Preparation of 2-arylindole-4-carboxylic amide derivatives

Article abstract of DOI:10.1016/j.tet.2006.05.007

A practical, highly efficient protocol has been developed for the synthesis of functionalized 2-arylindole-4-carboxylic amide derivatives. Commercially available methyl 2-methyl-3-nitrobenzoate gave substituted nitrostyrene benzoic acids by reaction with aromatic aldehydes in the presence of DBU in DMSO. Conversion of these products to the desired amides was followed by Pd-catalyzed reductive cyclization employing carbon monoxide as the terminal reductant to provide the 2-arylindole-4-carboxylic amide derivatives in excellent overall yield for the simple three-step sequence.

Full text of DOI:10.1016/j.tet.2006.05.007

Tetrahedron 62 (2006) 11381–11390
Preparation of 2-arylindole-4-carboxylic amide derivatives
*
Jeffrey T. Kuethe and Ian W. Davies
Department of Process Research, Merck & Co., Inc., Rahway, NJ 07065, USA
Received 30 January 2006; revised 2 May 2006; accepted 4 May 2006
Available online 5 June 2006
Abstract—A practical, highly efficient protocol has been developed for the synthesis of functionalized 2-arylindole-4-carboxylic amide
derivatives. Commercially available methyl 2-methyl-3-nitrobenzoate gave substituted nitrostyrene benzoic acids by reaction with aromatic
aldehydes in the presence of DBU in DMSO. Conversion of these products to the desired amides was followed by Pd-catalyzed reductive
cyclization employing carbon monoxide as the terminal reductant to provide the 2-arylindole-4-carboxylic amide derivatives in excellent
overall yield for the simple three-step sequence.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
(Scheme 1). In this paper, we document the implementation
of this strategy.
The synthesis and functionalization of indoles continues to
be a major area of focus for both academic and industrial
researchers.1,2 The prevalence of this important heterocycle
as the central pharmacophore in a wide range of medicinal
agents is a testament to the powerful biological activity
that this key subunit provides as it is recognized as one of
the most important ‘privileged structures’.3 Recently, we
have outlined highly efficient methodologies for the synthe-
sis of variously functionalized indoles4 and tetrahydro-
benzofurans5 by taking advantage of the underlying
versatility of nitrobenzenes. In a continuing program to ex-
ploit these methodologies which rapidly enhance molecular
complexity with excellent atom economy and synthetic
practicality, we have identified that commercially available
methyl 2-methyl-3-nitrobenzoate 3 is an extremely attractive
raw material for the preparation of indoles of type 1.
R2
N
O
R1
CO2H
MeO2C
R
Me
R
N
H
NO2
NO2
3
1
2
Scheme 1.
2. Results and discussion
The widespread use of ortho-nitrostyrenes as synthetically
useful intermediates has been limited by available methods
for their preparation. Traditional approaches have relied on
Wittig reactions of either 2-nitrobenzaldehydes or 2-nitro-
phosphonium and phosphonate salts.15 Alternatively,
cross-coupling approaches involving 2-halonitrobenzenes
or 2-nitrophenylstannanes have received considerable atten-
tion as an attractive method for the preparation of a range of
ortho-nitrostyrenes.16 While each of these approaches offers
certain advantages, they often require multiple steps for the
construction of the appropriate starting materials and gener-
ally require purification by chromatography. In addition,
these strategies have a high environmental burden since
they suffer from poor atom economy and generate a signifi-
cant amount of phosphorous or tin by-products. We have
recently demonstrated that reactions of 2-nitrotoluenes
or 2-trimethylsilylmethylnitrobenzenes with aromatic alde-
hydes via an addition/elimination protocol is an effective,
high yielding method for the construction of ortho-nitrostyr-
enes.4 In order to access indoles of class 1, an efficient
synthesis of nitrostyrenes of type 2 was imperative and we
Indoles of general type 1 have been shown to possess a wide
range of biological activity including CC chemokine recep-
tor 5 (CCR5) antagonists,6 serotonin (5-HT) subtype 2A
receptor antagonist,7 muscarinic M2 receptor antagonists,8
bradycardic agents,9 histone deacetylase inhibitors,10 p38a
mitogen activated protein kinases (MAPK) inhibitors,11 ma-
trix metalloproteinases (MMPs) inhibitors,12 and poly(ADP-
ribose) polymerase-1-inhibitors.13 Typically indoles of this
subclass have been prepared from commercially available
indole 4-carboxylic acid or 4-bromoindole,14 both of which
are expensive reagents and require extensive manipulation if
a more substituted pharmacophore is needed. A concise
route to indoles 1 from 3 would feature reaction with
a substituted aldehyde followed by reductive cyclization
* Corresponding author. Tel.: +1 732 594 9522; fax: +1 732 594 5170;
e-mail: jeffrey_kuethe@merck.com
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.007

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J. T. Kuethe, I. W. Davies / Tetrahedron 62 (2006) 11381–11390
Table 1
envisioned that reaction of commercially available nitro-
toluene 3 with simple aldehydes would allow for a remark-
ably straightforward synthesis of these high value targets.
Entry
1
Aldehyde
Nitrostyrene
CO2H
O
O
OHC
O
O
Our investigations began with the reaction of methyl
2-methyl-3-nitrobenzoate
3 with 4-fluorobenzaldehyde
NO2
(Scheme 2). It has previously been demonstrated that the
reaction of ortho-nitrotoluenes with aromatic aldehydes in
the presence of DBU in DMSO is a reversible process5
and only modest to good yields of the corresponding nitro
alcohols are obtained.17 Based on the juxtaposition of the
methyl ester with the reacting center and its capacity to serve
as an intramolecular electrophilic trap of the intermediate
nitro alcohol, reaction of 3 with aldehydes was anticipated
to lead to formation of a lactone intermediate. Treatment
of 3 with 1.0 equiv of 4-fluorobenzaldehyde 5 with 1.0 equiv
of DBU in DMSO for 6 h at rt gave nitrostyrene benzoic acid
6 in 57% yield. Analysis of the crude reaction mixture by
HPLC and NMR revealed the presence of unreacted starting
material 3 (36%), 4-fluorobenzaldehyde 5, and carboxylic
acid 4 (7%). The presence of acid 4 suggested that compet-
itive hydrolysis of the starting material was occurring under
the reaction conditions. The overall sequence involved
deprotonation of the nitrotoluene 3 by DBU followed by
the addition to 5 to give nitro alcohol intermediate 7, which
undergoes intramolecular cyclization to lactone 8. Deproto-
nation of 8 by DBU was followed by elimination of the car-
boxylate anion to furnish the observed nitrostyrene benzoic
acid product 6 upon workup. Optimization of the reaction
parameters revealed that upon treatment of 3 with 1.5 equiv
of 5 with 2.0 equiv of DBU in dry DMSO for 12 h followed
by heating to 50 ꢀC for 30 min afforded 6 in 90% HPLC
assay yield.18 Under these conditions, <5% of the corre-
sponding hydrolyzed starting material 4 was observed. Fur-
thermore, none of the intermediate lactone 8 was observed in
the crude reaction mixture. After an extractive workup to
remove excess 5, the product 6 was obtained in 84% isolated
yield by crystallization from MeOH/water. The reaction
sequence was general and allowed for the preparation of
an array of structurally diverse nitrostyrene benzoic acids
in good to excellent yield (Table 1). Substrates containing
electron donating (entries 1–5) or electron withdrawing
9
10 68%
OMe
CO2H
OHC
2
3
OMe
Br
NO2
11
12 61%
Br
CO2H
OHC
HO
OH
O
NO2
13
14 79%
CO2H
OHC
O
4
5
NO2
15
16 90%
CO2H
O
OHC
O
NO2
17
18 82%
F
OHC
F
CO2H
Cl
6
Cl
19
NO2
20 88%
NO2
CO2H
OHC
NO2
7
NO2
21
22 82%
RO2C
F
Me
CO2H
DBU, DMSO
OHC
NO2
F
groups (entries 6 and 7) participated equally as well. In all
cases, the trans-nitrostyrene benzoic acids were the exclu-
sive products.
NO2
3 R = Me
4 R = H
5
6
Interesting reactivity was noted when nitrobenzoate 3 was
allowed to react with excess paraformaldehyde and indole-
2-carboxaldehydes 27 and 28 (Scheme 3). For example,
treatment of 3 with an excess of paraformaldehyde in the
presence of 2 equiv of DBU in DMSO at 50 ꢀC for 12 h fol-
lowed by an extractive workup and acidification with aque-
ous HCl did not give the expected vinyl nitrobenzoic acid 24.
Isochromanone 23 was isolated as the sole product in 76%
yield.19 Presumably, reaction of 3 with paraformaldehyde
was followed by deprotonation and reaction with a second
equivalent of paraformaldehyde leading to intermediate
F
F
HO
O
O
MeO2C
- MeOH
DBU
H
NO2
NO2
7
8
Scheme 2.

