Palladium-catalyzed synthesis of 3-alkoxysubstituted indoles

Article abstract of DOI:10.1016/j.tet.2006.08.101

Indoles having an electron-donating alkoxy-group in the 3-position were prepared from 1-(2-nitrophenyl)-1-alkoxyalkene derivatives via a palladium-catalyzed reductive N-heteroannulation using carbon monoxide as the ultimate reducing agent. The required st

Full text of DOI:10.1016/j.tet.2006.08.101

Tetrahedron 62 (2006) 10829–10834
Palladium-catalyzed synthesis of 3-alkoxysubstituted indoles
Ronald W. Clawson Jr., Robert E. Deavers III, Novruz G. Akhmedov
*
€
and Bjorn C. G. Soderberg
€
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV 26506-6045, United States
Received 7 July 2006; accepted 29 August 2006
Available online 2 October 2006
Abstract—Indoles having an electron-donating alkoxy-group in the 3-position were prepared from 1-(2-nitrophenyl)-1-alkoxyalkene
derivatives via a palladium-catalyzed reductive N-heteroannulation using carbon monoxide as the ultimate reducing agent. The required
starting materials were prepared by a Stille coupling of 2-halonitroarenes with tributyl(1-ethoxyethenyl)stannane or tributyl(3,4-dihydro-
2H-pyran-6-yl)stannane.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
3-diazoindole,13 and benzoylperoxide oxidation of N-alkyl-
indoles.14
Indoles oxygenated in the 3-position are relatively rare in
nature but a few have been isolated, for example, indican
the precursor to indigo,1 the anti-tumor compound
BE-54017,2 and koniamborine (Fig. 1).3 In addition, a
variety of synthetic 3-alkoxyindoles have been prepared as
potential 5-HT1A receptor antagonism with SSRI activi-
ties,4 reversible inhibitors of aminopeptidase N/CD13,5
tubulin polymerization inhibitors,6 and selective serotonin
5-HT2 receptor ligands.7
Palladium-catalyzed reductive N-heteroannulation of
1-(2-nitroaryl)-1-alkenes is emerging as a versatile method-
ology for the preparation of a variety of functionalized
indoles.15–19 Synthetic application of this reaction include
tjipanazoles,20 1H-indole-2-yl-1H-quinolin-2-ones,21 mur-
rayaquinone,22 bauerine A,23 and mushroom metabolites.24
The 1-(2-nitrophenyl)-1-alkenes used to date has been lim-
ited to substrates with alkyl-, aryl-, or electron-withdrawing
groups on the alkene moiety. In an attempt to extend the
palladium-catalyzed heteroannulation reaction to substrates
having an electron-rich alkene and to develop ashort method-
ology for the synthesis of 3-alkoxysubstituted indoles, 1-(2-
nitrophenyl)-1-alkoxyethene (3) was prepared via a Stille
coupling of 2-iodo-1-nitrobenzene (1) and tributyl(1-ethoxy-
ethenyl)stannane (2). Submitting 3 to the annulation condi-
tions previously used to prepare tetrahydrocarbazolones,
bis(dibenzylideneacetone)palladium (6 mol %), 1,3-bis(di-
phenylphosphino)propane (6 mol %), and 1,10-phenanthro-
line (6 mol %) in the presence of carbon monoxide, gave the
expected 3-ethoxyindole (4) in good yield. With this initial re-
sult in hand, a number of additional examples were examined
and herein is presented the formation of 3-alkoxysubstituted
indoles via palladium-catalyzed reductive N-heteroannula-
tion of 1-(2-nitrophenyl)-1-alkoxyalkenes (Scheme 1).
3-Alkoxyindole-2-carboxylic acid derivatives are readily
prepared by direct O-alkylation of the corresponding anion
using alkyl halides, diazomethane8 or dialkylsulfates.9 In
contrast, 2-unsubstituted or 2-alkylated 3-alkoxyindoles
cannot be selectively prepared in this manner due to compet-
ing C-2-alkylation. Thus, 3-alkoxyindole derivatives of this
type are usually prepared by decarboxylation of 3-alkoxy-
indole carboxylic acids at elevated temperatures.10,11 More
recently developed methodologies include palladium-
catalyzed cyclization of N-alkyl-2-siloxyallylanilines,12
rhodium-catalyzed oxygen–hydrogen bond insertion using
OH
N
O
O
O
OH
OH
O
HO
OH
O
Cl
MeO
N
HO
N
H
N
N
2. Results and discussion
O
OMe
Indican
BE-54017
Koniamborine
Seven additional nitroaryl-substituted alkenes (12–18) were
prepared using a Stille coupling of 2-nitroarylbromides or
iodides (5–11) employing either stannane 2 or tributyl(3,4-
dihydro-2H-pyran-6-yl)stannane. The results of the cross-
coupling reactions are summarized in Table 1. A 52–82%
Figure 1.
* Corresponding author. Tel.: +1 304 293 3435; fax: +1 304 293 4904;
e-mail: bjorn.soderberg@mail.wvu.edu
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.08.101

10830
R. W. Clawson et al. / Tetrahedron 62 (2006) 10829–10834
OEt
OEt
I
OEt
Pd(dba)2, PPh3
Pd(dba)2, phenanthroline
dppp, CO (6 atm), 120 C, 72%
+
Bu3Sn
°
PhMe, Δx, 90%
N
NO2
NO2
H
1
2
3
4
Scheme 1.
yield was obtained after chromatography in the cases
examined. The compounds were selected to have either elec-
tron-donating or electron-withdrawing substituents on the
benzene ring, to be sterically congested around the alkene
(entries 1 and 2), one heterocyclic substrate (entry 6), and
one substrate having a substituent adjacent to the alkoxy-
group on the alkene (entry 7).
