Palladium-catalyzed aerobic oxidative cyclization of N-aryl imines: Indole synthesis from anilines and ketones

Article abstract of DOI:10.1021/ja3030824

We report here an operationally simple, palladium-catalyzed cyclization reaction of N-aryl imines, affording indoles via the oxidative linkage of two C-H bonds under mild conditions using molecular oxygen as the sole oxidant. The process allows quick and atom-economical assembly of indole rings from inexpensive and readily available anilines and ketones and tolerates a broad range of functional groups.

Full text of DOI:10.1021/ja3030824

Subscriber access provided by EDINBURGH UNIVERSITY LIBRARY | @ http://www.lib.ed.ac.uk
Communication
Palladium-Catalyzed Aerobic Oxidative Cyclization of N-
Aryl Imines: Indole Synthesis from Anilines and Ketones
Ye Wei, Indubhusan Deb, and Naohiko Yoshikai
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 21 May 2012
Downloaded from http://pubs.acs.org on May 21, 2012
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Palladium-Catalyzed Aerobic Oxidative Cyclization of N-Aryl
Imines: Indole Synthesis from Anilines and Ketones
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Ye Wei, Indubhusan Deb, and Naohiko Yoshikai*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological
University, Singapore 637371, Singapore
Supporting Information Placeholder
(a) Åkermark–Knölker
ABSTRACT: We report here an operationally simple, palla-
O
O
(cat.) Pd(OAc)2
(oxidant)
H H
dium-catalyzed cyclization reaction of N-aryl imines, affording
indoles via the oxidative linkage of two C–H bonds under
mild conditions using molecular oxygen as the sole oxidant.
The process allows quick and atom-economical assembly of
indole rings from inexpensive and readily available anilines
and ketones and tolerates a broad range of functional groups.
N
H
O
N
H
O
(b) Glorius
cat. Pd(OAc)2
Cu(OAc)2, K2CO3
EWG
EWG
H
H
R
DMF, 80–140 °C
N
R
N
H
H
(c) This work
The indole ring system represents a key structural element
that occurs ubiquitously in biologically active natural and un-
natural compounds as well as in optoelectronic functional
materials.1 Consequently, practical and atom-economical syn-
thesis of indoles from simple starting materials is critical to
the pharmaceutical and fine chemical industries.2 Given the
low cost and wide variety of commercially available anilines,
their use as starting materials for indole synthesis is highly
attractive, while well-established methods often require modi-
fied aniline derivatives such as aryl hydrazines (Fischer indole
synthesis) and o-haloanilines (e.g., Larock indole synthesis).3,4
In this context, a significant breakthrough was recently made
by Glorius and coworkers, who developed a palladium(II)-
catalyzed, copper(II)-mediated oxidative cyclization reaction
of N-aryl enamines derived from anilines and β-dicarbonyl
compounds to afford the corresponding indoles (Scheme
1b).5,6,7 The origin of this novel palladium(II) catalysis can be
traced back to the long-standing seminal studies of Åkermark
and Knölker on palladium(II)-mediated or -catalyzed oxidative
synthesis of carbazoloquinones and carbazoles (Scheme 1a).8
Building on these pioneering works, we have now developed a
palladium(II)-catalyzed oxidative cyclization reaction of N-
aryl imines to indoles that likely involves palladation of N-aryl
enamines formed via imine–enamine tautomerization (Scheme
1c). The reaction features operational simplicity, mild aerobic
conditions, and tolerance of a broad range of functional
groups, thus allowing expedient and atom-economical assem-
bly of indole rings from readily available anilines and ketones.
