Synthesis of Polysubstituted 3-Chalcogenated Indoles through Copper(I) Iodide-Catalyzed Three-Component Domino Reactions

Article abstract of DOI:10.1055/s-0037-1611691

Polysubstituted 3-chalcogenated indoles were synthesized by a three-component, one-pot, domino reaction of a N -(2-bromophenyl)trifluoroacetamide, a 1-alkyne, a disulfides or diselenides, CuI, and proline in DMF. In this process, tandem Sonogashira coupling, N-cyclization, and sulfenyl/selenyl electrophilic substitution occurred sequentially and smoothly to form the anticipated products in good to excellent yields (20 examples; 65-96%). Notably, no palladium catalyst was used in this catalytic system, supporting its cost effectiveness and potential industrial application.

Full text of DOI:10.1055/s-0037-1611691

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–F
letter
A
en
R. Gou et al.
Letter
Synlett
Synthesis of Polysubstituted 3-Chalcogenated Indoles through
Copper(I) Iodide-Catalyzed Three-Component Domino Reactions
R2
Rui Gou
S(Se)Ar
Br
Yi Zhang
20 examples; up to 96% yield
One-pot, three-component
[Pd] free
Ar2S2 or Ar2Se2
O
R2
Sheng-wei Wu
CuI, proline
Cs2CO3, DMF
N
N
H
CF3
R1
R1
H
Feng Liu*
0
0
0
0-
0
0
0
1-7
9
1
0-7
2
7
0
School of Perfume and Aroma Technology, Shanghai Institute of
Technology, 100 Haiquan Rd., Shanghai 201418, P. R. of China
liufeng@sit.edu.cn
Received: 05.10.2018
Accepted after revision: 18.11.2018
Published online: 11.12.2018
ment of general and efficient methodologies for the synthe-
sis of polysubstituted 3-chalcogenated indoles is highly de-
sired.
DOI: 10.1055/s-0037-1611691; Art ID: st-2018-w0637-l
Abstract Polysubstituted 3-chalcogenated indoles were synthesized
by a three-component, one-pot, domino reaction of a N-(2-bromophe-
nyl)trifluoroacetamide, a 1-alkyne, a disulfides or diselenides, CuI, and
proline in DMF. In this process, tandem Sonogashira coupling, N-cycliza-
tion, and sulfenyl/selenyl electrophilic substitution occurred sequential-
ly and smoothly to form the anticipated products in good to excellent
yields (20 examples; 65–96%). Notably, no palladium catalyst was used
in this catalytic system, supporting its cost effectiveness and potential
industrial application.
S
O
N
N
CO2Na
Cl
MK-0591
OMe
MeO
Key words indoles, copper catalysis, Sonogashira reaction, cycliza-
tion, electrophilic substitution, One-pot reaction
MeO
R2–5
O
Se
O
O
R
Indole moieties are widely present in materials, dyes, bi-
ologically active compounds, natural products, and phar-
maceutical agents.1 Among the numerous indole nuclei,
polysubstituted 3-chalcogenated indoles have recently at-
tracted considerable attention from both academia and the
pharmaceutical industry, due to their curative effects in a
variety of diseases such as HIV, cancer, heart disease, aller-
gies, and obesity.2 For instance, MK-0591 (Figure 1) is a po-
tential leukotriene biosynthesis inhibitor of calcium iono-
phore (A-23187)-stimulated LTB4 formation in intact cells,
with an IC50 value of 8 nM.2a A series of arylthioindole (ATI)
derivatives have been shown to inhibit tubulin polymeriza-
tion, leading to a large increase in HeLa cells (56%) in the
G2/M phase at 24 hours and hyperploid cells (26%) at 48
hours.2c Furthermore, 3-(3,4,5-trimethoxyphenyl)seleno-
1H-indoles and the corresponding selenoxides have been
designed as a new class of combretastatin A-4 analogues
that exhibit significant antiproliferative activity, with some
showing nanomolar IC50 values.2e Therefore, the develop-
S
N
O
O
R1
H
R6–8
3-[(3,4,5-trimethoxyphenyl)seleninyl]-1H-indoles
N
H
1st series ATIs
R1 = Me, Et; R2–6 = H, Cl, OMe
Figure 1 Biologically active polysubstituted 3-chalcogenated indoles
Many efforts have been made in this regard [Scheme
1(a)], including direct sulfenylation/selenylation at the 3-
position of the indole nucleus by using various sulfenylat-
ing/selenylating agents,3 palladium/copper-catalyzed cross-
coupling of N,N-dialkyl-o-iodoanilines to terminal alkynes and
subsequent electrophilic cyclization with arylsulfenyl chlo-
rides,4 palladium-catalyzed annulation of 2-(1-alkynyl)ben-
zenamines with disulfides,5 and tandem reactions of 2-
[gem-dibromo(chloro)vinyl]anilines with disulfides/disele-
nides.6 However, most of the reported methods involve the
use of expensive catalysts or reagents, require multistep re-
actions, or have a certain degree of complexity. Thus, the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