J. T. Kuethe, I. W. Davies / Tetrahedron 62 (2006) 11381–11390
11383
25. Although the exact order of transformations leading to
25 was not explicitly clear, elimination of the carboxylate
anion affords intermediate 26, which upon acidification
and intramolecular cyclization gave 23. Reaction of 3 with
27 or 28 only led to trace amounts of the corresponding
nitrostyrene benzoic acids (<8%), and isochromanones 29
and 30 were isolated in 75% and 80% yields, respectively.
A satisfactory rationale to account for the interruption of
the pathway leading to the expected nitrostyrene carboxylic
acid products in the presence of N-methyl- or N-benzyl sub-
stituents is currently unavailable. However, we speculate
that steric influences of the indole substituents and the close
proximity of the nitro group prevent the approach of the base
and elimination of the carboxylate anion.
nitrostyrene benzoic acid 33 was obtained in 89% yield
when reacted with aldehyde 28.
Reductive cyclization of aromatic nitrocompounds is an
extremely powerful method for the preparation of the indole
nucleus.21 Transition metal catalyzed reductive cyclizations
employing carbon monoxide as the stoichiometric reductant
has recently emerged as a highly versatile method for the
construction of indoles due to superior yields, diminished
amounts of reaction by-products, and favorable environmen-
tal impact.16,17,21 For the preparation of indoles of subclass 1
bearing an amido-substituent in the four position of the
indole ring, a two-step sequence involving either reductive
cyclization of the ortho-nitrostyrenes followed by amide
formation or amide formation followed by reductive cycliza-
tion was required. With nitrostyrene benzoic acids in hand,
initial efforts were focused on reductive cyclization of these
substrates (Scheme 5). For example, reductive cyclization
of nitrostyrenes 6 and 10 was accomplished under the con-
MeO2C
O
O
HO2C
DBU, DMSO
(CH2O) (excess)
n
Me
CH2
NO2
NO2
NO2
ditions discovered by Soderberg.16 Reaction of 6 and 10
¨
76%
3
23
24
with 6 mol % Pd(OAc)2, 24 mol % PPh3 in acetonitrile at
70 ꢀC under an atmosphere of 60 psi CO for 16 h afforded
indole carboxylic acids 34 and 35 in 89% and 92% HPLC
assay yields,18 respectively. The isolation of 34 and 35 in
pure form was plagued by both solubility issues of the
corresponding products and the difficulty in removing the
excess triphenylphosphine and triphenylphosphine oxide.
Consequently, the isolated yields of 34 and 35 were <50%
after crystallization. Due to this difficulty, our attention
turned to conversion of the benzoic acid moiety to the
required amide functionality prior to reductive cyclization.
not observed
H+
- H2O
DBU
OH
OH
O
O
HO2C
H
NO2
NO2
26
25
O
O
DBU, DMSO
CO2H
3
N
R
CHO
F
6
N
R
O2N
N
H
34
Pd(OAc)2 (6 mol%)
29 R = Me, 75%
30 R = Bn, 80%
27 R = Me
28 R = Bn
PPh3 (24 mol%)
MeCN, 70 °C, 60 psi CO
Scheme 3.
CO2H
10
We have also examined the reaction of the regio-isomeric
methyl 2-methyl-5-nitrobenzoate 31 with aldehydes 5 and
28 (Scheme 4).20 Reaction of 31 with 5 under the optimized
reaction conditions described above led to the formation of
nitrostyrene benzoic acid 32 in 95% isolated yield. In this
case, the product could be obtained by direct crystallization
from the crude reaction mixture. In similar fashion,
O
N
H
O
35
Scheme 5.
Treatment of nitrostyrene benzoic acid 6 with oxalyl
chloride in the presence of a catalytic amount of DMF in
CH2Cl2 afforded the intermediate acid chloride, which was
not isolated (Scheme 6). Reaction with 4-(2-keto-1-benzimi-
dazolinyl)piperadine 36 in the presence of NEt3 gave, after
workup, amido nitrostyrene 37, which was isolated as
a highly crystalline solid in 96% yield. The reductive cycli-
zation of 37 was conducted under the optimized reaction
conditions previously disclosed from these laboratories.17,22
Thus, reaction of 37 with 1 mol % Pd(OAc)2, 7 mol % 1,10-
phenanthroline (phen), in DMF at 80 ꢀC under an atmo-
sphere of 30 psi CO for 16 h afforded indole 38 in 98%
HPLC assay yield.18 In this case, isolation of 38 was simply
a matter of filtering the reaction mixture through Celite, fol-
lowed by the addition of 1 M H3PO4, which precipitated the
F
CO2H
DBU, DMSO
5
NO2
CO2Me
95%
32
Me
NO2
31
CO2H
DBU, DMSO
N
28
Bn
NO2
89%
33
Scheme 4.

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J. T. Kuethe, I. W. Davies / Tetrahedron 62 (2006) 11381–11390
product in analytically pure form and in 94% isolated yield.
1. oxalyl chloride
cat. DMF, CH2Cl2
The sequence whereby the appropriately substituted nitro-
styrene carboxylic acid was converted to the required amide
followed by reductive cyclization provided an excellent,
high yielding means of preparing the highly functionalized
derivatives shown in Table 2. The use of 1 M H3PO4 for
the isolation of the product aided in the removal of trace
amounts of 1,10-phenanthroline from the product and was
mild enough that sensitive functionalities such as a Boc-
protecting group were preserved (see Table 2, entry 3).
HN
N
6
2.
N
O
F
O
HN
N
NH
HN
O
NO2
36
37 96%
NEt3, CH2Cl2
In conclusion, a concise three-step method for the prepara-
tion of many highly functionalized ‘drug-like’ 2-aryl-
indole-4-carboxylic amide derivatives has been developed.
This efficient protocol involved reaction of nitrotoluene 3
with substituted aldehydes in the presence of DBU in
DMSO to provide the nitrostyrene benzoic acids, which
were subsequently converted to their amide derivatives.
Catalytic reductive cyclization provided the desired 2-aryl-
indole-4-carboxylic amide derivatives in excellent overall
Pd(OAc)2, phen
30 psi CO, DMF
80 °C, 16 h
N
N
O
O
98% HPLC Assay
94% Isolated
F
N
H
38
Scheme 6.
Table 2
Entry, acid
Amine
Amide
Indolea
Me
N
Me
N
O
O
Me
Me
O
O
1, 16
NHMe2
N
H
NO2
39 99%
40 98%, (91%)
N
O
F
N
O
H
N
2, 6
F
N
H
NO2
41
42 99%
43 97% (93%)
Boc
Boc
N
N
O
H
N
O
N
O
N
O
O
N
Boc
3, 10
O
N
H
NO2
44
45 98%
46 99% (95%)
MeO2S
MeO2S
N
F
N
H
N
N
O
N
O
F
Cl
N
4, 20
SO2Me
N
H
NO2
Cl
23
47
48 98%
49 98% (94%)
O
O
O
O
N
O
N
O
H
N
O
O
5, 10
N
H
NO2
50
O
51 97%
Yield in parenthesis reflects isolated yield after crystallization from the crude reaction mixture.
52 98% (92%)
a

J. T. Kuethe, I. W. Davies / Tetrahedron 62 (2006) 11381–11390
11385
yield. The overall sequence does not require the use of
chromatography and offers an extremely attractive strategy
for direct entry into this uniquely substituted pharmaco-
phore. The biological activity of these substrates is currently
under active investigation and will be reported in due
course.
3.1.3. Preparation of 2-[trans-2-(4-methoxyphenyl)-
vinyl]-3-nitrobenzoic acid (12). According to the general
procedure, treatment of a mixture of 1.50 g (7.69 mmol) of
3 and 1.57 g (11.50 mmol) of 4-methoxybenzaldehyde 11
with 2.34 g (15.38 mmol) of DBU afforded 1.40 g (61%)
of 12 as a yellow solid: mp 158–159 ꢀC; 1H NMR
(DMSO-d6, 400 MHz) d 3.74 (s, 3H), 6.47 (d, 1H,
J¼16.6 Hz), 6.91 (d, 2H, J¼8.7 Hz), 7.32 (d, 1H, J¼
16.6 Hz), 7.41 (d, 2H, J¼8.7 Hz), 7.57 (t, 1H, J¼8.1 Hz),
8.01 (d, 1H, J¼8.1 Hz), 8.02 (d, 1H, J¼8.1 Hz), 12.10 (br
s, 1H); 13C NMR (DMSO-d6, 100 MHz) d 55.7, 114.7,
120.9, 126.6, 128.6, 128.7, 129.4, 132.1, 133.3, 133.6,
134.7, 150.5, 160.1, 168.2. Anal. Calcd for C16H13NO5: C,
64.21; H, 4.38; N, 4.68. Found: C, 63.92; H, 4.22; N, 4.21.
