A highly active catalyst for the reductive cyclization of ortho-nitrostyrenes under mild conditions

Article abstract of DOI:10.1016/j.tet.2005.03.142

A mild and efficient method for the palladium-catalyzed reductive cyclization of ortho-nitrostyrenes to afford indoles is reported. Treatment of ortho-nitrostyrenes with 0.1 mol% palladium (II) trifluoroacetate [Pd(TFA) ₂] and 0.7 mol% 3,4,7,8-tetramethyl-1,10-phenanthroline (tm-phen) in DMF at 15 psig CO and 80°C afforded indoles in good to excellent yields. When the reaction was conducted in toluene, the corresponding N-hydroxyindole was isolated. A mechanism that accounts for the formation of N-hydroxyindole is proposed.

Full text of DOI:10.1016/j.tet.2005.03.142

Tetrahedron 61 (2005) 6425–6437
A highly active catalyst for the reductive cyclization of
ortho-nitrostyrenes under mild conditions
!
Ian W. Davies, Jacqueline H. Smitrovich, Rick Sidler, Chuanxing Qu, Venita Gresham
and Charles Bazaral
*
Department of Process Research, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065-0900 USA
Received 1 November 2004; revised 28 February 2005; accepted 4 March 2005
Available online 17 May 2005
Dedicated to the memory of Jackie Smitrovich – a dear friend and a talented colleague
Abstract—A mild and efficient method for the palladium-catalyzed reductive cyclization of ortho-nitrostyrenes to afford indoles is reported.
Treatment of ortho-nitrostyrenes with 0.1 mol% palladium (II) trifluoroacetate [Pd(TFA)2] and 0.7 mol% 3,4,7,8-tetramethyl-1,10-
phenanthroline (tm-phen) in DMF at 15 psig CO and 80 8C afforded indoles in good to excellent yields. When the reaction was conducted in
toluene, the corresponding N-hydroxyindole was isolated. A mechanism that accounts for the formation of N-hydroxyindole is proposed.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
Substituted indoles are privileged structures1 that are
present in a wide range of pharmacophores.2 As such, the
synthesis of indoles represents a long and rich area of
synthetic organic chemistry.3 KDR kinase inhibitor 1 was
identified as part of Merck’s efforts4 for blocking tumor-
induced angiogenesis.5 Due to the low solubility of 1
imparted by the quinilone ring, we proposed unmasking the
quinolone in the final step, making methoxy-protected 2 our
synthetic target (Scheme 1). Of the synthetic approaches
investigated,6 construction of the indol-2-yl methoxy-
quinoline core of 2 by reductive cyclization of ortho-
nitrostyrene 3 was appealing in that this substrate could be
convergently assembled in a short number of steps.7 This
strategy would require a mild method for the reductive
cyclization.
Scheme 1.
The Cadogan deoxygenation of nitroaromatics using boiling
triethyl phosphite is now a classic synthetic method for the
construction of a wide range of nitrogen-containing
1940 using stoichiometric iron oxalate at 200 8C.10 In
recent years, transition metal catalyzed variants of this
reaction using CO as the stoichiometric reductant have
aromatic heterocycles and remains the most common
been developed,11 however, the moderate yields and
method to affect deoxygenative cyclization.8,9 While
broad in scope, the generation of a large amount of
phosphorous waste detracts from this approach. Transition
systems have subsequently been identified as more
metal promoted deoxygenation of nitroaromatics to give
extreme conditions (1175 psi CO and 220 8C) significantly
limit the synthetic utility of this system. Palladium-based
efficient catalysts for this transformation. The palladium-
catalyzed reductive cyclization of ortho-nitrostyrenes in
heterocycles was first realized by Waterman and Vivian in
the presence of stoichiometric SnCl2 at 100 8C and
¨
Keywords: Nitrostyrene; Reductive cyclization; Palladium.
*
275 psi CO was developed by Watanabe.12 Soderberg
reported a Pd/triphenylphoshphine system effective at
Corresponding author. E-mail: ian_davies1@merck.com
! Deceased.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.03.142

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I. W. Davies et al. / Tetrahedron 61 (2005) 6425–6437
Table 1. Reductive cyclization of 3 using Pd(OAc)2/triphenylphosphine
Entry
Pd(OAc)2 (mol%)
PPh3 (mol%)
CO (psig)
Temp (8C)
2 (% yield)a
1
2
3
4
5
6
6
6
6
6
2
1
24
24
24
24
4
60
60
30
15
60
60
70
40
70
70
70
70
95 (45)b
32
90
50
71
2
63
a HPLC assay yield.
b Yield reported for material isolated by crystallization.
highly efficient catalytic system relied upon systematic
screening using a 6!8 parallel Parallel Pressure Reactor
(PPRw). Results of these studies and investigations into the
reaction mechanism are presented herein.
2. Results and discussion
The relatively mild pressure and temperature required for
Pd/phosphine catalytic systems motivated us to apply this
system towards the reductive cyclization of 3. Using the
Figure 1.
lower temperatures and pressures (70 8C and 60 psi) at
6 mol% palladium loading.13 Catalysts derived from
palladium(II) salts and bidentate nitrogen ligands effect
cyclization of ortho-nitrostyrenes at low catalyst loading,
however, these reactions require harsh conditions (300 psi
CO and 120 8C).14 Catalytic alternatives effective at mild
temperatures and pressures would enhance widespread
uptake of this technology. Our approach to developing a
¨
conditions reported by Soderberg [6 mol% Pd(OAc)2,
24 mol% PPh3, CO (60 psig), 70 8C in ACN],13 indole 2
was produced in high assay yield (95%, Table 1, entry 1).
The only by-product was dimer 4 (3%, Fig. 1). Crystal-
lization from the reaction stream resulted in a disappointing
isolated yield (45%) due to the presence of triphenyl-
phosphine and triphenylphosphine oxide. Reducing the
ligand and catalyst loading resulted in decreased yields due
Table 2. Reductive cyclization using palladium/phenanthroline catalystsa
Entry
Catalyst (mol%)
Ligand (mol%)
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
Pd(OAc)2 (1.0)
Pd(OAc)2 (1.0)
Pd(OAc)2 (1.0)
Pd(OAc)2 (1.0)
Pd(OAc)2 (1.0)
Pd(OAc)2 (0.5)
Pd(OAc)2 (0.25)
Pd(OAc)2 (0.10)
Pd(OAc)2 (0.10)
Pd(OAc)2 (0.10)
Pd(OAc)2 (0.10)
Pd(OAc)2 (0.10)
Pd(OAc)2 (0.10)
phen (2.0)
phen (2.0)
phen (2.0)
phen (2.0)
phen (2.0)
phen (1.0)
phen (0.5)
phen (0.2)
phen (0.5)
phen (1.0)
tm-phen (0.2)
tm-phen (0.5)
tm-phen (1.0)
—
ACN
THF
56
37
40
58
Toluene
ODCBc
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
98 (94)d
93
24
0
6
25
25
79
92
99
89
74
32
33
68
78
100
9
10
11
12
13
14
15
16
17
18
19
20
21
e
phen2Pd(BF4)2 (1.0)
phen2Pd(BF4)2 (0.5)
phen2Pd(BF4)2 (0.25)
Pd(TFA)2 (0.1)
—
—
phen (0.5)
phen (1.0)
tm-phen (0.2)
tm-phen (0.5)
tm-phen (1.0)
Pd(TFA)2 (0.1)
Pd(TFA)2 (0.1)
Pd(TFA)2 (0.1)
Pd(TFA)2 (0.1)
a Reactions performed at 70 8C and 15 psig CO.
b HPLC assay yield.
c ortho-Dichlorobenzene.
d Number in parentheses is yield reported for material isolated by crystallization.
e Pre-formed catalyst.

