Synthesis of 1,2,3,4-tetrahydrocarbazoles and related tricyclic indoles

Article abstract of DOI:10.1016/j.tet.2006.11.052

Reduction of 2-(2-nitrophenyl)-2-cyclohexene-1-ones using palladium on carbon under 1 atm of hydrogen gas at ambient temperature affords 1,2,3,4-tetrahydrocarbazoles in excellent isolated yields. The starting materials were prepared by intermolecular Stille coupling of 2-iodo-2-cyclohexen-1-ones with 2-(tributylstannyl)-1-nitrobenzenes.

Full text of DOI:10.1016/j.tet.2006.11.052

Tetrahedron 63 (2007) 1183–1190
Synthesis of 1,2,3,4-tetrahydrocarbazoles and related
tricyclic indoles
*
ꢀ
Tricia L. Scott, Nicholas Burke, Grissell Carrero-Martınez and Bjorn C. G. Soderberg
€
€
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV 26506-6045, United States
Received 30 October 2006; accepted 16 November 2006
Available online 13 December 2006
Abstract—Reduction of 2-(2-nitrophenyl)-2-cyclohexene-1-ones using palladium on carbon under 1 atm of hydrogen gas at ambient
temperature affords 1,2,3,4-tetrahydrocarbazoles in excellent isolated yields. The starting materials were prepared by intermolecular Stille
coupling of 2-iodo-2-cyclohexen-1-ones with 2-(tributylstannyl)-1-nitrobenzenes.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Reduction of 2-nitroarenes having an adjacent saturated
cyclohexanone with a variety of reducing agents, such as
TiCl3,16–18 zinc,19,20 and palladium on carbon–hydrogen
gas21,22 has been described to afford 1,2,3,4-tetrahydro-
carbazoles (Scheme 2). In addition, a general method for
the formation of N-hydroxyindoles was reported using a
lead-promoted reductive cyclization of related ketones and
aldehydes under transfer hydrogenation conditions.23
We and others have developed mild and very efficient routes
to substituted indoles,1–10 b-carbolines,11 carbazoles,12 and
1,2-dihydro-4(3H)-carbazolones13,14 using a palladium-
catalyzed reductive N-heteroannulation as the key step.
For example, 1,2-dihydro-4(3H)-carbazolone (2) was pre-
pared in good isolated yield by reductive cyclization of
2-(2-nitrophenyl)-2-cyclohexene-1-one (1) (Scheme 1). A
mechanism involving the formation of a palladium-bound
nitrene followed by electrocyclization has been proposed
for the annulation reaction.5 The starting 2-(2-nitrophenyl)-
2-cyclohexenones were prepared by a Stille-type cross-
coupling of the appropriate 2-nitrophenylstannanes with
2-iodo-2-cycloalken-1-ones.
O
TiCl3, H2O
acetone, 88%
N
H
NO2
Scheme 2.
It was perceived that initial reduction of the nitro group of 1,
using palladium on carbon and hydrogen gas, to an amine
followed by condensation with the carbonyl moiety would
afford a product with a different oxidation state and regio-
chemistry. This idea was corroborated in our initial experi-
ment wherein 1 was reduced under mild conditions to give
1,2,3,4-tetrahydrocarbazole (3) (Scheme 1).15
Herein is reported a study of the reduction of 2-(2-nitro-
phenyl)-2-cycloalkene-1-one to give reduced carbazoles
and related tricyclic compounds. It should be noted that
while working on this manuscript, Banwell et al. communi-
cated a related methodology involving an Ullman-type
coupling of 2-nitro-1-halobenzenes with a-halo-enones and
O
O
Pd(dba)2, dppp
Pd/C
2 (1 atm)
H
CO (4 atm), DMF
1,10-Phenanthroline
N
H
N
H
NO2
3 (95%)
2 (83%)
1
Scheme 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.2006.11.052

1184
T. L. Scott et al. / Tetrahedron 63 (2007) 1183–1190
-enals followed by a palladium on carbon catalyzed
reductive annulation.24
gas, regioisomeric compounds can be obtained although in
different oxidation states.
2. Results and discussion
The inherent regioselectivity in the present methodology is
important to stress. For example, preparation of compound
22 is problematic using more conventional methods such
as the Fischer indole synthesis. For example, reaction of
3-methylcyclohexanone with phenylhydrazine affords a 10:1
mixture of 20:22.27 In addition, a more recently developed
palladium-catalyzed annulation between 2-iodoaniline and
3-methylcyclohexanone also gave 20 as the major product
(8:1 mixture of 20:22).28 In contrast, both 20 and 22 can read-
ily be prepared in high yields using the present methodology.
A variety of 2-(2-nitrophenyl)-2-cycloalkenones were pre-
pared using published procedures or modifications thereof.