3. Experimental
Melting points are uncorrected. All solvents and reagents
were used as received from commercial sources. Analytical
samples were obtained by chromatography on silica gel
using an ethyl acetate/hexanes mixture as the eluent unless
specified otherwise.
3.1.4. Preparation of 2-[trans-2-(5-bromo-2-hydroxy-
phenyl)-vinyl]-3-nitrobenzoic acid (14). According to the
general procedure, treatment of a mixture of 1.20 g
(6.15 mmol) of 3 and 1.85 g (9.22 mmol) of 5-bromosalicyl-
aldehyde 13 with 1.87 g (12.30 mmol) of DBU afforded
1.77 g (79%) of 14 as a tan solid: mp 154 ꢀC (decomp.);
1H NMR (DMSO-d6, 400 MHz) d 6.70 (d, 1H, J¼
16.7 Hz), 6.82 (d, 1H, J¼8.5 Hz), 7.28 (d, 1H, J¼8.5 Hz),
7.65 (m, 3H), 8.05 (m, 2H), 10.15 (br s, 1H), 12.10 (br s,
1H); 13C NMR (DMSO-d6, 100 MHz) d 111.1, 118.4,
124.2, 125.9, 126.5, 127.6, 128.9, 129.4, 131.9, 132.1,
133.3, 134.7, 150.4, 154.8, 168.1. Anal. Calcd for
C15H10BrNO5: C, 49.47; H, 2.77; N, 3.85. Found: C,
49.11; H, 2.76; N, 3.89.
3.1. General procedure for the preparation of 2-[trans-2-
(aryl)-vinyl]-3-nitrobenzoic acid (2)
To a stirred containing 1.50 g (7.69 mmol) of methyl 2-
methyl-3-nitrobenzoate 3 and 11.5 mmol of the appropri-
ately substituted aldehyde in 10 mL of dry DMSO was
added 2.34 g (15.38 mmol) of DBU. The resulting mixture
was stirred at rt for 12 h, heated to 50 ꢀC for 30 min, and
then cooled to rt. To the crude reaction mixture was added
20 mL of 1 N NaOH solution and the mixture was washed
with EtOAc (2ꢁ25 mL) to remove the excess aldehyde.
The aqueous layer was then made acidic with concd HCl,
extracted with EtOAc, and dried over MgSO4. The solvent
was removed under reduced pressure and the crude residue
recrystallized from MeOH/water to give the 2-[trans-2-
(aryl)-vinyl]-3-nitrobenzoic acid (2) in analytically pure
form.
3.1.5. Preparation of 2-(trans-2-furan-2-yl-vinyl)-3-nitro-
benzoic acid (16). According to the general procedure,
treatment of a mixture of 2.50 g (12.81 mmol) of 3 and
1.85 g (19.21 mmol) of 2-furaldehyde 15 with 3.90 g
(25.62 mmol) of DBU afforded 2.99 g (90%) of 16 as a yel-
3.1.1. Preparation of 2-[trans-2-(4-fluorophenyl)-vinyl]-
3-nitrobenzoic acid (6). According to the general proce-
dure, treatment of a mixture of 2.32 g (11.90 mmol) of 3
and 2.21 g (17.83 mmol) of 4-fluorobenzaldehyde 5 with
3.61 g (23.77 mmol) of DBU afforded 2.87 g (84%) of 6
as a bright yellow solid: mp 156–157 ꢀC; 1H NMR
(CDCl3, 400 MHz) d 6.50 (d, 1H, J¼16.5 Hz), 7.03 (m,
2H), 7.46 (m, 4H), 7.95 (dd, 1H, J¼8.0 and 1.0 Hz), 8.17
(dd, 1H, J¼8.0 and 1.0 Hz), 12.71 (br s, 1H); 13C NMR
(CDCl3, 100 MHz) d 115.7 (d, J¼22 Hz), 122.4, 127.7,
128.0, 128.6 (d, J¼8 Hz), 131.3, 132.6, 133.2, 134.2,
134.4, 151.0, 162.3 (d, J¼247 Hz), 171.4; 19F NMR
(CDCl3, 75 MHz) d ꢂ113.2. Anal. Calcd for C15H10FNO4:
C, 62.72; H, 3.51; N, 4.88. Found: C, 62.43; H, 3.22; N, 4.79.
1
low solid: mp 122–123 ꢀC; H NMR (CDCl3, 400 MHz)
d 6.40 (m, 3H), 7.47 (m, 3H), 7.90 (dd, 1H, J¼7.9 and
1.2 Hz), 8.15 (dd, 1H, J¼7.9 and 1.2 Hz), 12.13 (br s, 1H);
13C NMR (CDCl3, 100 MHz) d 110.5, 111.6, 120.1, 122.7,
127.5, 127.7, 131.2, 133.6, 134.0, 143.1, 150.8, 151.9,
171.4. Anal. Calcd for C13H9NO5: C, 60.24; H, 3.50; N,
5.40. Found: C, 59.99; H, 3.51; N, 5.43.
3.1.6. Preparation of 2-(trans-2-benzofuran-2-yl-vinyl)-
3-nitrobenzoic acid (18). According to the general proce-
dure, treatment of a mixture of 630 mg (3.23 mmol) of 3
and 708 mg (4.85 mmol) of 2-benzofurancarboxaldehyde
17 with 983 mg (6.46 mmol) of DBU afforded 820 mg
1
(82%) of 18 as a yellow solid: mp 154–155 ꢀC; H NMR
3.1.2. Preparation of 2-(trans-2-benzo[1,3]dioxol-5-yl-
vinyl)-3-nitrobenzoic acid (10). According to the general
procedure, treatment of a mixture of 1.50 g (7.69 mmol) of
3 and 1.73 g (11.50 mmol) of piperonal 9 with 2.34 g
(15.38 mmol) of DBU afforded 1.64 g (68%) of 10 as a bright
yellow solid: mp 134–135 ꢀC; 1H NMR (DMSO-d6,
400 MHz) d 6.01 (s, 2H), 6.43 (d, 1H, J¼16.5 Hz), 6.88
(m, 2H), 7.16 (s, 1H), 7.32 (d, 1H, J¼16.5 Hz), 7.57 (t,
1H, J¼7.9 Hz), 8.01 (d, 1H, J¼7.9 Hz), 8.02 (d, 1H,
J¼7.9 Hz), 12.0 (br s, 1H); 13C NMR (DMSO-d6,
100 MHz) d 101.7, 106.2, 108.9, 121.6, 122.5, 126.6,
128.8, 131.3, 132.0, 133.4, 133.5, 134.7, 148.0, 148.4,
150.5, 168.2. Anal. Calcd for C16H11NO4: C, 61.35; H,
3.54; N, 4.47. Found: C, 60.99; H, 3.49; N, 4.43.
(DMSO-d6, 400 MHz) d 6.63 (m, 1H), 7.01 (s, 1H), 7.25
(m, 1H), 7.35 (m, 1H), 7.65 (m, 4H), 8.12 (m, 2H), 12.03
(br s, 1H); 13C NMR (DMSO-d6, 100 MHz) d 107.5,
111.5, 121.9, 122.0, 123.8, 124.6, 125.9, 126.9, 128.8,
129.4, 131.0, 133.6, 134.5, 150.3, 153.9, 154.7, 167.9.
Anal. Calcd for C17H11NO5: C, 66.02; H, 3.58; N, 4.53.
Found: C, 66.10; H, 3.66; N, 4.54.
3.1.7. Preparation of 2-[trans-2-(3-chloro-5-fluoro-
phenyl)-vinyl]-3-nitrobenzoic acid (20). According to the
general procedure, treatment of a mixture of 1.58 g
(8.10 mmol) of 3 and 1.92 g (12.14 mmol) of 3-chloro-
5-fluorobenzaldehyde 19 with 2.47 g (15.38 mmol) of
DBU afforded 2.29 (88%) of 20 as a yellow solid: mp

11386
J. T. Kuethe, I. W. Davies / Tetrahedron 62 (2006) 11381–11390
142–143 ꢀC; 1H NMR (DMSO-d6, 400 MHz) d 6.41 (d, 1H,
J¼16.4 Hz), 7.05 (m, 2H), 7.21 (s, 1H), 7.55 (m, 2H), 7.99
(d, 1H, J¼7.4 Hz), 8.23 (d, 1H, J¼7.4 Hz), 11.49 (br s,
1H); 13C NMR (DMSO-d6, 100 MHz) d 111.9 (d,
J¼20 Hz), 115.9 (d, J¼20 Hz), 123.0, 125.8, 126.6, 127.8,
128.4, 131.2, 131.3, 133.7, 134.3, 135.4 (d, J¼10 Hz),
139.5 (d, J¼10 Hz), 150.8, 162.4 (d, J¼250 Hz), 170.9;
19F NMR (DMSO-d6, 75 MHz) d ꢂ111.2. Anal. Calcd for
C15H9ClFNO4: C, 56.00; H, 2.82; N, 4.35. Found: C,
55.83; H, 2.73; N, 4.33.