R2
cat. Pd(OAc)2
1 atm O2, Bu4NBr
R2
R1
H H
N
R1
DMSO, 60 °C
N
H
An illustrative example is the gram-scale reaction of imine
1a derived from p-anisidine and acetophenone (eq 1). A mix-
ture of 1a (2.25 g, 10 mmol), Pd(OAc)2 (0.22 g, 1 mmol), and
Bu4NBr (6.45 g, 20 mmol) in DMSO (50 mL) was stirred un-
der oxygen atmosphere (1 atm) at 60 °C for 24 h to afford 1.87
g of indole 2a (84% yield). The discovery of this deceptively
simple yet unprecedented transformation was serendipitously
guided by our interests in ortho C–H bond functionalization of
aromatic imines9,10 and oxidative palladium catalysis.11,12 Thus,
while our initial intention was to oxidatively functionalize the
ortho C–H bond of the phenyl ring of 1a via imine-directed
cyclopalladation,13,14 we did not observe any products arising
from ortho C–H functionalization under any conditions exam-
ined in this study.
Pd(OAc)2 (10 mol%)
Bu4NBr (2 equiv)
O2 (1 atm)
MeO
MeO
(1)
N
N
DMSO, 60 °C, 24 h
H
1a
2a
2.25 g
(10 mmol)
1.87 g
(8.4 mmol, 84%)
Table 1 summarizes key results obtained during the optimi-
zation of the reaction on a small scale (0.2 mmol).15 The Pd-
catalyzed reaction of 1a using O2 only at 40 °C afforded 2a in
27% yield (entry 1). A clear improvement of the yield was
observed when Bu4NBr (1 equiv) was added (entry 2), while
other ammonium salts did not show apparent positive effects
(entries 3–5). By using 2 equiv of Bu4NBr, 2a was obtained in
76% and 89% yields at 25 °C and 60 °C, respectively (entries
6 and 7). A change of the oxygen atmosphere to an open air in
the latter case afforded 2a in 67% yield. The use of Cu(OAc)2
instead of O2/Bu4NBr also allowed efficient and scalable cy-
clization, affording 2a in 93% and 87% yields on 0.2 mmol
Scheme
1.
Indole
Synthesis
via
Palladium-
Catalyzed/Mediated Oxidative Cyclization
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
and 50 mmol scales, respectively (entries 8 and 9). Curiously, the yield was only modest for the indole derived from o-
1
2
3
4
5
6
7
8
Glorius' catalytic system (Scheme 1b) did not promote the
reaction at all, while its difference from the present Pd/Cu
system is merely the use of K2CO3 additive and DMF solvent.
Thus, DMSO appears to play a critical role in the oxidative
cyclization. Other oxidants examined were either poorly effec-
tive (BzOOtBu, BQ; entries 10 and 11) or entirely ineffective
(CuCl2, AgOAc, PhI(OAc)2 etc.). Note that the reaction took
place in 52% yield with a stoichiometric amount of Pd(OAc)2
in the absence of an oxidant (entry 12).
bromoacetophenone (2t).
Scheme 2. Indole Synthesis from N-Aryl Imines
Pd(OAc)2 (10 mol %)
R3
Bu4NBr (2 equiv)
R3
O
2 (1 atm)
R1
R1
R2
N
N
R2
DMSO, 60 °C, 24 h
H
1
2
F
F
MeO
R
MeO
R
9
N
N
H
N
H
Table 1. Influence of Reaction Conditions on Oxidative Cy-
clization of 1aa
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
2a (R = H), 89%
2b (R = NO2), 92%
2c (R = CN), 91%
2d (R = CONR'2), 81%a,b