For example, compound 4 was synthesized starting from
4-methylcyclohexanone (5) (Scheme 3). Formation of silyl
enol ether 6 followed by palladium-catalyzed dehydrosilyla-
tion (a Saegusa oxidation)22 gave 4-methyl-2-cyclohexen-1-
one (7). The relatively low yield of 7 may be attributed to the
volatility of this product. Iodide 8 was prepared in 65% yield
employing iodine in a pyridine–carbon tetrachloride mixture
as described by Johnson et al.25 Stille-type cross-coupling of
8 with 2-nitrophenyl-substituted stannane 9, using bis(ben-
zonitrile)palladium dichloride, triphenylarsine, and copper
iodide in N-methylpyrrolidinone gave 4 in good yield (80%).
Two additional new compounds, 11 and 12 (Table 1), were
prepared in a similar fashion by coupling of 2-iodo-5-methyl-
cyclohexenone and 2-iodo-3-methylcyclohexenone with 9,
respectively.
Substitution on the benzene ring affected the oxidation state
of products isolated. Upon reduction of compounds 13 and
14, in addition to the expected tetrahydrocarbazoles (23
and 25), hexahydrocarbazoles (24 and 26) were formed as
well (entries 5 and 6). Over-reduction was observed to
give 1,2,3,3a,4,8b-hexahydrocyclopent[b]indole (29) as the
only product upon reaction of 2-(2-nitrophenyl)-2-cyclo-
penten-1-one (17, entry 9). Reduction of 1,2,3,4-tetrahydro-
cyclopent[b]indole to 29 in 69% yield using 5 mol % Pd/C
under 3 atm of hydrogen gas has been reported.29 A related
over-reduction of 2-(2,4-dinitrophenyl)cyclopentanone to
give 6-amino-hexahydrocyclopent[b]indole was reported
by Kuehne employing 2.6 mol % palladium.30 In contrast,
the formation of 29 was not observed by Banwell et al. using
the same starting material (17) and 2 mol % palladium.
Interestingly, we did not isolate the over-reduction product
from the corresponding cycloheptenone derivative 18, which
smoothly was reduced to the 5,6,7,8,9,10-hexahydrocyclo-
hept[d]indole (30) (entry 10).
With a variety of substrates readily available, the N-hetero-
annulation was examined next and the results of the reduc-
tive cyclizations are summarized in Table 1. Most of the
reductions were performed in methanol using 10% Pd/C
(w20 mol % Pd) and hydrogen gas (1 atm) at ambient tem-
perature. The starting materials were completely consumed
within 20 min to 2 h as monitored by thin layer chromato-
graphy. Compounds related to those described in Table 1
have been shown to be sensitive to oxidation on silica.26
For compounds where this was a noticeable problem, pre-
cautions were taken such as using base-washed glassware,
filtering the NMR solvents through potassium carbonate
prior to use, and adding a small amount of triethylamine to
the eluent (approximately 0.2–1% of triethylamine per
100 mL of eluent) used for chromatography.
Finally, reductive annulation of dione 15 gave not only the
expected carbazolone 2 but also 1,2,3,4-tetrahydrocarbazole
(3) (Table 1, entry 7). We speculated that 2 was initially
formed followed by a second reduction to give 3, under
the reaction conditions.31 Reduction of carbonyl groups ad-
jacent to the 3-position of the indole ring using palladium on
carbon and hydrogen gas has been reported previously.32 In
a control experiment, subjecting carbazolone 2 to the hydro-
genation conditions did produce tetrahydrocarbazole 3, but
39% of the starting material was still present after 3 days.
Due to the vastly different reaction kinetics of the reductions
described in entry 7 (2 h) and Scheme 4 (3 days), it is
unlikely that 2 is a major intermediate to 3.
For the methyl-substituted starting materials (10–12 and 4,
entries 1–4), excellent yields of methyl-substituted 1,2,3,4-
tetrahydrocarbazoles were obtained upon reduction. It
should be noted that the connectivity between the indole
nitrogen and the reduced six-membered ring is different
from that obtained using the palladium–carbon monoxide
catalyst system shown in Scheme 1. Thus, by simply chang-
ing the reducing agent, carbon monoxide versus hydrogen
O
O
OTMS
1) LDA
Pd(OAc)2
O2
2) TMS-Cl, NEt3
6 (100%)
7 (36%)
5
SnBu3
O
9
O
I2, CCl4
NO2
Pyridine
PdCl2(PhCN)2
AsPh3, CuI
I
NO2
4 (80%)
8 (65%)
Scheme 3.