7.09 (m, 2H), 7.22 (m, 4H), 7.51 (d, 1H, J¼7.8 Hz), 7.67
(t, 1H, J¼7.8 Hz), 8.09 (d, 1H, J¼7.8 Hz), 8.45 (dd, 1H,
J¼8.0 and 0.6 Hz); 13C NMR (CDCl3, 100 MHz) d 30.4,
46.5, 81.3, 103.4, 109.9, 119.9, 120.4, 121.8, 125.8, 127.4,
127.8, 128.9, 129.5, 129.9, 131.3, 132.0, 133.6, 137.4,
137.7, 143.3, 143.5, 167.3. Anal. Calcd for C24H18N2O4:
C, 72.35; H, 4.55; N, 7.03. Found: C, 72.43; H, 4.66; N, 7.00.
3.1.12. Preparation of 2-[trans-2-(4-fluorophenyl)-vinyl]-
5-nitrobenzoic acid (32). According to the general proce-
dure, treatment of a mixture of 2.00 g (10.25 mmol) of 31
and 1.91 g (15.37 mmol) of 4-fluorobenzaldehyde 5 with
3.12 g (20.50 mmol) of DBU afforded 2.80 g (95%) of 32
as a bright yellow solid: mp 216–217 ꢀC; 1H NMR
(DMSO-d6, 400 MHz) d 7.21 (m, 2H), 7.37 (d, 1H,
J¼16.4 Hz), 7.61 (m, 2H), 7.89 (d, 1H, J¼16.4 Hz), 8.03
(d, 1H, J¼8.8 Hz), 8.29 (m, 1H), 8.53 (s, 1H), 12.61 (br s,
1H); 13C NMR (DMSO-d6, 100 MHz) d 116.3 (d, J¼
20.0 Hz), 125.6, 126.0, 126.6, 128.5, 129.6 (d, J¼8.0 Hz),
130.7, 133.5, 134.1, 144.7, 146.2, 163.1 (d, J¼245.0 Hz),
167.3. Anal. Calcd for C15H10FNO4: C, 62.72; H, 3.51; N,
4.88. Found: C, 62.77; H, 3.55; N, 4.93.
3.1.8. Preparation of 3-nitro-2-[trans-(4-nitrophenyl)-
vinyl]-benzoic acid (22). According to the general proce-
dure, treatment of a mixture of 1.50 g (7.69 mmol) of 3
and 1.74 g (11.50 mmol) of 4-nitrobenzaldehyde 21 with
2.34 g (15.38 mmol) of DBU afforded 1.98 (82%) of 22 as
a yellow solid: mp 172–173 ꢀC; 1H NMR (DMSO-d6,
400 MHz) d 6.64 (d, 1H, J¼16.6 Hz), 7.65 (t, 1H, J¼
8.0 Hz), 7.77 (m, 3H), 8.10 (m, 2H), 8.20 (d, 2H, J¼
8.8 Hz), 12.12 (br s, 1H); 13C NMR (DMSO-d6, 100 MHz)
d 124.6, 127.1, 128.1, 129.0, 129.7, 130.9, 131.9, 133.9,
134.5, 143.3, 147.3, 150.3, 167.8. Anal. Calcd for
C15H10N2O6: C, 57.33; H, 3.21; N, 8.91. Found: C, 57.32;
H, 3.19; N, 8.88.
3.1.13. Preparation of 2-[trans-2-(1-benzyl-1H-indol-2-
yl)-vinyl]-5-nitrobenzoic acid (33). According to the
general procedure, treatment of a mixture of 2.30 g
(11.78 mmol) of 31 and 4.16 g (17.68 mmol) of 1-benzylin-
dole-2-carboxaldehyde 28 with 3.59 g (23.57 mmol) of
DBU afforded 4.18 g (89%) of 33 as a red solid: mp 168–
3.1.9. Preparation of 4-methylene-5-nitro-isochroman-1-
one (23). According to the general procedure, treatment of
a mixture of 1.00 g (5.12 mmol) of 3 and 2.00 g of solid
paraformaldehyde with 1.56 g (10.25 mmol) of DBU
afforded 799 mg (76%) of 23 as a white solid: mp 130–
1
169 ꢀC; H NMR (DMSO-d6, 400 MHz) d 5.67 (s, 2H),
1
131 ꢀC; H NMR (CDCl3, 400 MHz) d 5.00 (s, 2H), 5.55
6.97 (s, 1H), 7.14 (m, 7H), 7.43 (d, 1H, J¼8.3 Hz), 7.56
(d, 1H, J¼7.8 Hz), 7.64 (d, 1H, J¼16.1 Hz), 8.13 (m, 2H),
8.26 (dd, 1H, J¼8.8 and 2.3 Hz), 8.54 (s, 1H), 13.56 (br s,
1H); 13C NMR (DMSO-d6, 100 MHz) d 46.2, 110.9,
120.7, 121.1, 123.1, 124.0, 126.0, 126.4, 126.8, 126.9,
127.7, 128.1, 128.2, 129.1, 130.9, 137.9, 138.4, 139.0,
144.2, 146.0, 167.5. Anal. Calcd for C24H18N2O4: C,
72.35; H, 4.55; N, 7.03. Found: C, 72.36; H, 4.66; N, 7.05.
(s, 1H), 5.72 (s, 1H), 7.61 (t, 1H, J¼8.0 Hz), 7.86 (d, 1H,
J¼8.0 Hz), 8.33 (d, 1H, J¼8.0 Hz); 13C NMR (CDCl3,
100 MHz) d 72.2, 121.8, 126.7, 128.5, 129.6, 129.8, 130.1,
134.0, 147.3, 162.3. Anal. Calcd for C10H7NO4: C, 58.54;
H, 3.44; N, 6.83. Found: C, 58.79; H, 3.78; N, 6.69.
3.1.10. Preparation of 3-(1-methyl-1H-indol-2-yl)-5-
nitro-isochroman-1-one (29). According to the general pro-
cedure, treatment of a mixture of 2.00 g (10.25 mmol) of 3
and 2.45 g (15.4 mmol) of 1-methylindole-2-carboxalde-
hyde 27 with 3.12 g (20.50 mmol) of DBU afforded 2.48 g
3.1.14. Preparation of 2-(4-fluorophenyl)-1H-indole-
4-carboxylic acid (34). In a 10 mL pressure tube was
added sequentially 115 mg (0.400 mmol) of 6, 5.4 mg
(0.024 mmol) of Pd(OAc)2, 25.2 mg of PPh3
(0.096 mmol), and 3 mL of MeCN. The resulting mixture
was heated at 70 ꢀC under an atmosphere of 60 psi CO for
16 h and then cooled to rt. HPLC assay of the crude reaction
mixture revealed 91 mg (89%) of 34. The reaction mixture
was filtered through a pad of Celite and concentrated under
reduced pressure. The crude residue was recrystallized (2ꢁ)
from an EtOAc/hexane mixture followed by recrystalliza-
tion from MeOH/water to afford 50 mg (49%) of 34 as a light
tan solid: mp 170 ꢀC (decomp.); 1H NMR (CDCl3,
400 MHz) d 7.17 (m, 2H), 7.27 (m, 1H), 7.53 (s, 1H), 7.64
(d, 1H, J¼8.0 Hz), 7.29 (m, 2H), 8.04 (d, 1H, J¼7.5 Hz),
8.58 (br s, 1H), 12.12 (br s, 1H); 13C NMR (CDCl3,
100 MHz) d 101.5, 116.2 (d, J¼20 Hz), 116.5, 120.4,
121.5, 124.8, 127.3, 128.1, 129.4, 137.7, 139.4, 163.2
(d, J¼250.0 Hz), 173.0; 19F NMR (CDCl3, 75 MHz)
d ꢂ113.2. Anal. Calcd for C15H10FNO2: C, 70.58; H, 3.95;
N, 5.49. Found: C, 70.66; H, 3.98; N, 5.53.
