The regioselective Larock indole synthesis catalyzed by NHC-palladium complexes

Article abstract of DOI:10.1039/c3ra42788a

The first practical and regioselective process for the synthesis of 2,3-disubstituted indoles from the reaction of o-iodoanilines or o-bromoanilines and their derivatives with symmetrical and unsymmetrical internal alkynes catalyzed by a ferrocene-functionalized N-heterocyclic carbene (NHC)-palladium complex has been developed, and the indoles were isolated in good yields with high regioselectivity.

Full text of DOI:10.1039/c3ra42788a

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The regioselective Larock indole synthesis catalyzed by
NHC–palladium complexes3
Cite this: RSC Advances, 2013, 3,
18345
Pan He,a Yufeng Du,a Gang Liu,a Changsheng Cao,*a Yanhui Shi,*ab Juan Zhanga
and Guangsheng Pangc
Received 5th June 2013,
Accepted 29th July 2013
The first practical and regioselective process for the synthesis of 2,3-disubstituted indoles from the reaction
of o-iodoanilines or o-bromoanilines and their derivatives with symmetrical and unsymmetrical internal
alkynes catalyzed by a ferrocene-functionalized N-heterocyclic carbene (NHC)–palladium complex has
been developed, and the indoles were isolated in good yields with high regioselectivity.
DOI: 10.1039/c3ra42788a
www.rsc.org/advances
heteroannulation based on N-heterocyclic carbene as the
ligand is relatively scarce.6 We have developed an interest in
Introduction
The indoles, as very important ubiquitous heterocycles, are
abundantly found in numerous natural products, pharmaceu-
ticals, agrochemicals and functional materials.1 For over a
century, the synthesis and functionalization of indoles has
been a major area of focus for synthetic organic chemists, and
numerous methods for the preparation of indoles have been
developed up to now.2,3 In recent years, the palladium-
catalyzed heteroannulation discovered by Larock has emerged
as a versatile and practical method for the construction of
indole rings.4 This approach is extremely attractive to form
complex indole targets in a single operation, as both anilines
and internal alkynes can possess considerable functionality.
Originally, Larock’s heteroannulation was performed under
‘ligandless’ conditions, however, it only allowed the use of
2-iodoaniline as the reactant. To improve the Larock protocol,
cheaper 2-bromo and 2-chloroanilines were applied with the
use of additives and ligands.4h,i,j However, these methodolo-
gies suffer from drawbacks linked to the usage of a high
loading catalyst, excess ligand, and unstable, expensive and
toxic phosphine to maintain high activity. Furthermore, the Pd
complex was not well defined and it is difficult to understand
the composition of the active species and mechanistically
explain the result. Consequently, it is necessary to develop air-
stable, robust and well-defined Pd complexes with inexpensive
ligands. Although the N-heterocyclic carbenes have been used
widely in organometallic chemistry and catalysis,5 Larock’s
exploring the utility of N-heterocyclic carbenes in chemical
catalysis.7 In an extension of our previous work, herein we
describe the first efficiently regioselective synthesis of 2,3-
disubstituted indole derivatives catalyzed by the ferrocenyl
NHC–Pd complex (1).
Results and discussion
The structure of the ferrocenyl NHC–Pd–Py complex 1 used in
this study is shown in Scheme 1. The synthesis of 1 in 77%
yield was achieved by the reaction of PdCl2 with ferrocenyl
imidazolium chloride in pyridine in the presence of K2CO3.7
The complex 1 is very stable and not sensitive to air or
moisture. From the previous result of screening the solvents,
bases, catalyst loadings, and temperature, the indolization of
diphenylacetylene with bromoaniline catalyzed by 1 can be
effectively performed with 1 mol% of catalyst, with K2CO3 as
base and tetra-n-butylammonium bromide (TBAB) as additive,
in the solvent dioxane at 140 uC for 24 h.6
To probe the scope of the application of the NHC–Pd
complex in the indolization reaction, more symmetrical
internal aromatic alkynes were chosen to react with iodo and
bromoanilines under the optimized conditions. The results
are presented in Table 1. It was found that the indolization of
aromatic alkynes would take place smoothly not only with the
aSchool of Chemistry and Chemical Engineering and Jiangsu Key Laboratory of Green
Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou,
Jiangsu 221116, P. R. China. E-mail: yhshi@jsnu.edu.cn; Tel: +86 516 8350 0349
bState Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing,
Jiangsu 210093, P. R. China
cState Key Laboratory of Inorganic Synthesis and Preparative Chemistry, Jilin
University, Changchun, Jilin 130012, P. R. China
Electronic supplementary information (ESI) available. See DOI: 10.1039/
3
Scheme 1 Ferrocenyl NHC–Pd–Py complex 1.