T. L. Scott et al. / Tetrahedron 63 (2007) 1183–1190
1185
Table 1. Synthesis of 1,2,3,4-tetrahydrocarbazoles
Entry
Nitrobenzene
Carbazolea,b
6
4
3
O
5
Me
2
Me
4
N
H
3
1
NO2
1
2
3
4
10 (6-Me)
11 (5-Me)
4 (4-Me)
19 (1-Me, 94%)
20 (2-Me, 93%)
21 (3-Me, 89%)
22 (4-Me, 79%)
12 (3-Me)
O
MeO
MeO
N
H
N
H
NO2
MeO
5
6
7
13
23 (62%)
24 (10%)c
O
CO2Me
CO2Me
MeO2
C
NO2
N
H
N
H
14
25 (28%)
26 (41%)
O
O
N
H
N
OH
NO2
15
H
2 (43%)
3 (22%)
O
O
N
H
NO2
NO2
8
9
16
16
27 (43%)
27 (18%)
28 (0%)
28 (35%)d
O
N
H
NO2
17
10
29 (83%)
O
N
H
NO2
18
11
30 (71%)
a
For experimental details, see Section 4.
Isolated yields in parenthesis.
As an inseparable mixture with 23.
Using 2% palladium.
b
c
d
A number of mechanistic pathways wherein the timing of
the reductive steps differs can be envisioned. Some details
have been obtained in the present study. It is likely that ini-
tially the cyclohexenone double bond is reduced. This is sup-
ported by the following experiment. Reductive annulation of
16 for 20 min produced the expected tetrahydrocarbazole
(27, 18%) and 2-(3-methyl-2-nitrophenyl)-1-cyclohexanone
(28, 36%), the latter derived from reduction of the a,b-
unsaturated ketone (entry 8). This type of by-product was
also observed in one case by Banwell et al.24 When we
reduced the amount of palladium from 20 mol % to
2 mol %, a 95% yield of 28 was obtained. This result sug-
gests an initial reduction of the cycloalkenone to a cycloalka-
none prior to reduction of the nitro group, at least for some
substrates. It should be noted that 28 is transformed to 27
(26% yield) upon reaction with Pd/C–H2 for 2 h.

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T. L. Scott et al. / Tetrahedron 63 (2007) 1183–1190
O
O
Pd/C (20 mol% Pd)
H2 (1 atm)
MeOH, 3 days
N
H
N
H
N
H
2 (39% recovered)
3 (35%)
2
Scheme 4.
O
O
O
Pd/C/H2
NO2
NO2
NH2
-H2O
or
N
H
N
H
N
OH
N
H
Scheme 5.
Submitting indole 23 to the reaction conditions did not
result in reduction to the hexahydroindole 24, even after
prolonged reaction time, indicating that hexahydroindoles
are formed via a different intermediate. Based on the exper-
iments described above, we propose the following series
of events for the reductive annulation of 2-(2-nitrophenyl)-
2-cyclohexene-1-ones. The alkene is initially reduced to
an alkane, which is followed by a reduction of the nitro
group to an amine (Scheme 5). Subsequently an aminal
is formed that eliminates water forming either a (9H)-
1,2,3,4-tetrahydrocarbazole or an isomeric (4aH)-1,2,3,4-
tetrahydrocarbazole (an imine). Further reduction of the
imine would give a hexahydroindole, the product observed
in some cases.
to Me4Si (0.0 ppm, 1H and 13C) or CDCl3 (77.0 ppm, 13C) 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 experiments 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. Tolu-
ene, pyridine, hexanes, acetonitrile, methanol, and ethyl
acetate were distilled from calcium hydride. Chemicals pre-
pared according to literature procedures have been footnoted
first time used; all other reagents were obtained from com-
mercial sources and used as received. All reactions were per-
formed under an argon atmosphere in oven-dried glassware
unless otherwise stated. Solvents were removed from reac-
tion 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.
3. Conclusion
A short synthetic sequence to 1,2,3,4-tetrahydrocarbazoles
and related tricyclic indoles employing a Stille-type cross-
coupling and a palladium-catalyzed reductive annulation
as the key steps has been described. Over-reduction is ob-
served at times affording the corresponding fused indoline.
4. Experimental section
4.1. General procedures
4.1.1. Trimethyl[(4-methyl-1-cyclohexen-1-yl)oxy]silane
(6).16 n-Butyllithium (20 mL of a 2.5 M solution in hexanes,
50.0 mmol) was added dropwise to a ꢀ78 ꢁC cold solution
of diisopropylamine (8.15 mL, 58.2 mmol) in THF (160 mL)
under an argon atmosphere. The reaction mixture was stirred
(10 min) and a solution of 4-methylcyclohexanone (5.01 g,
44.6 mmol) in THF (40 mL) was added slowly to the
NMR spectra were determined in CDCl3 at 270 MHz or
600 MHz (1H NMR) and 67.5 MHz or 150 MHz (13C
NMR). The chemical shifts are expressed in d values relative

T. L. Scott et al. / Tetrahedron 63 (2007) 1183–1190
1187
1
reaction mixture. The reaction was stirred for 30 min, fol-
lowed by slow addition of trimethylsilyl chloride (6.80 mL,
53.6 mmol) and triethylamine (12.5 mL, 89.7 mmol). The
reaction mixture was allowed to warm to room temperature
over 1 h. The mixture was diluted with diethyl ether
(400 mL), washed with water (3ꢂ100 mL), dried (MgSO4),
filtered, and concentrated under reduced pressure. The crude
product was purified by chromatography (hexanes–EtOAc,
9:1) to give 6 (8.23 g, 44.6 mmol, 100%) as a colorless oil.