B
R. Gou et al.
Letter
Synlett
development of easily handled, nonprecious-metal-cata-
lyzed, and highly substance-adaptable strategies for syn-
thesizing polysubstituted 3-chalcogenated indoles remains
a challenging area.
being recovered (Table 1, entry 1). We then tested several
protecting groups on 1a (R = COCF3, Ac, Ts, Boc) in an at-
tempt to promote the coupling/cyclization process (entries
2–5). The results indicated that the ortho-substituent effect
of the NHCOCF3 group plays a key role in this transforma-
tion (entry 2). A series of copper salts were then tested, and
CuI was found to be the most effective, affording the target
product 3a in 75% yield (entry 2). Various additives were
also studied, of which proline was the most efficient in this
reaction system (entries 2 and 9–14). To identify the opti-
mal conditions, various bases (K2CO3, Na2CO3, Cs2CO3, DBU,
and Et3N) were screened (entries 2 and 15–18). Cs2CO3 gave
the best results, forming 3a in 87% yield (entry 16). Organic
bases such as DBU and Et3N were totally ineffective, and no
product was obtained (entries 17 and 18). Finally, the effect
of the solvent was investigated, and it was found that polar
aprotic solvents were necessary for this reaction (entries 16
and 19–25); DMF appeared to be the most suitable solvent.
Increasing the loading of diphenyl disulfide (4a) to one
equivalent resulted in no improvement in the yield (entry
26). When the reaction mixture was stirred at 100 °C under
an inert atmosphere for 24 hours and then cooled to room
temperature, only 15% of the target compound was ob-
tained after workup; this was accompanied by a large
amount of 2-phenylindole as a byproduct (entry 27).
R3
a) Previous work:
S(Se)
R2
R2
Various starting materials
N
N
H
R1
R1
H
Ar
S(Se)
R3
N
R2
R3
R3
I
NMeR2
NMeR2
Pd/Cu
R1
R1
R1
Ph
Br
S(Se)
Br
COMe
NO2
Br
NHMs
N
R1
R1
H
R1
b) This work:
S(Se)R3
R2
R32S2 or R32Se2
Br
R2
One-pot, three-component
[Pd] free
O
N
CuI, proline
R1
H
N
CF3
Cs2CO3, DMF
R1
H
With the optimal reaction condition in hand, the gener-
ality and substrate scope of the N-(2-bromophenyl)trifluo-
roacetamide 1, the 1-alkyne 2, and the disulfide/diselenide
4 were examined (Scheme 2). First, a series of commercially
available 1-alkynes were tested, and it was found that both
aromatic and aliphatic alkynes reacted smoothly with N-(2-
bromophenyl)trifluoroacetamides and diphenyl disulfide
to afford the corresponding polysubstituted 3-sulfenylin-
doles 3a–m in good to excellent yields. These results
demonstrated that aryl alkynes containing an electron-
withdrawing group (Cl) had a positive effect on the reac-
tion; compare 3a (87% yield) with 3c (91%) or 3f (93%) with
3h (96%). On the other hand, electron-donating groups
(OMe) had the opposite effect; compare 3a (87%) with 3b
(85%) or 3f (93%) with 3g (91%). Also, 2-ethynylthiophene
was a good coupling partner, forming the expected product
3m in 91% yield. When an aliphatic alkyne (hex-1-yne) was
treated with substituted N-(2-bromophenyl)trifluoroacet-
amides and diphenyl disulfide (4a) under the usual reaction
conditions, the corresponding product 3d and 3i were ob-
tained yields of 78% and 80%, respectively. It was interesting
that ethynyl(trimethyl)silane also readily reacted in this
system to generate the 3-sulfenylindoles 3e, 3j, and 3l in
good yields. In these three cases, the TMS group was
cleaved spontaneously when the cyclized product was
formed. Next, various N-(2-bromophenyl)trifluoroacet-
amides were tested in this one-pot process. An electron-do-
nating 5-methyl group on the N-(2-bromophenyl)trifluoro-
acetamide improved the yield from 85% (3b) to 91% (3g).
The same electronic effect was partly observed in the yield
Scheme 1 (a) Published protocols. (b) One-pot three-component reac-
tion for the synthesis of polysubstituted 3-chalcogenated indoles
Here, we report a novel and efficient tandem reaction of
N-(2-bromophenyl)trifluoroacetamides, 1-alkynes, and di-
sulfides or diselenides to give polysubstituted 3-sulfe-
nyl(selenyl)indoles by a copper-catalyzed, three-compo-
nent, one-pot reaction (Scheme 1b).
At the beginning, we used a model reaction to screen for
optimal conditions (Table 1). We proposed that this reac-
tion might be performed as a tandem sequence, with a Cu-
catalyzed Sonogashira coupling and cyclization as the first
step7 and sulfenylation of the indole skeleton intermediate
as the second step. For the second step, we surmised that
0.5 equivalents of phenyl disulfide should be enough to
permit sulfenylation, once this was oxidized to PhS+.8 We
then designed a one-pot stepwise reaction with a 2-bro-
moaniline 1a (1 equiv), ethynylbenzene (2a; 2 equiv), and
diphenyl disulfide (4a; 0.5 equiv) as starting materials. Af-
ter the first coupling/cyclization step under an inert gas at-
mosphere, we exposed the reaction system to air so that O2
would act as a green oxidant in the second reaction step.
Initially, we coupled 2-bromoaniline (1aa) to ethynylben-
zene (2a), and diphenyl disulfide (4a) in the presence of
CuI, proline, and K2CO3 by heating to 100 °C in DMF under
N2 for 12 hours. The cap of the reaction tube was then
opened, and the mixture was stirred for another 12 hours
at 100 °C. In this case, the target product was obtained, but
in a relatively low yield, with most of the starting materials
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

