ZnCl2 and Pd/C catalyzed synthesis of 2-substituted indoles

Article abstract of DOI:10.1016/j.tetlet.2013.09.061

A facile, mild, efficient, and copper-free method has been developed for the synthesis of 2-substituted indoles via domino Sonogashira coupling/cyclization reaction catalyzed by ZnCl₂ and palladium on carbon with simultaneous formations of C-C and C-N bonds.

Full text of DOI:10.1016/j.tetlet.2013.09.061

Accepted Manuscript
ZnCl and Pd/Ccatalyzed synthesis of 2-substituted indoles
2
Atiur Ahmed, Munmun Ghosh, Pompy Sarkar, Jayanta K. Ray
PII:
S0040-4039(13)01615-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.09.061
TETL 43561
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
7 August 2013
13 September 2013
14 September 2013
Please cite this article as: Ahmed, A., Ghosh, M., Sarkar, P., Ray, J.K., ZnCl and Pd/Ccatalyzed synthesis of 2-
2
substituted indoles, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.09.061
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Graphical Abstract:
ZnCl2 and Pd/C catalyzed synthesis of 2-substituted indoles
Atiur Ahmed, Munmun Ghosh, Pompy Sarkar, and Jayanta K. Ray*
10% Pd/C (5 mol%)
ZnCl2 (10 mol%)
R'
I
R'
R
+
R
N
NHTs
DMF, Et3N, PPh3
110 0C, 2-3h
Ts
upto 97 % yield
1

ZnCl2 and Pd/C catalyzed synthesis of 2-substituted indoles
Atiur Ahmed, Munmun Ghosh, Pompy Sarkar, and Jayanta K. Ray*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
ABSTRACT: A facile, mild, efficient and copper-free method has been developed for the
synthesis of 2-substituted indoles via domino Sonogashira coupling / cyclization reaction
catalyzed by ZnCl2 and palladium on carbon with simultaneous formations of C-C and C-N
bonds.
Keywords: 2-Substituted indoles, palladium on carbon, ZnCl2, Sonogashira coupling
Indole nucleus is present as a prominent structural motif in a wide range of both natural and
unnatural biologically active compounds, pharmaceutical agents and polymer materials (Figure
1).1 The 2-aryl indole skeleton is found in diverse biologically active molecules exhibiting
antiestrogen 5-H-T2A antagonist, anti-inflammatory and cytotoxic properties.2 Due to such
biological importance, indole moieties have become the synthetic targets of many organic and
medicinal chemistry groups over the last few decades.1a,3 Substrate availability, a variety of
functional group tolerance and one -pot synthesis have made palladium-catalyzed annulation of
2-haloanilines with alkynes an attractive and powerful methodology.4-7 The annulation with
monosubstituted alkynes was first reported by Yamanaka in which 2-substituted indoles were
afforded with Pd(PPh3)2Cl2-CuI-Et3N system.4,5 And now the strategies have been widely used in
the synthesis of bioactive materials and natural products.6,7
COOR
CH3
CONHR
CH3
H3CO
H3CO
N
N
O
O
Cl
Cl
Figure 1: Biologically active compounds containing indole moieties.
2

Recently palladium on carbon (Pd/C), a heterogeneous catalyst system has proven its versatility
8
in the development of carbon-carbon, and carbon-heteroatom9 bond formations. The great
significance of the heterogeneous system, particularly its stability in air, reusability and no
contamination in the desire product, 10 has drawn our attention to extrapolate the course of our
ongoing research work on palladium catalyzed cyclization to heterocycles based on the „one-pot‟
annulation strategy.
Sonogashira reactions are mostly done with Pd(II) complex as catalyst, CuI as co-catalyst and
amine as a base,11 whereas Negishi reactions are best achieved by performing cross-coupling
between either discrete or in situ generated zinc (II) acetylides and aryl halides in the presence of
palladium-phosphine catalyst.12 ,13 Crisp et al. reported an efficient coupling method between
terminal alkynes and ArX (X = Br, I ) in the presence of [Pd(PPh3)4]-ZnCl2-amine-NaI or iodine
system.8 According to the best of our knowledge, ZnCl2 has not been used as co-catalyst in the
synthesis of 2-substituted indoles particularly with regard to the yield of the desire product.
Herein, we report ZnCl2 and Pd/C catalyzed mild and efficient synthesis of 2-substituted indoles
from monosubstituted alkynes in the absence of NaI or I2 (Scheme 1).
10% Pd/C (5 mol%)
I
ZnCl2 (10 mol%)
R
+
R
N
Solvent, Base, Ligand
Heat, 2-3h
NHTs
Ts
Scheme 1: Synthesis of 2-substituted indoles
Our first investigation was to synthesize 2-substituted indoles by 10% Pd/C catalyzed annulation
of N-substituted 2-iodoanilines with 1.05 equiv of phenylacetylene in the presence of anhydrous
ZnCl2, 7 equiv of Et3N and PPh3 in DMF solvent. Although room temperature reaction was
unable to afford any product, diyne via homocoupling of the alkyne was produced predominantly
with minor amount of desired indole at 110 0C. But when the reaction was carried out with moist
ZnCl2, the desired indole was noticed as the sole product without the formation of the
0
homocoupling by-product at 110 C (Table 1). A gravimetric analysis showed that the water
content of the moist ZnCl2 was 27-30 mol%. Then after performing a thorough screening by
varying solvents, bases, additives, ligands and temperature we found the optimal condition when
substrate 1a (1 mmol) was heated with 2a (1.05 mmol) at 110 0C in presence of 10% Pd/C (5 mol
3