Spectral data (1H NMR) were in complete accordance with
literature values.33
2960, 2871, 1682, 1525, 1352 cmꢀ1; H NMR (270 MHz)
d 1.26 (d, J¼7.1 Hz, 3H), 1.74–1.91 (m, 1H), 2.14 (m,
1H), 2.46–2.84 (m, 3H), 6.81 (s, 1H), 7.25 (d, J¼5.9 Hz,
1H), 7.47 (t, J¼6.3 Hz, 1H), 7.60 (t, J¼7.9 Hz, 1H), 8.02
(d, J¼8.1 Hz, 1H); 13C NMR (67.5 MHz) d 20.2 (ꢀ), 30.5
(+), 31.6 (ꢀ), 37.0 (+), 124.1 (ꢀ), 128.7 (ꢀ), 131.6 (ꢀ),
131.9 (+), 133.2 (ꢀ), 138.1 (+), 148.5 (+), 152.1 (ꢀ),
196.4 (+).
4.1.5. 5-Methyl-2-(2-nitrophenyl)-2-cyclohexen-1-
one (11). Reaction of 2-iodo-5-methyl-2-cyclohexen-1-
one13 (241 mg, 1.02 mmol), 9 (455 mg, 1.10 mmol),
PdCl2(PhCN)2 (20.6 mg, 0.0537 mmol), AsPh3 (31.6 mg,
0.103 mmol), and CuI (19.1 mg, 0.100 mmol) in NMP
(1 mL), as described for 4 (80 ꢁC, 2 d), gave after chromato-
graphy (hexanes–EtOAc, 9:1) 11 (175 mg, 0.757 mmol,
75%) as a pale yellow solid. Mp 107–109 ꢁC; IR (neat)
4.1.2. 4-Methyl-2-cyclohexen-1-one (7).34 To a solution of
6 (3.14 g, 17.0 mmol) in dimethylsulfoxide (100 mL) was
added palladium diacetate (366 mg, 1.63 mmol). The reac-
tion flask was flushed with O2 for 5 min and the mixture
was stirred at 40 ꢁC under O2 (1 atm, 24 h). The reaction
mixture was allowed to cool, diluted with EtOAc (400 mL),
and washed with water (3ꢂ100 mL). The organic phase was
dried (MgSO4), filtered, and concentrated under reduced
pressure. The crude product was purified by chromatography
(hexanes–EtOAc, 9:1) to give 7 (676 mg, 6.14 mmol, 36%)
as a colorless oil. Spectral data (1H NMR) were in complete
accordance with literature data.35
1672, 1517, 1340 cmꢀ1; H NMR (600 MHz) d 1.13 (d,
1
J¼6.0 Hz, 3H), 2.20 (dd, J¼16.8, 12.6 Hz, 1H), 2.34 (ddd,
J¼18.6, 10.8, 2.4 Hz, 1H), 2.42–2.54 (m, 2H), 2.59
(dd, J¼16.8, 4.2 Hz, 1H), 5.98 (d, J¼2.4 Hz, 1H), 7.30 (dd,
J¼7.2, 1.2 Hz, 1H), 7.56 (dt, J¼8.4, 0.6 Hz, 1H), 7.67 (dt,
J¼7.2, 0.6 Hz, 1H), 8.10 (dd, J¼8.4, 1.2 Hz, 1H); 13C
NMR (150 MHz) d 21. 0 (+), 30.8 (+), 38.9 (ꢀ), 45.5 (ꢀ),
124.9 (+), 127.3 (+), 129.5 (+), 129.7 (+), 133.8 (+), 136.6
(ꢀ), 146.6 (ꢀ), 159.8 (ꢀ), 199.1 (ꢀ). Anal. Calcd for
C13H13NO3: C, 67.52; H, 5.67; N, 6.06. Found: C, 66.65;
H, 6.12; N, 5.67.38 HRMS calcd for C13H14NO3 (M+H+)
232.0974, found 232.0969.
4.1.3. 2-Iodo-4-methyl-2-cyclohexen-1-one (8). A solution
of iodine (2.97 g, 11.7 mmol) in CCl4 (10 mL) and pyridine
(10 mL) was added dropwise to a solution of 7 (628 mg,
5.70 mmol) in CCl4 (10 mL) and pyridine (10 mL) at 0 ꢁC.