3-alkoxysubstituted indole in 63–87% isolated yield after
column chromatography on silica gel. As was earlier
observed, the substituents on the aromatic ring had little or
no effect on the annulation reaction.17 It should be noted
that all compounds prepared (12–25) were relatively unsta-
ble and slowly decomposed upon standing. The alkoxy-
alkenes decomposed to the corresponding ketones and the
indoles to deep blue or purple colored products of unknown
identity. The pyranoindole 25 was particularly problematic
and the compound could not be isolated without significant
or complete oxidation. The oxidation product was identified
as the spiroindolone 26 (Scheme 2) and its structure was
Subjecting the nitro alkenyl ethers to the reaction conditions
described above for compound 3, produced the anticipated
1
determined by H, 13C, HETCOR, long-range HETCOR,
Table 1. Stille coupling and reductive N-heteroannulation
and DPFGSENoE NMR experiments. Compound 26 is prob-
ably formed via the peroxide 27 and the alcohol 28. Related
oxidative-rearrangements in air have been reported in a
number of cases.25–30
Entry
Nitroarene
Stille producta,b
3-Alkoxyindolea,b
Me
Me OEt
Me
I
OEt
1
N
H
19 (84%)
NO2
NO2
The mechanism of the palladium-catalyzed reductive
N-heteroannulation of 1-(2-nitroaryl)-1-alkenes to give in-
doles has previously been examined in some detail and
a few different reaction paths have been proposed (A–C,
Scheme 3). It is generally accepted that the initial transfor-
mation involves a reduction (deoxygenation) of the nitro to
a nitroso group via the metallacycle 29. The nitroso group
may either be metal bound (30) or free (31). In path A, the
nitrosoarene 31 undergoes an intramolecular electrocyclic
reaction to give nitronate 32 followed by a 1,5-hydrogen
shift and tautomerization (32/33/34) to give an N-
hydroxyindole (34). Reduction of 34 using palladium and
a second molecule of carbon monoxide would give the prod-
uct (40).31 Path A has been demonstrated to be viable using
computational methods.32 N-Hydroxyindoles have been
isolated in a few cases from 1-(2-nitroaryl)-1-alkenes via
palladium-catalyzed annulations using carbon monox-
ide33,31 or tin dichloride34 as the reducing agent. In addition,
in situ formation of nitrosoarenes by oxidation of 1-(2-hy-
droxylaminoaryl)-1-alkenes also furnished N-hydroxy-
indoles.35–37 However, N-hydroxyindoles are not isolated
12 (81%)
5
MeO2C
OEt
MeO2C
OEt
MeO2C
Br
2
3
4
5
6
N
H
20 (87%)
NO2
OEt
NO2
1
3 (66%)
6
OEt
Br
O2N
MeO
Cl
NO2
N
O2N
O2N
MeO
Cl
NO2
H
7
21 (85%)
1
4 (52%)
OEt
OEt
I
NO2
N
MeO
NO2
H
8
22 (79%)
1
5 (68%)
OEt
OEt
Br
NO2
N
H
23 (63%)
Cl
NO2
6 (56%)
9
1
O
O
OEt
OEt
1) Pd(dba)2, phenanthroline
O
N
Br
N
N
dppp, CO (6 atm), 120
2) SiO2, air, 74%
°C
N
H
NO2
NO2
N
NO2
H
10
24 (85%)
17 (67%)
18
26
O
O
I
H
O
OH
O
O
O
O
7
NO2
N
H
NO2
18 (81%)
N
H
25
11
N
N
25 (decomposed)
27
28
a
For experimental details and analytical data, see Section 2.
Isolated yields in parentheses.
b
Scheme 2.

R. W. Clawson et al. / Tetrahedron 62 (2006) 10829–10834
10831
-CO2
[Pd(0)]
CO
-[Pd(0)]
A
O
N
O
N
O
NO2
N
O
N
O
Pd
N
O
O
Pd
29
30
CO
31
32
33
B
-CO2
Pd
Pd
N
OH
N
O
N
N
Pd
O
35
36
37
34
[Pd(0)]
CO
-[Pd(0)]
N
-[Pd(0)]
C
N
N
H
38
39
40
Scheme 3.
in an overwhelming majority of palladium-catalyzed reduc-
tive N-heteroannulations. This may be due to a very rapid
reduction of the intermediately formed N-hydroxyindole or
a different mechanism. Path B involves a second deoxygen-
ation prior to cyclization, most likely via the metallacyclo-
butane 35. Loss of carbon dioxide from 35 would furnish
a palladium-bound nitrene 36 that via a 6p-electron electro-
cyclic reaction affords a six-membered heterocycle 37. A
related rhodium-bound nitrene has been isolated and char-
acterized by X-ray diffraction.38 Reductive elimination
regenerating the palladium(0) catalyst followed by a 1,5-hy-
drogen-shift (37/39/40) affords the observed product.
An alternative path C can also be envisioned involving
a free nitrene (38) followed by an electrocyclization to
give 39 and 1,5-hydrogen shift to give 40.
Benzene and diethyl ether were distilled from sodium
benzophenone ketyl prior to use. Hexanes, dichloromethane,
and ethyl acetate were distilled from calcium hydride. Tolu-
ene was dried by filtration through activated alumina prior to
use. Chemicals prepared according to literature procedures
have been footnoted; all other reagents were obtained from
commercial sources and used as received. All reactions
were performed under a nitrogen atmosphere in an oven-
dried glassware unless otherwise stated. Solvents were
removed from reaction mixtures and products on a rotary
evaporator at water aspirator pressure. Chromatography
was performed on silica gel 60 (35–75 mm, VWR). Melting
points were determined on a MelTemp and are uncorrected.
Elemental analyses were performed in the Department of
Chemical Engineering, College of Engineering and Mineral
Resources, West Virginia University.