I. W. Davies et al. / Tetrahedron 61 (2005) 6425–6437
6427
to lower conversion (entries 5 and 6). The CO pressure
could be reduced to 30 psig without adversely affecting
yield, but at 15 psig yield decreased due to lower conversion
(entries 3 and 4). Due to the necessity for high catalyst and
ligand loading, a more efficient catalytic system was sought.
Catalysts derived from palladium(II) salts and bidentate
nitrogen ligands are highly reactive systems for the
reduction of nitroarenes to isocyanates and carbamates15
and have been applied to the reductive cyclization of ortho-
nitrostyrenes at high temperatures and pressures.13a,14 The
efficiency of these systems, we proposed, may allow the
reductive cyclization of 3 to occur at low catalyst and ligand
loading and hence simplify isolation of indole 2. Initial
results were encouraging, with the reaction occurring at
mild temperature and pressure: treatment of 3 with 1 mol%
Pd(OAc)2 and 2 mol% 1,10-phenanthroline (phen) in ACN
at 15 psig CO and 70 8C afforded 2 in 56% yield (Table 2,
entry 1). A screen of solvents identified DMF as optimal,
and under identical conditions 2 was produced in 98% assay
yield and 94% isolated yield (entry 5).16 Other solvents
resulted in lower conversion.
Figure 2. Temperature and pressure response surface for the cyclization
of 3.
Optimization of reaction parameters was accomplished
using a 6!8 module Parallel Pressure Reactor (PPRw) from
Symyx Technologies, Inc. With a 1:2 Pd(OAc)2/phen ratio,
high yield is maintained at 0.5 mol% palladium (93%,
Table 2, entry 6), but at lower palladium loading the yield
dropped drastically due to decreased conversion (entry 7)
and no reaction occurred at 0.1 mol% catalyst loading (entry
8). The catalyst loading could be reduced to 0.1 mol% by
increasing the ligand/palladium ratio,17 but conversion was
low (entries 9 and 10). For the reductive carbonylation of
nitro-arenes to afford isocyanates, increased catalytic
activity is obtained with palladium (II) salts with non-
coordinating counter ions and electron rich phenanthro-
19
lines.15d,e,18 The pre-formed catalyst phen2Pd(BF4)2
performed similarly to the catalyst generated in situ from
0.5 mol% Pd(OAc)2 and 0.5 mol% phen (compare entries 5
and 14) and conversion dropped with decreased catalyst
loading (entries 15 and 16). Due to ease of operation, the in
situ catalyst system was chosen for further optimization.
Palladium trifluoroacetate [Pd(TFA)2] gave similar results
at 0.1 mol% loading with excess phen (entries 17 and 18).
Use of the more electron donating ligand and 3,4,7,8-
tetramethyl-1,10-phenanthroline (tm-phen) gave higher
conversion at a 10:1 ratio with Pd(OAc)2 (92% assay
yield, entry 13). Best results were obtained with 0.1 mol%
Pd(TFA)2 and 1 mol% tm-phen, affording indole 2 in 100%
assay yield (entry 21).
Scheme 2.
Table 3. Preparation of substituted ortho-nitrostyrenes 7b–d,i,j
Entry
X
Ar
Alcohol
Yield (%)a
Styrene
Yield (%)a
1
2
3
4
CO2Me
Cl
Me
Ph
Ph
Ph
6b
6c
6d
6i
—
61
59
80
7b
7c
7d
7i
75
64
70
87
CO2Me
5
Cl
Ph
6j
84
7j
93
a Isolated yield.

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I. W. Davies et al. / Tetrahedron 61 (2005) 6425–6437
Table 4. Reductive cyclization of substituted ortho-nitrostyrenesa
Entry
1c
Substrate
Product
Yield (%)b
87
(E)-7a
7a 1:1 E/Z
7b
10a
10a
2c
86
98
3d
10b
10c
4
96
89
61
7c
7d
7e
5
10d
10e
6e
7e
18
72
10f
7f
8e
10g
7g
9f
72
78
10h
10i
7h
10d
7i
11
91
10j
7j
12
13
84g
84
7k
10k
10l
7l
a Reaction conditions: 1 mol% Pd(OAc)2, 2 mol% phen, 15 psig CO, 80 8C for 16 h in DMF, unless otherwise noted.
b Isolated yield.
c 1.5 mol% Pd(OAc)2, 3 mol% phen employed.
d 0.1 mol% Pd(TFA)2, 0.7 mol% tm-phen employed.
e 1.0 mol% Pd(TFA)2, 2.0 mol% tm-phen employed.
f
1.5 mol% Pd(OAc)2, 3 mol% phen, 30 psig CO. 70 8C for 16 h in DMF.
g HPLC assay yield.

I. W. Davies et al. / Tetrahedron 61 (2005) 6425–6437
6429
With this catalyst system, the optimal temperature and
pressure were identified by DOE (design of experiments,
Fig. 2). The ranges investigated spanned 40–120 8C and
5–65 psig CO. Temperature had the greater effect of the two
variables. The effect of pressure was minimal, with high
yields occurring at both low and high pressure at the optimal
temperatures. At 5–15 psig CO, the optimal temperature
was 80 8C, with decreased conversion at temperatures
!80 8C. At 65 psig, highest yields were obtained at
100 8C. Due to ease of operation, the milder reaction
conditions were selected for further optimization.
1.5 mol% Pd(OAc)2 and 3 mol% phen at 30 psig CO
pressure and 70 8C. Use of 1 mol% of the more reactive
catalyst Pd(TFA)2 with 2 mol% tm-phen was required to
obtain good conversion with 7e and 7g and afforded indoles
10e and 10g in 61 and 72% isolated yields, respectively.
Even under these conditions, 7f afforded only an 18% yield
due to poor conversion (entry 7).
The widely accepted mechanism for the formation of
heterocyclic products from nitro aromatics involves
exhaustive deoxygenation to a singlet nitrene 12 which
undergoes a downstream insertion into the adjacent p-bond
to form 13 followed by a hydrogen migration to afford the
indole (Scheme 3). This rationalization is primarily
supported by the product distribution from reactions of
At 15 psig CO and 80 8C the ligand/palladium can be
reduced to 7:1 without adversely effecting conversion. At
low catalyst loadings, (0.1 mol%) rigorous air free con-
ditions are necessary for reproducibility. Optimized con-
ditions (0.1 mol% Pd(TFA)2, 0.7 mol% tm-phen, 15 psig
CO, 80 8C in DMF) afforded 2 in 94% isolated yield.
aromatic nitro compounds and their analogous azides.22
A
significant study of the chemistry of biphenylnitrenes by
laser flash photolysis and time-resolved IR experiments and
by theoretical calculations has recently been published.23
These data indicate that cyclization proceeds via a singlet
nitrene with an open-shell electronic structure to form
isocarbazole and a 1,5-hydrogen shift to form carbazole.
The scope was investigated using a panel of substituted
ortho-nitrostyrenes. Substrates were commercially avail-
able, previously reported, or readily available in a few steps
from commercially available starting materials. Substituted
styrenes 7b–d,i,j were prepared from the corresponding
alcohols in a one pot acylation/elimination sequence with
TFAA and DBU (Scheme 2, Table 3). Alcohol 6b was
prepared following the literature procedure.20 Alcohols
6c,d,i,j were prepared by DBU-mediated addition of the
requisite ortho-nitrotoluene to either benzaldehyde or
2-methoxyquinoline-3-carboxaldehyde. Alcohol 6d was
N-Hydroxy- and N-ethoxyindoles have been observed by
Sundberg in the reduction of 11a with triethylphosphite,
prepared using the sequence optimized for
2
(Scheme 2).6b Addition of trimethylsilylmethylmagnesium
bromide to 4-nitrotoluene followed by oxidation of the
resulting nitronate intermediate with iodine afforded 9.
Treatment of 9 with catalytic tetrabutylammonium fluoride
(TBAF, 0.20 mol%) in the presence of benzaldehyde
afforded 6d in 59% isolated yield. Styrenes 7e and 7l
were prepared from the commercially available nitro-
benzaldehydes by reaction with diethyl benzylphosphonate.
Scheme 3.
ortho-Nitrostyrenes 7b–l were submitted to the reductive
cyclization (Table 4). With 1 mol % Pd(OAc)2 and 2 mol%
phen, the catalyst and ligand can be weighed in air and
added to the reaction as solids. For small scale reactions,
solutions of Pd(OAc)2 and phen in DMF were added to a
solution of the substrate on the bench top. At 0.1 mol%
catalyst loading, solutions of Pd(TFA)2 and tm-phen were
prepared on the bench top and then added to a solution of
substrate in a nitrogen atmosphere glove box. The reductive
conditions tolerate a wide range of functional groups, for
example esters, aromatic chlorides, anilines and amides
(entries 3, 4, 6 and 8). a,b-Unsaturated amides and ketones
undergo the reaction (entries 8 and 13). Methoxy-substi-
tuted quinolines and pyridines are compatible with the
conditions (entries 9–11). The olefin geometry does not
effect the reaction, as demonstrated by reaction of a 1:1
mixture of (E)/(Z) isomers of 7a,21 which gave a
comparable yield to reaction of isomerically pure (E)-7a
(compare entries 1 and 2). The alkene is not required to be
cross-conjugated as exemplified by entry 12, where the
alkene has a methyl substituent. Electron rich substrates
gave low yields under standard conditions due to poor
conversion. High conversion of 7h was obtained using
which suggests a competitive pathway might be available
involving partially deoxygenated intermediates.8c
N-Hydroxyindoles have been identified in the palladium-
catalyzed reductive cyclization of ortho-nitrostyrenes in
THF at 170 8C and 440 psi CO.14a We have observed
analogous products under our milder reductive cyclization
conditions. When the cyclization of styrene 3 was
performed in toluene, two products were formed (Scheme 4).
Expected indole 2 was isolated in 40% yield and
N-hydroxyindole 14 was isolated in 20% yield. When 14
Scheme 4.