C
R. Gou et al.
Letter
Synlett
Table 1 Optimization of the Conditions for the Model Reactiona
L1: proline
L2: N-methylglycine
L3: N,N-dimethylglycine
L4: glycine
Ph
2 a
SPh
Br
Ph2S2 4 a
L5: PPh3
L6: 1,10-phenanthroline
L7: bis(diphenylphosphino)methane
"Cu", additive(L)
base, solvent
N
NHR
H
3 a
1 aa: R = H
1 ab: R = COCF3
1 ac: R = COCH3
1 ad: R = Ts
1 ae: R = Boc
Entry
[Cu]
ArBr
L
Base
K2CO3
Solvent
Yieldb (%)
1
CuI
CuI
CuI
CuI
CuI
1aa
1ab
1ac
1ad
1ae
1ab
1ab
1ab
1ab
1ab
1ab
1ab
1ab
1ab
1ab
1ab
1ab
1ab
1ab
1ab
1ab
1ab
1ab
1ab
1ab
1ab
1ab
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
DMF
8
2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Cs2CO3
DBU
DMF
75
18
5
3
DMF
4
DMF
5
DMF
–
6
CuCl
DMF
29
15
29
61
55
37
11
35
25
9
7
CuBr
Cu2O
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
DMF
8
DMF
9
DMF
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26c
27d
DMF
DMF
DMF
DMF
DMF
DMF
DMF
87
–
DMF
Et3N
DMF
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
EtOH
CH3CN
NMP
10
18
56
64
–
DMSO
pyridine
toluene
1,4-dioxane
DMF
–
10
87
15
DMF
a Reaction conditions: ArBr 1a (1 mmol), 2a (1 mmol), 4a (0.5 mmol), base (2 mmol), CuX (0.1 mmol), additive (L) (0.3 mmol), solvent (2 mL), sealed tube, N2,
100 °C, 12 h; then, exposure to air, 12 h.
b Isolated yield.
c Ph2S2 (1 mmol) was added.
d The reaction was stirred under N2 for 24 h.
of other substrates: compare 3a (87%) and 3f (93%) or 3c
(91%) and 3h (96%). In contrast, electron-withdrawing
groups were less effective; compare 3b (85%) and 3k (78%).
Likewise, the reaction system tolerated substitution of the
diaryl disulfide with chloro or methyl groups on the aryl
ring, forming the respective products 3n–p in reasonable
yields.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

