Regioselective Pd-catalyzed indolization of 2-bromoanilines with internal alkynes using phosphine-free ligands

Article abstract of DOI:10.1016/j.tetlet.2008.03.112

The possibility of using phosphine-free ligands to promote Pd-catalyzed indolization of 2-bromoanilines with internal alkynes was examined for the first time. Phenylurea was found to be the optimal ligand, which could mediate the synthesis of 2,3-disubsti

Full text of DOI:10.1016/j.tetlet.2008.03.112

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3458–3462
Regioselective Pd-catalyzed indolization of 2-bromoanilines
with internal alkynes using phosphine-free ligands
Xin Cui a, Juan Li a, Yao Fu a, Lei Liu a,b,*, Qing-Xiang Guo a,*
a Department of Chemistry, Joint Laboratory of Green Synthetic Chemistry, University of Science and Technology of China, Hefei 230026, China
b Department of Chemistry, Tsinghua University, Beijing 100084, China
Received 2 December 2007; revised 16 January 2008; accepted 21 March 2008
Available online 28 March 2008
Abstract
The possibility of using phosphine-free ligands to promote Pd-catalyzed indolization of 2-bromoanilines with internal alkynes was
examined for the first time. Phenylurea was found to be the optimal ligand, which could mediate the synthesis of 2,3-disubstituted indoles
in good yields (ca. 60–85%) with high regioselectivity.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Indole; Larock indolization; Palladium catalyst; Phosphine-free ligand; Heteroannulation
R3
The indole ring is prevalent in a wide variety of natural
and synthetic products, many of which are capable of bind-
ing to biological receptors with high affinity.1 Accordingly
indoles have been referred to as ‘‘privileged structures” in
pharmaceutical studies, whose synthesis has been a focus
in organic chemistry for many years.2 Up to now numerous
methods for the preparation of indoles have been devel-
oped. Some famous methods such as Fischer, Bartoli,
Nenitzescu, Wittig, and Madelung-Houlihan indole syn-
theses have found extensive applications.3 Nonetheless,
regioselective synthesis of 2,3-disubstituted indoles remains
a challenging problem with all the above classical
approaches.
To tackle the problem Larock et al. recently developed a
method of Pd-catalyzed indolization which in principal was
a heteroannulation reaction of internal alkynes with 2-iod-
oanilines (Scheme 1).4 Using this method Konno et al.
recently synthesized fluoroalkylated indole derivatives.5
Watterson et al. synthesized novel indole-based inhibitors
of 50-inosine monophosphate dehydrogenase.6 Lanter
R3
R2
I
Pd(OAc)2
R1
+
R1
R2
LiCl, KOAc
DMF, 100 o
NHR
N
C
(R = H, Ac)
R
Scheme 1. Larock indole synthesis.
et al. synthesized a potent orally efficacious indole andro-
gen receptor antagonist.7 Besides, by attaching 2-iodoani-
lines onto the resins Smith’s and Zhang’s groups
developed interesting solid-phase methods to synthesize
2,3-disubstituted indoles.8 These applications showed that
the Larock indole synthesis allows easy access to a variety
of indoles in terms of substitution and functionality.
Noteworthy, Larock’s original indolization reaction was
performed under ‘ligandless’ conditions (Scheme 1), which
unfortunately only allowed for the use of 2-iodoanilines as
reactant. The much cheaper 2-bromo or 2-chloroanilines
cannot be applied to the Larock protocol, presumably
because the oxidative insertion to C–Br or C–Cl bonds
requires electron-rich Pd. To overcome this problem Lu
and co-workers recently examined the possibility of using
bulky, electron-rich phosphine ligands to improve Larock’s
protocol.9 It was found that 2-bromo and 2-chloroanilines
*
Corresponding authors. Tel.: +86 10 62780027; fax: +86 10 62771149
(L.L).
E-mail address: lliu@mail.tsinghua.edu.cn (L. Liu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.112