2e (R = CF3), 86%
2f (R = Cl), 90%
2j (R = H), 87%
2r, 88%
2k (R = NO2), 58%
2l (R = CF3), 81%
2m (R = CO2Et), 82%
2n (R = Cl), 88%
2o (R = Br), 93%
2p (R = Me), 92%
2q (R = NHAc), 64%
NC
Pd(OAc)2 (10 mol %)
oxidant/additive
MeO
MeO
N
H
N
OMe
N
DMSO, temp
H
2g (R = Br), 77%
2s, 89%
2h (R = Me), 86%
2i (R = OMe), 82%
1a
2a
EtO2C
MeO
MeO
Entry Oxidant/additive
Temp
(°C)
Yield
(%)b
N
H
N
H
O
N
H
Br
1
O2 (1 atm)
40 °C
40 °C
40 °C
40 °C
40 °C
25 °C
60 °C
40 °C
40 °C
40 °C
40 °C
40 °C
27
48
24
31
22
76c
89c
93c
87c
23
8
2t, 22%
2u, 78%
2v, 76%
MeO
MeO
2
O2 (1 atm)/Bu4NBr (1 equiv)
O2 (1 atm) /Bu4NCl (1 equiv)
O2 (1 atm) /Bu4NI (1 equiv)
O2 (1 atm) /Bu4NOAc (1 equiv)
O2 (1 atm)/Bu4NBr (2 equiv)
O2 (1 atm)/Bu4NBr (2 equiv)
Cu(OAc)2 (3 equiv)
N
N
H
N
H
O
N
H
3
MeO
2y, 74%c
2w, 84%
2x, 80%
4
5
N
H
N
H
N
H
F3C
6
OMe
2z, 72%
2aa, 67%
2ab, 88%
7
NC
MeO
MeO
Ph
8
CN
N
H
9d
10
11
Cu(OAc)2 (2 equiv)
N
H
N
H
CN
Me
BzOOtBu (3 equiv)
2ac, 87%
2ad, 74%
2ae, 78%
Ph
CN
Benzoquinone (2 equiv)
None
MeO
MeO
R
12e
52
R
N
N
H
N
H
H
a
b
c
Reaction was performed on a 0.2 mmol scale for 12–16 h.
2af (R = H), 86%b
2ag (R = OMe), 82%b
2ah (R = F), 74%b
2ak, 85%d
2ai (R = c-C3H5), 84%
2aj (R = tBu), 61%
GC yield determined using n-tridecane as an internal standard.
d
Isolated yield. The reaction was performed on a 50 mmol scale
using 5 mol % of Pd(OAc)2. e 1 equiv of Pd(OAc)2 was used.
a NR'2 is a morpholino group. b Cu(OAc)2 was used as the oxi-
We next explored the scope of the oxidative cyclization
with the Pd/Bu4NBr/O2 system (Scheme 2).16 A series of 2-
(hetero)arylindoles could be obtained in good to excellent
yields from the corresponding imines derived from substituted
anilines and acetophenones (2a to 2ad). A variety of electron-
donating, electron-withdrawing, and potentially sensitive func-
tional groups could be tolerated on both the aniline- and ace-
tophenone-derived moieties, including nitro (2b and 2k), cy-
ano (2c, 2s, 2ac, and 2ad), amide (2d and 2q), trifluoromethyl
(2e, 2l, and 2z), chloro (2f and 2n), bromo (2g, 2o, and 2t),
ester (2m and 2t), and fluoro (2r) groups. Note that the dicy-
anoindole 2ad is a precursor of an acid-sensing ion channel-3
inhibitor that was previously synthesized by Suzuki coupling
of an expensive protected indole boronic acid.17 Heteroaryl
groups such as 2-furyl, 2-benzofuryl, and 4-pyridyl groups
could be tolerated (2v–2x). Imines derived from m-methoxy
and -trifluoromethyl anilines underwent cyclization preferen-
tially at the less-hindered position to afford the indoles 2y and
2z, respectively, while the former case was accompanied by a
small amount (7%) of the minor regioisomer. Substituents at
the ortho positions of the acetophenone- and the aniline-
derived moieties (2s, 2t, and 2aa–2ac) were tolerated, while
c
dant (conditions in Table 1, entry 8). A regioisomeric product
d
was obtained in 7% yield. The starting material was in the form
of enamine.