1
(75%) of 29 as a yellow solid: mp 166–167 ꢀC; H NMR
(CDCl3, 400 MHz) d 3.47 (dd, 1H, J¼15.7 and 5.7 Hz),
3.73 (s, 3H), 3.78 (dd, 1H, J¼15.7 and 3.3 Hz), 6.05 (s,
1H), 6.36 (m, 1H), 7.03 (dt, 1H, J¼7.9 and 0.8 Hz), 7.15
(dt, 1H, J¼7.9 and 0.8 Hz), 7.23 (d, 1H, J¼8.3 Hz), 7.41
(d, 1H, J¼7.9 Hz), 7.70 (t, 1H, J¼7.9 Hz), 8.06 (d, 1H,
J¼7.9 Hz), 8.50 (d, 1H, J¼7.9 Hz); 13C NMR (CDCl3,
100 MHz) d 29.8, 81.5, 102.4, 109.4, 119.6, 120.2, 121.5,
127.4, 129.3, 130.0, 131.2, 132.0, 133.2, 137.6, 143.2,
167.1. Anal. Calcd for C18H14N2O4: C, 67.07; H, 4.38; N,
8.69. Found: C, 66.89; H, 4.22; N, 8.66.
3.1.11. Preparation of 3-(1-benzyl-1H-indol-2-yl)-5-
nitro-isochroman-1-one (30). According to the general
procedure, treatment of a mixture of 1.56 g (7.99 mmol) of
3 and 2.82 g (12.00 mmol) of 1-benzylindole-2-carboxalde-
hyde 28 with 2.43 g (15.99 mmol) of DBU afforded 2.55 g
(80%) of 30 as a yellow foam: 1H NMR (CDCl3,
400 MHz) d 3.29 (dd, 1H, J¼15.8 and 6.6 Hz), 3.71 (dd,
1H, J¼15.8 and 3.1 Hz), 5.45 (d, 1H, J¼17.5 Hz), 5.54 (d,
1H, J¼17.5 Hz), 6.26 (m, 1H), 6.28 (s, 1H), 6.90 (m, 2H),
3.1.15. Preparation of 2-benzo[1,3]dioxol-5-yl-1H-
indole-4-carboxylic acid (35). In a 10 mL pressure tube

J. T. Kuethe, I. W. Davies / Tetrahedron 62 (2006) 11381–11390
11387
was added sequentially 198 mg (0.632 mmol) of 10, 8.51 mg
(0.038 mmol) of Pd(OAc)2, 39.8 mg (0.152 mmol) of PPh3,
and 4 mL of MeCN. The resulting mixture was heated at
70 ꢀC under an atmosphere of 60 psi CO for 16 h and then
cooled to rt. HPLC assay of the crude reaction mixture
revealed 163 mg (92%) of 35. The reaction mixture was
filtered through a pad of Celite and concentrated under
reduced pressure. The crude residue was recrystallized
(2ꢁ) from an EtOAc/hexane mixture followed by recrystal-
lization from MeOH/water to afford 76 mg (43%) of 35 as
a tan solid: mp 275–276 ꢀC; 1H NMR (DMSO-d6,
400 MHz) d 6.05 (s, 2H), 6.99 (d, 1H, J¼8.0 Hz), 7.13 (t,
1H, J¼7.8 Hz), 7.25 (s, 1H), 7.38 (d, 1H, J¼8.0 Hz), 7.44
(s, 1H), 7.58 (d, 1H, J¼8.0 Hz), 7.67 (d, 1H, J¼7.8 Hz),
11.69 (br s, 1H), 12.61 (br s, 1H); 13C NMR (DMSO-d6,
100 MHz) d 99.7, 101.8, 106.3, 109.3, 116.2, 119.9, 120.9,
121.5, 123.2, 126.5, 128.9, 138.3, 140.2, 147.7, 148.5,
169.0. Anal. Calcd for C16H11NO4: C, 68.32; H, 3.94; N,
4.98. Found: C, 68.49; H, 4.01; N, 4.99.
a yellow solid: mp 242–243 ꢀC; 1H NMR (CDCl3,
400 MHz) d 1.76 (m, 1H), 1.92 (m, 1H), 2.07 (m, 1H),
2.25 (m, 1H), 2.47 and 2.48 (m, due to rotamers, 1H), 2.92
and 3.12 (m, due to rotamers, 1H), 3.52 (m, 1H), 4.41 and
4.52 (m, due to rotamers, 1H), 5.01 (m, 1H), 6.15 and 6.55
(m, due to rotamers, 1H), 6.86–7.70 (m, 11H), 7.95 (m,
1H), 10.30 and 10.41 (m, due to rotamers, 1H); 13C NMR
(CDCl3, 100 MHz) d 28.7 and 29.2 (due to rotamers), 29.3
and 30.1 (due to rotamers), 41.5, 46.1, and 46.9 (due to
rotamers), 50.6 and 50.7 (due to rotamers), 108.8, 109.9, and
110.1 (due to rotamers), 116.1 and 116.3 (d, due to rotamers
J¼22 Hz), 120.4 and 120.5 (due to rotamers), 121.1 and
121.2 (due to rotamers), 121.5 and 121.6 (due to rotamers),
125.1 and 125.2 (due to rotamers), 128.0 and 128.2 (due to
rotamers), 128.5 and 128.6 (due to rotamers), 128.7 (d,
J¼10 Hz), 128.9 and 129.0 (due to rotamers), 129.5 and
129.9 (due to rotamers), 131.6 and 131.7 (due to rotamers),
132.5 and 132.6 (due to rotamers), 135.5 and 135.8 (due to
rotamers), 137.8, 148.8, and 148.9 (due to rotamers), 155.0
and 155.1 (due to rotamers), 163.1 (d, J¼250 Hz), 167.9
and 168.1 (due to rotamers); 19F NMR (CDCl3, 75 MHz)
d ꢂ113.2. Anal. Calcd for C27H23FN4O4: C, 66.66; H,
4.77; N, 11.52. Found: C, 66.43; H, 4.63; N, 11.51.
3.2. General procedure for the preparation of 2-[trans-
2-(aryl)-vinyl]-3-nitrobenzamides
To a stirred solution of 10 mmol of the appropriate nitro-
styrene benzoic acid in 30 mL of CH2Cl2 was added
1.65 g (13.00 mmol) of oxalyl chloride followed by one
drop of DMF. The resulting mixture was stirred for 1.5 h
at rt and concentrated under reduced pressure and then
re-dissolved in 15 mL of CH2Cl2. The resulting solution of
the acid chloride was then added dropwise to a mixture of
13.0 mmol of the appropriately substituted amine and
1.52 g (15.00 mmol) of NEt3. The mixture was stirred at rt
for 30 min, diluted with 15 mL of 1 N HCl, and the layers
separated. The organic layer was washed with 15 mL of
2 N NaOH, washed with 15 mL of brine, and then dried
over MgSO4. The solvent was removed under reduced pres-
sure to give the crude amide, which was recrystallized from
MeOH/water.
3.3.2. Preparation of 1-{1-[2-(4-fluorophenyl)-1H-indole-
4-carbonyl]-piperidin-4-yl}-1,3-dihydro-benzoimidazol-
2-one (38). According to the general procedure, reductive
cyclization of 98 mg (0.201 mmol) of 37 in the presence
of 0.500 mg (2.02 mmol) of Pd(OAc)2 and 2.54 mg
(0.014 mmol) of 1,10-phenanthroline afforded 90 mg
(98%) of 38 by HPLC assay of the crude reaction mixture.
Workup afforded 86 mg (94%) of 38 as a colorless solid:
1
mp 215–216 ꢀC; H NMR (DMSO-d6, 400 MHz) d 1.90
(br m, 2H), 2.54 (br m, 2H), 3.24 (br m, 2H), 3.80 (br m,
1H), 4.56 (m, 1H), 4.96 (br m, 1H), 6.96 (m, 4H), 7.11 (m,
4H), 7.29 (m, 1H), 7.41 (m, 1H), 7.91 (m, 2H), 10.10 (s,
1H), 11.05 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) d
29.1, 30.2, 41.5, 46.5, 50.7, 98.3, 108.6, 109.0, 112.2,
115.7 (d, J¼10 Hz), 118.2, 120.7, 121.6, 125.8, 126.6,
127.2, 127.4, 128.7, 129.1, 137.6, 138.2, 155.5, 163.3 (d,
J¼250 Hz), 168.0; 19F NMR (DMSO-d6, 75 MHz) d
ꢂ113.3. Anal. Calcd for C27H23FN4O2: C, 71.35; H, 5.10;
N, 12.33. Found: C, 70.99; H, 5.05; N, 12.29.
3.3. General procedure for the preparation of 2-aryl-
indole-4-carboxylic amides
In a 20 mL pressure tube was sequentially added 1.0 mmol
of the appropriately substituted 2-[trans-2-(aryl)-vinyl]-3-
nitrobenzamide, 0.01 mmol of Pd(OA)2, 0.07 mmol of
1,10-phenanthroline, and 4 mL of DMF. The resulting mix-
ture was then heated at 80 ꢀC under an atmosphere of 30 psi
CO for 16 h, and cooled to rt, and was filtered through a pad
of Celite eluting with 2 mL of DMF. Quantitative HPLC
analysis of the crude reaction mixture was conducted at
this point. The solution was then added dropwise to a solu-
tion of 10 mL of 1 M H3PO4. The resulting slurry of the
product was stirred at rt for 30 min and filtered. The solid
was dried under vacuum/N2 sweep for 6–12 h to give the
desired indole.
