as indole based tosylhydra-
zone. When, we used N-methyl indole (4) with indole-3-tosylhy-
drazone (2a), no product formation was observed (Scheme 2a).
Whereas, in the reaction of unsubstituted indole (1a) with N-
methyl-indole based tosylhydrazone (5) only undesired product
(6) was isolated (Scheme 2b). These results proves the importance
of substitution on N-1 position in this reaction which was also
observed previously by Shi et al. [5b].
In order to show the scalability of this methodology, we have
started a reaction of indole (1a) (0.56 g, 4.78 mmol) with tosylhy-
drazone (2a) (1 g, 3.19 mmol) under the optimized reaction condi-
tions (Scheme 3). Gratifyingly, we obtained the isolated product
(3a) in 52% yield (0.41 g) from this reaction which demonstrated
the synthetic utility of this transformation.
Please cite this article as: P. Kamboj, S. Dutt, S. Chakroborty et al., CuI-catalyzed highly regioselective CAH functionalization of indoles using indole-3-
tosylhydrazones as carbene precursor: An efficient synthesis of 3,3-bis(indolyl)methane derivatives, Tetrahedron Letters, https://doi.org/10.1016/j.
tetlet.2019.151162

4
P. Kamboj et al. / Tetrahedron Letters xxx (xxxx) xxx
Table 2
Substrate scope for the regioselective CAH functionalization of indole using indole-3-tosylhydrazone.a
entry
R1
R2
product, %yield
1
2
3
4
5
6
7
8
H
H
5-Br
3a, 59
3b, 63
3c, 69
3d, 39
3e, 61
3f, 71
3g, 63
3h, 67
3i, 58
3j, 65
3k, 69
3l, 56
3m, 43
3n, 0b
5-Br
2-CH3
5-NO2
H
H
H
2-CH3
5-NO2
2-CH3
5-OMe
5-Br
H
4-Br
9
5-Br
4-Br
5-Br
5-Br
5-NO2
H
2-CH3
2-CH3
5-OMe
4-Br
5-Br
3-CH3
10
11
12
13
14
a
Reaction conditions: All reactions were performed in a 10 mL sealed tube using indole 1a (1.2 equiv., 0.96 mmol), indole-3-tosylhydrazone (1.0 equiv., 0.64 mmol), CuI
(10 mol %) and Cs2CO3 (2.0 equiv., 1.27 mmol) in 1,4-dioxane (2 mL) as solvent at 110 °C for overnight,
b
no reaction.
Scheme 2. Control experiments to examine the role of substitutions on N-1 position.
Scheme 3. Gram-scale reaction to synthesize the bisindole (3a).
Please cite this article as: P. Kamboj, S. Dutt, S. Chakroborty et al., CuI-catalyzed highly regioselective CAH functionalization of indoles using indole-3-
tosylhydrazones as carbene precursor: An efficient synthesis of 3,3-bis(indolyl)methane derivatives, Tetrahedron Letters, https://doi.org/10.1016/j.
tetlet.2019.151162

P. Kamboj et al. / Tetrahedron Letters xxx (xxxx) xxx
5
Scheme 4. Plausible mechanism for the synthesis of bisindoles.
fashion starting from indole-3-carboxyaldehyde which gave result
very close to step-wise protocol. The biological screening of the
synthesized compound is under progress in our lab and will be
reported in due course.
Acknowledgement
Scheme 5. Synthesis of bisindole (3a) in a one-pot fashion.
We acknowledge the financial support from Department of
Science and Technology, India (DST/INSPIRE/04/2017/000095).
Further, we have proposed a possible mechanism for the CuI-
catalyzed regioselective formation of bisindoles (3a) based on rel-
evant reports (Scheme 4) [13,8g,9b]. Initially, diazo (A) as the key
intermediate was formed via base (Cs2CO3) mediated decomposi-
tion of indole-3-tosylhydrazone (2a). Next, the diazo intermediate
reacts with CuI to generate Cu(I) carbene complex (B), which
reacted with deprotonated indole (1a0) [13] regioselectively at
the C-3 position to form a metal associated intermediate (C). Then,
Appendix A. Supplementary data
All the experimental procedure and characterization data and
copies of NMR spectra to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151162.
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Please cite this article as: P. Kamboj, S. Dutt, S. Chakroborty et al., CuI-catalyzed highly regioselective CAH functionalization of indoles using indole-3-
tosylhydrazones as carbene precursor: An efficient synthesis of 3,3-bis(indolyl)methane derivatives, Tetrahedron Letters, https://doi.org/10.1016/j.
tetlet.2019.151162