An α,β-unsaturated imine underwent cyclization smoothly
to give 2-alkenylindole 2ae in 78% yield. An imine derived
from 2-phenylacetophenone afforded 2,3-diphenylindole 2af
in 40% yield, which was accompanied by a ketone byproduct
(33%) arising from benzylic oxidation.18 However, by using
Cu(OAc)2 as the oxidant, the yield of 2af was improved to
86% with a complete suppression of benzylic oxidation. Simi-
larly, 2,3-diarylindoles 2ag and 2ah were obtained in good
yields. These examples demonstrate the utility of the present
cyclization for regiocontrolled synthesis of 2,3-diarylindoles,
which is difficult with the Larock- and Fagnou-type annulation
reactions using diarylalkynes.2,7 2-Cyclopropyl- and 2-t-
butylindoles 2ai and 2aj were also obtained in good yields
from the corresponding imines, while attempts to synthesize 2-
n-alkylindoles have not been successful. In addition to these
examples, the present method was also applicable to an
enamine derived from benzoylacetonitrile,5 resulting in the
formation of 2-phenyl-3-cyanoindole 2ak in 85% yield.
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
Twofold cyclization of phenylenediamine-derived diimines tions suggest that the aromatic C–H activation is one of turno-
1
2
3
4
5
6
7
8
ver-controlling steps of the reaction but is not an exclusive
1al and 1am readily provided the fused indoles 2al and 2am,
respectively, albeit in modest yields (Scheme 3a, b). These
products particularly underline the power of the present cy-
clization reaction, as any of conventional methods would not
allow their synthesis with such great ease. The regioselectivity
observed for the latter case poses an intriguing mechanistic
question that cannot be answered at present. Twofold cycliza-
tion was also achieved for a diimine 1an derived from 1,3-
diacetylbenzene, affording a 1,3-bis(indolyl)benzene 2an in
90% yield (Scheme 3c). Such multifold cyclizations may serve
as attractive routes to extended π-conjugated systems for po-
tential applications in organic electronics.19
turnover-limiting step.21
Scheme 4. H/D Kinetic Isotope Effect Experiments
Pd(OAc)2 (10 mol %)
Bu4NBr (2 equiv)
O2 (1 atm)
(a)
H
N
Cl
N
H
DMSO, 60 °C, 12 h
84% yield
D
D/H
Cl
2aq-d/2aq
kH/kD = 5.2
1aq-d
9
(b)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cl
Pd(OAc)2 (10 mol %)
Bu4NBr (2 equiv)
O2 (1 atm)
N
N
H
2aq
Cl
Cl
1aq
Scheme 3. Twofold Oxidative Cyclizations
+
+
DMSO, 60 °C, 3 h
22% combined yield
(a)
Ph
Pd(OAc)2 (20 mol %)
Bu4NBr (4 equiv)
O2 (1 atm)
Cl
Cl
H
N
N
H
N
kH/kD = 1.7
D5
(c)
N
D4
Ph
Ph
1aq-d5
2aq-d4
DMSO, 60 °C, 24 h
N
N
N
Ph
Ph
H
1al
2al, 29%
Pd(OAc)2 (10 mol %)
Bu4NBr (2 equiv)
O2 (1 atm)
(b)
as above
N
N
H
HN
H5/D5
DMSO
60 °C, 0–20 min
H4/D4
Ph
N
Cl
N
H
Ph
Ph
1aq or 1aq-d5
2aq or 2aq-d4
kH/kD = 1.6 ± 0.4
1am
2am, 50%
(c)
From the above results and the fact that a stoichiometric
amount of Pd(OAc)2 promotes the reaction in the absence of
oxidant (Table 1, entry 12), we suggest a possible catalytic
cycle that involves a Pd(II)/Pd(0) redox process (Scheme 5a).
Enamine 1' generated via tautomerization of imine 1 would be
electrophilically attacked by Pd(OAc)2 (A), followed by elimi-
nation of HOAc to give an α-palladated imine B.22 The inter-
mediate B would then undergo intramolecular aromatic C–H
palladation to give a six-membered palladacycle C. Subse-
quent reductive elimination affords 3H-indole 2' and Pd(0).