3.3.3. Preparation of 2-(trans-2-furan-2-yl-vinyl)-N,N-di-
methyl-3-nitrobenzamide (39). According to the general
procedure, treatment of a mixture of 650 mg (2.51 mmol)
of 16 with 414 mg (3.26 mmol) of oxalyl chloride followed
by reaction with 170 mg (3.13 mL of a 2 M solution in THF,
3.77 mmol) of N,N-dimethylamine afforded 710 mg (99%)
1
of 39 as a yellow oil: H NMR (CDCl3, 400 MHz) d 2.74
(s, 3H), 3.03 (s, 3H), 6.40 (m, 2H), 6.71 (d, 1H, J¼
16.4 Hz), 7.19 (d, 1H, J¼16.4 Hz), 7.44 (m, 2H), 7.53 (d,
1H, J¼7.6 Hz), 7.88 (dd, 1H, J¼8.1 and 1.4 Hz); 13C
NMR (CDCl3, 100 MHz) d 35.0, 38.1, 111.2, 111.9, 118.2,
124.0, 124.8, 128.2, 129.1, 131.5, 137.9, 143.3, 148.9,
152.0, 169.4. Anal. Calcd for C15H14N2O4: C, 62.93; H,
4.93; N, 9.79. Found: C, 62.01; H, 4.95; N, 9.80.
3.3.1. Preparation of 1-(1-{2-[trans-2-(4-fluorophenyl)-
vinyl]-3-nitrobenzoyl}-piperidin-4-yl)-1,3-dihydro-benz-
imidazol-2-one (37). According to the general procedure,
treatment of a mixture of 600 mg (2.09 mmol) of 6 with
345 mg (2.72 mmol) of oxalyl chloride followed by reaction
with 590 mg (2.72 mmol) of 36 in the presence of 317 mg
(3.13 mmol) of NEt3 afforded 980 mg (96%) of 37 as
3.3.4. Preparation of 2-furan-2-yl-1H-indol-4-carboxylic
acid kemethylamide (40). According to the general proce-
dure, reductive cyclization of 150 mg (0.524 mmol) of 39 in
the presence of 1.18 mg (5.24 mmol) of Pd(OAc)2 and

11388
J. T. Kuethe, I. W. Davies / Tetrahedron 62 (2006) 11381–11390
6.61 mg (0.037 mmol) of 1,10-phenanthroline afforded
131 mg (98%) of 40 by HPLC assay of the crude reaction
mixture. Workup afforded 121 mg (91%) of 40 as a white
solid: mp 233 ꢀC (decomp.); 1H NMR (DMSO-d6,
400 MHz) d 2.84 (br s, 3H), 3.02 (br s, 3H), 6.59 (m, 2H),
6.90 (d, 1H, J¼3.2 Hz), 6.96 (d, 1H, J¼7.5 Hz), 7.11 (t,
1H, J¼7.5 Hz), 7.40 (d, 1H, J¼7.5 Hz), 7.74 (s, 1H),
11.73 (br s, 1H); 13C NMR (DMSO-d6, 100 MHz) d 35.0,
38.9, 97.3, 107.0, 112.5, 112.7, 118.7, 121.9, 126.0, 128.7,
130.8, 137.1, 143.4, 147.8, 170.5. Anal. Calcd for
C15H14N2O2: C, 70.85; H, 5.55; N, 11.02. Found: C,
70.55; H, 5.32; N, 10.89.
41.6, 43.4, 45.9, 46.4, 80.5, 101.5, 105.7, 108.6, 118.4,
122.5, 125.1, 128.2, 130.0, 130.5, 131.7, 136.8, 137.5,
148.5, 148.6, 148.8, 154.3, 168.1. Anal. Calcd for
C25H27N3O7: C, 62.36; H, 5.65; N, 8.73. Found: C, 62.33;
H, 5.66; N, 8.71.
3.3.8. Preparation of (2-benzo[1,3]dioxol-5-yl-1H-indol-
4-yl)-piperazin-1-yl methanone hydrochloride (46).
According to the general procedure, reductive cyclization
of 160 mg (0.332 mmol) of 45 in the presence of 0.75 mg
(3.32 mmol) of Pd(OAc)2 and 4.19 mg (0.023 mmol) of
1,10-phenanthroline afforded 147 mg (99%) of 46 by
HPLC assay of the crude reaction mixture. Workup afforded
142 mg (95%) of 46 as a colorless solid: mp 157–158 ꢀC; 1H
NMR (CDCl3, 400 MHz) d 1.48 (s, 9H), 3.30–4.10 (br m,
8H), 6.01 (s, 2H), 6.64 (s, 1H), 6.83 (d, 1H), 7.11 (m, 4H),
7.35 (m, 1H), 9.16 (br s, 1H); 13C NMR (CDCl3,
100 MHz) d 28.4, 25.9, 27.3, 43.1, 62.6, 80.3, 97.7, 101.3,
106.2, 108.8, 112.5, 118.9, 119.2, 121.5, 126.3, 126.6,
126.7, 137.0, 139.4, 147.6, 148.3, 154.6, 170.6. Anal.
Calcd for C25H27ClN3O5: C, 66.80; H, 6.05; N, 9.35.
Found: C, 66.79; H, 6.01; N, 9.32.
3.3.5. Preparation of {2-[trans-2-(4-fluorophenyl)-vinyl]-
3-nitrophenyl}-pyrrolidin-1-yl-methanone (42). Accord-
ing to the general procedure, treatment of a mixture of
300 mg (1.04 mmol) of 6 with 172 mg (1.36 mmol) of
oxalyl chloride followed by reaction with 111 mg
(1.36 mmol) of pyrrolidine 41 in the presence of 158 mg
(1.57 mmol) of NEt3 afforded 352 mg (99%) of 42 as a yel-
low solid: mp 94–95 ꢀC; 1H NMR (CDCl3, 400 MHz) d 1.78
(m, 4H), 3.05 (t, 2H, J¼6.2 Hz), 3.52 (t, 2H, J¼6.2 Hz), 6.90
(d, 1H, J¼16.4 Hz), 7.02 (m, 2H), 7.23 (d, 1H, J¼16.4 Hz),
7.42 (m, 3H), 7.58 (d, 1H, J¼8.0 Hz), 7.92 (dd, 1H, J¼8.0
and 1.0 Hz); 13C NMR (CDCl3, 100 MHz) d 24.3, 25.8,
45.9, 47.8, 115.8 (d, J¼20.0 Hz), 120.2, 124.9, 128.4 (d,
J¼10.0 Hz), 128.6, 129.2, 131.5, 132.6, 135.3, 139.2,
148.7, 163.0 (d, J¼250.0 Hz), 167.5; 19F NMR (CDCl3,
75 MHz) d ꢂ113.2. Anal. Calcd for C19H17FN2O3: C,
67.05; H, 5.03; N, 8.23. Found: C, 66.82; H, 4.99; N, 8.15.
3.3.9. Preparation of {2-[trans-2-(3-chloro-5-fluoro-
phenyl)-vinyl]-3-nitrophenyl}-(4-methanesulfonyl-pipera-
zin-1-yl)-methanone (48). According to the general
procedure, treatment of a mixture of 890 mg (2.77 mmol) of
20 with 457 mg (3.60 mmol) of oxalyl chloride followed by
reaction with 591 mg (3.60 mmol) of 4723 in the presence
of 420 mg (4.15 mmol) of NEt3 afforded 1.27 g (98%) of
1
48 as a yellow solid: mp 179–180 ꢀC; H NMR (CDCl3,
3.3.6. Preparation of [2-(4-fluorophenyl)-1H-indol-4-yl]-
pyrrolidin-1-yl-methanone (43). According to the general
procedure, reductive cyclization of 140 mg (0.411 mmol)
of 42 in the presence of 0.923 mg (4.11 mmol) of
Pd(OAc)2 and 5.19 mg (0.029 mmol) of 1,10-phenanthro-
line afforded 123 mg (97%) of 43 by HPLC assay of the
crude reaction mixture. Workup afforded 118 mg (93%) of
400 MHz) d 2.57 (s, 3H), 2.79 (m, 2H), 3.24 (m, 4H), 3.69
(m, 1H), 3.95 (m, 1H), 6.78 (d, 1H, J¼16.4 Hz), 7.07 (m,
2H), 7.25 (m, 1H), 7.33 (d, 1H, J¼16.4 Hz), 7.59 (m, 2H),
8.06 (dd, 1H, J¼7.6 and 1.7 Hz); 13C NMR (CDCl3,
100 MHz) d 34.3, 41.3, 45.5, 45.6, 46.3, 1120 (d, J¼
22 Hz), 116.6 (d, J¼25 Hz), 122.8, 123.9, 125.6, 129.0,
129.3, 131.9, 134.1, 136.0 (d, J¼11 Hz), 137.4, 139.2
(d, J¼8.0 Hz), 148.5, 163.4 (d, J¼250 Hz), 167.5; 19F
NMR (CDCl3, 75 MHz) d ꢂ111.1. Anal. Calcd for
C20H19ClFN3O5S: C, 51.34; H, 4.09; N, 8.98. Found: C,
51.22; H, 4.02; N, 8.96.