c3ra42788a
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Table 1 Synthesis of 2,3-disubstituted indoles via NHC–Pd-catalyzed hetero-
Table 2 Synthesis of 2,3-disubstituted indoles via NHC–Pd-catalyzed hetero-
annulation of symmetrical internal aromatic alkynes
annulation of symmetrical internal aliphatic alkynes with 2-bromoanilines
Entrya
1
Aniline
R2
Et
Product
Yield (%)b
81
Entrya Aniline
1
Aryl alkyne
Product
Yield (%)b
86
2
3
4
5
6
nPr
Et
70
83
82
79
69
2
3
4
5
6
7
8
9
78
87
73
77
90
88
85
80
nPr
Et
nPr
a
Reaction conditions: 1 mmol of aniline, 2 mmol of alkyne, 1 mmol
b
of TBAB and 3 mmol of K2CO3 in 2 mL dioxane. Average isolated
yield from two runs.
yield, however, the elelctron-rich anilines generally gave the
higher yields (entries 6 and 7 vs. entries 8 and 9). Interestingly,
2-bromophenyl acetamide, a derivative of bromoaniline, is
also
a
good substrate in the indolization, affording
N-deacylated indoles as the final product (entries 4 and 5).
Unfortunately, the ferrocenyl NHC–Pd complex is not effective
with 2-chloroaniline.
To determine the scope of this system with other kinds of
alkynes, we also investigated the reaction of symmetrical
internal aliphatic alkynes with bromoanilines (Table 2). The
results showed that both electron-rich and electron-poor
bromoanilines reacted with aliphatic alkynes in good yield
(69–83%).
This methodology has also been extended to use unsym-
metrical internal alkynes in the indole synthesis, which
represents an even more challenging task (Table 3). Good
yields were achieved in all the examples (73–90%) and good
regioselectivities were observed in most of the tested reactions.
a
Reaction conditions: 1 mmol of aniline, 2 mmol of alkyne, 1 mmol
b
of TBAB and 3 mmol of K2CO3 in 2 mL dioxane. Average isolated
yield from two runs.
more reactive iodoanilines, but also with the less reactive
bromoanilines. A better yield was generally achieved with
iodoanilines, compared to bromoanilines (Table 1, entry 1 vs.
2). Furthermore, both electron-rich and electron-deficient
bromoanilines were reacted with aromatic alkynes in good
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Table 3 Synthesis of 2,3-disubstituted indoles via NHC–Pd-catalyzed heteroannulation of unsymmetrical internal alkynes
Entrya
1
Aniline
Aryl alkyne
Major isomer
Yieldb (ratio)c
86% (.99 : 1)
2
78% (89 : 11)
3
4
5
87% (.99 : 1)
73% (96 : 4)
77% (86 : 14)
6
7
8
90% (.99 : 1)
88% (.99 : 1)
85% (84 : 16)
9
80% (.99 : 1)
10
82% (55 : 45)
11
12
75% (56 : 40)
79% (92 : 8)
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Table 3 (Continued)
Entrya
Aniline
Aryl alkyne
Major isomer
Yieldb (ratio)c
a
b
Reaction conditions: 1 mmol of aniline, 1 mmol of TBAB, 2 mmol of alkyne and 3 mmol of K2CO3 in 2 mL dioxane. Average isolated yield
from two runs. The ratios were determined by GC and 1H NMR.
c
The regioselectivities of the products were largely dependent
on the difference in size between the two substituents on the
alkynes, and the more sterically hindered group (RL) of the
alkyne occupies the 2-position of the indole ring.
catalyst. The role of TBAB may be to stabilize the charged Pd(II)
intermediate B and transition states.
On the basis of our results and other studies on Pd-
catalyzed reactions, we propose that the indolization reaction
proceeds through the following steps, as shown in Scheme 2.