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S(Se)Ar
R2
CuI (0.1 equiv)
proline (0.3 equiv)
NHCOCF3
R2
+
Ar2S2 or Ar2Se2
+
R1
Br
Cs2CO3 (2 equiv), DMF
100 °C, 12 h
N
R1
H
2
4
1
3
SPh
SPh
SPh
SPh
n-C4H9
Cl
OMe
N
N
H
N
H
N
H
H
3d, 78%
3c, 91%
3b, 85%
3a, 87%
SPh
SPh
SPh
SPh
OMe
Cl
N
N
N
N
Me
Me
Me
H
H
H
H
3g, 91%
SPh
3f,93%
3h, 96%
3e, 68%
SPh
SPh
SPh
OMe
n-C4H9
N
H
O2N
N
N
N
H
O2N
Cl
Me
Me
H
H
3k, 78%
3l, 65%
3j, 73%
3i, 80%
Cl
Me
SPh
S
S
S
S
N
H
Me
N
H
N
N
H
H
3m, 91%
3p, 85
SePh
3n, 82%
3o, 79%
SePh
SePh
SePh
OMe
n-C4H9
N
Me
N
N
N
H
H
H
H
3t, 88%
3r, 84%
3q, 85%
3s, 80%
Scheme 2 CuI-catalyzed multicomponent reaction with disulfides/diselenides
We then explored the use of this catalyzed system for
the synthesis of polysubstituted 3-selenylindoles by using
diphenyl diselenide as the selenylating reagent. To our de-
light, the general reaction conditions worked efficiently
with 1-alkynes and substituted N-(2-bromophenyl)trifluo-
roacetamides to give 3q–t in good to excellent yields. How-
ever, efforts to synthesis 3-(alkylthio)indoles were unsuc-
cessful, as only the 2-substituted indole product was
formed under the general coupling conditions.
To further explore the reaction mechanism, we per-
formed the following control experiments (Scheme 3). First,
1ab was treated with 2a to form 2-phenyl-1H-indole (5),7
which was subjected to sulfenylation at the 3-position in
the presence of 0.5 equivalents of Ph2S2 and Cs2CO3 under
air (Scheme 3, upper). Next, 2-bromoaniline (1aa) was cou-
pled with 2a9 and, after amide formation, the resulting
compound 6 was subjected to a tandem cyclization/sulfenyl
substitution to form 3a; in this case CuI/proline was neces-
sarily to obtain the target product 3a.
On the basis of these results, we propose two catalytic
reaction mechanisms (Scheme 4). First, the alkyne 2 is
deprotonated and reacts with the Cu complex A to form the
copper acetylide intermediate B. Complex C, generated in
situ, then couples with aryl bromide 1 to give the four-cen-
tered transition state D.10 Next, the coupling intermediate E
is formed by elimination of the copper complex F. Mean-
while, the disulfide/diselenide is oxidized to PhS+/PhSe+; for
Path I, PhS+/PhSe+ undergoes electrophilic addition with E
to form G, and trifluoroacetyl-promoted annulation of in-
termediate G gives the target product 3.7 For Path II, inter-
mediate E cyclizes to form indole anion H, and then cap-
tured the PhS+/PhSe+ ion to form target product 3 with re-
lease of an iodide anion. In both paths, halogen exchange of
the departing iodide ion with intermediate F regenerates
the copper complex A to complete the catalytic cycle.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