In summary, we have developed a rapid and expedient
synthesis of 3-alkoxysubstituted indoles based on two
palladium-catalyzed reactions. The indoles were prepared
in good yield from readily available starting materials in a
few synthetic steps.
3.1.1. 1-Ethoxy-1-(2-nitrophenyl)ethene (3). A solution of
2-iodonitrobenzene (1) (236 mg, 0.948 mmol), bis(dibenzyl-
ideneacetone)palladium Pd(dba2) (27.4 mg, 0.0476 mmol),
and triphenylphosphine (PPh3) (50 mg, 0.19 mmol) in tolu-
ene (55 mL) was stirred (5 min) under a positive flow of
nitrogen. To the yellow solution was added tributyl(1-ethoxy-
1-ethenyl)stannane (2)39 (391 mg, 1.08 mmol) dissolved in
toluene (10 mL). The yellow solution was heated at reflux
(36 h) whereupon a dark brown solution was formed. The
progress of the reaction was monitored to completion using
TLC (hexanes). The reaction mixture was cooled to ambient
temperature, washed with NH4OH (10% aqueous, 50 mL),
and dried over anhydrous MgSO4. Filtration and removal of
solvent gave a black viscous oil that was purified by
chromatography (hexanes/EtOAc, 7:3) to give 3 (166 mg,
0.859 mmol, 90%) as a pale yellow oil. 1H NMR d 7.75 (d,
J¼7.9 Hz, 1H), 7.65–7.38 (m, 3H), 4.48 (d, J¼2.8 Hz, 1H),
4.37 (d, J¼2.8 Hz, 1H), 3.86 (q, J¼6.9 Hz, 3H), 1.29 (t,
J¼7.1 Hz, 2H); 13C NMR d 158.4 (+), 149.4 (+), 132.3 (+),
132.1 (ꢀ), 130.4 (ꢀ), 129.2 (ꢀ), 123.8 (ꢀ), 86.5 (+), 64.4
(+), 13.9 (ꢀ); IR (neat) 2983, 1533 cmꢀ1; MS (EI) m/z 193
(M+), 135, 79 (100%); Anal. Calcd for C10H11NO3: C,
62.17; H, 5.74; N, 7.25. Found: C, 61.84; H, 6.04; N, 7.08.
3. Experimental
3.1. General procedures
NMR spectra were determined in CDCl3 at 270 MHz (1H
NMR) and 67.5 MHz (13C NMR) and for compound 26 at
600 and 150 MHz. The chemical shifts are expressed in
d values relative to Me4Si (0.0 ppm, 1H and 13C) or CDCl3
(77.0 ppm, 13C) used as internal standards. 1H–1H coupling
constants are reported as calculated from spectra; thus a
slight difference between Ja,b and Jb,a is usually obtained.
Results of APT (attached proton test)—13C NMR experi-
ments are shown in parentheses where, relative to CDCl3,
(ꢀ) denotes CH3 or CH and (+) denotes CH2 or C.
Tetrahydrofuran (THF), 1,4-dioxane, and diethyl ether were
distilled from sodium benzophenone ketyl prior to use.

10832
R. W. Clawson et al. / Tetrahedron 62 (2006) 10829–10834
3.1.2. 1-Ethoxy-1-(6-methyl-2-nitrophenyl)ethene (12).
Reaction of 2-iodo-3-nitrotoluene (5)40 (270 mg,
1.03 mmol) with 2 (447 mg, 1.24 mmol) in the presence of
Pd(dba)2 (30 mg, 0.051 mmol) and PPh3 (54 mg,
0.21 mmol) in toluene (65 mL), as described for 3 (76 h),
gave, after extraction and chromatography (hexanes/EtOAc,
95:5), 12 (172 mg, 0.830 mmol, 81%) as a pale yellow oil.
1H NMR d 7.63 (d, J¼7.9 Hz, 1H), 7.43 (d, J¼7.5 Hz,
1H), 7.33 (t, J¼7.9 Hz, 1H), 4.41 (d, J¼2.8 Hz, 1H), 4.13
(d, J¼2.8 Hz, 1H), 3.93 (q, J¼6.9 Hz, 2H), 2.44 (s, 3H),
1.37 (t, J¼7.1 Hz, 3H); 13C NMR d 155.6 (+), 150.0 (+),
139.4 (ꢀ), 134.1 (ꢀ), 131.5 (+), 128.5 (ꢀ), 121.0 (ꢀ),
87.0 (+), 63.8 (+), 19.6 (ꢀ), 14.3 (ꢀ); IR (neat) 2983,
1531 cmꢀ1; MS (EI) m/z 207 (M+), 149, 120 (100%);
Anal. Calcd for C11H13NO3: C, 63.76; H, 6.32; N, 6.76.
Found: C, 64.09; H, 6.42; N, 6.87.
223 (M+), 165, 109 (100%); Anal. Calcd for C11H13NO4:
C, 59.19; H, 5.87; N, 6.27. Found: C, 59.17; H, 6.22; N, 6.43.
3.1.6. 1-Ethoxy-1-(4-chloro-2-nitrophenyl)ethene (16).