Firstly, oxidative addition of the C–X bond to Pd(0), which is
generated in situ from the ferrocenyl NHC–Pd(II) complex (1),
produces a Pd(II)–aryl complex A; and then coordination and
regioselective insertion of the Pd(II) complex into the alkyne
gives intermediate B. The insertion of the Pd(II)–aryl bond into
the alkyne occurs such that the bulky group in the alkyne is
preferentially set near the smaller Pd(II) side, as the aryl group
in the Pd(II)–aryl bond is geometrically more bulky than Pd(II),
which is consistent with the regioselectivities observed in the
NHC–Pd-catalyzed indolization reactions. Deprotonation of B
by base gives complex C. Finally, the indole product is formed
via the reductive elimination of C, regenerating the Pd(0)
Experimental section
General considerations
Complex
1 was synthesized according to our previous
procedure.6 All the other reagents were commercially available
and were used without further purification. H and 13C NMR
1
spectra were recorded on a Bruker DPX 400 MHz spectrometer
at room temperature and referenced to the residual signals of
the solvent. The coupling constants (J) are given in Hz. HRMS
was recorded on a Fisher LTQ-Orbitrap XL combined-type
mass spectrometer.
General procedure for the synthesis of 2,3-disubstituted indole
derivatives
Aniline (1 mmol), alkyne (2 mmol), Pd catalyst 1 (1 mol%),
TBAB (1 mmol), and K2CO3 (3 mmol) were dissolved in
dioxane (2 mL) in a 5 mL vial in air and heated at 140 uC for 24
h. After the reaction was completed, the mixture was diluted
with ethyl acetate (10 mL), filtered through a pad of Celite, and
washed multiple times with ethyl acetate. The combined
organic layer was dried over anhydrous Na2SO4, and evapo-
rated under reduced pressure. The residue was purified by
flash chromatography on silica gel to afford the desired
product.
Characterization data for indoles
2,3-Diphenyl-1H-indole. (Table 1, entry 1): yield: 86%; white
1
solid; H NMR (400 MHz, CDCl3): d = 8.23 (s, 1H), 7.69 (d, J =
8.0 Hz, 1H), 7.45–7.14 (m, 13H).
2,3-Di-p-tolyl-1H-indole. (Table 1, entry 3): yield: 87%; white
1
solid; H NMR (400 MHz, CDCl3): d = 8.14 (s, 1H), 7.66 (d, J =
8.0 Hz, 1H), 7.32 (t, J = 8.0 Hz, 5H), 7.11–7.22 (m, 6H), 2.38 (s,
3H), 2.34 (s, 3H).
5-Methyl-2,3-diphenyl-1H-indole. (Table 1, entry 6): yield:
90%; colorless oil; 1H NMR (400 MHz, CDCl3): d = 8.13 (s, 1H),
7.49–7.30 (m, 12H), 7.11–7.09 (m, 1H), 2.43 (s, 3H).
5-Methyl-2,3-di-p-tolyl-1H-indole. (Table 1, entry 7): yield:
1
88%; colorless oil; H NMR (400 MHz, CDCl3): d = 7.93 (d, J =
4.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H),
7.24–7.17 (m, 6H), 2.38 (s, 9H). 13C NMR (CDCl3, 100 MHz):
138.6, 138.2, 137.6, 136.9, 134.1, 133.6, 131.4, 130.9, 129.7,
Scheme 2 Possible mechanism.
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129.2, 129.1, 129.0, 128.8, 126.3, 120.6, 21.6, 21.4, 21.2. HRMS
(ESI): m/z calcd: 311.1590 [M 2 H]2, found: 310.1583.
5-Fluoro-2,3-diphenyl-1H-indole. (Table 1, entry 8): yield:
85%; colorless oil; 1H NMR (400 MHz, CDCl3): d = 8.22 (s, 1H),
7.44–7.30 (m, 12H), 7.03–6.98 (m, 1H).
2-(tert-Butyl)-3-methyl-1H-indole. (Table 3, entry 3): yield:
87%; colorless oil; 1H NMR (400 MHz, CDCl3): d = 7.82 (s, 1H),
7.39–7.43 (m, 1H), 7.11–7.23 (m, 2H), 6.98–7.05 (m, 1H), 2.32
(s, 3H), 1.38 (s, 9H).
3,5-Dimethyl-2-phenyl-1H-indole. (Table 3, entry 4, major
product): yield: 73%; colorless oil; 1H NMR (400 MHz, CDCl3):
d = 7.91 (s, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.47 (t, J = 8.0 Hz, 2H),
7.38 (s, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.27 (s, 1H), 7.03 (d, J = 8.0
Hz, 1H), 2.48 (s, 3H), 2.44 (s, 3H).