1
43 as a white solid: mp 130–131 ꢀC; H NMR (CDCl3,
400 MHz) d 1.82 (m, 2H), 1.95 (m, 2H), 3.37 (t, 2H,
J¼6.7 Hz), 3.75 (t, 2H, J¼6.7 Hz), 6.71 (s, 1H), 6.94 (m,
2H), 7.05 (t, 1H, J¼7.5 Hz), 7.12 (d, 1H, J¼7.5 Hz), 7.35
(d, 1H, J¼7.5 Hz), 7.60 (m, 2H), 10.4 (br s, 1H); 13C
NMR (CDCl3, 100 MHz) d 24.6, 26.2, 45.9, 49.0, 98.3,
112.8, 115.5 (d, J¼30.0 Hz), 118.3, 121.1, 126.2, 127.2,
128.5 (d, J¼10.0 Hz), 128.6, 137.6, 138.5, 162.3 (d,
J¼250.0 Hz), 170.3; 19F NMR (CDCl3, 75 MHz)
d ꢂ111.1. Anal. Calcd for C19H17FN2O: C, 74.01; H, 5.56;
N, 9.08. Found: C, 74.36; H, 5.73; N, 8.89.
3.3.10. Preparation of [2-(3-chloro-5-fluorophenyl)-1H-
indol-4-yl]-(4-methanesulfonyl-piperazin-1-yl)-meth-
anone (49). According to the general procedure, reductive
cyclization of 145 mg (0.310 mmol) of 48 in the presence
of 0.70 mg (3.10 mmol) of Pd(OAc)2 and 3.91 mg
(0.022 mmol) of 1,10-phenanthroline afforded 132 mg
(98%) of 49 by HPLC assay of the crude reaction mixture.
Workup afforded 127 mg (94%) of 49 as a colorless solid:
3.3.7. Preparation of 4-[2-trans-(2-benzo[1,3]-dioxol-5-
yl-vinyl)-3-nitrobenzoyl]-piperazine-1-carboxylic acid
tert-butyl ester (45). According to the general procedure,
treatment of a mixture of 2.00 g (6.38 mmol) of 10 with
1.05 g (8.30 mmol) of oxalyl chloride followed by reaction
with 1.55 g (8.30 mmol) of 44 in the presence of 1.00 g
(9.60 mmol) of NEt3 afforded 3.00 mg (98%) of 45 as a yel-
1
mp 143–144 ꢀC; H NMR (CDCl3/DMSO-d6, 400 MHz)
d 2.77 (s, 3H), 3.17 (br m, 4H), 3.70 (br m, 4H), 6.78 (s,
1H), 6.95 (d, 1H, J¼8.0 Hz), 7.00 (d, 1H, J¼7.9 Hz), 7.11
(t, 1H, J¼7.9 Hz), 7.41 (d, 1H, J¼7.9 Hz), 7.45 (d, 1H,
J¼7.9 Hz), 7.61 (d, 1H, J¼7.9 Hz), 11.5 (br s, 1H); 13C
NMR (CDCl3/DMSO-d6, 100 MHz) d 27.0, 34.9, 46.0,
99.3, 110.8 (d, J¼30.0 Hz), 113.4, 114.8 (d, J¼20.0 Hz),
118.8, 121.4, 122.1, 126.0, 126.8, 135.2 (d, J¼10.0 Hz),
135.6 (d, J¼10.0 Hz), 136.9, 137.8, 162.3 (d, J¼
250.0 Hz), 170.0; 19F NMR (CDCl3/DMSO-d6, 75 MHz)
d ꢂ110.9. Anal. Calcd for C20H19ClFN3O3S: C, 55.11; H,
4.39; N, 9.64. Found: C, 55.23; H, 4.38; N, 9.66.
1
low solid: mp 122–123 ꢀC; H NMR (CDCl3, 400 MHz)
d 1.42 (s, 9H), 3.08 (m, 2H), 3.29 (m, 3H), 3.41 (m, 1H),
3.61 (m, 1H), 3.70 (m, 1H), 5.98 (s, 2H), 6.88 (m, 3H),
6.99 (s, 1H), 7.10 (d, 1H, J¼16.4 Hz), 7.46 (t, 1H,
J¼7.8 Hz), 7.55 (dd, 1H, J¼7.8 and 1.2 Hz), 7.94 (dd, 1H,
J¼8.1 and 1.2 Hz); 13C NMR (CDCl3, 100 MHz) d 28.4,

J. T. Kuethe, I. W. Davies / Tetrahedron 62 (2006) 11381–11390
11389
3. (a) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Verber,
D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino,
D. H.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer,
J. P.; Hirshfield, J. J. Med. Chem. 1988, 31, 2235–2246; (b)
Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev.
2003, 103, 893–930 and references cited therein.
4. (a) Kuethe, J. T.; Wong, A.; Davies, I. W. Org. Lett. 2003, 5,
3721–3723; (b) Kuethe, J. T.; Wong, A.; Davies, I. W. Org.
Lett. 2003, 5, 3975–3978; (c) Wong, A.; Kuethe, J. T.;
Davies, I. W.; Hughes, D. L. J. Org. Chem. 2004, 69, 7761–
7764; (d) Kuethe, J. T.; Wong, A.; Qu, C.; Smitrovich,
J. H.; Davies, I. W.; Hughes, D. L. J. Org. Chem. 2005, 70,
255–2567.
3.3.11. Preparation of [2-trans-2-benzo[1,3]dioxol-5-yl-
vinyl]-morpholin-4-yl methanone (51). According to the
general procedure, treatment of a mixture of 2.50 g
(7.98 mmol) of 10 with 1.32 g (10.4 mmol) of oxalyl chlo-
ride followed by reaction with 900 mg (10.4 mmol) of mor-
pholine 50 in the presence of 1.21 g (12.0 mmol) of NEt3
afforded 2.96 g (97%) of 51 as a yellow solid: mp 134–
1
135 ꢀC; H NMR (CDCl3, 400 MHz) d 3.11 (m, 2H), 3.50
(m, 3H), 3.67 (m, 3H), 5.99 (s, 2H), 6.77–6.91 (m, 3H),
7.01 (s, 1H), 7.10 (d, 1H, J¼16.4 Hz), 7.45 (t, 1H,
J¼7.9 Hz), 7.55 (dd, 1H, J¼7.6 and 1.3 Hz), 7.93 (dd, 1H,
J¼7.9 and 1.3 Hz); 13C NMR (CDCl3, 100 MHz) d 41.8,
46.7, 66.2, 66.4, 101.3, 105.5, 108.4, 118.2, 122.4, 124.9,
128.0, 129.8, 129.9, 130.3, 131.7, 136.6, 137.2, 148.3,
148.5, 167.8. Anal. Calcd for C20H18N2O6: C, 62.82; H,
4.74; N, 7.33. Found: C, 62.49; H, 4.55; N, 7.29.
5. Kuethe, J. T.; Wong, A.; Journet, M.; Davies, I. W. J. Org.
Chem. 2005, 70, 3727–3729.
6. Thoma, G.; Nuninger, F.; Schaefer, M.; Akyel, K. G.; Albert,
R.; Beerli, C.; Bruns, C.; Francotte, E.; Luyten, M.;
MacKenzie, D.; Oberer, L.; Streiff, M. B.; Wagner, T.;
Walter, H.; Weckbecker, G.; Zerwes, H.-G. J. Med. Chem.
2004, 47, 1939–1955.
7. Kumar, K.; Michalik, D.; Castro, I. G.; Tillack, A.; Zapf, A.;
Arlt, M.; Heinrich, T.; Boettcher, H.; Beller, M. Chem.—Eur.
J. 2004, 10, 746–757.
8. Palani, A.; Dugar, S.; Clader, J. W.; Greenlee, W. J.; Ruperto,
V.; Duffy, R. A.; Lachowicz, J. E. Bioorg. Med. Chem. Lett.
2004, 14, 1791–1794.
9. Kakefuda, A.; Watanabe, T.; Taguchi, Y.; Masuda, N.; Tanaka,
A.; Yanagisawa, I. Chem. Pharm. Bull. 2003, 51, 390–398.