Reaction of 1-bromo-4-chloro-2-nitrobenzene (9) (118 mg,
0.499 mmol) with 2 (206 mg, 0.570 mmol) in the presence
of Pd(dba)2 (15 mg, 0.025 mmol) and PPh3 (26 mg,
0.10 mmol) in toluene (70 mL), as described for 3 (72 h),
gave, after extraction and chromatography (hexanes/EtOAc,
95:5), 16 (65 mg, 0.27 mmol, 56%) as a pale yellow oil. 1H
NMR d 7.73 (d, J¼1.6 Hz, 1H), 7.51–7.43 (m, 2H), 4.45 (d,
J¼3.0 Hz, 1H), 4.36 (d, J¼3.0 Hz, 1H), 3.82 (q, J¼6.9 Hz,
2H), 1.26 (t, J¼6.9 Hz, 3H); 13C NMR d 159.9 (+), 158.3
(+), 149.5 (ꢀ), 131.5 (+), 124.7 (+), 118.0 (ꢀ), 109.1 (ꢀ),
85.7 (+), 64.3 (+), 14.0 (ꢀ); IR (neat) 2349, 1531 cmꢀ1
;
MS (EI) m/z 229 (M++2), 227 (M+), 171, 169 (100%),
113; Anal. Calcd for C10H10ClNO3: C, 52.76; H, 4.43; N,
6.15. Found: C, 52.87; H, 4.51; N, 6.23.
3.1.3. 1-Ethoxy-1-(6-methoxycarbonyl-2-nitrophenyl)-
ethene (13). Reaction of methyl 2-bromo-3-nitrobenzoate
(6)22 (120 mg, 0.46 mmol) and 2 (220 mg, 0.55 mmol) in
the presence of Pd(dba)2 (13 mg, 0.023 mmol) and PPh3
(24 mg, 0.092 mmol) in toluene (70 mL), as described
for 3 (52 h), gave, after extraction and chromatography
(hexanes/EtOAc, 9:1), 13 (76 mg, 0.30 mmol, 66%) as
3.1.7. 1-Ethoxy-1-(3-nitro-2-pyridyl)ethene (17). Re-
action of 2-bromo-3-nitropyridine (10) (176 mg,
0.867 mmol) with 2 (376 mg, 1.04 mmol) in the presence
of Pd(dba)2 (25 mg, 0.044 mmol) and PPh3 (45 mg,
0.17 mmol) in toluene (55 mL), as described for 3 (42 h),
gave, after extraction and chromatography (hexanes/EtOAc,
95:5), 17 (113 mg, 0.582 mmol, 67%) as a pale yellow oil.
1H NMR d 8.73 (dd, J¼4.7, 1.8 Hz, 1H), 7.98 (dd, J¼8.1,
1.4 Hz, 1H), 7.42 (dd, J¼8.1, 4.8 Hz, 1H), 5.10 (d,
J¼2.6 Hz, 1H), 4.56 (d, J¼2.6 Hz, 1H), 3.91 (q, J¼6.9 Hz,
2H), 1.31 (t, J¼6.9 Hz, 3H); 13C NMR d 157.2 (+), 151.2
(ꢀ), 148.1 (+), 146.2 (+), 131.6 (ꢀ), 123.4 (ꢀ), 89.2 (+),
64.6 (+), 13.9 (ꢀ); IR (neat) 2984, 1537 cmꢀ1; MS (EI)
m/z 194 (M+), 136, 78 (100%); Anal. Calcd for
C9H10N2O3: C, 55.67; H, 5.19; N, 14.43. Found: C, 55.88;
H, 5.50; N, 14.06.
1
a dark yellow oil. H NMR d 7.90–7.83 (m, 2H), 7.52 (t,
J¼7.9 Hz, 1H), 4.36 (d, J¼3.0 Hz, 1H), 4.27 (d, J¼3.0 Hz,
1H), 3.97 (s, 3H), 3.88 (q, J¼7.1 Hz, 2H), 1.33 (t,
J¼7.1 Hz, 3H); 13C NMR d 168.4 (+), 154.9 (+), 151.8
(+), 151.2 (+), 150.0 (+), 133.0 (+), 132.6 (ꢀ), 125.9 (ꢀ),
87.4 (+), 64.5 (+), 52.7 (ꢀ), 14.2 (ꢀ); IR (neat) 2942,
1774, 1542 cmꢀ1; MS (EI) m/z 251 (M+), 193, 161
(100%); Anal. Calcd for C12H13NO5: C, 57.37; H, 5.22; N,
5.58. Found: C, 57.33; H, 5.63; N, 5.49.
3.1.4. 1-Ethoxy-1-(2,4-dinitrophenyl)ethene (14). Reac-
tion of 1-bromo-2,4-dinitrobenzene (7) (140 mg,
0.57 mmol) with 2 (246 mg, 0.681 mmol) in the presence
of Pd(dba)2 (16 mg, 0.028 mmol) and PPh3 (30 mg,
0.11 mmol) in toluene (75 mL), as described for 3 (64 h),
gave, after extraction and chromatography (hexanes/EtOAc,
95:5), 14 (70 mg, 0.29 mmol, 52%) as a yellow oil. 1H NMR
d 8.59 (d, J¼2.2 Hz, 1H), 8.40 (dd, J¼8.5, 2.2 Hz, 1H), 7.77
(d, J¼8.5 Hz, 1H), 4.62 (d, J¼3.2 Hz, 1H), 4.53 (d,
J¼3.1 Hz, 1H), 3.88 (q, J¼7.1 Hz, 2H), 1.30 (t, J¼7.1 Hz,
3H); 13C NMR d 156.5 (+), 148.8 (+), 147.5 (ꢀ), 137.8
(ꢀ), 131.5 (ꢀ), 126.5 (ꢀ), 119.5 (+), 89.1 (+), 64.9 (+),
13.8 (ꢀ); IR (neat) 2984, 1545 cmꢀ1; MS (EI) m/z 238
(M+), 180 (100%), 134; Anal. Calcd for C10H10N2O5: C,
50.42; H, 4.23; N, 11.76. Found: C, 50.42; H, 4.63; N, 11.19.