5-Fluoro-2,3-di-p-tolyl-1H-indole. (Table 1, entry 9): yield:
80%; colorless oil; 1H NMR (400 MHz, CDCl3): d = 8.19 (s, 1H),
7.31 (t, J = 8.0 Hz, 6H), 7.20 (d, J = 8.0 Hz, 2H), 7.14 (d, J = 8.0
Hz, 2H), 6.99–6.94 (m, 1H), 2.40 (s, 3H), 2.36 (s, 3H). 13C NMR
(CDCl3, 100 MHz): 158.5 (d, J = 936.0 Hz; CF), 137.8, 135.9 (d, J
= 36.0 Hz; C), 132.3, 131.7, 130.9, 129.7, 129.6, 129.4, 129.3,
128.8, 127.9, 114.7 (d, J = 16.0 Hz; C), 111.4 (d, J = 36.0 Hz; C),
110.6 (d, J = 100.0 Hz; C), 104.5 (d, J = 96.0 Hz; C), 21.3, 19.2.
HRMS (ESI): m/z calcd: 315.3834 [M 2 H]2, found: 314.3844.
2,3-Diethyl-1H-indole. (Table 2, entry 1): yield: 81%; color-
less oil; 1H NMR (400 MHz, CDCl3): d = 7.64 (br, 1H), 7.52 (d, J
= 7.6 Hz, 1H), 7.23 (d, J = 7.0 Hz, 1H), 7.10–7.06 (m, 2H), 2.72
(m, 4H), 1.24 (m, 6H). 13C NMR (CDCl3, 100 MHz): 135.2,
135.1, 128.4, 120.8, 118.2, 118.0, 113.1, 110.2, 19.3, 17.3, 15.8,
14.5.
2,5-Dimethyl-3-phenyl-1H-indole. (Table 3, entry 4, minor
product): colorless oil. 1H NMR (CDCl3, 400 MHz): d 7.87 (s,
1H), 7.50–7.45 (m, 5H), 7.31 (t, J = 8.0 Hz, 1H) , 7.23 (d, J = 8.0
Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 2.50 (s, 3H), 2.43 (s, 3H).
5-Methyl-2-phenyl-3-propyl-1H-indole. (Table 3, entry 5):
1
yield: 77%; colorless oil; H NMR (400 MHz, CDCl3): d = 7.88
(s, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.41–7.47 (m, 3H), 7.33–7.36
(m, 1H), 7.21–7.26 (m, 1H), 7.02 (d, J = 8.0 Hz, 1H), 2.83 (t, J =
8.0 Hz, 2H), 2.47 (s, 3H), 1.70–1.80 (m, 2H), 0.99 (t, J = 8.0 Hz,
3H).
2-(tert-Butyl)-3,5-dimethyl-1H-indole. (Table 3, entry 6):
1
2,3-Dipropyl-1H-indole. (Table 2, entry 2): yield: 70%; color-
less oil; 1H NMR (400 MHz, CDCl3): d = 7.58 (br, 1H), 7.43 (d, J
= 8.0 Hz, 1H), 7.15 (m, 1H), 6.98–7.02 (m, 2H) 2.59 (m, 4H),
1.58 (m, 4H), 0.88 (m, 6H). 13CNMR (CDCl3, 100 MHz): 135.4,
135.3, 132.7, 129.0, 128.5, 120.9, 119.0, 118.5, 115.9, 112.3,
110.3, 28.3, 26.4, 24.2, 23.3, 14.4, 14.1, 11.2.
yield: 90%; colorless oil; H NMR (400 MHz, CDCl3): d = 8.95
(s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.06–7.09 (m, 2H), 2.30 (s, 3H),
1.63 (s, 3H), 1.43 (s, 9H). 13C NMR (CDCl3, 100 MHz): 135.9,
131.8, 130.3, 125.1, 122.3, 120.7, 120.1, 110.5, 29.3, 27.6, 21.3,
20.8. HRMS (ESI): m/z calcd: 201.3074 [M 2 H]2, found:
200.3018.
2,3-Diethyl-5-methyl-1H-indole. (Table 2, entry 3): yield:
83%; colorless oil; 1H NMR (400 MHz, CDCl3): d = 7.68 (s,
1H), 7.35 (m, 1H), 6.98 (m, 2H), 2.48 (s, 3H), 1.64 (m, 4H), 0.96
(m, 6H). HRMS (ESI): m/z calcd: 186.1277 [M + H]+, found:
186.1256.