The reaction mixture was allowed to warm to ambient tem-
perature overnight. The mixture was diluted with ether
(100 mL) and washed successively with water (40 mL), HCl
(5%-aq, 2ꢂ40 mL), water (40 mL), and Na2S2O3 (20%-aq,
40 mL). The organic phase was dried (MgSO4), filtered,
and the solvents were removed at reduced pressure. The
crude product was purified by chromatography (hexanes–
EtOAc, 9:1) to give 8 (873 mg, 3.70 mmol, 65%) as a
4.1.6. 3-Methyl-2-(2-nitrophenyl)-2-cyclohexen-1-
one (12). Reaction of 2-iodo-3-methyl-2-cyclohexen-1-
one25 (404 mg, 1.71 mmol), 9 (850 mg, 2.06 mmol),
PdCl2(PhCN)2 (32.9 mg, 0.0858 mmol), AsPh3 (52.4 mg,
0.171 mmol), CuI (32.8 mg, 0.172 mmol), in NMP (4 mL)
as described for 4 (80 ꢁC, 20 h), gave after chromatography
(hexanes–EtOAc, 9:1) 12 (309 mg, 1.33 mmol, 78%) as
a pale yellow solid. Mp 75–77 ꢁC; IR (neat) 2943, 2873,
yellow oil. IR (neat) 2958, 2870, 1686, 1585, 1454 cmꢀ1
;
1H NMR (600 MHz) d 1.19 (d, J¼7.2 Hz, 3H), 1.76 (dddd,
J¼13.8, 13.2, 9.0, 3.6 Hz, 1H), 2.17 (ddq, J¼14.4, 4.8,
1.2 Hz, 1H), 2.55 (ddd, J¼16.8, 12.6, 4.8 Hz, 1H), 2.66–
2.71 (m, 1H), 2.77 (dt, J¼16.8, 4.8 Hz, 1H), 7.60 (dd,
J¼3.0, 1.2 Hz, 1H); 13C NMR (150 MHz) d 19.9 (+), 30.8
(ꢀ), 35.7 (+), 35.8 (ꢀ), 103.2 (ꢀ), 164.7 (+), 192.2 (ꢀ).
Anal. Calcd for C7H9IO: C, 35.62; H, 3.84. Found: C,
35.28; H, 4.07.
1663, 1622, 1522, 1356 cmꢀ1; H NMR (600 MHz) d 1.78
1
(s, 3H), 2.03–2.09 (m, 2H), 2.10–2.18 (m, 2H), 2.46–2.59
(m, 2H), 7.17 (dd, J¼7.8, 1.2 Hz, 1H), 7.47 (dt, J¼8.4,
1.8 Hz, 1H), 7.60 (dt, J¼7.8, 1.8 Hz, 1H), 8.07 (dd, J¼8.4,
1.2 Hz, 1H); 13C NMR (150 MHz) d 21.8 (ꢀ), 22.4 (+),
32.3 (ꢀ), 37.5 (ꢀ), 124.4 (+), 128.4 (+), 131.7 (+), 132.5
(+), 133.0 (ꢀ), 135.1 (ꢀ), 148.8 (ꢀ), 156.4 (ꢀ), 196.6
(ꢀ). Anal. Calcd for C13H13NO3: C, 67.52; H, 5.67. Found:
C, 67.33; H, 5.99.
4.1.4. 4-Methyl-2-(2-nitrophenyl)-2-cyclohexen-1-one (4)
and 1-nitro-2-(2-nitrophenyl)benzene. A solution of 2-
iodo-4-methyl-2-cyclohexen-1-one (8) (405 mg, 1.72 mmol),
1-(tributylstannyl)-2-nitrobenzene (9)36 (854 mg, 2.07 mmol),
PdCl2(PhCN)2 (32.9 mg, 0.0858 mmol), AsPh3 (52.6 mg,
0.172 mmol), and CuI (32.7 mg, 0.172 mmol), in NMP
(4 mL) was heated at 80 ꢁC (2 d). The reaction mixture was
diluted with EtOAc (100 mL) and washed successively with
NH4OH (10%-aq, 3ꢂ30 mL) and H2O (2ꢂ30 mL). The
aqueous portions were combined and extracted with EtOAc
(50 mL). The combined organic phases were dried (MgSO4),
filtered, and concentrated at reduced pressure. The crude
product was purified by chromatography (hexanes–EtOAc,
9:1) to give an 11:1 mixture of 4 and 1-nitro-2-(2-nitrophe-
nyl)benzene (318 mg) as a faint yellow oil.37 Data from the
mixture of 4 and 1-nitro-2-(2-nitrophenyl)benzene: IR (neat)
4.1.7. 1,2,3,4-Tetrahydrocarbazole (3).39 Hydrogen gas
was bubbled through a mixture of 2-(2-nitrophenyl)-2-
cyclohexen-1-one (1)13 (54 mg, 0.25 mmol) and Pd/C (10%-
Pd, 51 mg, 0.048 mmol) in MeOH (10 mL) for 5 min. The
reaction was stirred under H2 (1 atm, ambient temperature,
2 h). The mixture was filtered through Celite, the solvent
was removed under reduced pressure, and the resulting crude
product was purified by chromatography (hexanes–EtOAc,
8:2) to give 3 (41 mg, 0.24 mmol, 96%) as a white solid.