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I. W. Davies et al. / Tetrahedron 61 (2005) 6425–6437
Scheme 5.
cyclization reaction of ortho-nitrostyrene 7a in the presence
of 2,3-dimethylbutadiene were unsuccessful. Oxazine 2217
was produced in 29% yield from the reaction of ortho-
nitrobenzene and 2,3-dimethylbutadiene with 1 mol%
Pd(OAc)2 and 2 mol% phen at 15 psig CO and 70 8C
(Scheme 6). The remainder of the reaction mixture was
starting material. This result indicates that aromatic nitro
groups are reduced to the nitroso species under the reaction
conditions. For the reaction of 7a, intramolecular cycliza-
tion onto the pendant alkene may be faster than inter-
molecular cycloaddition with the diene.
Scheme 6.
was resubjected to the standard reductive cylization
conditions in DMF, indole 2 was formed quantitatively.
The formation of hydroxyindole 14 and its conversion to
indole 2 gives some insight into the reaction mechanism.
Reduction of the nitro to the nitrene does not account for the
formation of 14. We propose the following mechanism
(Scheme 5). Reaction of the nitrostyrene with the catalyst
and carbon monoxide gives palladacycle 16,24 which
undergoes extrusion of CO2 to give nitrosostyrene 17. For
the reduction of nitroaromatics to isocyanates, the nitroso
species undergoes further reduction and incorporation of
CO.25 We propose that in the presence of the pendant olefin,
intramolecular 6p-electron 5-atom electrocyclic reaction
occurs faster than reduction, giving nitronate 18.26 Sub-
sequent 1,5-hydrogen shift and isomerization affords
N-hydroxyindole 20, which is subsequently reduced by a
second equivalent of CO to give indole 21. The viability of
the 1,5-electrocylization pathway under experimental reac-
tion conditions has been demonstrated computationally.27,28
In order to explore the electronic effect on the rate of
reaction, competition experiments of substituted ortho-
nitrostyrenes 7b–f with unsubstituted 7a (XZH) were
conducted (Table 5). A 1:1 molar ratio of the substituted
styrene and 7a was submitted to the following cyclization
conditions: 0.1 mol% Pd(TFA)2, 0.7 mol% tm-phen, 15 psi
CO, 80 8C, DMF. Relative rates were determined by HPLC
assay yield of the amount of starting material remaining in
the reaction mixture and are reported as an average of three
experiments.
A r value of C1.77 was obtained by plotting log krel versus
s parameter29 (Fig. 3), indicative of a build-up of negative
charge on the nitroarene in the rate determining step of the
reaction. This finding is also supported by an increase in
reaction rate with the reduction potential of the nitro-
styrene30 (Fig. 4). The rate of reaction 7f, bearing a methoxy
substituent ortho to the nitro group, correlated well with the
Attempts to trap nitrosostyrene 17 by conducting the
Table 5. Substituent effects on the reductive cyclization of substituted ortho-nitrostyrenes
E8a
krel
sp
b
Entry
X
Substrate
1
2
3
4
5
6
4-CO2Me
4-Cl
H
4-Me
5-NMe2
6-OMe
7b
7c
7a
7d
7e
7f
K0.95
K1.09
K1.13
K1.20
K1.23
K1.40
6.8
3.5
—
0.57
0.51
0.15
0.50
0.23
0
K0.17
K0.15c
—
a E8Z(EpcCEpa)/2.
b Values from Ref 30.
c Value reported is sm.

I. W. Davies et al. / Tetrahedron 61 (2005) 6425–6437
6431
just 15 psig CO. Using CO as the stoichiometric reductant
and 0.1 mol% palladium trifluoroacetate, CO2 is the only
stoichiometric by-product, which offers significant
economic and environmental advantages over the standard
triethylphosphite deoxygenation procedure.
4. Experimental
4.1. General methods
1H NMR and 13C NMR were recorded at ambient
temperature at a frequency of 400.13 and 100.61 MHz,
respectively. The chemical shifts are reported in ppm
relative to residual CHCl3 for proton (dZ7.27) and CDCl3
for carbon (dZ77.0). The data are reported as follows:
proton multiplicities (sZsinglet, dZdoublet, tZtriplet, qZ
quartet, mZmultiplet and brZbroad), coupling constants,
and integration. Microanalyses were performed by Quanti-
tative Technologies, Inc. Melting points are reported
uncorrected. Flash chromatography was performed using
the indicated solvent system on EM Reagents silica gel
(SiO2) 60 (230–400 mesh). All reactions were carried out
under an atmosphere of nitrogen, except where indicated.
All reagents used were commercially available from
Aldrich Chemical Co., except the following: 2-methoxy-
quinoline-3-carboxaldehyde6b was purchased from Daito
Chemix Corporation, 7g was purchased from Menai
Organics, Ltd and 7l was purchased from Acros. DMF,
Figure 3. Hammett plot for the reaction of substituted ortho-nitrostyrenes
7a–e.
˚
DMSO, toluene and DBU were dried over 4 A molecular
sieves. Solutions of Pd(OAc)2, Pd(TFA)2, 1,10-phenanthro-
line (phen) and 3,4,7,8-tetramethyl-1,10-phenanthroline
(tm-phen) in DMF were prepared in air.
4.1.1. Reductive cyclization of 3 with Pd(OAc)2 and
PPh3:2-methoxy-3-(5-{[4-(methylsulfonyl)-1-piperazinyl]-
methyl}-1H-indol-2-yl)-quinoline (2). An autoclave was
charged with 36b (4.0 g, 8.3 mmol), Pd(OAc)2 (0.112 g,
0.50 mmol), PPh3 (0.520 g, 2.00 mmol) and acetonitrile
(40 mL). The vessel was purged three times successively
with N2 and CO. The reactor was pressurized to 30 psig with
CO heated to 70 8C. After 15 h, the reaction mixture was
filtered washing with hot acetonitrile, affording dimer 4 as a
pale green solid (0.224 g, 0.25 mmol, 3%) inO95% purity
Figure 4. Plot of log krel versus reduction potential for the reductive
cyclization of ortho-nitrostyrenes 7a–f.
reduction potential. Severe drops in the rate of reduction of
ortho-substituted nitroarenes by Ru(dppe)(CO)3 complexes
were found in arenes bearing three or more substituents.25
Presumably, in these sterically encumbered systems, the
nitro group rotates out of plane with the aromatic ring.
1
as determined by H NMR spectroscopic analysis. HPLC
analysis of the filtrate indicated a 95% assay yield of 2. The
filtrate was concentrated in vacuo. Crystallization from 2:1
EtOAc/hexanes provided 2 as a pale yellow solid (1.79 g,
45%): mp 197–198 8C; 1H NMR (CDCl3, 400 MHz) d 9.68
(br s, 1H), 8.48 (s, 1H), 7.88 (d, JZ8.4 Hz, 1H), 7.81 (d, JZ
8.1 Hz, 1H), 7.64 (t, JZ8.4 Hz, 1H), 7.57 (s, 1H), 7.44 (m,
2H), 7.18 (dd, JZ8.3, 1.4 Hz, 1H), 7.07 (s, 1H), 4.31 (s,
3H), 3.66 (s, 2H), 3.27 (m, 4H), 2.78 (s, 3H), 2.61 (m, 4H);
13C NMR (CDCl3, 100 MHz) d 158.3, 145.3, 136.0, 135.2,
134.0, 129.6, 129.0, 128.3, 127.6, 127.0, 125.5, 124.8,
124.2, 121.1, 116.8, 111.3, 101.5, 63.3, 54.1, 52.3, 46.0,
34.0; Anal. Calcd for C24H26N4O3S: C, 63.98; H, 5.82; N,
12.44. Found: C, 64.28; H, 5.68; N, 12.05.
The electrocyclization of 17 to give 18 (Scheme 5) would
not be expected to be accelerated by electron withdrawing
groups.31 A competition experiment between nitrostyrene
7b and N-hydroxyindole 20a (Scheme 5, RZPh) indicated
that the reduction of 20a is faster than the reduction of 7b.
We propose that rate determining reduction of nitroarene 15
to nitroso intermediate 17 is followed by a faster cyclization
to N-hydroxyindole 20, which is then reduced to indole 21.
3. Conclusion
We have developed a palladium-catalyzed reduction of
ortho-nitrostyrenes to afford indoles in good to excellent
yields. A range of functionality is tolerated. The cyclization
occurs under much milder conditions and at lower catalyst
loadings than previously reported, giving excellent yields at
4.1.2. 2,20-Bis(2-methoxyquinolin-3-yl)-5,50-bis{[4-
(methylsulfonyl)piperazin-1-yl]methyl}-1H,10H-3-30-
biindole (4). Mp 324–326 8C (dec); H NMR (DMSO-d6,
1
400 MHz) d 11.3 (br s, 2H), 7.96 (s, 2H), 7.67 (d, JZ8.3 Hz,

