Hydrogen-Bond-Catalyzed Arylation of 3-(Aminoalkyl)indoles via C-N Bond Cleavage with Thiourea under Microwave Irradiation: An Approach to 3-(α,α-Diarylmethyl)indoles

Article abstract of DOI:10.1055/s-0036-1588887

We have developed a simple and efficient method for the arylation of 3-(aminoalkyl)indoles with aryl alcohols and other aromatic nucleophiles through C-N bond cleavage under microwave irradiation to synthesize 3-(α,α-diarylmethyl)indoles. The method uses thiourea as catalyst, which is environmentally benign, water-tolerant and easy to handle. Notably, acid-sensitive substrates are tolerated under the reaction conditions. Thiourea activates the tertiary amine through double hydrogen bonding and converts it into a better leaving group. The reaction proceeds through the formation of vinylogous iminium ion as an intermediate.

Full text of DOI:10.1055/s-0036-1588887

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© Georg Thieme Verlag Stuttgart · New York
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A
M. L. Deb et al.
Letter
Synlett
Hydrogen-Bond-Catalyzed Arylation of 3-(Aminoalkyl)indoles via
C–N Bond Cleavage with Thiourea under Microwave Irradiation:
An Approach to 3-(α,α-Diarylmethyl)indoles
Mohit L. Deb*a
Churnika Dasa
Bhaskar Dekaa
Prakash J. Saikiab
Pranjal K. Baruah*a
R3
R3
NMe2
R1
Ar
R1
metal-free
H-bond-catalyzed
microwave-promoted
high yielding
Ar-H
R2
R2
thiourea (30 mol%)
MeCN
MW, 100 °C
5–7 min
N
N
R
R
R, R1 = H, Me
R2 = H, Br
a Department of Applied Sciences, GUIST, Gauhati University,
Guwahati 781014, Assam, India
baruah.pranjal@gmail.com
mohitdd.deb@gmail.com
b Analytical Chemistry Division CSIR-NEIST, Jorhat 785006,
Assam, India
up to 98% yield
35 examples
R3 = Ph, 4-XC6H4 (X = Cl, Me, OMe, NO2, F),
3-ClC6H4, 2-ClC6H4, 2-thienyl
Received: 16.05.2016
Accepted after revision: 30.08.2016
Published online: 14.09.2016
mosphere. They work under mild and neutral conditions
and, hence, acid-sensitive substrates are tolerated. More-
over, it is metal-free, relatively nontoxic, water-tolerant,
and environmentally benign. Microwave-assisted reactions
have several advantages compared with conventional ther-
mal methods. Higher yield and shorter reaction time are
two of the intriguing factors that may prompt organic
chemists to choose this technique.2
The indole nucleus is an important structural motif in
medicinal chemistry. Indole derivatives act as free radical
scavengers and have a broad spectrum of antioxidant activ-
ity.3 Furthermore, the indole nucleus is a vital component
in several drugs used for the treatment of nausea and vom-
iting induced by chemotherapy, and used as antimitotic,
antihypertensive and antineoplastic agents.4
DOI: 10.1055/s-0036-1588887; Art ID: st-2016-b0345-l
Abstract We have developed a simple and efficient method for the
arylation of 3-(aminoalkyl)indoles with aryl alcohols and other aromatic
nucleophiles through C–N bond cleavage under microwave irradiation
to synthesize 3-(α,α-diarylmethyl)indoles. The method uses thiourea as
catalyst, which is environmentally benign, water-tolerant and easy to
handle. Notably, acid-sensitive substrates are tolerated under the reac-
tion conditions. Thiourea activates the tertiary amine through double
hydrogen bonding and converts it into a better leaving group. The reac-
tion proceeds through the formation of vinylogous iminium ion as an
intermediate.
Key words hydrogen-bond-catalyzed, thiourea, microwave, indoles,
vinylogous iminium ion
C-3-Substituted indoles are the key units of many
promising therapeutic agents.5 They are venerable pharma-
cophores for medicinal chemists, especially in the neurosci-
ence arena. They have a wide range of biological applica-
tions; for example, compound A is potent antifungal and
antibacterial agent,6 compound B is a HIV-1 integrase in-
hibitor,7 and compound C functions as an aromatase inhibi-
tor against breast cancer (Figure 1).8
Thiourea/urea based compounds are capable of forming
double hydrogen bonds to substrates. This characteristic of
thiourea compounds enables the development of attractive
methods to activate proton-acceptor substrates such as car-
bonyl compounds or imine-like compounds. Thiourea and
its derivatives are extensively utilized as organocatalysts,
including in asymmetric catalysis.1 Thiourea catalyzed re-
actions are easy to handle and do not require inert gas at-
H
OH
OH
N
N
F
N
O
OH
Br
O
HO
N
N
N
Et
H
H
A, Antifungal, antibacterial
B, HIV-1 integrase
C, Aromatase inhibitor for breast cancer
Figure 1 Some bioactive indole derivatives
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