Mp 116–118 ꢁC (Aldrich Chem. Co. 118–120 ꢁC).
Reaction of 2-(2-nitrophenyl)-1,3-cyclohexanedione (15)40
(53 mg, 0.23 mmol) and Pd/C (10%, 52 mg, 0.049 mmol)
in MeOH (10 mL), as described above (1 atm H2,
ambient temperature, 2 h), gave after chromatography

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T. L. Scott et al. / Tetrahedron 63 (2007) 1183–1190
(hexanes–EtOAc, 8:2 followed by 1:1) in order of elution 3
(8.5 mg, 0.049 mmol, 22%) and 213 (19 mg, 0.10 mmol,
43%).
6.27 (br s), 3.75 (s), 3.75–3.69 (m), 3.04 (q, J¼6.0 Hz),
1.74–1.30 (m); 13C NMR (150 MHz) d 159.6, 152.0,
126.1, 123.3, 103.3, 97.2, 60.0, 55.3, 40.1, 29.3, 27.2,
22.4, 21.6; lit.44 1H NMR (300 MHz) d 6.90 (d, J¼8.0 Hz,
1H), 6.30–6.15 (m, 2H), 3.70 (s, 3H), 3.76–3.56 (m, 1H),
3.36 (br s, 1H), 2.98 (dd, J¼13.0, 12.0 Hz, 1H), 1.87–1.20
(m, 8H).
Reaction of 5 (18 mg, 0.10 mmol) and Pd/C (10%, 19 mg,
0.018 mmol) in MeOH (5 mL), as described above (1 atm
H2, ambient temperature, 3 d), gave after chromatography
(hexanes–EtOAc, 19:1 followed by 1:1) in order of elution
3 (6.0 mg, 0.035 mmol, 35%) and 5 (7.3 mg, 0.039 mmol,
39%).
4.1.13. Methyl 2,3,4,9-tetrahydro-1H-carbazole-5-car-
boxylate (25)45 and methyl 2,3,4,4a,9,9a-hexahydro-1H-
carbazole-5-carboxylate (26). Reaction of 2-(6-carbo-
methoxy-2-nitrophenyl)-2-cyclohexen-1-one (14)13 (50.8
mg, 0.18 mmol) and Pd/C (10%, 54.9 mg, 0.052 mmol) in
MeOH (10 mL), as described for 3 (2 h), gave after chroma-
tography (hexanes–EtOAc, 19:1) in order of elution 26
(16.8 mg, 0.073 mmol, 41%) and 25 (10.7 mg, 0.05 mmol,
28%) as white solids.46 Spectral data for 25: IR: 3414,
4.1.8. 1-Methyl-1,2,3,4-tetrahydrocarbazole (19).41
Reaction of 6-methyl-2-(2-nitrophenyl)-2-cyclohexen-1-
one (10)13 (37 mg, 0.16 mmol), and Pd/C (10%, 37 mg,
0.035 mmol) in MeOH (10 mL), as described for 3 (2 h),
gave after chromatography (hexanes–EtOAc, 19:1) 19
(27 mg, 0.15 mmol, 94%) as a white solid. Mp 56–62 ꢁC
(lit.41 mp 63–65 ꢁC).
1
2930, 1692, 1644 cmꢀ1; H NMR (270 MHz) d 1.77–1.93
(m, 4H), 2.75 (t, J¼5.9 Hz, 2H), 2.88 (t, J¼5.7 Hz, 2H),
3.94 (s, 3H), 7.11 (t, J¼7.7 Hz, 1H), 7.43 (dd, J¼8.1,
1.7 Hz, 1H), 7.64 (dd, J¼7.4, 1.7 Hz, 1H), 7.93 (s, 1H).
Partial spectral data for 26: 1H NMR (270 MHz) d 1.58–1.77
(m, 4H), 1.89–2.06 (m, 2H), 3.51 (p, J¼6.2 Hz, 1H), 3.80–
3.87 (m, 2H), 3.88 (s, 3H), 6.84 (d, J¼7.9 Hz, 1H), 7.07 (t,
J¼7.9 Hz, 1H), 7.36 (d, J¼7.9 Hz, 1H).