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I. W. Davies et al. / Tetrahedron 61 (2005) 6425–6437
2H), 7.57 (dt, JZ7.0, 1.2 Hz, 2H), 7.50 (d, JZ7.9 Hz, 2H),
7.37 (d, JZ8.3 Hz, 2H), 7.29 (dt, JZ7.9, 0.8 Hz, 2H), 7.01
(m, 4H), 3.67 (s, 6H), 3.44 (d, JZ12.4 Hz, 2H), 3.22 (d, JZ
12.4 Hz, 2H), 2.92 (m, 8H), 2.82 (s, 6H), 2.22 (m, 4H), 2.15
(m, 4H); 13C NMR (DMSO-d6, 100 MHz) d 159.0, 144.8,
138.4, 135.6, 130.2, 129.3, 127.3, 126.9, 126.1, 124.3,
123.9, 123.1, 120.2, 118.2, 110.9, 108.2, 62.4, 52.8, 51.3,
45.1, 35.6, 33.8; HRMS calcd for C48H51N8O6S2: 899.3373
(MCH). Found: 899.3372 (MCH).
After a 36 h age, the reaction mixture was diluted with IPAc
(60 mL) and washed with brine (60 mL). The layers were
separated. The organic layer was dried (Na2SO4), filtered
and concentrated in vacuo. Purification by flash chroma-
tography (1:15 to 1:8 EtOAc/hexanes) afforded 6c as a
green tacky oil (7.03 g, 61%) inO95% purity as determined
by 1H NMR spectroscopic analysis: 1H NMR (CDCl3,
400 MHz) d 7.94–7.91 (m, 1H), 7.44–7.32 (m, 7H), 5.04–
5.02 (m, 1H), 3.37 (dd, JZ13.6, 3.7 Hz, 1H), 3.21 (dd, JZ
13.6, 9.0 Hz, 1H), 2.09 (d, JZ3.4 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) d 147.8, 143.6, 138.7, 135.7, 133.4,
128.5, 127.7, 127.5, 126.1, 125.6, 73.6, 42.4.
4.1.3. Reductive cyclization of 3 with Pd(OAc)2 and
phen: (2). An autoclave was charged with was charged with
3 (45.02 g, 93.3 mmol), Pd(OAc)2 (0.210 g, 0.935 mmol),
1,10-phenathroline (0.336 g, 1.87 mmol) and DMF (1.3 L).
The vessel was purged three times successively with N2 and
CO. The reactor was pressurized to 15 psig with CO and the
mixture heated to 70 8C. After 14 h, the vessel was allowed
to cool to rt. The reaction mixture was filtered through solka
flok. The filtrate was concentrated to 150 mL and heated to
50 8C. MeOH (50 mL) was added and the mixture was
allowed to cool to rt. Filtration afforded 2 as a pale yellow
solid (39.39 g, 94%). Spectral data was identical to that
prepared by Method A.
4.1.7. 4-Chloro-1-nitro-2[(E)-2-phenylvinyl]benzene
(7c).32 To a solution of 6c (2.01 g, 7.24 mmol) in toluene
(25 mL) was added PTSA (0.275 g, 1.45 mmol). The
reaction vessel was equipped with a Dean Stark apparatus
and heated at 110 8C for 1 h. The mixture was cooled to rt
and washed with NaHCO3 (saturated aq, 2!10 mL) and
water (10 mL). The organic layer was dried (Na2SO4) and
concentrated in vacuo to a yellow solid. Crystallization from
1:2 toluene/hexanes afforded 7c as a yellow solid (0.950 g,
51%). A second crop was obtained by crystallization from
1:5 EtOAc/hexanes (0.247 g, 13%): mp 94.2–95.3 8C (lit.30
1
mp 91–93 8C); H NMR (CDCl3, 400 MHz) d 7.96 (d, JZ
4.1.4. Reductive cyclization of 3 with Pd(TFA)2 and tm-
phen: (2). An Endeavore glass liner was charged with 3
(100 mg, 0.207 mmol) and the liner was inserted into an
Endeavore pressure reactor. To the liner was charged
Pd(TFA)2 (6.02!10K3 M solution in DMF, 34 mL,
2.05!10K4 mmol), 3,4,7,8-tetramethyl-1,10-phenanthro-
line (1.20!10K2 M solution in DMF, 121 mL, 1.45!
10K3 mmol) and DMF (2.85 mL). The reactor system was
sealed and purged three times with N2 followed by CO. The
system was pressurized with CO (15 psig) and heated at
80 8C for 16 h. The mixture was cooled to rt and
concentrated in vacuo. Purification by flash chromatography
(2:1 EtOAc/hexanes to 4:1 EtOAc/hexanes) afforded 2 as a
pale yellow solid (87 mg, 94%). Spectral data was identical
to that prepared by Method A.
8.8 Hz, 1H), 7.75 (d, JZ2.2 Hz, 1H), 7.62–7.55 (m, 3H),
7.43–7.35 (m, 4H); 7.10 (d, JZ16.1 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) d 146.0, 139.4, 136.0, 135.0, 134.9,
128.9, 128.8, 127.9, 127.8, 127.2, 126.3, 122.4.
4.1.8. Trimethyl(5-methyl-2-nitrobenzyl)silane (9). To a
cooled (K40 8C) solution of 4-nitrotoluene (13.7 g,
99.9 mmol) in THF (200 mL) was added TMSCH2MgCl
(1.0 M in THF, 130 mL, 130 mmol) at such a rate to
maintain the reaction temperature ! K30 8C. After 1 h, the
reaction was warmed to K10 8C. Iodine (1 M aq, 130 mL,
130 mmol) was added and the mixture was allowed to warm
to rt. After 15 min, Na2SO3 (saturated aq, 75 mL) was
charged. The mixture was extracted with MTBE (100 mL).
The layers were separated and the organic layer was washed
with Na2SO3 (saturated aq, 50 mL) and brine (50 mL). The
organic layer was dried (Na2SO4), filtered and concentrated
in vacuo to an orange liquid. Purification by flash
chromatography (1:20 EtOAc/hexanes) afforded 9 as a
pale yellow liquid (15.44 g, 69%): 1H NMR (CDCl3,
400 MHz) d 7.88 (d, JZ8.4 Hz, 1H), 7.00 (dd, JZ8.4,
1.0 Hz, 1H), 6.94 (s, 1H), 2.58 (s, 2H), 2.37 (s, 3H), 0.01 (s,
9H); 13C NMR (CDCl3, 100 MHz) d 145.6, 143.7, 137.7,
131.9, 125.7, 125.4, 24.9, 21.3, K1.5; Anal. Calcd for
C11H17NO2Si: C, 59.15; H, 7.67; N, 6.27. Found: C, 59.21;
H, 7.74; N, 6.16.
4.1.5. Methyl 4-nitro-3-[(E)-2-phenylvinyl]benzoate (7b).
To a solution of 6b20 (1.50 g, 4.98 mmol) in isopropyl
acetate (IPAc, 20 mL) was added trifluoroacetic anhydride
(2.07 mL, 14.9 mmol). After 1 h, DBU (3.72 mL,
24.9 mmol) was added. After 1 h, the reaction was diluted
with IPAc (20 mL) and washed with 2 N HCl (10 mL),
water (10 mL) and brine (10 mL). The organic layer was
dried (Na2SO4) and concentrated in vacuo to a yellow solid.
Crystallization from 1:5 EtOAc/hexanes afforded 7b as
1
yellow needles (1.06 g, 75%): mp 122–123 8C; H NMR
(CDCl3, 400 MHz) d 8.44 (d, JZ1.6 Hz, 1H), 8.03 (dd, JZ
8.5, 1.7 Hz, 1H), 7.96 (d, JZ8.5 Hz, 1H), 7.58–7.55 (m,
2H), 7.51 (s, 1H), 7.43–7.34 (m, 3H), 7.22 (d, JZ16.1 Hz,
1H), 4.01 (s, 3H); 13C NMR (CDCl3, 100 MHz) d 165.2,
150.3, 136.1, 135.1, 133.9, 132.9, 129.4, 128.9, 128.8,
128.6, 127.2, 124.8, 122.0, 52.8; Anal. Calcd for
C16H13NO4: C, 67.84; H, 4.63; N, 4.94. Found: C, 67.62;
H, 4.53; N, 4.94.
4.1.9. 2-(5-Methyl-2-nitrophenyl)-1-phenylethanol (6d).
To a solution of 9 (14.21 g, 63.6 mmol) in IPAc (250 mL)
was added benzaldehyde (6.75 mL, 66.8 mmol) followed by
TBAF (1 M solution in THF, 12.7 mL, 12.7 mmol). After
2 h, NH4Cl (saturated aq, 100 mL) was added to the reaction
mixture. The layers were separated. The organic layer was
washed with brine (50 mL), dried (Na2SO4), filtered and
concentrated in vacuo to an orange oil. Purification by flash
chromatography (1:7 to 1:3 EtOAc/hexanes) afforded 6d as
an off-white solid (9.59 g, 59%): mp 77.8–78.2 8C; 1H NMR
(CDCl3, 400 MHz) d 7.91 (d, JZ8.3 Hz, 1H), 7.44–7.36 (m,
4.1.6.
2-(5-Chloro-2-nitrophenyl)-1-phenylethanol
(6c).20 To a solution of 5-chloro-2-nitrotoluene (9.68 g,
56.0 mmol) and benzaldehyde (4.80 mL, 47.0 mmol) in
DMSO (60 mL) was added DBU (8.40 mL, 56.0 mmol).