3.1.8. 3,4-Dihydro-6-(2-nitrophenyl)-2H-pyran (18).41,42
Reaction of 1 (180 mg, 0.72 mmol), Pd(dba)2 (21 mg,
0.036 mmol), and PPh3 (38 mg, 0.14 mmol) with
tributyl(3,4-dihydro-2H-pyran-6-yl)stannane43
(324 mg,
0.868 mmol) in toluene (75 mL total), as described above
for 3 (48 h), gave, after extraction and chromatography (hex-
anes), 18 as a yellow oil (120 mg, 0.58 mmol, 81%). Spectral
data (1H NMR) in complete accordance with literature
values.41
3.1.9. 3-Ethoxyindole (4). 1-Ethoxy-1-(2-nitrophenyl)-
ethene (3) (47 mg, 0.24 mmol), Pd(dba)2 (9 mg,
0.02 mmol), 1,3-bis-(diphenylphosphino)propane (dppp)
(6 mg, 0.01 mmol), and 1,10-phenanthroline (phen) (6 mg,
0.03 mmol) were dissolved in anhydrous DMF (2 mL) in
a threaded ACE glass pressure tube. The tube was fitted
with a pressure head, and the solution was saturated with
carbon monoxide (four cycles of 6 atm of CO). The reaction
mixture was heated at 120 ꢁC (oil bath temperature) under
CO (6 atm) until all starting material was consumed
(96 h), as judged by TLC. Water (10 mL) was added and
the brown solution was extracted with ethyl acetate
(3ꢂ20 mL). The combined organic phases were dried
(MgSO4), filtered, and the solvent was removed. The result-
ing crude product was purified by chromatography (hexanes/
EtOAc, 7:3) to afford 4 (28 mg, 0.17 mmol, 72%) as a purple
oil. 1H NMR d 7.68 (d, J¼7.9 Hz, 1H), 7.45 (br s, 1H), 7.25
3.1.5. 1-Ethoxy-1-(4-methoxy-2-nitrophenyl)ethene (15).
Reaction of 4-iodo-3-nitro-1-methoxybenzene (8) (279 mg,
1.00 mmol) with 2 (412 mg, 1.14 mmol) in the presence of
Pd(dba)2 (28.9 mg, 0.0503 mmol) and PPh3 (53 mg,
0.20 mmol) in toluene (75 mL), as described for 3 (56 h),
gave, after extraction and chromatography (hexanes/EtOAc,
8:2), 15 (151 mg, 0.676 mmol, 68%) as a dark yellow oil. 1H
NMR d 7.44 (d, J¼8.5 Hz, 1H), 7.26 (d, J¼2.6 Hz, 1H), 7.04
(dd, J¼8.5, 2.6 Hz, 1H), 4.40 (d, J¼2.8 Hz, 1H), 4.30 (d,
J¼2.8 Hz, 1H), 3.91–3.80 (m, 5H), 1.28 (t, J¼6.9 Hz, 3H);
13C NMR d 159.9 (+), 158.3 (+), 149.5 (+), 131.5 (ꢀ),
124.7 (+), 118.0 (ꢀ), 109.1 (ꢀ), 85.7 (+), 64.3 (+), 55.9
(ꢀ), 14.0 (ꢀ); IR (neat) 2359, 1537 cmꢀ1; MS (EI) m/z

R. W. Clawson et al. / Tetrahedron 62 (2006) 10829–10834
10833
(dd, J¼8.0, 1.0 Hz, 1H), 7.18 (dt, J¼8.1, 1.2 Hz, 1H), 7.07
(dt, J¼7.4, 1.2 Hz, 1H), 6.67 (d, J¼2.6 Hz, 1H), 4.07 (q,
J¼6.9 Hz, 2H), 1.46 (t, J¼7.1 Hz, 3H); 13C NMR d 140.8
(+), 134.3 (+), 122.7 (ꢀ), 120.0 (+), 118.9 (ꢀ), 118.0 (ꢀ),
111.1 (ꢀ), 105.2 (ꢀ), 66.7 (+), 15.1 (ꢀ); IR (neat) 3478,
909, 731 cmꢀ1; MS (EI) m/z 161 (M+), 132 (100%); Anal.
Calcd for C10H11NO: C, 74.51; H, 6.88; N, 8.69. Found:
C, 74.79; H, 6.95; N, 8.75.
3H), 1.45 (t, J¼6.9 Hz, 3H); 13C NMR d 140.8 (+), 134.5
(+), 122.3 (+), 118.8 (ꢀ), 109.1 (ꢀ), 94.5 (ꢀ), 66.6 (+),
60.6 (+), 55.7 (ꢀ), 15.2 (ꢀ), 14.3 (ꢀ); IR (neat) 3422,
908, 741 cmꢀ1; MS (EI) m/z 191 (M+), 162 (100%).
3.1.14. 6-Chloro-3-ethoxyindole (23). Reaction of 16
(126 mg, 0.553 mmol) in the presence of Pd(dba)2 (19 mg,
0.033 mmol), dppp (14 mg, 0.033 mmol), phen (13 mg,
0.066 mmol), and CO (6 atm) in DMF (2 mL), as described
for 4 (72 h), gave, after chromatography (hexanes/EtOAc,
7:3) 23 (62 mg, 0.32 mmol, 63%) as a yellow solid.44 Mp
85.5–86.5 ꢁC; 1H NMR d 7.57 (d, J¼8.5 Hz, 1H), 7.45
(br s, 1H), 7.22 (d, J¼1.2 Hz, 1H), 7.05 (dd, J¼8.3, 1.8 Hz,
1H), 6.63 (d, J¼2.4 Hz, 1H), 4.03 (q, J¼6.9 Hz, 2H), 1.42
(t, J¼7.1 Hz, 3H); 13C NMR d 140.9 (+), 134.6 (+), 128.8
(ꢀ), 119.7 (ꢀ), 119.1 (+), 118.6 (ꢀ), 111.1 (+), 105.5 (ꢀ),
66.8 (+), 15.1 (ꢀ); IR (neat) 3478, 908, 731 cmꢀ1; MS (EI)
m/z 197 (M++2), 195 (M+), 168, 166 (100%).