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M. L. Deb et al.
Letter
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In this context, the synthesis and selective functional-
ization of indoles has been the focus of active research over
the years. Aryl alcohols, such as naphthol derivatives, also
possess many important biological properties, including
antibacterial,9a anti-inflammatory,9b hypotensive and bra-
dycardiac activities.9c Phenolic compounds, most of which
are of plant origin, play a variety of important roles in
plants. Most phenolic substances have important effects on
the defense of plants against herbivores and pathogens.10
They have strong antioxidant properties and therefore,
function as protective agents against many free-radical-
mediated diseases.11
The bioactivity of 3-alkylated indoles (a selection are
depicted in Figure 1) encouraged us to synthesize 3-(α,α-di-
arylmethyl)indoles 3, bearing an aryl hydroxyl functional
group. Only a few reports are available concerning the syn-
thesis of 3. Grimaud and co-workers described a method for
the synthesis of similar compounds.12 They used a three-
component, one-pot approach involving phenol, aldehyde,
and N-benzyl pyrazine and heating at reflux in toluene for
more than two days. The resultant compounds were then
treated with indole in the presence of LiClO4 and dibro-
moethane. The main drawback of the procedure is the re-
quirement for a long reaction time and relatively low yield
of product. Jing and co-workers enantioselectively synthe-
sized 3-substituted indoles having an aromatic hydroxyl
group through the reaction of 2-naphthols and arenesulfo-
nyl alkylindoles in the presence of asymmetric organocata-
lysts.13 The key to this method is the cleavage of a C–S bond,
catalyzed by the thiourea derivative. The reaction has fur-
ther scope for improvement in terms of atom economy,
substrate scope, reaction time, preparation of starting ma-
terial, and catalyst. Wu and co-workers reported another
enantioselective Friedel–Crafts reaction of indole with ter-
minal 1,1-diarylalkene to synthesize phenolic derivatives of
compound 3.14
Despite the progress discussed above, the development
of more proficient routes for the synthesis of such com-
pounds is still required. In a continuation of our work15 on
the development of novel methodologies for the synthesis
of valuable compounds, herein we disclose an efficient
method for the synthesis of 3-(α,α-diarylmethyl)indoles
through arylation of the 3-(aminoalkyl)indoles16 with aryl
alcohols through deamination (Scheme 1). We attempted to
synthesize 3 by using a three-component, one-pot ap-
proach from indole, aldehyde and naphthol or phenol, and a
range of Lewis and Brønsted acid catalysts were screened
for this purpose. However, unfortunately we isolated only
bisindolylmethanes (BIM) instead of the desired product 3.
Therefore, we switched our reaction route to a two-compo-
nent strategy, wherein 3-(aminoalkyl)indoles 1 reacted
with naphthols or phenols 2 in the presence of catalyst. We
chose the synthesis of 3a from the reaction of 1a and 2a as a
model reaction for the optimization of the conditions (Table
1). Low yields were obtained under thermal conditions, ir-
respective of the catalyst and solvent used. A maximum
yield of 64% was obtained by using p-TsOH as catalyst (20
mol%) and MeCN as solvent under reflux (Table 1, entry 4).
Therefore, we performed the reaction under microwave ir-
radiation in an attempt to improve the product yield. Inter-
estingly, when the model reaction was performed in a mi-
crowave reactor, we found that, compared with the result
obtained with p-TsOH as catalyst (80% of 3a; entry 4), the
use of thiourea (30 mol%) as catalyst in MeCN provided ex-
cellent yield of 3a (96%; entry 10) within a few minutes. We
also noted that whereas an increase in the catalyst loading
did not increase the product yield, a reduction in catalyst
loading had a detrimental influence on the yield (entries 11
and 9). Considering that a polar solvent might increase the
yield, water was also used as solvent; however, we observed
a decrease in the product yield in this case, which might be
due to insolubility of the starting materials in H2O (entry
R3
R2
N
R1
R3
R2
HO
thiourea (30 mol%)
N
MeCN
MW, 100 °C
R1
HO
N
R
R
2
1
3
R2
R2
R3
R3CHO
R2
HO
R1
N
N
N
R1
R1
R
R
R
BIM
(unwanted)
Scheme 1 Synthesis of 3-(α,α-diarylmethyl)indoles
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