I. W. Davies et al. / Tetrahedron 61 (2005) 6425–6437
6433
4H), 7.32–7.31 (m, 1H), 7.20–7.18 (m, 1H), 7.14 (br s, 1H),
5.07–5.03 (m, 1H), 3.40 (dd, JZ13.5, 3.7 Hz, 1H), 3.19 (dd,
JZ13.5, 9.1 Hz, 1H), 2.40 (s, 3H), 2.15 (d, JZ3.6 Hz, 1H);
13C NMR (CDCl3, 100 MHz) d 147.5, 144.0, 143.9, 134.1,
133.6, 128.5, 128.3, 127.8, 125.6, 125.1, 74.3, 43.1, 21.3;
Anal. Calcd for C15H15NO3: C, 70.02; H, 5.88; N, 5.44.
Found: C, 69.95; H, 5.84; N, 5.43.
Calcd for C15H13NO3: C, 70.58; H, 5.13; N, 5.49. Found: C,
70.40; H, 4.92; N, 5.36.
4.1.13. Methyl 3-[2-hydroxy-2-(2-methoxyquinolin-3-
yl)ethyl]-4-nitrobenzoate (6i). To a solution of methyl
3-methyl-4-nitrobenzoate (1.19 g, 6.41 mmol) and
2-methoxyquinoline-3-carboxaldehyde (1.00 g, 5.34 mmol)
in DMSO (20 mL) was added DBU (0.96 mL, 6.4 mmol).
After 3 h the mixture was diluted with IPAc (100 mL) and
washed with brine (100 mL). The organic layer was
concentrated and purified by chromatography (4:1 EtOAc/
hexanes) to afford 6i as a pale yellow solid (1.60 g, 80%): mp
130.0–131.0 8C; 1H NMR (CDCl3, 400 MHz) d 8.11 (s, 1H),
8.05–8.03 (m, 2H), 7.92–7.86 (m, 2H), 7.73 (d, JZ8.8 Hz,
1H), 7.65–7.61 (m, 1H), 7.42–7.38 (m, 1H), 5.19 (br s, 1H),
4.17 (s, 3H), 3.94 (s, 3H), 3.55–3.45 (m, 2H), 2.90–2.80 (m,
1H); 13C NMR (CDCl3, 100 MHz) d 165.2, 159.1, 152.7,
145.6, 135.4, 134.7, 134.3, 133.2, 133.1, 129.3, 128.5, 127.4,
127.1, 126.7, 125.0, 124.2, 70.0, 53.4, 52.6, 39.4; Anal. Calcd
for C20H18N2O6: C, 62.82; H, 4.74; N, 7.33. Found: C, 62.82;
H, 4.62; N, 7.30.
4.1.10. 4-Methyl-1-nitro-2-[(E)-2-phenylvinyl]benzene
(7d). To a solution of 6d (8.56 g, 33.3 mmol) in IPAc
(150 mL) was added trifluoroacetic anhydride (14.1 mL,
99.9 mmol). After 1 h, DBU (24.9 mL, 167 mmol) was
added. The mixture was heated at reflux for 14 h. Upon
cooling to rt, a white solid precipitated. The mixture was
filtered, washing with EtOAc. The filtrate was washed with
2 N HCl (75 mL), water (75 mL), brine (75 mL) and
concentrated in vacuo to a brown oil. Purification by flash
chromatography (1:10 to 1:5 toluene/hexanes) afforded 7d
as a yellow oil (5.6 g, 70%): 1H NMR (CDCl3, 400 MHz) d
7.92 (d, JZ8.4 Hz, 1H), 7.65 (d, JZ16.1 Hz, 1H), 7.57–
7.55 (m, 3H), 7.42–7.38 (m, 2H), 7.35–7.33 (m, 1H), 7.20
(d, JZ8.3 Hz, 1H), 7.07 (d, JZ16.1 Hz, 1H), 2.48 (s, 3H);
13C NMR (CDCl3, 100 MHz) d 145.7, 144.2, 136.6, 133.4,
133.2, 128.7, 128.6, 128.4, 127.0, 125.0, 124.0, 21.5; 13C
NMR (CD3CN, 100 MHz) d 147.0, 145.8, 137.9, 134.1,
133.7, 130.0, 129.9, 129.7, 129.5, 128.0, 125.9, 124.9, 21.6;
Anal. Calcd for C15H13NO2: C, 75.30; H, 5.48; N, 5.85.
Found: C, 75.59; H, 5.28; N, 5.78.
4.1.14. Methyl 3-[(E)-2-(2-methoxyquinolin-3-yl)vinyl]-
4-nitrobenzoate (7i). To a solution of 6i (1.60 g,
4.18 mmol) in IPAc (60 mL) was added trifluoroacetic
anhydride (1.75 mL, 12.6 mmol). After the reaction was
aged for 1 h, DBU (1.88 mL, 12.6 mmol) was added. After
14 h, the reaction mixture was washed with brine (20 mL)
and concentrated in vacuo. Purification by flash chroma-
tography (1:4 EtOAc/hexanes) afforded 7i as a white solid
(1.32 g, 87%): mp 186–187 8C; 1H NMR (CDCl3,
400 MHz) d 8.53 (s, 1H), 8.23 (s, 1H), 8.01 (d, JZ8.4 Hz,
1H), 8.00 (d, JZ8.4 Hz, 1H), 7.85 (d, JZ8.1 Hz, 1H), 7.77
(m, 2H), 7.64 (t, JZ7.6 Hz, 1H), 7.52 (d, JZ16.8 Hz, 1H),