3.1.10. 3-Ethoxy-4-methylindole (19). Reaction of 12
(37 mg, 0.18 mmol) in the presence of Pd(dba)2 (6 mg,
0.01 mmol), dppp (6 mg, 0.01 mmol), phen (4 mg,
0.02 mmol), and CO (6 atm) in DMF (2 mL), as described
for 4 (48 h), gave, after chromatography (hexanes/EtOAc,
1
9:1), 19 (27 mg, 0.15 mmol, 84%) as a dark green oil. H
NMR d 7.76–7.01 (m, 3H), 6.83–6.78 (m, 1H), 6.64 (d,
J¼2.6 Hz, 1H), 3.99 (q, J¼6.9 Hz, 2H), 2.70 (s, 3H), 1.45
(t, J¼6.9 Hz, 3H); 13C NMR d 142.6 (+), 134.5 (+), 130.4
(+), 122.7 (ꢀ), 120.0 (ꢀ), 118.9 (+), 108.5 (ꢀ), 104.4 (ꢀ),
66.8 (+), 18.9 (ꢀ), 15.1 (ꢀ); IR (neat) 3470, 908,
734 cmꢀ1; MS (EI) m/z 175 (M+), 147 (100%); Anal. Calcd
for C11H13NO: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.41;
H, 7.58; N, 8.00.
3.1.15. 3-Ethoxy-1H-pyrrolo[3,2-b]pyridine (24). Reac-
tion of 17 (31 mg, 0.16 mmol) in the presence of Pd(dba)2
(6 mg, 0.01 mmol), dppp (4 mg, 0.01 mmol), phen (4 mg,
0.02 mmol), and CO (6 atm) in DMF (2 mL), as described
for 4 (72 h), gave, after chromatography (hexanes/EtOAc,
8:2), 24 (22 mg, 0.14 mmol, 85%) as a yellow solid.44 Mp
3.1.11. Methyl 3-ethoxyindole-4-carboxylate (20). Reac-
tion of 13 (21 mg, 0.084 mmol) in the presence of Pd(dba)2
(3 mg, 0.005 mmol), dppp (2 mg, 0.005 mmol), phen (2 mg,
0.01 mmol), and CO (6 atm) in DMF (2 mL), as described
for 4 (72 h), gave, after chromatography (hexanes/EtOAc,
1
84–85 ꢁC; H NMR d 8.44 (dd, J¼4.7, 1.5 Hz, 1H), 7.83
(br s, 1H), 7.58 (dd, J¼8.2, 1.2 Hz, 1H), 7.11 (dd, J¼8.4,
4.7 Hz, 1H), 6.96 (d, J¼2.7 Hz, 1H), 4.19 (q, J¼6.9 Hz,
2H), 1.49 (t, J¼7.2 Hz, 3H); 13C NMR d 142.7 (ꢀ), 127.5
(+), 118.5 (+), 118.4 (ꢀ), 117.6 (+), 114.9 (ꢀ), 109.4 (ꢀ),
66.9 (+), 15.1 (ꢀ); IR (neat) 3418, 909, 734 cmꢀ1; MS
(EI) m/z 162 (M+), 147, 79 (100%).
1
95:5) 20 (16 mg, 0.078 mmol, 87%) as a yellow oil. H
NMR d 7.78 (br s, 1H), 7.53 (dd, J¼7.2, 0.7 Hz, 1H), 7.43
(dd, J¼8.2, 0.8 Hz, 1H), 7.18 (t, J¼7.7 Hz, 1H), 6.85 (d,
J¼2.5 Hz, 1H), 4.00 (q, J¼6.9 Hz, 2H), 3.97 (s, 3H), 1.46
(t, J¼6.9 Hz, 3H); 13C NMR d 169.1 (+), 140.6 (+), 134.9
(+), 124.0 (+), 121.7 (ꢀ), 121.5 (ꢀ), 115.8 (+), 114.8 (ꢀ),
108.0 (ꢀ), 67.2 (+), 51.9 (ꢀ), 15.1 (ꢀ); IR (neat) 3251,
1742, 908, 734 cmꢀ1; MS (EI) m/z 219 (M+), 190, 159
(100%); Anal. Calcd for C12H13NO3: C, 65.74; H, 5.98;
N, 6.39. Found: C, 65.59; H, 6.12; N, 6.38.