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M. L. Deb et al.
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Table 1 Optimization of the Reaction Conditionsa
Ph
N
Ph
HO
catalyst
+
N
solvent
MW/Thermal
HN
H
HO
3a
1a
2a
Entry
Catalyst (mol%)
Solvent
Time (min) MW [thermal]
Yield of 3a (%)b MW [thermal]
1
2
–
–
8 [240]
8 [240]
8 [240]
6 [180]
6 [180]
6 [180]
5 [180]
5 [180]
6 [180]
5 [180]
5 [180]
8 [240]
8 [240]
8 [240]
8 [240]
8 [240]
8 [300]
trace [NR]
trace [NR]
25 [20]
–
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
H2O
3
AcOH (20)
p-TsOH (20)
p-TsOH (25)
p-TsOH (15)
TFA (10)
4
80 [64]
5
80 [64]
6
66 [52]
7
75 [55]
8
TFA (15)
70 [55]
9
thiourea (20)
thiourea (30)
thiourea (40)
thiourea (30)
thiourea (30)
thiourea (30)
thiourea (30)
thiourea (30)
urea (30)
75 [40]
10
11
12
13
14
15
16
17
96 [45]
96 [52]
18 [trace]
22 [trace]
15 [20]
CHCl3
toluene
EtOH
DMF
30 [25]
trace [10]
20 [trace]
MeCN
a Reaction conditions (unless otherwise noted): 1a (1.0 mmol, 250 mg), 2 (1.0 mmol, 144 mg), 100 °C for reactions under microwave conditions; under thermal
conditions, the reactions were carried out at reflux except for entry 1 and 16, where the temperature was 100 °C.
b Products were purified by column chromatography and yields are of isolated products. NR: no reaction.
12). To our knowledge, there is no report of thiourea-cata-
lyzed C–N bond cleavage. In addition, one of the major ad-
vantages of the reaction is that the starting materials 1 for
the reactions were smoothly prepared by using the three-
component reaction of indole, aldehyde, and amine.16b
We then monitored the reaction of 2-naphthol with
several 3-(aminoalkyl)indoles, and examined how changes
of the amine moiety affected the yield of 3a. It was ob-
served that Betti bases of dimethylamine furnished the
highest yield of the product (Scheme 2). To examine the ef-
ficiency and generality of this method, a range of substitut-
O
N
N
N
N
Ph
Ph
Ph
Ph
N
N
H
N
H
N
H
1a
1a1
H
1a2
1a3
88%
86%
42%
96%
product 3a
Scheme 2 Screening of 3-(aminoalkyl)indoles. Reagents and conditions: 1 (1.0 mmol), 2-naphthol (1.0 mmol), thiourea (30 mol%), 100 °C (MW), 5 min.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