The former tautomerizes quickly to indole 2 while the latter is
oxidized back to Pd(II) with the aid of molecular oxygen and
HOAc.12 Note that, under the standard conditions, tetralone-
derived imine 1ar underwent dehydrogenative aromatization
to afford aminonaphthalene 3 presumably via β-hydride elimi-
nation of an α-palladated imine (Scheme 5b), which may indi-
rectly support the formation of the putative C(sp3)–Pd species
B in the proposed catalytic cycle.22,23 Further studies are un-
derway to address more details of the reaction mechanism
including the role of the ammonium salt.24
as above
MeO
NH
HN
OMe
N
N
PMP
PMP
1an
(PMP = 4-MeOC6H4)
2an, 90%
We further demonstrated the feasibility of one-pot oxidative
condensation of aniline and ketone. Thus, with the aid of the
Pd/Cu catalytic system, p-anisidine reacted with acetone and
ethyl pyruvate to afford the indoles 2ao and 2ap in 55% and
41% yields, respectively (eq 2), while no product formation
was observed with the Pd/O2 system. Attempts on one-pot
reaction of p-anisidine and acetophenone were not successful
under the standard reaction conditions, presumably because of
slow formation of the imine.
Pd(OAc)2 (20 mol %)
Cu(OAc)2 (3 equiv)
MeO
MeO
(2)
+
R
O
R
DMSO, 40 °C, 24 h
N
NH2
H
(5 equiv)
In summary, we have developed a simple, mild, and scala-
ble palladium-catalyzed aerobic oxidative cyclization reaction
of N-aryl imines, enabling two-step assembly of substituted
indoles, 2-arylindoles in particular, from readily available ani-
lines and ketones without any non-essential prefunctionaliza-
tion steps. Thus, the present method would not only serve as a
practical, versatile, and atom-economical alternative to exist-
ing synthetic methods but also allow facile construction of
indole skeletons that have not been easily accessible. Further
studies should lead to more robust, benign, and broadly appli-
cable catalytic systems that could find applications in complex
settings relevant to medicinal chemistry and materials science,
and hence could have a significant impact on the laboratory-
and industry-scale synthesis of indoles.25
2ao (R = CH3), 55%
2ap (R = CO2Et), 41%
We next performed a series of kinetic isotope effect (KIE)
experiments. First, we probed the nature of the aromatic C–H
bond activation step by an intramolecular competition experi-
ment using monodeuterated imine 1aq-d, which exhibited a
large KIE of 5.2 (Scheme 4a). The KIE value is of a similar
magnitude to those commonly observed in Pd-catalyzed aro-
matic C–H bond functionalization reactions involving a con-
certed metalation–deprotonation mechanism.5,20 On the other
hand, an intermolecular competition of imine 1aq and its
pentadeuterated analogue 1aq-d5 exhibited a modest KIE of
1.7 (Scheme 4b). Comparison of parallel independent reac-
tions of 1aq and 1aq-d5 also indicated a modest KIE of 1.6 ±
0.4 in their early stage (0–20 min, Scheme 4c). These observa-
Scheme 5. Possible Catalytic Cycle (a) and Dehydrogenative
Aromatization of Tetralone-Derived Imine (b)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
(a)
Rakshit, S.; Dröge, T.; Würtz, S.; Glorius, F. Chem. Eur. J. 2011, 17,
7298.
(6) For other reaction systems for oxidative cyclization of N-aryl
enamines, see: (a) Bernini, R.; Fabrizi, G.; Sferrazza, A.; Cacchi, S.
Angew. Chem., Int. Ed. 2009, 48, 8078. (b) Yu, W.; Du, Y.; Zhao, K.
Org. Lett. 2009, 11, 2417. (c) Guan, Z.-H.; Yan, Z.-Y.; Ren, Z.-H.;
Liua, X.-Y.; Liang, Y.-M. Chem Commun 2010, 46, 2823.