3.1.16. 2,3,4,5-Tetrahydropyrano[3,2-b]indole (25)45 and
4,5-dihydrospiro[furan-2(3H),20-[2H]indol]-30-(10H)-one
(26). Reaction of 18 (193 mg, 0.941 mmol), Pd(dba)2
(32 mg, 0.056 mmol), dppp (22 mg, 0.11 mmol), phen
(23 mg, 0.056 mmol), and CO (6 atm) in DMF (2 mL), as
described for 4 (80 h), gave, after chromatography (hex-
anes/EtOAc/acetone, 95:4:1), a 3.5:1 mixture of 25 and 26
as a yellow oil (152 mg). Spectral data of 25 from the mix-
3.1.12. 3-Ethoxy-6-nitroindole (21). Reaction of 14
(48 mg, 0.20 mmol) in the presence of Pd(dba)2 (7 mg,
0.01 mmol), dppp (5 mg, 0.01 mmol), phen (5 mg,
0.03 mmol), and CO (6 atm) in DMF (2 mL), as described
for 4 (72 h), gave, after chromatography (hexanes/EtOAc,
95:5), 21 (36 mg, 0.17 mmol, 85%) as a dark yellow oil.44
1H NMR (CDCl3+DMSO-d6) d 7.92 (d, J¼1.0 Hz, 1H),
7.69 (dd, J¼8.7, 1.6 Hz, 1H), 7.66 (d, J¼8.5 Hz, 1H), 7.10
(d, J¼2.4 Hz, 1H), 6.88 (d, J¼2.8 Hz, 1H), 4.11 (q,
J¼7.1 Hz, 2H), 1.49 (t, J¼6.9 Hz, 3H); 13C NMR (CDCl3)
d 149.9 (+), 141.6 (+), 135.4 (+), 132.7 (+), 118.6 (ꢀ),
112.9 (ꢀ), 109.7 (ꢀ), 109.5 (ꢀ), 66.9 (+), 15.4 (ꢀ); IR
1
ture: H NMR d 7.50 (d, J¼7.5 Hz, 1H), 7.39 (br s, 1H),
7.20 (d, J¼7.1 Hz, 1H), 7.11 (dt, J¼7.1, 1.4 Hz), 7.04 (dt,
J¼6.9, 1.2 Hz, 1H), 4.23 (t, J¼4.9 Hz, 2H), 2.77 (t,
J¼6.3 Hz, 2H), 2.10 (pent, J¼5.1 Hz, 2H); 13C NMR
d 133.1 (+), 132.2 (+), 122.4 (+), 121.5 (ꢀ), 119.2 (+),
118.9 (ꢀ), 116.4 (ꢀ), 110.7 (ꢀ), 67.2 (+), 22.6 (+), 20.1
(+). (Lit.31 1H NMR d 7.60–6.85 (m, 5H), 4.18 (t,
J¼5.0 Hz, 2H), 2.78 (t, J¼6.2 Hz, 2H), 2.30–1.86 (m, 2H).
Complete oxidative-rearrangement of 25 to 26 was accom-
plished using the following procedure. Silica gel (approx.
500 mg) was added to a solution of the mixture of 25 and
26 in acetone (10 mL). The solvent was removed and the re-
sidual solid was allowed to stand open to the air overnight
(14 h). Purification by chromatography (hexanes/EtOAc/
acetone, 95:4:1) afforded 26 as a bright yellow oil
(131 mg, 0.692 mmol, 74% from 18). 1H NMR (600 MHz)
d 7.55 (d, J¼7.8 Hz, 1H), 7.42 (dt, J¼7.8, 1.2 Hz, 1H),
6.81 (t, J¼7.8 Hz, 1H), 6.77 (d, J¼8.4 Hz, 1H), 4.77 (br s,
1H), 4.13 (m, 2H), 2.28 (m, 2H), 2.07 (m, 1H), 1.99 (m,
1H); 13C NMR d (150 MHz) 200.9 (+), 159.6 (+), 137.8
(ꢀ), 125.1 (ꢀ), 119.7 (ꢀ), 119.2 (+), 112.2 (ꢀ), 95.0 (+),
(neat) 3422, 1545, 1348, 908, 734 cmꢀ1
.
3.1.13. 3-Ethoxy-6-methoxyindole (22). Reaction of 15
(28 mg, 0.13 mmol) in the presence of Pd(dba)2 (5 mg,
0.008 mmol), dppp (3 mg, 0.008 mmol), phen (3 mg,
0.02 mmol), and CO (6 atm) in DMF (2 mL), as described
for 4 (96 h), gave, after chromatography (hexanes/EtOAc,
95:5) 22 (19 mg, 0.10 mmol, 79%) as a yellow solid.44 Mp
1
62–63 ꢁC; H NMR d 7.52 (d, J¼9.3 Hz, 1H), 7.29 (br s,
1H), 6.76 (d, J¼2.2 Hz, 1H), 6.74 (dd, J¼6.1, 2.1 Hz, 1H),
6.56 (d, J¼2.4 Hz, 1H), 4.05 (q, J¼6.9 Hz, 2H), 3.83 (s,

10834
R. W. Clawson et al. / Tetrahedron 62 (2006) 10829–10834
15. Akazome, M.; Kondo, T.; Watanabe, Y. J. Org. Chem. 1994, 59,
3375–3380.
16. Tollari, S.; Cenini, S.; Crotti, C.; Gianella, E. J. Mol. Catal.
1994, 87, 203–214.
69.3 (+), 34.0 (+), 25.8 (+); IR (neat) 3250, 1702,
1007 cmꢀ1 HRMS calcd for C11H12NO2 (M++H)
190.0868, found 190.0862.
;
€
17. Soderberg, B. C.; Shriver, J. A. J. Org. Chem. 1997, 62, 5838–
5845.
Acknowledgements
€
18. Soderberg, B. C.; Rector, S. R.; O’Neil, S. N. Tetrahedron Lett.
1999, 40, 3657–3660.
This work was supported by a research grant from the
National Institute of General Medical Sciences, National
Institutes of Health (R01 GM57416) and the Donors of the
American Chemical Society Petroleum Research Fund
(40665-AC1). NSF-EPSCoR (Grant #1002165R) is grate-
fully acknowledged for the funding of a 600 MHz Varian
Inova NMR and an LTQ-FT Mass Spectrometer and the
NMR and MS facilities in the C. Eugene Bennett Depart-
ment of Chemistry at West Virginia University.
19. Fe(CO)5, Ru3(CO)12 or Rh6(CO)16 were the first reported cat-
alysts for this type of annulation forming indoles. Crotti, C.;
Cenini, S.; Rindone, B.; Tollari, S.; Demartin, F. J. Chem.
Soc., Chem. Commun. 1986, 784–786.
20. Kuethe, J. T.; Wong, A.; Davies, I. W. Org. Lett. 2003, 5, 3721–
3723.
21. Kuethe, J. T.; Wong, A.; Davies, I. W. Org. Lett. 2003, 5, 3975–
3978.
€
22. Scott, T. L.; Soderberg, B. C. G. Tetrahedron 2003, 59, 6323–
6332.
23. Dantale, S. W.; Soderberg, B. C. G. Tetrahedron 2003, 59,
Supplementary data
€
5507–5514.