X. Cui et al. / Tetrahedron Letters 49 (2008) 3458–3462
3459
Table 1
Table 1 (continued)
Pd-catalyzed indolization of 2-bromoaniline under phosphine-free
conditionsa
Entry
19
Ligand
Pd loading (mol %)
1
Yieldb (%)
O
21
58
Pd(OAc)2
Ligand/Pd = 4:1
Ph
Ph
Br
H2N
NH2
+
Ph
O
O
K2CO3, DMF,
130 oC, 30 h
NH2
N
20
21
1
1
Ph
H
N
H
NH2
Entry
1
Ligand
—
Pd loading (mol %)
Yieldb (%)
Trace
35
48
1
N
H
N
H
O
2
3
1
54
28
N
N
N
N
N
N
22
23
Ph
Ph
Ph
1
N
N
H
H
S
1
1
1
Ph
Ph
1
1
0
0
N
H
N
H
S
24
4
5
22
N
NH2
H
a
Reaction conditions: 2-bromoaniline (0.25 mmol), alkyne (0.75 mmol),
K2CO3 (0.75 mmol), Pd(OAc)2:ligand = 1:4, DMF (1 mL), 130 °C, 30 h,
under Ar.
H
N
Trace
N
N
b
Isolated yield.
O
HN
NHCy
6
1
Trace
were applicable to the improved protocol. However, the
use of bulky, electron-rich phosphine ligands is still not
optimal from a cost and throughput perspective.
N
N
7
8
1
1
50
40
Cy
N
N
N Cy
In the present study we search for the further improve-
ment of the Larock indole synthesis method by using
low-priced, phosphine-free ligands. These ligands (mainly
including oxazolines,10 imines,11 diazabutadienes,12 bis-
pyridines,13 hydrazones,14 pyrazoles,15 phenanthrolines,16
guanidines,17 quinolines,18 carbazones,19 tetrazoles,20 imi-
dazoles,21 amino acids,22 amines,23 thioureas,24 and dicar-
bonyl compounds25) were recently found to be sufficiently
active to replace expensive phosphines or carbene ligands
in many Pd-catalyzed transformations.
To begin the study we focus on the Pd-catalyzed indoli-
zation of 2-bromoaniline (Table 1). The solvent, base, and
reaction temperature (i.e., DMF, K2CO3, and 130 °C) are
similar to the conditions previously reported by Lu and
co-workers (i.e., NMP, K2CO3, 110–130 °C).9 It is found
that in the absence of any ligand, only a trace amount of
product can be formed (entry 1). The addition of bipyridine
ligands13 (entries 2–4) leads to the production of some
indoles, but the yields remain low. On the other hand,
two recently reported bis-pyridine-type Pd-ligands
(namely, pyridylbenzoimidazole26 and di(2-pyridyl)methyl-
amine27) are found completely inactive (entries 5 and 6).
An additional bis-nitrogen ligand is diazabutadiene (entry
7) developed by Nolan and co-workers,12 and this ligand
gives an isolated yield of 50% for the indolization.
N
NH
9
10
11
12
13
14
15
1
1
1
1
1
1
1
32
61
25
37
16
16
45
N
N
N
N
NH2
HO
NMe2
O
Me2N
OH
O
COOH
N
O
N
N
OH
COOH
O
Ph
16
1
84
N
H
NH2
The failure with the bis-nitrogen ligands forced us to
examine other ligands including DABCO23 (entry 8) and
guanidines17 (entries 9 and 10). Unfortunately the yields
remain fairly low in a range from 30% to 60%. Besides, it
is surprising to find that the amino acid ligands (entries
11–15) that were recently shown to have good perfor-
O
Ph
Ph
17
18
0.5
5
51
8
N
H
NH2
O
N
H
NH2

3460
X. Cui et al. / Tetrahedron Letters 49 (2008) 3458–3462
Table 2
Synthesis of 2,3-disubstituted indoles via Pd/phenylurea-catalyzed heteroannulation of internal alkynes with 2-bromoanilinesa
RS
RS
Pd(OAc)2 1 mol %
Phenylurea 4 mol %
X
+
R1
R1
RL
K2CO3, DMF,
130 oC, 30 h
NHR
N
RL
R
Entry
1
Aniline derivative
Internal alkyne
Major product
Yield of major product (selectivity)
Ph
Br
84 (n/a)
Ph
NH2
Br
N
H
2
3
62 (96:4)
CH3
Ph
N
H
NH2
Br
C3H7
67 (82:18)
CH2CH2CH3
Ph
N
H
NH2
Br
C3H7
4
5
80 (n/a)
86 (n/a)
C3H7
N
H
NH2
Br
Ph
Ph
N
NH2
Br
H
6
65 (88:12)
CH3
Ph
N
H
NH2
Br
C3H7
7
8
55 (80:20)
CH2CH2CH3
Ph
N
H
NH2
Br
O
—
0
0
OH
O
NH2
Br
9
—
OPh
NH2
Br
Ph
10
67 (n/a)
Ph
N
NHMe
Br
11
51 (78:22)
CH3
Ph
N
NHMe
Ph
Ph
Br
12
13
74 (n/a)
N
NHAc
Br
H
59 (93:8)
CH3
Ph
N
H
NHAc
Br
Ph
Ph
14
15
70 (n/a)
NHAc
Cl
N
H
—
0
NH2
Br
Ph
O
O
16
71 (70:30)
52 (64:36)
NH2
O
O
N
H
Ph
Br
17
NHMe
N
a
Reaction conditions: aniline (0.25 mmol), alkyne (0.75 mmol), K2CO3 (0.75 mmol), Pd(OAc)2:ligand = 1:4, DMF (1 mL), 130 °C, 30 h, under Ar.