7.41 (t, JZ8.4 Hz, 1H), 4.18 (s, 3H), 4.03 (s, 3H); 13C NMR
(CDCl3, 100 MHz) d 165.2, 159.7, 150.3, 146.2, 135.4,
133.9, 132.9, 129.9, 129.5, 129.1, 128.8, 127.7, 126.9,
125.1, 124.8, 124.7, 124.4, 121.3, 53.7, 52.8; Anal. Calcd
for C19H16N2O4: C, 65.93; H, 4.43; N, 7.69. Found: C,
65.73; H, 4.35; N, 7.63.
4.1.11. N,N-Dimethylamino-3-nitro-4-[(E)-2-phenylvinyl]-
aniline (7e). To a solution of diethyl benzylphosphonate
(0.800 mL, 3.84 mmol) and 4-dimethylamino-2-nitro-
benzaldehyde (500 mg, 2.57 mmol) in DMF (20 mL) was
added KOt-Bu (288 mg, 2.57 mmol). After 14 h, the
mixture was diluted with MTBE (20 mL) and washed
with water (2!5 mL). The organic layer was dried
(Na2SO4), filtered and concentrated in vacuo to a red oil.
Purification by flash chromatography (1:4 EtOAc/hexanes)
afforded 7e as a red solid (363 mg, 53%): mp 105.8–
106.4 8C, 1H NMR (CDCl3, 400 MHz) d 7.64 (d, JZ8.8 Hz,
1H), 7.52–7.48 (m, 3H), 7.38–7.36 (m, 2H), 7.28–7.25 (m,
1H), 7.17 (d, JZ2.8 Hz, 1H), 6.95 (d, JZ16.2 Hz, 1H),
6.93–6.90 (m, 1H), 3.05 (s, 6H); 13C NMR (CDCl3,
100 MHz) d 149.6, 149.0, 137.2, 129.6, 128.6, 128.4,
127.6, 126.5, 123.4, 119.7, 116.4, 106.6, 40.1; Anal. Calcd
for C16H16N2O2: C, 71.62; H, 6.01; N, 10.44. Found: C,
71.52; H, 5.96; N, 10.25.
4.1.15. 2-(5-Chloro-2-nitrophenyl)-1-(2-methoxyquino-
lin-3-yl)ethanol (6j). To a solution of 5-chloro-2-nitro-
toluene (1.65 g, 9.62 mmol), 2-methoxy-3-quinoline
carboxaldehyde (1.64 g, 8.74 mmol) in DMSO (40 mL)
was added DBU (1.57 mL, 10.5 mmol). After 3 h, the
mixture was diluted with IPAc (100 mL), washed with brine
(100 mL) and concentrated in vacuo. Purification by flash
chromatography (4:1 EtOAc/hexanes) afforded 6j as a white
solid (2.65 g, 84%): mp 127.1–128.0 8C; 1H NMR (CDCl3,
400 MHz) d 8.02 (s, 1H), 7.98–7.84 (m, 2H), 7.72 (d, JZ
7.6 Hz, 1H), 7.64–7.61 (m, 1H), 7.44–7.34 (m, 3H), 5.18 (br
s, 1H), 4.15 (s, 3H), 3.47–3.35 (m, 2H), 3.01–2.97 (m, 1H);
13C NMR (CD3CN, 100 MHz) d 159.1, 148.3, 145.6, 138.6,
135.4, 134.8, 132.9, 129.3, 127.5, 127.4, 127.1, 126.7,
125.9, 125.0, 124.2, 69.9, 53.4, 39.6. Anal. Calcd for
C18H15ClN2O4: C, 60.26; H, 4.41; N, 7.81. Found: C, 60.13;
H, 4.13; N, 7.73.
4.1.12. 4-Methoxy-2-nitro-1-[(E)-2-phenylvinyl]benzene
(7f). To a solution of diethyl benzylphosphonate (0.860 mL,
4.14 mmol) and 3-methoxy-2-nitrobenzaldehyde (500 mg,
2.76 mmol) in DMF (10 mL) was added NaOMe (194 mg,
3.6 mmol). After 14 h, the mixture was partitioned between
water (5 mL) and MTBE (10 mL). The layers were
separated. The organic layer was washed with water (2!
5 mL), dried (Na2SO4), filtered and concentrated in vacuo to
an oil that solidified upon standing. Crystallization from 1:9
EtOAc/hexanes afforded 7f as a pale orange solid (435 mg,
1
62%): mp 112.0–113.6 8C; H NMR (CDCl3, 400 MHz) d
7.50–7.48 (m, 2H), 7.43–7.31 (m, 5H), 7.17 (d, JZ16.1 Hz,
1H); 6.96–6.92 (m, 2H), 3.92 (s, 3H); 13C NMR (CDCl3,
100 MHz) d 150.8, 140.5, 136.0, 134.1, 130.7, 130.6,
128.74, 128.71, 127.0, 120.1, 117.6, 111.0, 56.3; Anal.
4.1.16. 3-[(E)-2-(5-Chloro-2-nitropheyl)vinyl]-2-methoxy-
quinoline (7j). To a solution of 6j (1.00 g, 2.79 mmol) in
IPAc (20 mL) was added trifluoroacetic anhydride
(1.24 mL, 14.0 mmol). After 1 h, DBU (3.34 mL,