5-Methyl-2,3-dipropyl-1H-indole. (Table 2, entry 4): yield:
82%; colorless oil; 1H NMR (400 MHz, CDCl3): d = 7.61 (s, 1H),
7.31 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H),
2.71–2.63 (m, 4H), 2.46 (s, 3H), 1.71–1.63 (m, 4H), 1.00–0.95
(m, 6H).
5-Fluoro-3-methyl-2-phenyl-1H-indole. (Table 3, entry 7):
yield: 88%; colorless oil; H NMR (400 MHz, CDCl3): d = 8.13
1
(s, 1H), 7.57 (d, J = 8.0 Hz, 2H), 7.48 (t, J = 8.0 Hz, 2H), 7.35–
7.38 (m, 1H), 7.21–7.29 (m, 2H), 6.91–6.96 (m, 1H), 2.41 (s, 3H).
13C NMR (CDCl3, 100 MHz): 161.7 (d, J = 244.0 Hz), 132.1,
131.1, 128.8, 128.6 (d, J = 15.0 Hz), 128.3 (d, J = 38.0 Hz), 127.7
(d, J = 15.0 Hz), 127.4, 117.6 (d, J = 23.0 Hz), 115.9 (d, J = 23.0
Hz), 110.9 (d, J = 65.0 Hz), 103.8 (d, J = 23.0 Hz), 19.9. HRMS
(ESI): m/z calcd: 225.2609 [M 2 H]2, found: 224.3617.
5-Fluoro-2-phenyl-3-propyl-1H-indole. (Table 3, entry 8,
1
major product): yield: 85%; colorless oil; H NMR (400 MHz,
2,3-Diethyl-5-fluoro-1H-indole. (Table 2, entry 5): yield: 79%;
1
CDCl3): d = 8.09 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.28–7.50 (m,
5H), 6.95 (d, J = 8.0 Hz, 1H), 2.81 (t, J = 8.0 Hz, 2H), 1.70–1.76
(m, 2H), 0.99 (t, J = 8.0 Hz, 3H).
colorless oil; H NMR (400 MHz, CDCl3): d = 7.72 (s, 1H), 7.19
(d, J = 4.0 Hz, 1H), 7.17 (d, J = 4.0 Hz, 1H), 6.88–6.83 (m, 1H),
2.78–2.65 (m, 4H), 1.31–1.20 (m, 6H). 13C NMR (CDCl3, 100
MHz): 157.7 (d, J = 924.0 Hz), 138.1, 131.6, 128.9 (d, J = 36.0
Hz), 113.4 (d, J = 20.0 Hz), 110.7 (d, J = 40.0 Hz), 108.8 (d, J =
102.0 Hz), 103.2 (d, J = 96.0 Hz), 19.4, 17.3, 15.5, 14.3. HRMS
(ESI): m/z calcd: 191.1027 [M 2 H]2, found: 190.1031.
5-Fluoro-2,3-dipropyl-1H-indole. (Table 2, entry 6): yield:
69%; colorless oil; 1H NMR (400 MHz, CDCl3): d = 7.72 (s, 1H),
7.18–7.15 (m, 2H), 6.88–6.83 (m, 1H), 2.70 (t, J = 8.0 Hz, 2H),
2.64 (t, J = 8.0 Hz, 2H), 1.72–1.61 (m, 4H), 1.02–0.95 (m, 6H).
3-Methyl-2-phenyl-1H-indole. (Table 3, entry 1): yield: 86%;
colorless oil; 1H NMR (400 MHz, CDCl3): d = 8.04 (s, 1H), 7.56–
7.61 (m, 2H), 7.42–7.49 (m, 3H), 7.31–7.37 (m, 2H), 7.12–7.24
(m, 2H), 2.46 (s, 3H).
5-Fluoro-3-phenyl-2-propyl-1H-indole. (Table 3, entry 8,
1
minor product): colorless oil; H NMR (400 MHz, CDCl3): d =
8.09 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.28–7.50 (m, 5H), 6.95 (d,
J = 8.0 Hz, 1H), 3.02 (t, J = 8.0 Hz, 2H), 2.00–2.06 (m, 2H), 1.05
(t, J = 8.0 Hz, 3H).
