Palladium-catalyzed synthesis of 2-allylindole and 2-allylbenzofuran derivatives from 2-((trimethylsilyl)ethynyl)arenes

Article abstract of DOI:10.1016/j.tetlet.2014.10.049

A new protocol for the synthesis of 2-allylindole and 2-allylbenzofuran derivatives has been developed from readily accessible starting material, 2-((trimethylsilyl)ethynyl)arenes via Pd-catalysis. The presence of trimethylsilyl group in the alkyne is vit

Full text of DOI:10.1016/j.tetlet.2014.10.049

Tetrahedron Letters 55 (2014) 6795–6798
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Tetrahedron Letters
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Palladium-catalyzed synthesis of 2-allylindole and 2-allylbenzofuran
derivatives from 2-((trimethylsilyl)ethynyl)arenes
⇑
Amrita Chakraborty, Konanki Jyothi, Surajit Sinha
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 July 2014
Revised 6 October 2014
Accepted 8 October 2014
Available online 23 October 2014
A new protocol for the synthesis of 2-allylindole and 2-allylbenzofuran derivatives has been developed
from readily accessible starting material, 2-((trimethylsilyl)ethynyl)arenes via Pd-catalysis. The presence
of trimethylsilyl group in the alkyne is vital for this reaction. Stereoselectivity of 2-allylindole derivatives
is controlled by the use of different nitrogen-protecting groups for 2-((trimethylsilyl)ethynyl)aniline. The
CO2Me protection gives Z-isomers, whereas acetyl protection gives E-isomers.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Heterocycles
2-((Trimethylsilyl)ethynyl)arenes
Palladium catalysis
Regioselective allylation
Stereoselective allylation
Synthesis of functionalized indoles and benzofurans has been of
considerable interest, because of their wide occurrence in natural
products1 and bioactive synthetic compounds.2 In this context,
the transition-metal catalyzed allylation has emerged as a power-
ful tool for access to functionalized indole and benzofuran deriva-
tives.3 Particularly, the allylative cyclization of 2-alkynylanilines or
2-alkynylphenols, mediated by palladium catalysts, is one of the
most effective synthetic strategies for the construction of 2,3-
disubstituted indoles and benzofuran rings.4 In our earlier report5
on indole-based heterocycle synthesis, we prepared several 3-ally-
lindoles as starting materials by Utimoto’s method4a in the pres-
ence of catalytic amount of Pd(MeCN)2Cl2 and propylene oxide in
THF (Scheme 1A). Interestingly, a 2-allylated indole namely methyl
2-(4-chlorobut-2-enyl)-1H-indole-1-carboxylate was obtained in
49% yield5 when methyl 2-((trimethylsilyl)ethynyl)phenylcarba-
mate was used as starting material under Utimoto’s conditions
(Scheme 1B).
As 2-((trimethylsilyl)ethynyl)arene derivatives 3 are the start-
ing material for this reaction, a variety of 2-iodoarenes 1 were cou-
pled with trimethylsilyl acetylene (2) under Sonogashira coupling
conditions9 to afford 3a–g (Table 1, entries 1–7) in very good to
excellent yields.
Next we focused our attention on the synthesis of 2-allylindoles
via palladium-catalyzed coupling between 2-((trimethylsilyl)ethy-
nyl)aniline derivatives and allyl chlorides. In order to improve the
yield (Scheme 1 and 49%) for allylative cyclization, we tried to
R
Cl
(R = Aryl, Alkyl)
NHCO2Me
(A)
R
Pd(MeCN)2Cl2
N
Despite the obvious synthetic potential of 2-allylindoles,6 the
C2-allylation of indole7 has been less explored compared to the
C3-allylation.8 This led us to a closer view of the regio- and
stereo-selective syntheses of 2-allylindole and 2-allylbenzofuran
CO2Me
O
,
THF, rt, 1 h
Utimoto and co-workers
Cl
SiMe3
Cl
Cl
derivatives further. Herein, we report
a palladium-catalyzed
synthesis of 2-allylindole and 2-allylbenzofuran derivatives from
2-((trimethylsilyl)ethynyl)anilines and 2-((trimethylsilyl)ethynyl)
phenols, respectively, (Scheme 2).
NHCO2Me
(B)
N
Pd(MeCN)2Cl2
CO2Me
O
49%
,
THF, reflux, 2 h
Our previous finding
⇑
Corresponding author. Tel.: +91 33 2473 4971; fax: +91 33 2473 2805.
E-mail address: ocss5@iacs.res.in (S. Sinha).
Scheme 1. Reactions of 3,4-dichloro-1-butene with 2-alkynylanilines.
http://dx.doi.org/10.1016/j.tetlet.2014.10.049
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