%), moist ZnCl2 (10 mol %), 7 equiv Et3N and PPh3 (0.25 mmol) in dry DMF (6 mL) for 3h with
95% isolated yield through column chromatography (Table 1 Entry 4).
Table1 Screening of Pd/C -catalyzed annulations of N-substituted 2-iodoanilines and
phenylacetylene a,b
10% Pd/C (5 mol%)
I
Additive
Ph
+
Ph
+
Ph
Ph
N
NHTs
Solvent, Base
Heat, 3h
4a
2a
Ts
3a
1a
Yield % c
Entry
1
Additive
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
ZnCl2
Solvent
Ligand
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
Temp (0C)
Base
3a
4a
DMF
DMF
DMF
DMF
DMA
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
35
Et3N
Et3N
Et3N
Et3N
Et3N
Bu3N
Et3N
Et3N
0
10
0
0
2
110
35
85
3
0
4
110
110
110
110
110
110
110
110
110
110
95
90
65
10
0
0
5
0
8
6
d
7
P(Cy)3
10
0
8
9
PPh3
PPh3
PPh3
PPh3
PPh3
7
57
90
0
10
11
12e
13f
Et3N
0
ZnCl2
ZnCl2
ZnCl2
LiOH
NaOH
KOH
0
86
6
92
0
a,b1a (1mmol) and 2a (1.05 mmol) taken in a two necked round – bottomed flask fitted with
condenser in Ar atmosphere were allowed for annulation at temperature mentioned in presence
of 10% Pd/C (5 mol%), ZnCl2 (10 mol%), 7 equiv Et3N and PPh3 (0.25 mmol) in 6 mL of
solvent. cYields refer to the isolated yields after purification through column chromatography. In
entries 1, 2, 11, 12 and 13, ZnCl2 refers to anhydrous one whereas in each of the remaining
4

d
entries, moist ZnCl2 containing 27-30 mol% of water was used. Cy refers to the cyclo hexyl
group.e ,f Required time of reactions are 2 and 1h respectively.
The above observations help us to conclude that annulation reaction to indole synthesis is
dependent on additive, base, ligand and temperature. Now keeping the optimal condition in hand
we extrapolated our scope to various 2-substituted indole syntheses by combining different N-
substituted 2-iodoanilines with monosubstituted alkynes (Table 2).
g
Table 2 Synthesis of 2-substituted indoles through annulation promoted by catalytic ZnCl2
10% Pd/C (5 mol%)
ZnCl2 (10 mol%)
R'
R'
I
R
+
R
N
DMF, Et3N, PPh3
110 0C
NHTs
2
3
Ts
1
Substrate
Entry
1
1
2
Time (h)
3
Product
N
Yeild (%)h
95
I
Ph
2a
Ph
3a
NHTs
I
Ts
1a
OMe
2
3
3
OMe
3b
97
2
3
2b
NHTs
I
N
1a
Ts
Br
Br
91
90
O
N
O
NHTs
I
Ts
1a
1a
2c
3c
4
5
O
Me
NHTs
I
N
O
3d
Me
Ts
2d
Me
Me
Ph
Ph
2a
3
93
97
N
NHTs
3e
Ts
1b
Me
Me
Me
I
OMe
3f
6
7
OMe
2
3
N
2b
NHTs
I
Ts
1b
1b
Me
O
95
N
O
3g
NHTs
Ts
2d
5