1
2
3
4
N
R
N
R
H
1
1'
Pd(OAc)2
1/2O2 + H2O
H2O2
O2, 2HOAc
Pd0
5
–OAc
PdOAc
6
7
8
9
(7) For aniline–alkyne annulation approaches to indoles, see: (a)
Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.; Fagnou, K. J.
Am. Chem. Soc. 2008, 130, 16474. (b) Stuart, D. R.; Alsabeh, P.;
Kuhn, M.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 18326. (c) Hues-
tis, M. P.; Chan, L. N.; Stuart, D. R.; Fagnou, K. Angew. Chem., Int.
Ed. 2011, 50, 1338. (d) Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.;
Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2009, 48, 4572. (e) Acker-
mann, L.; Lygin, A. V. Org. Lett. 2012, 14, 764.
(8) For representative references, see: (a) Åkermark, B.; Eberson,
L.; Jonsson, E.; Pettersson, E. J. Org. Chem. 1975, 40, 1365. (b)
Knölker, H.-J.; O'Sullivan, N. Tetrahedron 1994, 50, 10893. (c)
Hagelin, H.; Oslob, J. D.; Åkermark, B. Chem. Eur. J. 1999, 5, 2413.
(d) Knölker, H.-J. Chem. Lett. 2009, 38, 8.
(9) (a) Lee, P.-S.; Fujita, T.; Yoshikai, N. J. Am. Chem. Soc. 2011,
133, 17283. (b) Gao, K.; Yoshikai, N. Angew. Chem., Int. Ed. 2011,
50, 6888. (c) Gao, K.; Yoshikai, N. J. Am. Chem. Soc. 2011, 133,
400.
(10) (a) Ackermann, L.; Hofmann, N.; Vicente, R. Org. Lett. 2011,
13, 1875. (b) Tredwell, M. J.; Gulias, M.; Bremeyer, N. G.; Johans-
son, C. C. C.; Collins, B. S. L.; Gaunt, M. J. Angew. Chem., Int. Ed.
2011, 50, 1076. (c) Yoshikai, N.; Matsumoto, A.; Norinder, J.;
Nakamura, E. Angew. Chem., Int. Ed. 2009, 48, 2925. (d) Acker-
mann, L.; Althammer, A.; Born, R. Tetrahedron 2008, 64, 6115. (e)
Kuninobu, Y.; Nishina, Y.; Okaguchi, K.; Shouno, M.; Takai, K.
Bull. Chem. Soc. Jpn.. 2008, 81, 1393. (f) Ackermann, L. Org. Lett.
2005, 7, 3123.
N
R
H+
A
R
R
N
HOAc
2'
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Pd
PdOAc
N
R
N
R
N
C
B
H
2
HOAc
(b)
Pd(OAc)2 (10 mol %)
Bu4NBr (2 equiv)
O2 (1 atm)
PMP
PMP
N
N
H
DMSO, 60 °C, 12 h
1ar
3, 78%
AcOPd
PMP
N
PMP
N
–HPdOAc
ASSOCIATED CONTENT
(
11) Wei, Y.; Yoshikai, N. Org. Lett. 2011, 13, 5504.
Supporting Information. Detailed experimental procedures,
characterization data and complete ref 17. This material is availa-
ble free of charge via the Internet at http://pubs.acs.org.
(12) For selected reviews, see: (a) Campbell, A. N.; Stahl, S. S.
Acc. Chem. Res. DOI: 10.1021/ar2002045. (b) Yeung, C. S.; Dong,
V. M. Chem. Rev. 2011, 111, 1215. (c) Liu, C.; Zhang, H.; Shi, W.;
Lei, A. Chem. Rev. 2011, 111, 1780. (d) Stahl, S. S. Angew. Chem.,
Int. Ed. 2004, 43, 3400.
AUTHOR INFORMATION
(
13) (a) Molnar, S. P.; Orchin, M. J. Organomet. Chem. 1969, 16,
196. (b) Onoue, H.; Moritani, I. J. Organomet. Chem. 1972, 43, 431.