6796
A. Chakraborty et al. / Tetrahedron Letters 55 (2014) 6795–6798
as CsF, KOAc, K2CO3, and Cs2CO3 instead of propylene oxide (used
SiMe3
as a proton scavenger4a), gave cyclized product in poor yields
(Table 2, entries 4, 5, 13, and 14). When a higher equivalent
(10 equiv) of 3,4-dichloro-1-butene (4a) was used, yield was sub-
stantially increased to 68% (Table 2, entry 6). A variety of other pal-
ladium catalysts were also screened to check whether less
concentration of 4a can provide comparable yield (Table 2, entries
7–10). Among them Pd(PhCN)2Cl2 was found to be the best catalyst
to give the product in a higher yield (76%, Table 2, entry 10). Fur-
ther, the effect of catalyst loading was checked and it was observed
that the yield got reduced to 35% when 2.5 mol % of catalyst
(Table 2, entry 11) was used and no significant improvement was
observed with 10 mol% catalyst (Table 2, entry 12).
I
(2)
SiMe3
R
R
Pd(PPh3)2Cl2
ZH
ZH
1
CuI, Et3N, rt, 4 h
3
R2
ZH = NHCO2Me, NHAc,
R1
X
OH
R3
(4)
R2
R3
Pd(PhCN)2Cl2
THF, reflux, 2 h
R
R1
Z
O
,
5
65-82% yield
This work
With the optimum conditions on hand,10 the substrate scope of
our present procedure was investigated and the results are sum-
marized in Table 3. A wide range of both 2-((trimethylsilyl)ethy-
nyl)arenes (3a–g) and allyl halides (4a–g) were deployed to
prove the general applicability of the allylative cyclization process
(Table 3, entries 1–13). In accordance with Utimoto’s proposition4a
for a related reaction (Scheme 1) the coupling took place between
Scheme 2. Palladium-catalyzed synthesis of 2-allyl heteroarenes.
Table 1
Synthesis of 2-((trimethylsilyl)ethynyl)arenes
SiMe3
I
(2)
SiMe3
2-((trimethylsilyl)ethynyl)arenes and
c-position of allyl halides
R
R
Pd(PPh3)2Cl2, CuI
THF/Et3N (2:1)
regioselectively to afford the desired products in good yields. The
reaction is equally effective for indole rings and benzofurans as
well. The most significant feature of the reaction is the stereo-
chemical control of the allylindole derivatives by suitable choice
of the protecting group either carbomethoxy or acetyl of 2-((tri-
methylsilyl)ethynyl)aniline (Table 3, entries 1–5). Thus carbome-
thoxy protected substrates provided selectively (Z)-2-allylindole
derivatives (Table 3, entries 1–3) whereas acetyl protected sub-
strates produced the corresponding (E)-isomers (Table 3, entries
4 and 5). However, 2-allylbenzofurans were obtained as E/Z mix-
tures (Table 3, entries 6 and 7). Using this standard reaction condi-
tions, when indolization reactions were carried out with allyl
halides 4d, 4e, and 4f, the desired products were obtained in poor
yields (12–18%). In an attempt to solve this problem, excess
amount of allyl halides (4d, 4e, and 4f), propylene oxide, and pal-
ladium catalyst were employed in the allylation reaction. Under
this modified conditions, 3g and 3a furnished very good yields of
5gd, 5ge, and 5af (Table 3, entries 10–12). In case of allyl halides
4d and 4e, a trace amount of 2,3-diallylindoles (Table 3, entries
ZH
ZH
1
3
Entry
R
ZH
Product
Yielda,b (%)
1
2
3
4
5
6
7
H
4-Cl
5-Cl
H
4-Me
H
NHCO2Me
NHCO2Me
NHCO2Me
NHAc
NHAc
NHAc
3a
3b
3c
3d
3e
3f
89
85
86
77
79
87
86
4-Me
NHCO2Me
3g
a
All reactions were carried out with substrate (1 mmol), alkyne (1.2 equiv),
CuI (5 mol %), and Pd(PPh3)2Cl2 (2.5 mol %) in THF/Et3N (2:1) mixture at room
temperature under Ar atmosphere for 4 h.
b
Isolated yield.
optimize the reaction conditions with 3a (Table 2). The choice of
solvent proved to be crucial and only THF promoted this reaction
(Table 2, entries 1–3). Notably, treatment with common bases such
Table 2
Optimization of the reaction conditions for the allylative cyclization of 3a
SiMe3
Cl
Cl
+
N
Cl
CO2Me
NHCO2Me
5aa
3a
4a
Entry
Catalyst (mol %)
Proton scavenger/base (equiv)
4a (equiv)
Solvent
Temp (°C)
Time (h)
Yielda,b (%)
1
2
3
4
5
6
7
8
Pd(MeCN)2Cl2 (5)
Pd(MeCN)2Cl2 (5)
Pd(MeCN)2Cl2 (5)
Pd(MeCN)2Cl2 (5)
Pd(MeCN)2Cl2 (5)
Pd(MeCN)2Cl2 (5)
Pd(PPh3)2Cl2 (5)
PdCl2 (5)
Propylene oxide (5)
Propylene oxide (5)
Propylene oxide (5)
KOAc (2.5)
4
4
4
4
4
10
5
5
5
5
5
5
5
5
THF
MeCN
DMF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
66
75
100
66
66
66
66
66
66
66
66
66
66
66
2
12
12
12
12
2
12
10
10
2
49
nrc
nrc
19
22
68
nrc
16
37
76
35
76
22
18
CsF (2.5)
Propylene oxide (5)
Propylene oxide (5)
Propylene oxide (5)
Propylene oxide (5)
Propylene oxide (5)
Propylene oxide (5)
Propylene oxide (5)
K2CO3 (2.5)
9
Pd(OAc)2 (5)
10
11
12
13
14
Pd(PhCN)2Cl2 (5)
Pd(PhCN)2Cl2 (2.5)
Pd(PhCN)2Cl2 (5)
Pd(PhCN)2Cl2 (5)
Pd(PhCN)2Cl2 (5)
2
2
12
12
Cs2CO3 (2.5)
Entry 10 is showing the optimum conditions of this reaction.
a
All reactions were carried out in 0.20 mmol scale in solvent (2 mL) under Ar atmosphere.
Isolated yield.
No conversion was observed.
b
c