6434
I. W. Davies et al. / Tetrahedron 61 (2005) 6425–6437
22.3 mmol) was added. After 14 h, the reaction mixture was
washed with brine (20 mL) and concentrated in vacuo.
Purification by flash chromatography (1:5 EtOAc/hexanes)
afforded 7j as a pale yellow solid (0.88 g, 93%): mp 189.0–
189.5 8C; 1H NMR (CDCl3, 400 MHz) d 8.22 (s, 1H), 7.98
(d, JZ9.2 Hz, 1H), 7.90–7.74 (m, 4H), 7.63 (t, JZ8.4 Hz,
1H), 7.43 (s, 1H), 7.39 (d, JZ7.6 Hz, 2H), 4.17 (s, 3H); 13C
NMR (CD3CN, 100 MHz) d 159.6, 146.3, 140.5, 139.5,
135.3, 134.9, 129.9, 129.0, 128.1, 128.0, 127.7, 126.9,
126.3, 125.1, 125.1, 124.4, 121.2, 53.7; Anal. Calcd for
C18H13ClN2O3: C, 63.44; H, 3.85; Cl, 10.40; N, 8.22.
Found: C, 63.22; H, 3.68; Cl, 10.33; N, 8.10.
and DMF (2.3 mL) afforded 10c, after purification by flash
chromatography (1:1 toluene/hexanes) as a white solid
(109 mg, 96%): mp 202.9–203.7 8C (lit.31c mp 197–198 8C);
1H NMR (d6-DMSO, 400 MHz) d 11.27 (br s, 1H), 7.86–
7.84 (m, 2H); 7.56 (d, JZ2.0 Hz, 1H), 7.49–7.45 (m, 2H),
7.39 (d, JZ8.6 Hz, 1H), 7.35–7.31 (m, 1H), 7.08 (dd, JZ
8.6, 2.1 Hz, 1H), 6.88 (d, JZ1.7 Hz, 1H); 13C NMR (d6-
DMSO, 100 MHz) d 139.3, 135.6, 131.7, 129.8, 129.0,
127.8, 125.2, 123.9, 121.4, 119.1, 112.7, 98.4.
4.1.21. 5-Methyl-2-phenyl-1H-indole (10d).35 Using
Method B with 7d, (110 mg, 0.462 mmol), phen2Pd(OAc)2
(3.6!10K3
M
solution in DMF, 1.30 mL, 4.7!
10K3 mmol) and DMF (2.4 mL) afforded 10d, after
purification by flash chromatography (1:3 to 1:1 toluene/
hexanes) as an off-white solid (85 mg, 89%): mp 221.8–
223.0 8C (lit.33b mp 218–219 8C); 1H NMR (CDCl3,
400 MHz) d 8.23 (br s, 1H), 7.68–7.66 (m, 2H), 7.47–7.43
(m, 3H), 7.35–7.29 (m, 2H), 7.03 (dd, JZ8.2, 1.2 Hz, 1H),
6.77 (d, JZ1.4 Hz, 1H), 2.47 (s, 3H); 13C NMR (CDCl3,
100 MHz) d 137.9, 135.2, 132.5, 129.5, 129.5, 129.0, 127.6,
125.0, 124.0, 120.3, 110.5, 99.6, 21.5.
4.1.17. Reductive cyclization, method A: 2-phenyl-1H-
indole (10a).33 On the bench top, an Endeavore glass liner
was charged with (E)-7a,8c (169 mg, 0.750 mmol) and the
liner was inserted into an Endeavore pressure reactor. To
the liner was charged phen2Pd(OAc)2 {3.28!10K3
M
solution in DMF [prepared by dissolving Pd(OAc)2
(36.9 mg, 0.164 mmol) and 1,10-phenanthroline (62.0 mg,
0.328 mmol) in DMF (50 mL)], 3.43 mL, 0.011 mmol}, and
DMF (2.6 mL). The reactor system was sealed and purged
three times with N2 followed by CO. The system was
pressurized with CO (15 psig) and heated at 80 8C for 16 h.
The mixture was cooled to rt and filtered through solka flok.
The filtrate was concentrated in vacuo. Purification by flash
chromatography (1:9 to 1:5 EtOAc/hexanes) afforded 10a as
a white solid (128 mg, 87%): mp 193.4–193.9 8C (lit.31c mp
191–192 8C).
4.1.22. N,N-Dimethyl-2-phenyl-1H-indole-6-amine (10e).
Using Method A with 7e (56 mg, 0.21 mmol), Pd(TFA)2
(3.0!10K3
M solution in DMF, 0.690 mL, 2.07!
10K3 mmol), 3,4,7,8-tetramethyl-1,10-phenathroline
(7.1!10K3 M solution in DMF, 0.58 mL, 4.1!
10K3 mmol) and DMF (2.4 mL) afforded 10e, after
purification by flash chromatography (1:4 EtOAc/hexanes)
as an off-white solid (30 mg, 61%): mp 190.4–190.7 8C; 1H
NMR (CDCl3, 400 MHz) d 8.11 (br s, 1H), 7.63–7.61 (m,
2H), 7.48 (d, JZ8.6 Hz, 1H), 7.44–7.40 (m, 2H), 7.29–7.25
(m, 1H), 6.79–6.73 (m, 3H), 2.99 (s, 6H); 13C NMR (CDCl3,
100 MHz) d 147.4, 138.8, 135.2, 132.7, 128.8, 126.4, 124.2,
120.8, 120.3, 109.1, 98.5, 94.3, 41.2; Anal. Calcd for
C16H16N2O2: C, 81.32; H, 6.82; N, 11.85. Found: C, 81.58;
H, 6.85; N, 11.70.
4.1.18. Reaction of mixture of isomeric olefins, (10a).
Using Method
A
with 1:1 (E/Z)-4a,21 (169 mg,
0.750 mmol), phen2Pd(OAc)2 (3.28!10K3 M solution in
DMF, 3.43 mL, 0.011 mmol) and DMF (2.6 mL) afforded
10a, after purification by flash chromatography (1:9 to 1:4
EtOAc/hexanes) as a white solid (126 mg, 86%).
4.1.19. Reductive cyclization, method B: methyl
2-phenyl-1H-indole-5-carboxylate (10b).34 In a nitrogen
atmosphere glove box, a PPRw glass liner was charged with
7b (141 mg, 0.500 mmol) and the liner was inserted into
the Parallel Pressure Reactor system. To the liner was
charged Pd(TFA)2 (6.02!10K3 M solution in DMF,
83 mL, 5.0!10K4 mmol), 3,4,7,8-tetramethyl-1,10-
phenathroline (1.20!10K2 M solution in DMF, 292 mL,
3.5!10K3 mmol) and DMF (2.65 mL). The reactor system
was sealed and purged three times with N2 followed by CO.
The system was pressurized with CO (15 psig) and heated at
80 8C for 16 h. The mixture was cooled to rt and filtered
through solka flok. The filtrate was concentrated in vacuo.
Purification by flash chromatography afforded 10b as a
4.1.23. 7-Methoxy-2-phenyl-1H-indole (10f). Using
Method B with 7f (100 mg, 0.391 mmol), Pd(TFA)2
(6.0!10K3
M
solution in DMF, 1.30 mL, 3.91!
10K3 mmol), 3,4,7,8-tetramethyl-1,10-phenathroline
(1.2!10K2 M solution in DMF, 0.650 mL, 7.8!
10K2 mmol), and DMF (1.05 mL) afforded 10f, after
purification by flash chromatography as an off-white solid
(16 mg, 18%). Spectral data matched that reported in the
literature.36
4.1.24. Methyl N-(5H-[1,3]dioxolo[4,5-f]indol-6-ylcar-
bonyl)glycinate (10g). Using Method A with 7g (231 mg,
0.750 mmol), Pd(TFA)2 (3.56!10K3 M solution in DMF,
2.1 mL, 7.5!10K3 mmol), 3,4,7,8-tetramethyl-1,10-
phenathroline (7.1!10K3 M solution in DMF, 2.1 mL,
1.5!10K2 mmol) and DMF (1.8 mL) afforded 10g, after
purification by flash chromatography (1:4 EtOAc/hexanes)
as an off-white solid (149 mg, 72%): mp 259.2–261.4 8C;
1H NMR (d6-DMSO, 400 MHz) d 11.39 (s, 1H), 8.73 (t, JZ
5.9 Hz, 1H), 7.06–7.01 (m, 2H), 6.86 (s, 1H), 5.95 (s, 2H),
4.00 (d, JZ10.7 Hz, 2H), 3.65 (s, 3H); 13C NMR (d6-
DMSO, 100 MHz) d 170.9, 161.7, 146.4, 143.4, 132.4,
130.0, 121.3, 104.0, 100.8, 99.6, 92.5, 52.1, 41.1; Anal.
1
white solid (123 mg, 98%): mp 191.0–191.6 8C; H NMR
(CDCl3, 400 MHz) d 8.57 (br s, 1H), 8.41 (s, 1H), 7.92 (dd,
JZ8.6, 1.5 Hz, 1H), 7.69 (dd, JZ8.5, 1.1 Hz, 2H), 7.50–
7.35 (m, 4H), 6.91 (d, JZ1.6 Hz, 1H), 3.96 (s, 3H); 13C
NMR (d6-DMSO, 100 MHz) d 167.2, 139.7, 139.5, 131.6,
129.0, 128.2, 127.9, 125.2, 122.54. 122.51, 120.9, 111.2,
99.9, 51.6; Anal. Calcd for C16H13NO4: C, 76.48; H, 5.21;
N, 5.57. Found: C, 76.47; H, 5.14; N, 5.47.
4.1.20. 5-Chloro-2-phenyl-1H-indole (10c).31c Using
Method A with 7c, (130 mg, 0.500 mmol), phen2Pd(OAc)2
(7.3!10K3 M solution in DMF, 0.70 mL, 5.1!10K3 mmol)