Table 2 continued….
Substrate
Entry
8
1
2
Time (h)
3
Product
Yeild (%)h
90
Me
Br
Br
Me
Me
I
N
O
O
Ts
NHTs
I
3h
1b
2c
Me
9
92
3
3
O
Me
N
O
Me
Ts
NHTs
I
1b
1c
1d
3i
2d
Br
Cl
Br
Cl
10
11
91
90
Ph
2a
N
NHTs
I
Ts
3j
3
Ph
2a
NHTs
N
Ts
3k
g Reagents and conditions: 1 (1 mmol), 2 (1.05 mmol), 10% Pd/C (5 mol%), ZnCl2 ( 10 mol%)
(containing 27-30 mol% of water), Et3N ( 7 equiv), PPh3 ( 0.25 mmol) and DMF (6 mL), 110 0C.
hAll the yields were calculated after purification through column chromatoghraphy.
In the mechanistic course of the reaction it can be concluded from the previous studies15 and also
from the above observations (Table 1) that liberated –OH from moist ZnCl2 facilitates an in situ
generation of zinc acetylide which undergoes annualtion with N-substituted 2-iodoanilines which
is further confirmed by addition of NaOH or KOH with anh ZnCl2 (Table 1 Entry 12 and 13).
The above result shows that the two cases (Table 2 Entry 2 and 6) in which alkyne part contains
p-OMe group afford products at a faster rate with high yields probably due to +R effect of p-
OMe group making in situ formed zinc acetylide more reactive. Again we found
regioselectivities in two cases (Table 2 Entry 10 and 11) in which annulations were associated
with the more reactive iodide. On comparing this catalytic protocol with the general
Sonogashira-type coupling in which CuI is used as co-catalyst, we did not get any distinct
advantage. However, our protocol is important because of inexpensive ZnCl2 and in order for the
in situ generation of zinc acetylide, no further addition of expensive bases such as LDA, BuLi
are required.
In conclusion, we have developed a general, mild, efficient, ZnCl2 and Pd/C catalyzed synthesis
6

of 2-substitued indoles via domino Sonogashira coupling/cyclization reaction between N-
substituted 2-iodoanilines and mono substituted acetylenes. It can also be utilized in other
“copper- free Sonogashira” cross- couplings as well as in the synthesis of various types of indole
based natural products.
Acknowledgement
AA thanks UGC, New Delhi for fellowship and also CSIR and DST (New Delhi) for the
financial support.
Supplementary data
Supplementary data (detailed experimental procedures and spectral data for the compounds 3a-
3k) associated with this article can be found, in the online version, at
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16. General procedure for the synthesis of 2-substituted indoles: 2-Iodoanilide1 (1mmol),
phenyl acetylene 2 (1.05 mmol), PPh3 (0.25 mmol), 10% Pd/C (5 mol %) and ZnCl2 (10
mol %) containing 27-30 mol% of water were taken together in a two necked round-
bottomed flask fitted with condenser. After making the system inert under argon
atmosphere, 7 equiv Et3N and DMF (6 mL) were added and the reaction mixture was
stirred at 110 0C. The progress of the reaction was monitored by TLC. Upon completion
of the reaction, the mixture was allowed to cool to r.t, diluted with water and then
extracted with EtOAc (3 x 20 mL). Then the organic layer was dried over Na2SO4 and
concentrated in vacuum to get crude product which was then purified through column
chromatography by using silica gel ( 60-120 mesh) and pet erther : EtOAc (5:1) as
eluent.
17. Spectral data of representative compounds, 2-Phenyl-1-tosyl-1H-indole 3a: Light
0
0
1
brown solid; mp 144-145 C (lit1 mp 146-147 C); H NMR (200 MHz, CDCl3) δ 2.15
(s, 3H), 6.43 (s, 1H), 6.90 (d, J= 8.2 Hz, 2H), 7.11-7.43 (m, 10H), 8.22 (d, J= 8.0 Hz,
13
1H); C NMR (50 MHz, CDCl3) δ 21.6, 113.8, 116.8, 120.9, 124.5, 124.9, 126.9,
127.7, 128.8, 129.4, 130.5, 130.7, 132.6, 134.8, 138.4, 142.3, 144.7. Anal. Calcd. for
C21H17NO2S: C, 72.60; H, 4.93; N, 4.03%. Found: C, 72.52; H, 4.98; N, 4.14%.
.
9