A. Chakraborty et al. / Tetrahedron Letters 55 (2014) 6795–6798
6797
Table 3
Synthesis of 2-allylindole and 2-allylbenzofuran derivatives
R3
SiMe3
R2
R2
Pd(PhCN)2Cl2
R1
X
+
R
R
R1
O
Z
R3
ZH
, THF, reflux, 2 h
3
4
5
Entry
1
Substrate (3)
Allyl halide (4)
Product (5)
Yielda,b (%)
Stereoselectivity (5)
SiMe3
Cl
N
3a
3b
3c
3d
3e
3f
4a
5aa
5ba
5ca
5da
5ea
5fa
5fb
5fe
76
Z
Cl
Cl
CO2Me
NHCO2Me
SiMe3
Cl
Cl
Cl
Cl
Cl
Cl
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4b
4c
72
79
74
71
82
80
65
Z
Cl
Cl
N
CO2Me
NHCO2Me
SiMe3
N
Z
Cl
Cl
CO2Me
NHCO2Me
SiMe3
Cl
E
Cl
Cl
N
NHAc
Ac
SiMe3
Cl
E
Cl
Cl
N
NHAc
SiMe3
Ac
Cl
O
O
E/Z
E/Z
—
Cl
Cl
OH
OH
OH
SiMe3
SiMe3
Cl
3f
Cl
Cl
Cl
3f
O
SiMe3
Cl
Cl
Cl
9
3g
4c
5gc
77
—
N
NHCO2Me
SiMe3
CO2Me
10c,d
11c,d
12c
3g
3g
3a
4d
4e
4f
5gd
5ge
5af
66
73
68
—
—
—
N
Br
CO2Me
NHCO2Me
SiMe3
N
Cl
CO2Me
NHCO2Me
SiMe3
Br
Br
N
Br
CO2Me
NHCO2Me
SiMe3
Br
13
3a
4g
5ag
0
—
NHCO2Me
N
CO2Me
a
All reactions were carried out with substrate 3 (0.50 mmol), allyl halide 4 (5 equiv), propylene oxide (5 equiv), and Pd(PhCN)2Cl2 (5 mol %) in THF (5 mL) under Ar
atmosphere at 66 °C for 2 h unless otherwise mentioned.
b
Isolated yield.
c
Reactions were carried out with allyl halide (>15 equiv), propylene oxide (>15 equiv), and Pd(PhCN)2Cl2 (10 mol %).
Trace amounts of 2,3-diallylindole derivatives were obtained.
d