4.1.9. 2-Methyl-1,2,3,4-tetrahydrocarbazole (20).28
Reaction of 5-methyl-2-(2-nitrophenyl)-2-cyclohexen-1-one
(11)13 (100 mg, 0.43 mmol) and Pd/C (10%, 100 mg,
0.094 mmol) in MeOH (10 mL), as described for 3 (2 h),
gave after chromatography (hexanes–EtOAc–Et3N, 490:10:
1) 20 (74 mg, 0.40 mmol, 93%) as a white solid. Mp
98.5–99.5 ꢁC (lit.42 mp 98–100 ꢁC).
4.1.10. 3-Methyl-1,2,3,4-tetrahydrocarbazole (21).27 Re-
action of 4 (150 mg, 0.65 mmol) and Pd/C (10%, 175 mg,
0.16 mmol) in MeOH (10 mL), as described for 3
(30 min), gave after chromatography (hexanes–EtOAc–
Et3N, 490:10:1) 21 (107 mg, 0.58 mmol, 89%) as a white
solid. Mp 109–110 ꢁC (lit.27 108–111 ꢁC).
4.1.14. 8-Methyl-1,2,3,4-tetrahydrocarbazole (27).47 Re-
action of 2-(3-methyl-2-nitrophenyl)-2-cyclohexen-1-one
(16)13 (24.5 mg, 0.106 mmol) and Pd/C (10%, 22.1 mg,
0.0208 mmol) in MeOH (5 mL), as described for 3 (2 h),
gave after chromatography (hexanes–EtOAc–Et3N, 95:5:1)
27 (9.1 mg, 0.049 mmol, 46%) as a white solid. Mp 85–
88 ꢁC (lit.48 92–94.5 ꢁC).
4.1.11. 4-Methyl-1,2,3,4-tetrahydrocarbazole (22). Reac-
tion of 12 (155 mg, 0.67 mmol) and Pd/C (10%, 151 mg,
0.14 mmol) in MeOH (10 mL), as described for 3
(30 min), gave after chromatography (hexanes–EtOAc–
Et3N, 490:10:1) 22 (98 mg, 0.53 mmol, 79%) as an unstable
solid.43 1H NMR (270 MHz) d 7.55 (d, J¼6.3 Hz, 1H), 7.49
(br s, 1H), 7.21–7.16 (m, 1H), 7.11–7.04 (m, 2H), 3.13–3.04
(m, 1H), 2.61 (apparent t, J¼5.3 Hz, 2H), 2.03–1.88 (m,
2H), 1.83–1.72 (m, 1H), 1.59–1.50 (m, 1H), 1.34 (d,
J¼6.9 Hz, 3H); lit.16 d 7.64 (br s, 1H), 7.57 (d, J¼7.5 Hz,
1H), 7.28 (d, J¼7.5 Hz, 1H), 7.11–7.06 (m, 2H), 3.13–
3.11 (m, 1H), 2.69–2.70 (m, 2H), 2.00–1.95 (m, 2H),
1.83–1.79 (m, 1H), 1.59–1.55 (m, 1H), 1.37 (d, J¼7.0 Hz,
3H).
Alternative method. Reaction of 2-(3-methyl-2-nitro-
phenyl)-cyclohexan-1-one (28, see below) (45.1 mg,
0.193 mmol) and Pd/C (10%, 41.7 mg, 0.0391 mmol) in
MeOH (10 mL), as described for 3 (2 h), gave after chroma-
tography (hexanes–EtOAc, 7:3) 27 (9.3 mg, 0.050 mmol,
26%) as a white solid.
4.1.15. 8-Methyl-1,2,3,4-tetrahydrocarbazole (27) and 2-
(3-methyl-2-nitrophenyl)-1-cyclohexanone (28). Reaction
of 16 (90.7 mg, 0.39 mmol) and Pd/C (10%, 90.5 mg,
0.085 mmol) in MeOH (10 mL), as described for 3
(20 min), gave after chromatography (hexanes–EtOAc–
Et3N, 490:10:1) in order of elution 27 (12.7 mg,
0.07 mmol, 18%) as a white solid and 28 (31.9 mg,
0.14 mmol, 36%) as a white solid. Analytical data for 28:
4.1.12. 7-Methoxy-1,2,3,4-tetrahydrocarbazole (23)24
and 7-methoxy-1,2,3,4,4a,9a-hexahydrocarbazole (24).44
Reaction of 2-(4-methoxy-2-nitrophenyl)-2-cyclohexen-1-
one (13)13 (105 mg, 0.42 mmol) and Pd/C (10%, 104 mg,
0.098 mmol) in MeOH (10 mL), as described for 3
(20 min), gave after chromatography (hexanes–EtOAc–
Et3N, 490:10:1) an inseparable mixture of 23 (52.5 mg,
0.26 mmol, 62%) and 24 (7.9 mg, 0.04 mmol, 10%). The
mp 113–114 ꢁC; IR (neat) 2934, 1707, 1516, 1370 cmꢀ1
;
1H NMR (600 MHz) d 1.74–1.86 (m, 2H), 1.94–2.05 (m,
2H), 2.15–2.22 (m, 1H), 2.33 (overlapping s and m, 4H),
2.41–2.49 (m, 1H), 2.51–2.57 (m, 1H), 3.64 (dd, J¼12.6,
4.8 Hz, 1H), 7.16 (d, J¼7.8 Hz, 1H), 7.21 (d, J¼7.8 Hz,
1H), 7.38 (t, J¼7.8 Hz, 1H); 13C NMR (150 MHz) d 17.8
(ꢀ), 25.5 (+), 27.7 (+), 35.3 (+), 42.2 (+), 52.6 (ꢀ), 127.5
(ꢀ), 129.7 (ꢀ), 130.0 (ꢀ), 130.0 (+), 130.9 (+), 151.5 (+),
207.8 (+). Anal. Calcd for C13H15NO3: C, 66.94; H, 6.48;
N, 6.00. Found: C, 67.34; H, 6.79; N, 5.73.