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M. L. Deb et al.
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Cl
NO2
Me
OMe
HN
HN
HO
HN
HN
HN
HO
HO
3e, 98%, 5 min
HO
HO
3a, 96%, 5 min
3d, 86%, 5 min
3b, 94%, 5 min
3c, 92%, 5 min
OMe
Br
Br
Cl
HN
Me
HO
HN
HO
HN
HN
HN
HO
HO
HO
3h, 93%, 5 min
3i, 91%, 5 min
3j, 86%, 5 min
3f, 96%, 5 min
3g, 91%, 5 min
Cl
Cl
Cl
OMe
S
Br
N
HN
HO
HN
HO
HO
HN
HO
HN
HO
3k, 83%, 5 min
3n, 91%, 5 min
3l, 87%, 5 min
3m, 90%, 5 min
3o, 90%, 5 min
Cl
Br
O
O
O
O
O
O
Me
N
N
HO
HO
HN
HO
HN
HN
HO
HO
3p, 87%, 5 min
3q, 80%, 6 min
NO2
3r, 82%, 6 min
3s, 86%, 6 min
3t, 72%, 7 min
Cl
Br
Me
Me
Me
OMe
Me
Me
HN
3v, 78%, 7 min
HN
HO
HN
HO
HN
HO
HN
HO
HO
3y, 82%, 7 min
3u, 75%, 7 min
3w, 72%, 7 mins.
3x, 71%, 7 min
F
t-Bu
Me
HN
HN
HO
3z1, 74%, 7 min
HO
3z, 78%, 7 min
Figure 2 Substrate scope for the synthesis of 3-(α,α-diarylmethyl)indoles by using aryl alcohols as the nucleophilic source. Reagents and conditions: 1
(1.0 mmol), 2 (1.0 mmol), thiourea (30 mol%, 23 mg), MeCN (0.5 mL), 100 °C. Products were purified by column chromatography and yields are for the
isolated products.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

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M. L. Deb et al.
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Synlett
ed 3-(aminoalkyl)indoles and aryl alcohols were investigat-
ed under the optimized conditions; the results are summa-
rized in Figure 2.17
We next extended our reaction methodology by using
other electron-rich aromatics such as indoles, methoxyben-
zenes, N,N-dimethylaniline, and pyrazoles as the nucleo-
philic sources and obtained very good yields of 3. Reactions
involving indole nucleophiles may provide an alternative
route for the synthesis of unsymmetrical bisindolylmeth-
anes 3aa–ad (Figure 4) that are otherwise difficult to syn-
thesize.
We propose a tentative mechanism for the reaction,
which follows an elimination-addition pathway (Scheme 3).
First, thiourea activates the amine moiety through double
hydrogen bonding and converts it into a better leaving
group. The reaction proceeds through the formation of vi-
nylogous iminium ion (A1) as intermediate. The iminium
ion is then attacked by a molecule of electron-rich aromatic
nucleophile (2), giving A2 (path a), which is subsequently
aromatized to the desired product 3. Similar mechanisms
have good precedent in the literature.19 We did not observe
any product from the C-2 attack of indole by the nucleop-
hile (path b).
The corresponding 3-(α,α-diarylmethyl)indoles, which
contain a wide range of substituents, were obtained in good
to excellent yields. To our delight, both electron-withdraw-
ing and electron-donating substituents on the aryl ring (R3)
of 3 were well tolerated. Electron-donating groups on R3 de-
creased the product yield, whereas electron-withdrawing
groups increased the yield (3d vs. 3e, Figure 2). As expected,
we obtained lower yield of 3, having a phenolic moiety (e.g.,
3t–1; Figure 2). Products 3 were characterized by NMR
spectroscopic as well as X-ray crystallographic analyses
(Figure 3).18
In conclusion, we have developed a simple and efficient
method for the synthesis of 3-(α,α-diarylmethyl)indoles
containing an aromatic hydroxyl functional group such as
naphthol and phenol. The strategy is also applicable to oth-
er electron-rich aromatics. The reaction does not require
the use of any hazardous metal catalyst or Lewis acid. The
method involves the inclusion of thiourea as catalyst, which
is an environmentally benign, easy to handle and inexpen-
sive reagent. Moreover, acid-sensitive substrates are toler-
ated under the reaction conditions. We anticipate that this
method will offer an efficient and cost effective approach to
Figure 3 Crystal structure of 3h; some hydrogen atoms have been re-
moved for clarity
Me
H
N
N
N
H
N
N
Me
Me
H
Me
NH
N
Me
N
Me
H
Me
H
3aa, 94%, 5 min
3ab, 98%, 5 min
3ac, 94%, 5 min
3ad, 51%, 8 min
NO2
OMe
Me
Me
N
N
H
N
H
NMe2
OMe
N
MeO
N
N
H
H2N
N
N
Ph
H
HO
Ph
3ae, 68%, 7 min
3af, 72%, 7 min
3ag, 93%, 6 min
3ah, 91%, 6 min
Figure 4 Substrate scope for the synthesis of 3-(α,α-diarylmethyl)indoles using electron-rich aromatics
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