X. Cui et al. / Tetrahedron Letters 49 (2008) 3458–3462
3461
mances in both Pd-catalyzed Heck and Suzuki reactions22
also fail to promote the indolization reaction. At this point
it is interesting to find that the addition of phenylurea pro-
vides an indolization yield of 84% (entry 16). This yield is
comparable to that of Lu’s protocol (63–99% for 2-bromo-
anilines)9 which utilized 10 mol % of expensive 1,10-bis(di-
tert-butylphosphino)ferrocene as the ligand. Noteworthy,
Lu’s protocol requires a Pd loading of 5 mol %, whereas
our Pd/phenylurea protocol28 only requires 1 mol % of
Pd. It is also interesting to find that the change of the Pd
loading to either 0.5 or 5 mol % causes a much lower ind-
olization yield (entries 17 and 18).
The applicability of the Pd/phenylurea protocol was
next examined for the coupling between various 2-
bromo-anilines and internal alkynes (Table 2). It is found
that the indolization can smoothly take place with diaryl
alkynes (entries 1 and 5), aryl alkyl alkynes (entries 2, 3,
6, and 7), and dialkyl alkynes (entry 4). The yields range
from 55% to 86%. Note that electron-deficient alkynoic
acid and ester cannot be used in the present protocol
(entries 8 and 9). On the other hand, 2-bromoaniline
derivatives with an alkyl or acyl substituent on the nitrogen
are also good substrates in the indolization (entries 10–14),
which afford N-alkylated or N-deacylated indoles as the
final product. Lastly, it is found that the Pd/phenylurea
protocol cannot activate 2-chloroaniline (entry 15), whose
indolization was only accomplished with bulky electron-
rich phosphine ligands.9
C–Br bond to Pd(0) producing a Pd(II)–aryl complex; (b)
coordination and regioselective addition of the Pd(II) com-
plex to the alkyne; and (c) Pd extrusion and product forma-
tion via reductive elimination. The role of phenylurea is to
stabilize the Pd(II) intermediates and transition states by
using its deprotonated form.29 Other ureas (such as N-
methylurea, Table 1, entry 22) cannot effectively promote
the same reaction, presumably because N-methylurea is less
acidic than N-phenylurea by about 5 pKa units30 and there-
fore, cannot use its deprotonated form in the catalysis. The
proposed mechanism is consistent with the regioselectivi-
ties observed in the Pd/phenylurea-catalyzed indolization
reactions (see Table 2), where the insertion of the Pd(II)-
aryl bond into the alkyne prefers to place the aryl group
(which is geometrically more bulky than Pd(II)) near the
smaller substituent.
In conclusion, the possibility of using phosphine-free
ligands to mediate palladium-catalyzed indolization of 2-
bromoanilines with internal alkynes is examined here for
the first time. Most of the recently popularized phos-
phine-free ligands fail to promote the indolization reaction
except for phenylurea. By using the optimized Pd/phenyl-
urea protocol, 2,3-disubstituted indoles can be successfully
produced in good yields (ca. 60–85%) with high regioselec-
tivity. This study provides an additional example to illus-
trate the advantage of using urea derivatives as potential
phosphine-free ligands to promote Pd-catalyzed transfor-
mations.31 Further studies to evolve phosphine-free ligands
to promote the indolization of 2-chloroanilines are in
progress.
Mechanistically phenylurea must be explicitly involved
in the catalytic cycle, because in its absence the reaction
does not take place with 2-bromoaniline. On the basis of
our previous examination of phenylurea as a phosphine-
free ligand in Pd-catalyzed Heck and Suzuki reactions,29
we propose that the indolization reaction proceeds through
the following steps (Scheme 2): (a) oxidation insertion of
Acknowledgement
This research was supported by the NSFC (No.
20472079).
Supplementary data
R
RHN
Br
N
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2008.
03.112.
RL
Pd(0)
+
PhNHCONH2
RS
Br
References and notes
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Pd(II)
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