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Letter
Synlett
SPh
Ph
2 a
NHCOCF3
Br
Ph2S2 (0.5 equiv)
CuI, proline
Cs2CO3 (2 equiv), DMF
air, 100 °C, 12 h
88%
N
N
K2CO3, DMF
N2, 80 °C, 12 h
95%
H
H
1 ab
5
3a
SPh
1)
Ph
2 a
Ph2S2
CuI (0.1 equiv)
proline (0.3 equiv)
NHCOCF3
CuI, N,N-dimethylglycine
K2CO3, DMF, N2, 100 °C
NH2
Br
N
H
Cs2CO3 (2 equiv), DMF
air, 100 °C, 12 h
75%
2) Tf2O, CH2Cl2, Et3N, r.t
6
3a
1 aa
Scheme 3 Control experiments
CuI
L
Ph
Y
L=proline
R2
R1
+ Cs2CO3
CsI
R2
2
Cu
Br
[O]
L
I
ArY
1/2 Ar2Y2
L
NH
CsHCO3
Base
A
I
O
CF3
G
Path I
L
R1
L
Cu
L
L
Br
Cu
L
R2
L
YAr
C
Y = S, Se
F
C
E
R2
NH
CF3
R2
B
O
Base
N
R1
H
3
L
L
CuL2
Br
Cu
C
C
R2
Path II
L
L
C
C
–
C
R2
R2
NH
[O]
Br
N
ArY
1/2 Ar2Y2
D
R1
H
O
CF3
H
NHCOCF3
R1
1
Scheme 4 Proposed mechanism
In conclusion, we have developed a novel and facile
route for the synthesis of polysubstituted 3-chalcogenated
indoles through a tandem Sonogashira coupling reaction,
trifluoroacetyl-promoted N-cyclization, and sulfenyl/sele-
nyl electrophilic substitution. The reactions were carried
out in one pot by using CuI/proline as the catalyst system,
and were applied to a range of N-(2-bromophenyl)trifluo-
roacetamides, aryl or aliphatic alkynes, and substituted dia-
ryl disulfides/diselenides as substrates. Further investiga-
tion on the application of this strategy is currently under-
way.
ipal Education Commission and Shanghai Institute of Technology for
financial support.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611691.
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References and Notes
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Funding Information
This work was supported by the National Natural Science Foundation
of China (Grants 21302126). The authors also thank Shanghai Munic-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

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Letter
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(11) 2-Phenyl-3-(phenylthio)-1H-indole (3a); Typical Procedure
A sealable reaction tube equipped with a magnetic stirrer bar
was charged with 2-N-(2-bromophenyl)-2,2,2-trifluoroacet-
amide (1ab; 1 mmol), ethynylbenzene (2a; 1 mmol), Ph2S2 (0.5
mmol), Cs2CO3 (2 mmol), CuI (0.1 mmol), proline (0.3 mmol),
and DMF (2 mL). The reaction vessel was placed in an oil bath at
100 °C under N2, and the mixture was stirred at this tempera-
ture for 12 h. The cap was then opened and the mixture was
stirred at the same temperature for another 12 h. It was then
cooled to r.t., diluted with EtOAc, and washed with H2O and
brine, then dried (MgSO4) and concentrated under reduced
pressure. The residue was purified by column chromatography
[silica gel, hexane–EtOAc (10:1)] to give a pale-yellow solid;
yield: 265 mg (88%); mp 139–141 °C.1H NMR (500 MHz, CDCl3):
 = 8.56 (s, 1 H), 7.80 (d, J = 7.2 Hz, 2 H), 7.71 (d, J = 7.9 Hz, 1 H),
7.48 (m, 3 H), 7.42 (t, J = 7.2 Hz, 1 H), 7.33 (t, J = 7.5 Hz, 1 H),
7.21 (m, 3 H), 7.17 (d, J = 7.5 Hz, 2 H), 7.10 (t, J = 7.2 Hz, 1 H). 13
C
NMR (125 MHz, CDCl3):  = 140.84, 139.11, 135.97, 134.65,
131.20, 129.83, 129.42, 129.05, 125.71, 124.98, 123.66, 121.47,
120.10, 111.45, 99.97. HRMS (ESI): m/z [M + Na]+ calcd for
(4) (a) Larock, R. C.; Yum, E. K. J. Am. Chem. Soc. 1991, 113, 6689.
(b) Chen, Y.; Cho, C.-H.; Larock, R. C. Org. Lett. 2009, 11, 173.
(c) Chen, Y.; Cho, C.-H.; Shi, F.; Larock, R. C. J. Org. Chem. 2009,
74, 6802.
C
20H15NNaS+ = 324.0817; found: 324.0819.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F