F
M. L. Deb et al.
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Synlett
S
C
H
H
N
H
N
H
–NMe2
R2
path a
path b
R3
R3
N
R3
R2
H
R2
R1
THU
R1
HO
path a
R1
2
N
N
N
HO
R
–NMe2
R
R
1
[A2]
[A1]
HNMe2
R2
R3
R1
N
R
HO
Scheme 3 A tentative mechanism for the reaction; THU = thiourea
obtain this important class of compounds. Screening of bio-
logical activities of the synthesized compounds is under-
way and will be disclosed in due course.
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Acknowledgment
M.L.D. is thankful to the Science and Engineering Research Board
(SERB), India, for financial support (Grant No. SB/FT/CS-073/2014)
under Fast Track Scheme. P.K.B. is thankful to the Department of Sci-
ence and Technology (DST), New Delhi (Grant No. SB/FT/CS-
100/2012), for financial support. The authors acknowledge Dr. Ranjit
Thakuria, Dept. of Chemistry, Gauhati University for X-ray crystal
structure analysis.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588887.
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p
p
ortioInfgrmoaitn
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ortiInfogrmoaitn
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G

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250 mg), 2-naphthol (1 mmol, 144 mg) and thiourea (30 mol%,
23 mg) in MeCN (0.5 mL) was irradiated in a closed vessel in a
microwave reactor at 100 °C for the specified time. The progress
of the reaction was monitored by TLC. Upon completion of the
reaction, solvent was removed under vacuum and the crude
mixture was purified by column chromatography (hex-
ane/EtOAc) to obtain the desired product 3a. Yield: 335 mg
(96%); gray solid; mp 168–170 °C. IR (KBr): 3420, 3369, 3065,
2925, 1619, 1455, 1207, 747 cm–1. 1H NMR (400 MHz, CDCl3): δ
= 8.08 (d, J = 8.5 Hz, 1 H), 8.04 (br s, 1 H), 7.80 (d, J = 8.1 Hz, 1 H),
7.73 (d, J = 8.8 Hz, 1 H), 7.45–7.14 (m, 10 H), 7.02 (d, J = 8.8 Hz,
1 H), 6.95 (t, J = 7.5 Hz, 1 H), 6.63 (s, 1 H), 6.50 (s, 1 H), 6.15 (br s,
1 H). 13C NMR (100 MHz, CDCl3): δ = 153.7, 141.5, 137.0, 133.0,
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N, 4.09.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–G