I. W. Davies et al. / Tetrahedron 61 (2005) 6425–6437
6435
Calcd for C13H12N2O5$1⁄3H2O: C, 55.32; H, 4.52; N, 9.93.
Found: C, 55.69; H, 4.38; N, 9.67.
chromatography (1:6 EtOAc/hexanes) as a white solid
(187 mg, 84%): mp 151.0–151.6 8C (lit.8c mp 151–152 8C).
4.1.25. 5-Methoxy-2-(2-methoxypyridin-3-yl)-1H-indole
(10h). Using Method A with 7h37 (215 mg, 0.750 mmol),
phen2Pd(OAc)2 (3.28!10K3 M solution in DMF, 3.43 mL,
0.015 mmol) and 2.6 mL DMF at 30 psig CO and 70 8C
afforded 10h, after purification by flash chromatography
(1:4 to 1:2 EtOAc/hexanes) as an off-white solid (138 mg,
4.1.30.
2-(2-Methoxyquinolin-3-yl)-5-{[4-(methyl-
sulfonyl)piperazine-1-yl]methyl}-1H-indol-1-ol (14).6a
Using Method B with 3 (100 mg, 0.207 mmol), phen2-
Pd(OAc)2 (1.55!10K3 M solution in toluene, 1.33 mL,
2.07!10K3 mmol) and toluene (1.7 mL) afforded 14, after
purification by flash chromatography (1:1 toluene/hexanes)
as an off-white solid (20 mg, 20%). Spectral data matched
that reported in the literature.6a
1
72%): mp 120.7–121.4 8C; H NMR (CDCl3, 400 MHz) d
9.59 (br s, 1H), 8.12 (dd, JZ5.8, 1.8 Hz, 1H), 8.09 (dd, JZ
7.6, 1.9 Hz, 1H), 7.33 (d, JZ8.8 Hz, 1H), 7.09 (d, JZ
2.4 Hz, 1H), 7.02 (dd, JZ7.6, 4.8 Hz, 1H), 6.90–6.87 (m,
2H), 4.18 (s, 3H), 3.88 (s, 3H); 13C NMR (CDCl3,
100 MHz) d 159.0, 154.3, 145.1, 135.6, 134.0, 131.4,
128.4, 117.6, 115.3, 112.9, 111.8, 101.5, 100.0, 55.7, 53.8;
Anal. Calcd for C15H14N2O2: C, 70.85; H, 5.55; N, 11.02.
Found: C, 70.68; H, 5.53; N, 10.90.
4.1.31. 4,5-Dimethyl-2-phenyl-3,6-dihydro-2H-1,2-oxa-
zine (22).17 Using Method B with nitrobenzene (43 mL,
0.41 mmol), phen2Pd(OAc)2 (3.56!10K3 M solution in
DMF, 1.16 mL, 4.13!10K3 mmol), 2,3-dimethylbutadiene
(0.5 mL, 4.4 mmol) and DMF (4.3 mL) at 15 psig CO and
70 8C afforded 22 in 29% assay yield.
4.1.26. Methyl 2-(2-methoxyquinolin-3-yl)-1H-indole-5-
carboxylate (10i). Using Method B with 7i (182 mg,
0.50 mmol), Pd(TFA)2 (6.02!10K3 M solution in DMF,
83 mL, 5.00!10K4 mmol), 3,4,7,8-tetramethyl-1,10-phena-
throline (1.20!10K2 M solution in DMF, 292 mL, 3.5!
10K3 mmol) and DMF (2.65 mL) afforded 10i, after
purification by flash chromatography (1:2 EtOAc/hexanes)
as an off-white solid (130 mg, 78%): mp 206.2–206.8 8C;
1H NMR (d6-DMSO, 400 MHz) d 11.89 (br s, 1H), 8.73 (s,
1H), 8.31 (s, 1H), 7.94 (d, JZ8.0 Hz, 1H), 7.84–7.78 (m,
2H), 7.72–7.68 (m, 1H), 7.56 (d, JZ8.6 Hz, 1H), 7.52–7.48
(m, 1H), 7.32 (d, JZ1.8 Hz, 1H), 4.18 (s, 3H), 3.86 (s, 3H);
13C NMR (d6-DMSO, 100 MHz) d 167.1, 158.3, 144.7,
139.4, 135.4, 134.2, 129.9, 127.8, 127.7, 126.4, 124.85,
124.83, 123.0, 122.9, 120.9, 116.5, 111.3, 104.7, 53.8, 51.7;
Anal. Calcd for C20H16N2O3: C, 72.28; H, 4.85; N, 8.43.
Found: C, 72.28; H, 4.80; N, 8.36.
4.2. Electrochemical measurements
All electrochemical measurements were performed with a
Bioanalytical Systems (BAS) Model C-3 electrochemical
analyzer and were conducted at room temperature. Experi-
ments were carried out with tetra-n-butylammonium hexa-
fluorophosphate (0.45 M solution in DMF) electrolyte
which was degassed with nitrogen while in the electro-
chemical cell. A polished working Pt electrode, a Pt
auxiliary electrode, and a Ag/AgCl pseudoreference
electrode were used. Potentials were referenced to FcC/Fc
couple versus Ag/AgCl pseudoreference electrode, which
was observed at 0.41 V. Reversible reduction was observed
for 7a–f at a scan rate of 100 mV/s.
4.3. Competition experiments, sample experimental
4.1.27. 3-(5-Chloro-1H-indol-2-yl)-2-methoxyquinoline
(10j). Using Method A with 7j (71 mg, 0.21 mmol),
A PPRw glass liner was charged with 7a (37.0 mg,
0.164 mmol) and 7e (44.0 mg, 0.164 mmol). The liner was
taken into a nitrogen atmosphere glove box and inserted into
the Parallel Pressure Reactor system. To the liner was
charged Pd(TFA)2 (6.02!10K3 M solution in DMF,
27 mL, 1.6!10K4 mmol), 3,4,7,8-tetramethyl-1,10-
phenathroline (1.20!10K2 M solution in DMF, 96 mL,
1.1!10K3 mmol) and DMF (2.9 mL). The reactor system
was sealed and purged three times with N2 followed by CO.
The system was pressurized with CO (15 psig) and heated at
80 8C for 1 h. The mixture was cooled to rt and diluted with
acetonitrile. HPLC analysis of the amounts of 7a and 7e
remaining in the reaction were as follows: 7a (7.9 mg,
0.035 mmol), 7e (19.9 mg, 0.074 mmol).
phen2Pd(OAc)2 (3.56!10K3
M solution in DMF,
0.58 mL, 2.1!10K3 mmol) and 2.4 mL DMF afforded
10j, after purification by flash chromatography (1:8
EtOAc/hexanes) as an off-white solid (58 mg, 91%): mp
1
172–174 8C; H NMR (d6-DMSO, 400 MHz) d 9.71 (br s,
1H), 8.46 (s, 1H), 7.87 (d, JZ7.8 Hz, 1H), 7.79 (d, JZ
7.9 Hz, 1H), 7.67–7.63 (m, 2H), 7.46–7.42 (m, 1H), 7.38 (d,
JZ8.5 Hz, 1H), 7.17 (d, JZ8.2 Hz, 1H), 7.01 (s, 1H), 4.30
(s, 3H); 13C NMR (d6-DMSO, 100 MHz) d 158.0, 145.3,
135.4, 134.9, 134.6, 129.7, 129.1, 127.4, 126.9, 125.7,
125.3, 124.8, 122.7, 119.6, 116.0, 112.1, 100.5, 54.0. Anal.
Calcd for C18H13ClN2O$0.25H2O: C, 69.01; H, 4.34; N,
8.94. Found: C, 69.85; H, 4.27; N, 9.11.
4.1.28. 2-Methyl-6-(trifluoromethoxy)-1H-indole (5k).6a
Using Method A with 4k6a (124 mg, 0.500 mmol), tm-
phen2Pd(TFA)2 (6.0!10K3 M solution in DMF, 0.833 mL,
5.0!10K3 mmol), and DMF (2.2 mL) afforded 5k in 84%
assay yield.
Acknowledgements
The authors thank Prof. Donna Blackmond for helpful
discussions, Dr. Jeff Kuethe for the synthesis of 7j, Dr. Jeff
Marcoux for the synthesis of 7k, Dr. Peter Skrdla for
assistance with cyclic voltammetry, Dr. Peter Dormer for
assistance with NMR analyses and Mr. Tony Houck, Mr.
Anthony Newell and Mr. Jess Sager for technical assistance.
4.1.29. 1H-Indol-2-yl(phenyl)methanone (10l).8c,38 Using
Method A with 7l, (253 mg, 1.0 mmol), phen2Pd(OAc)2
(7.3!10K3 M solution in DMF, 1.37 mL, 0.01 mmol) and
DMF (3.6 mL) afforded 10l, after purification by flash

6436
I. W. Davies et al. / Tetrahedron 61 (2005) 6425–6437
Todeschini, R.; Tollari, S. J. Chem. Soc. Faraday Trans.
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