2-(tert-Butyl)-5-fluoro-3-methyl-1H-indole. (Table 3, entry 9):
yield: 80%; colorless oil; 1H NMR (400 MHz, CDCl3): d = 7.86 (s,
1H), 7.32–7.36 (m, 1H), 7.16–7.19 (m, 1H), 7.11–7.14 (m, 1H),
2.35 (s, 3H), 1.45 (s, 9H). 13C NMR (CDCl3, 100 MHz): 158.9,
143.7, 130.1, 121.3 (d, J = 9.0 Hz), 116.1 (d, J = 23.0 Hz), 110.7
(d, J = 9.0 Hz), 108.9 (d, J = 26.0 Hz), 102.7 (d, J = 23.0 Hz), 37.4,
32.8, 20.7. HRMS (ESI): m/z calcd: 205.2712 [M 2 H]2, found:
204.2691.
3-Phenyl-2-(p-tolyl)-1H-indole. (Table 3, entry 10, major
product): yield: 82%; colorless oil; 1H NMR (400 MHz,
CDCl3): d = 8.23 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.12–7.43
(m, 13H), 2.37 (s, 3H).
2-Phenyl-3-propyl-1H-indole. (Table 3, entry 2): yield: 78%;
1
colorless oil; H NMR (400 MHz, CDCl3): d = 8.03 (s, 1H), 7.64
(d, J = 4.0 Hz, 1H), 7.44–7.50 (m, 4H), 7.29–7.36 (m, 2H), 7.09–
7.19 (m, 2H), 2.84 (t, J = 8.0 Hz, 2H), 1.70–1.76 (m, 2H), 0.97 (t,
J = 8.0 Hz, 3H).
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J.-C. Hierso, Chem. Soc. Rev., 2012, 41, 3929.
2-Phenyl-3-(p-tolyl)-1H-indole. (Table 3, entry 10, minor
product): colorless oil; 1H NMR (400 MHz, CDCl3): d = 8.23
(s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.12–7.43 (m, 13H), 2.35 (s, 3H).
2-(3-Fluorophenyl)-3-phenyl-1H-indole. (Table 3, entry 11,
1
major product): yield: 75%; colorless oil; H NMR (400 MHz,
CDCl3): d = 8.33 (s, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.10–7.42 (m,
11H), 6.97 (t, J = 8.0 Hz, 1H).
3-(3-Fluorophenyl)-2-phenyl-1H-indole. (Table 3, entry 11,
1
minor product): colorless oil; H NMR (400 MHz, CDCl3): d =
8.31 (s, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.10–7.42 (m, 11H), 6.97 (t,
J = 8.0 Hz, 1H).
3-Phenyl-2-(o-tolyl)-1H-indole. (Table 3, entry 12): yield: 79%;
1
colorless oil; H NMR (400 MHz, CDCl3): d = 8.35 (s, 1H), 7.44
(d, J = 8.0 Hz, 1H), 7.25–7.33 (m, 11H), 7.06–7.12 (m, 1H), 2.03
(s, 3H). 13C NMR (CDCl3, 100 MHz): 137.7, 135.8, 134.5, 133.8,
132.9, 131.5, 130.2, 129.6, 128.7, 127.4, 127.2, 126.7, 125.8,
122.6, 120.1, 120.0, 114.8, 110.7, 29.7. HRMS (ESI): m/z calcd:
283.1277 [M 2 H]2, found: 282.1294.
Conclusions
A well-defined ferrocenyl functionalized NHC–palladium com-
plex was found to be an efficient catalyst for Larock
heteroannulation. The process is practical and economical
for the synthesis of 2,3-disubstituted indoles from the
reactions of o-iodoanilines or o-bromoanilines and their
derivatives with various internal alkynes, and the indoles were
isolated in good yields (ca. 69–90%) with high regioselectivity.
The reactions occur in a broad scope and with a high tolerance
of functional groups. NHC–palladium complexes could be
excellent candidates to replace expensive palladium–phos-
phine complexes for Larock indole catalysis.
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Acknowledgements
We gratefully acknowledge National Natural Science Foundation
of China (NSFC) (21071121 and 21172188), Scientific Research
Foundation (SRF) for the Returned Overseas Chinese Scholars
(ROCS), State Education Ministry (SEM), the Priority Academic
Program Development of Jiangsu Higher Education Institutions
(PAPD), 333 project for the cultivation of high-level talents
(33GC10002), Graduate Foundation (2012YYB080) of Jiangsu
Normal University, and the State Key Laboratory of Inorganic
Synthesis and Preparative Chemistry at Jilin University (2013-03)
for financial support of this work.
¨
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This journal is ß The Royal Society of Chemistry 2013