€
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.08.101.
24. Soderberg, B. C.; Chisnell, A. C.; O’Neil, S. N.; Shriver, J. A.
J. Org. Chem. 1999, 64, 9731–9734.
25. Brown, D. W.; Mahon, M. F.; Ninan, A.; Sainsbury, M.
J. Chem. Soc., Perkin Trans. 1 1997, 1699–1706.
26. McLean, S.; Dmitrienko, G. I. Can. J. Chem. 1971, 49, 3642–
3647.
27. Rodriguez, J. G.; San Andres, A. J. Heterocycl. Chem. 1991,
28, 1293–1299.
References and notes
1. Hoogewerff, S.; ter Meulen, H. Recl. Trav. Chim. Pays-Bas
1900, 19, 166.
2. Nakase, K.; Nakajima, S.; Hirayama, M.; Kondo, H.; Kojiri, K.;
Suda, H. Jpn. Kokai Tokkyo Koho, 2000, JP200178274; [CAN
133:42244].
28. Mateo, C. A.; Urrutia, A.; Rodriguez, J. G.; Fonseca, I.; Cano,
F. H. J. Org. Chem. 1996, 61, 810–812.
3. Grougnet, R.; Magiatis, P.; Fokialakis, N.; Mitaku, S.;
Skaltsounis, A.-L.; Tillequin, F.; Sevenet, T.; Litaudon, M.
J. Nat. Prod. 2005, 68, 1083–1086.
29. Witkop, B.; Patrick, J. B. J. Am. Chem. Soc. 1951, 73, 2188–
2195.
30. Hewitt, M. C.; Shao, L. Arkivoc 2006, 37–46.
31. Davies, I. W.; Smitrovich, J. H.; Sidler, R.; Qu, C.; Gresham,
V.; Bazaral, C. Tetrahedron 2005, 61, 6425–6437.
32. Davies, I. W.; Guner, V. A.; Houk, K. N. Org. Lett. 2004, 6,
743–746.
33. Tollari, S.; Penoni, A.; Cenini, S. J. Mol. Catal. 2000, 152, 47–
54.
34. Stefanachi, A.; Leonetti, F.; Cappa, A.; Carotti, A. Tetrahedron
Lett. 2003, 44, 2121–2123.
35. Kuzmich, D.; Mulrooney, C. Synthesis 2003, 1671–1678.
36. Wrobel, Z.; Makosza, M. Tetrahedron 1997, 53, 5501–5514.
37. Hazard, R.; Tallec, A. Bull. Soc. Chim. Fr. 1974, 121–125.
38. Crotti, C.; Cenini, S.; Bassoli, A.; Rindone, B.; Demartin, F.
J. Mol. Catal. 1991, 70, 175–187.
4. Takeuchi, K.; Kohn, T. J.; Honigschmidt, N. A.; Rocco, V. P.;
Spinazze, P. G.; Atkinson, S. T.; Hertel, L. W.; Nelson, D. L.;
Wainscott, D. B.; Ahmad, L. J.; Shaw, J.; Threlkeld, P. G.;
Wong, D. T. Bioorg. Med. Chem. Lett. 2003, 13, 3939–3942.
5. Bauvois, B.; Puiffe, M.-L.; Bongui, J.-B.; Paillat, S.; Monneret,
C.; Dauzonne, D. J. Med. Chem. 2003, 46, 3900–3913.
6. Beckers, T.; Mahboobi, S.; Pongratz, H.; Frieser, M.; Hufsky,
H.; Hockemeyer, J.; Vanhoefer, U. PCT Int. Appl. 2003, WO
2003037861; [CAN 138:368759].
7. Hebeisen, P.; Mattei, P.; Muller, M.; Richter, H.; Roever, S.;
Taylor, S. PCT Int. Appl. 2002, WO 2002072584; [CAN
137:232679].
€
8. Bos, M.; Jenck, F.; Martin, J. R.; Moreau, J. L.; Mutel, V.;
Sleight, A. J.; Widmer, U. Eur. J. Med. Chem. 1997, 32, 253–
261.
39. Gadwood, R. C.; Rubino, M. R.; Nagarajan, S. C.; Michel, S. T.
J. Org. Chem. 1985, 50, 3255–3260.
9. Galun, A.; Kampf, A.; Marcus, A. J. Heterocycl. Chem. 1979,
16, 641–643.
10. Pappalardo, G.; Vitali, T. Gazz. Chim. Ital. 1958, 88, 574–590.
11. Balsiger, R. W.; Fischer, R. W.; Hirt, R.; Giovannini, E. Helv.
Chim. Acta 1953, 36, 708–712.
40. Gillespie, K. M.; Sanders, C. J.; O’Shaughnessy, P.;
Westmoreland, I.; Thickitt, C. P.; Scott, P. J. Org. Chem.
2002, 67, 3450–3458.
41. Lehmann, U.; Awasthi, S.; Minehan, T. Org. Lett. 2003, 5,
2405–2408.
12. Gowan, M.; Caille, A. S.; Lau, C. K. Synlett 1997, 1312–1313.
13. Kettle, J. G.; Faull, A. W.; Fillery, S. M.; Flynn, A. P.; Hoyle,
M. A.; Hudson, J. A. Tetrahedron Lett. 2000, 41, 6905–6907.
14. Kanaoka, Y.; Aiura, M.; Hariya, S. J. Org. Chem. 1971, 36,
458–460.
42. Denmark, S. E.; Neuville, L. Org. Lett. 2000, 2, 3221–3224.
43. Ghosal, S.; Luke, G. P.; Kyler, K. S. J. Org. Chem. 1987, 52,
4296–4298.
44. The compound decomposed rapidly upon standing.
45. Eiden, F.; Wanner, K. T. Arch. Pharmacol. 1985, 318, 548–555.