1
yields were estimated from the H NMR spectrum of the
mixture. Spectral data (1H and 13C NMR) of 2324 were in
complete agreement with literature values. Compound 24
was identified based on the following comparison with liter-
ature data from the mixture of compounds. 1H NMR
(600 MHz) d 6.95 (d, J¼9.0 Hz), 6.28 (dd, J¼7.8, 2.4 Hz),
4.1.16. 2-(3-Methyl-2-nitrophenyl)-1-cyclohexanone
(28). Reaction of 16 (141 mg, 0.61 mmol) and Pd/C (10%,

T. L. Scott et al. / Tetrahedron 63 (2007) 1183–1190
1189
14. Scott, T. L.; Yu, X.; Gorugantula, S. P.; Carrero-Martinez, G.;
€
13.4 mg, 0.013 mmol) in MeOH (10 mL), as described
above (80 min) gave 28 (136 mg, 0.58 mmol, 95%).
Soderberg, B. C. G. Tetrahedron 2006, 62, 10835–10842.
€
15. For initial communication, see: Soderberg, B. C.; Scott, T. L.
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16. Iwama, T.; Birman, V. B.; Kozmin, S. A.; Rawal, V. H. Org.
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17. Kozmin, S. A.; Iwama, T.; Rawal, V. H. J. Am. Chem. Soc.
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19. Ohshima, T.; Xu, Y.; Takita, R.; Shimizu, S.; Zhong, D.;
Shibasaki, M. J. Am. Chem. Soc. 2002, 124, 14546–14547.
20. Sole, D.; Bonjoch, J.; Garcia-Rubio, S.; Peidro, E.; Bosch, J.
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4.1.17. 1,2,3,3a,4,8b-Hexahydrocyclopent[b]indole
(29).29,49 Reaction of 2-(2-nitrophenyl)-2-cyclopenten-1-
one (17)13 (117 mg, 0.58 mmol) and Pd/C (10%, 115 mg,
0.11 mmol) in MeOH (10 mL), as described for 3 (20 min),
gave after solvent removal 29 (76.1 mg, 0.48 mmol, 83%) as
a colorless oil.50 1H NMR (600 MHz) d 7.02 (d, J¼7.3 Hz,
1H), 6.97 (t, J¼7.5 Hz, 1H), 6.66 (dt, J¼7.3, 1.0 Hz, 1H),
6.51 (d, J¼7.3 Hz, 1H), 4.34 (ddd, J¼8.5, 5.7, and 2.6 Hz,
1H), 3.76 (dt, J¼8.7 and 2.6 Hz, 1H), 3.68 (br s, 1H),
2.02–1.44 (m, 6H); 13C NMR (150 MHz) d 151.3, 133.2,
127.2, 124.4, 118.1, 108.3, 63.3, 47.1, 36.8, 34.8, 24.3.
4.1.18. 5,6,7,8,9,10-Hexahydrocyclohept[b]indole (30).24
Reaction of 2-(2-nitrophenyl)-2-cyclohepten-1-one (18)13
(66 mg, 0.28 mmol) and Pd/C (10%, 66 mg, 0.06 mmol) in
MeOH (10 mL), as described for 3 (2.5 h), gave after chro-
matography (hexanes–EtOAc, 95:5) 30 (38 mg, 0.20 mmol,
71%) as a white solid. Mp 134–136 ꢁC (lit.24 135–138 ꢁC).
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Acknowledgements
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 Spectrometer and an LTQ-FT Mass Spectrometer
and the NMR and MS facilities in the C. Eugene Bennett
Department of Chemistry at West Virginia University.
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