6798
A. Chakraborty et al. / Tetrahedron Letters 55 (2014) 6795–6798
TBAF
compound 8, copies of decoupled spectra of compound 5aa and
(7 equiv)
proposed mechanism of allylative cyclization reaction) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2014.10.049.
Cl
THF
N
H
N
CO2Me
reflux, 2 h
6
5aa
74%
H
N
References and notes
O
O
7
( )
N
H
H
H
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Figure 1. X-ray crystal structure of
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8 (thermal ellipsoids are drawn at 30%
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10 and 11) were obtained. We also tried to extend the synthetic
scope of this reaction by including cinnamyl bromide 4g; however
this did not give any positive result under our present experimen-
tal conditions (Table 3, entry 13).
In order to establish the regioselectivity of 5aa, we prepared 2-
(buta-1,3-dienyl)-1H-indole 6 by applying our previously devel-
oped methodology.9 Next, the Diels–Alder reaction was performed
between diene 6 and maleimide 7 at room temperature, which led
to the formation of crystallizable endo adduct 811 in 83% yield
(Scheme 3). The structure of the compound 8 was confirmed by
the X-ray crystallographic analysis (Fig. 1).
In summary, we have found a general method for the efficient
synthesis of 2-allylindoles and 2-allylbenzofurans from readily
accessible starting materials. Significantly, the stereoselectivity of
2-(4-chlorobut-2-enyl)-1H-indoles can be controlled by proper
choice of the nitrogen-protecting group of the corresponding 2-
((trimethylsilyl)ethynyl)anilines leading to either E or Z isomers.
To the best of our knowledge we are not aware of any report for
such a selective formation of 2-allylindole derivatives.
9. Chakraborty, A.; Sinha, S. Tetrahedron Lett. 2011, 52, 6635–6638.
10. General procedure for the synthesis of 2-allyl heteroarenes 5: To
degassed solution of silyl ethynylarenes 3 (0.50 mmol) in dry THF (3.0 mL)
under argon were added propylene oxide (2.5 mmol), allyl halides
a stirred
4
(2.5 mmol), and Pd(PhCN)2Cl2 (0.025 mmol). The yellowish solution was
degassed again and stirred under reflux for 2 h (TLC). Then the crude
reaction mixture was cooled to room temperature and concentrated under
reduced pressure. The residue was purified by flash column chromatography
over silica gel using diethyl ether in petroleum ether (0–4%) as eluent to
furnish 2-allyl heteroarenes 5 in good yields.
Acknowledgments
This procedure was followed for the preparation of 5aa–5gc (Table 3, entries
1–9).
Characterization data for the compound 5aa are given below:
S.S. thanks Department of Science and Technology (DST), India,
for financial support by a grant [SR/S1/OC/0087/2012]. For the
fellowships, A.C. is thankful to IACS and K.J. is thankful to NIPER,
CSIR-IICB. We also thank S. Ganguly and R. Dutta of this institute
for their help in crystal structure determination.
A
colorless liquid (94 mg, 76% yield) was isolated by flash column
chromatography over silica gel (1% diethyl ether/petroleum ether). IR (neat/
CHCl3) 3070, 3045, 3030, 2954, 2906, 2852, 1739, 1653, 1593, 1568, 1456,
1440, 1375, 1327, 1306 cmÀ1 1H NMR (CDCl3, 400 MHz) d 8.07 (d, J = 8.0 Hz,
m
;
1H), 7.46 (d, J = 7.6 Hz, 1H), 7.29–7.20 (m, 2H), 6.41 (s, 1H), 5.92–5.81 (m, 2H),
4.19 (dd, J = 5.2, 2.8 Hz, 2H), 4.06 (s, 3H), 3.87 (d, J = 6.4 Hz, 2H); 13C NMR
(CDCl3, 100 MHz) d 152.6, 139.2, 136.7, 130.8, 129.4, 127.6, 124.0, 123.3, 120.2,
115.8, 108.8, 53.8, 39.4, 28.1; HRMS (ESI): m/z [M+H]+ calcd for C14H15ClNO2:
264.0791, found: 264.0786.
Supplementary data
11. X-ray crystallographic data for compound
8 have been deposited to the
Supplementary data (procedures of compounds 3, 5gd, 5ge, 5af,
6 and 8, spectral data, copies of NMR spectra, crystal data of
Cambridge Crystallographic Data Centre and assigned the deposition numbers
CCDC 1002032 for 8.