10. Dai, Y.; Guo, Y.; Guo, J.; Pease, L. J.; Li, J.; Marcotte, P. A.;
Glaser, K. B.; Tapang, P.; Albert, D. H.; Richardson, P. L.;
Davidsen, S. K.; Michaelides, M. R. Bioorg. Med. Chem.
Lett. 2003, 13, 1897–1901.
3.3.12. Preparation of (2-benzo[1,3]dioxol-5-yl-1H-indol-
4-yl)-morphorlin-4-yl methanone (52). According to
the general procedure, reductive cyclization of 180 mg
(0.471 mmol) of 51 in the presence of 1.06 mg
(4.71 mmol) of Pd(OAc)2 and 5.94 mg (0.033 mmol) of
1,10-phenanthroline afforded 162 mg (98%) of 52 by
HPLC assay of the crude reaction mixture. Workup afforded
152 mg (92%) of 52 as a colorless solid: mp 181–182 ꢀC; 1H
NMR (CDCl3, 400 MHz) d 3.69 (br m, 8H), 5.90 (s, 2H),
6.61 (s, 1H), 6.73 (d, 1H, J¼8.0 Hz), 7.03 (m, 2H), 7.14
(dd, 1H, J¼8.0 and 1.1 Hz), 7.18 (s, 1H), 7.29 (dd, 1H,
J¼7.3 and 1.1 Hz), 10.3 (s, 1H); 13C NMR (CDCl3,
100 MHz) d 42.6, 46.0, 63.8, 67.2, 97.2, 101.2, 106.2,
108.6, 112.8, 118.7, 119.4, 121.1, 126.2, 126.5, 126.6,
137.3, 139.7, 147.4, 148.2, 170.8. Anal. Calcd for
C20H18N2O4: C, 68.56; H, 5.18; N, 8.00. Found: C, 68.66;
H, 5.20; N, 7.99.
11. Mavunkel, B. J.; Chakravarty, S.; Perumattam, J. J.; Luedtke,
G. R.; Liang, X.; Lim, D.; Xu, Y.-J.; Laney, M.; Liu, D. Y.;
Schreiner, G. F.; Lewicki, J. A.; Dugar, S. Bioorg. Med.
Chem. Lett. 2003, 13, 3087–3090.
References and notes
12. Chollet, A.-M.; Diguarher, T. L.; Kucharczyk, N.; Loynel, A.;
Bertrand, M.; Tucker, G.; Guilbaud, N.; Burbridge, M.;
1. (a) Sundberg, R. J. The Chemistry of Indoles; Academic: New
York, NY, 1970; (b) Sundberg, R. J. Pyrroles and Their
Benzoderivatives: Synthesis and Applications; Katritzky,
A. R., Rees, C. W., Eds.; Comprehensive Heterocyclic Chem-
istry; Pergamon: Oxford, 1984; Vol. 4, pp 313–376; (c)
Sundberg, R. J. Best Synthetic Methods, Indoles; Academic:
New York, NY, 1996; pp 7–11; (d) Joule, J. A. Indole and its
Derivatives; Thomas, E. J., Ed.; Science of Synthesis:
Houben-Weyl Methods of Molecular Transformations;
George Thieme: Stuttgart, Germany, 2000; Vol. 10, Category
2, Chapter 10.13; (e) Brown, R. K. Indoles; Houlihan, W. J.,
Ed.; Wiley-Interscience: New York, NY, 1972; (f) Sundberg,
R. J. Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Bird, C. W., Eds.;
Pergamon: Oxford, 1996; Vol. 2, p 119; (g) Gribble, G. W.
Comprehensive Heterocyclic Chemistry II; Katritzky, A. R.,
Rees, C. W., Scriven, E. F. V., Bird, C. W., Eds.; Pergamon:
Oxford, 1996; Vol. 2, p 207; (h) Indoles; Sundberg, R. J.,
Ed.; Academic: London, 1996.
`
Pastoureau, P.; Fradin, A.; Sabatini, M.; Fauchere, J.-L.;
Casara, P. Bioorg. Med. Chem. 2002, 10, 531–544.
13. Koch, S. S. C.; Thoresen, L. H.; Tikhe, J. G.; Maegley, K. A.;
Almassy, R. J.; Li, J.; Yu, X.-H.; Zook, S. E.; Kumpf, R. A.;
Zhang, C.; Boritzki, T. J.; Mansour, R. N.; Zhang, K. E.;
Ekker, A.; Calabrese, C. R.; Curtin, N. J.; Kyle, S.; Thomas,
S. E.; Wang, L.-Z.; Calvert, A. H.; Golding, B. T.; Griffin,
R. J.; Newell, D. R.; Webber, S. E.; Hostomsky, Z. J. Med.
Chem. 2002, 45, 4961–4974.
14. For a leading reference, see: Kumar, K.; Zapf, A.; Michalik, D.;
Tillack, A.; Heinrich, T.; Bottcher, H.; Arlt, M.; Beller, M. Org.
¨
Lett. 2004, 6, 7–10 and references cited therein.
15. (a) Sundberg, R. J. J. Org. Chem. 1965, 30, 3604–3610; (b)
Sundberg, R. J.; Yamazaki, T. J. Org. Chem. 1967, 32, 290–
294; (c) Fresneda, P. M.; Molina, P.; Delgado, S. Tetrahedron
2001, 57, 6197–6202.
16. For leading references, see: (a) Dantale, S. W.; Soderberg,
¨
B. C. G. Tetrahedron 2003, 59, 5507–5514; (b) Scott, T. L.;
2. For recent reviews on the synthesis of indoles, see: (a)
Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106, in press;
(b) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045–
1075; (c) Pindur, U.; Adam, R. J. Heterocycl. Chem. 1988, 25,
1–8; (d) Gilchrist, T. L. J. Chem. Soc., Perkin Trans. 1 2001,
2491–2515.
Soderberg, B. C. G. Tetrahedron Lett. 2002, 43, 1621–1624;
¨
(c) Soderberg, B. C.; Shriver, J. A. J. Org. Chem. 1997, 62,
¨
5838–5845; (d) Soderberg, B. C.; Rector, S. R.; O’Neil, S. N.
¨
Tetrahedron Lett. 1999, 40, 3657–3660.
17. Davies, I. W.; Smitrovich, J. H.; Sidler, R.; Qu, C.; Gresham,
V.; Bazaral, C. Tetrahedron 2005, 61, 6425–6437.

11390
J. T. Kuethe, I. W. Davies / Tetrahedron 62 (2006) 11381–11390
18. HPLC assay yield refers to quantitative HPLC analysis of the
crude reaction mixture using an analytically pure standard.
19. Isomeric isochromanones have reportedly been prepared by the
reaction of 3 or its corresponding benzoic acid by reaction with
DMF dimethyl acetal, see: (a) Somei, M.; Karasawa, Y.; Shoda,
T.; Kaneko, C. Chem. Pharm. Bull. 1981, 29, 249–253; (b)
Matsui, T.; Sugiura, T.; Nakai, H.; Iguchi, S.; Shigeoka, S.;
Takada, H.; Odagaki, Y.; Nagao, Y.; Ushio, Y.; Ohmoto, K.;
Iwamura, H.; Yamazaki, S.; Arai, Y.; Kawamura, M. J. Med.
Chem. 1992, 35, 3307–3319.
du Plessis, D. J.; Richarz, J.; Stallmann, B. J. Prakt. Chem.
1930, 127, 169–182; (d) Macovski, E.; Georgescu, J.;
Bachmeyer, C. Chem. Ber. 1941, 74, 1279–1284; (e)
Macovski, E.; Bachmeyer, C. Chem. Ber. 1944, 77, 487–
494; (f) Barry, R. D.; Balding, R. A. J. Heterocycl. Chem.
1972, 9, 1255–1257.
21. For a review on reductive cyclizations of aromatic nitrocom-
pounds, see: (a) Soderberg, B. C. G. Curr. Org. Chem. 2000,
¨
4, 727–763; (b) Tsoungas, P. G.; Diplas, A. I. Curr. Org.
Chem. 2004, 8, 1579–1606.
20. Similar compounds of type 32 and 33 have been prepared in
similar fashion by the reaction of 31 with NaOMe in MeOH
or with piperadine at high temperatures, see: (a) Pfeiffer, P.;
Matton, K. Chem. Ber. 1911, 44, 1113–1127; (b) Pfeiffer,
P. J. Prakt. Chem. 1925, 109, 191–229; (c) Pfeiffer, P.;
22. For a discussion of mechanism including computational stud-
ies, see: (a) Davies, I. W.; Guner, V. A.; Houk, K. N. Org.
Lett. 2004, 6, 743–746; (b) Leach, A. G.; Houk, K. N.;
Davies, I. W. Synthesis 2005, 3463–3467.
23. Jacob, R. M. German Patent DE 828,695, 1950.