14) Albrecht, M. Chem. Rev. 2010, 110, 576.
Corresponding Author
nyoshikai@ntu.edu.sg
(
(15) See the Supporting Information for more detail of the screen-
ing experiments.
(16) Results obtained with the Pd/Cu system (Table 1, entry 8) are
shown in the Supporting Information for comparison.
ACKNOWLEDGMENT
We thank Singapore National Research Foundation (NRF-RF-
2009-05) and Nanyang Technological University for financial
support, and Dr. Kalum Kathriarachchi for technical assistance.
(
17) Kuduk, S. D. et al. Bioorg. Med. Chem. Lett. 2009, 19, 4059.
(18) Chuang, G. J.; Wang, W.; Lee, E.; Ritter, T. J. Am. Chem.
Soc. 2011, 133, 1760.
REFERENCES
(
19) Tsuji, H.; Yokoi, Y.; Mitsui, C.; Ilies, L.; Sato, Y.; Nakamura,
(1) (a) Sundberg, R. J. Indoles; Academic Press: San Deigo, 1996.
E. Chem. Asian J. 2009, 4, 655.
(b) d'Ischia, M.; Napolitano, A.; Pezzella, A. In Comprehensive Het-
erocyclic Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E.
F. V., Taylor, R. J. K., Eds.; Elsevier: Oxford, 2008; Vol. 3, pp 353-
388.
(2) (a) Gribble, G. W. J. Chem. Soc. Perkin Trans. 1 2000, 1045.
(b) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, 2875. (c)
Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, PR215.
(3) Approximate prices of aniline derivatives (per mole, Sigma-
Aldrich): Aniline, $2; phenylhydrazine, $13; o-chloroaniline, $50; o-
(
(
20) Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1119.
21) Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012,
51, 3066.
(22) (a) Zhu, J.; Liu, J.; Ma, R.; Xie, H.; Li, J.; Jiang, H.; Wang,
W. Adv. Synth. Catal. 2009, 351, 1229. (b) Liu, J.; Zhu, J.; Jiang, H.;
Wang, W.; Li, J. Chem. Asian J. 2009, 4, 1712.
(
23) (a) Izawa, Y.; Pun, D.; Stahl, S. S. Science 2011, 333, 209.
(b) Diao, T.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133, 14566. (c)
Diao, T.; Wadzinski, T. J.; Stahl, S. S. Chem. Sci. 2012, 3, 887. (d)
Gao, W.; He, Z.; Qian, Y.; Zhao, J.; Huang, Y. Chem. Sci. 2012, 3,
883. (e) Chernyak, N.; Gorelsky, S. I.; Gevorgyan, V. Angew. Chem.,
Int. Ed. 2011, 50, 2342.
bromoaniline, $500; o-iodoaniline, $1,000.
(4) Numbers of commercially available aniline derivatives (accord-
ing to Reaxys analysis): Anilines (with at least one ortho-hydrogen
atom), ~24,000; arylhydrazines (with at least one ortho-hydrogen
atom), ~800; o-chloroanilines, ~900; o-bromoanilines, ~500; o-
iodoanilines, ~200.
(5) (a) Würtz, S.; Rakshit, S.; Neumann, J. J.; Dröge, T.; Glorius,
F. Angew. Chem., Int. Ed. 2008, 47, 7230. (b) Neumann, J. J.;
(24) (a) Jeffery, T. Tetrahedron 1996, 52, 10113. (b) Phan, N. T.
S.; Sluys, M. V. D.; Jones, C. W. Adv. Synth. Catal. 2006, 348, 609.
(
25) A provisional application of this work has been filed, applica-
tion no. 61577528.
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
cat. Pd(OAc)2
Bu4NBr
1 atm O2
R1
R3
R3
NH2
+
R2
R1
R1
R3
R2
–H2O
DMSO, 60 °C
N
R2
N
H
O
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
ACS Paragon Plus Environment