Palladium-catalyzed syntheses of tetrahydrocarbazolones as advanced intermediates to carbazole alkaloids

Article abstract of DOI:10.1016/j.tet.2006.08.100

Two sequential palladium-catalyzed reactions, an intermolecular Stille cross-coupling followed by a recently developed palladium-catalyzed reductive N-heteroannulation, have been employed as the key synthetic steps toward six tetrahydrocarbazolones. The p

Full text of DOI:10.1016/j.tet.2006.08.100

Tetrahedron 62 (2006) 10835–10842
Palladium-catalyzed syntheses of tetrahydrocarbazolones
as advanced intermediates to carbazole alkaloids
´
Tricia L. Scott, Xiaomei Yu, Sobha P. Gorugantula, Grissell Carrero-Martınez
*
€
and Bjorn C. G. Soderberg
€
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, WV 26506-6045, USA
Received 6 July 2006; revised 16 August 2006; accepted 29 August 2006
Available online 25 September 2006
Abstract—Two sequential palladium-catalyzed reactions, an intermolecular Stille cross-coupling followed by a recently developed
palladium-catalyzed reductive N-heteroannulation, have been employed as the key synthetic steps toward six tetrahydrocarbazolones. The
products are advanced intermediates toward a number of naturally occurring carbazole alkaloids.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Fischer indole synthesis works reasonably well for 2- and
4-substituted arylhydrazones. However, the reaction usually
affords regioisomeric cyclization products from the
3-substituted analogs,21,22 and the reaction fails completely
in some more substituted cases.12 Herein is reported a new
synthesis of tetrahydrocarbazolone compounds used as
advanced intermediates in the synthesis of a significant
number of functionalized oxygenated carbazoles.
Carbazole alkaloids are of significant synthetic interest due
to their range of biological activities. For example, these nat-
ural products show antitumor, antibiotic, antimalarial, and
antifungal properties.1 Several carbazole alkaloids have
been isolated from plants belonging to the Rutaceae family.2
Many of these compounds have a one-carbon substituent in
the 3-position and an oxygenated functionality in the 1- or
2-position. Dimeric- and quinoid-structures are also known
in this group.2 We have been interested in a number of these
natural products, many of which are from plants of the genus
Murraya. These plants consist of small trees and shrubs
endemic to Southern Asia that have been used for years in
folk medicine for analgesics and treatment of ailments
such as eczema and rheumatism.3
2. Result and discussion
We have recently described a novel route to tetrahydrocarba-
zolones using two consecutive palladium-catalyzed re-
actions, a Stille-type cross-coupling and a reductive
N-heteroannulation.23 This sequence was used in a formal
synthesis of murrayaquinone A as outlined in Scheme 1.
Tetrahydrocarbazolones have been used extensively as
advanced intermediates in synthetic efforts toward a number
of naturally occurring carbazole alkaloids including,
murrayaquinone A,4–6 murrayanine,7 koenigine-quinones
A and B,8 clausenalene,9 glycoborine,10 (+)-aspidospermi-
dine,11 clausenamine,12 clausenol and clausenine,13 clause-
nal,14 dimeric murrayafoline A,15 pyrrayaquinones A and
B,6 murrayafoline B and murrayaquinone B,16 hepazoli-
dine,17 glycozolinol,18 (ꢀ)-gilbertine,19 and glycozoline.20
The tetrahydrocarbazolones are usually prepared by a
Japp–Klingemann condensation of diazonium salts with
2-(hydroxymethylene)-1-cyclohexanones followed by a
Fischer indole synthesis of the formed hydrazones. The
While working on the synthesis of murrayaquinone A, we
initialized an alternative route to this compound via carbazo-
lone 4 (Scheme 2). The conditions developed by Piers and
Nagakura24 to prepare 3-iodo-a,b-unsaturated ketones
were used to synthesize 3-iodo-5-methyl-2-cyclohexen-
1-one (1) from 5-methyl-1,3-cyclohexanedione. Stille-type
cross-coupling of 3-iodocyclohexenone 1 and 2-nitrophenyl
tributylstannane (2) using bis(benzonitrile)palladium
dichloride, triphenylarsine, and copper iodide in N-methyl-
pyrrolidinone, produced the expected product 3 in excellent
yield. Palladium-catalyzed reductive N-heteroannulation of
3 gave uneventfully the expected carbazolone 4. Carbazo-
lone 4 is an advanced intermediate in reported syntheses of
four different carbazole alkaloids, murrayaquinone A,6 mur-
rayafoline A,6,7 murrayanine,7,25 and dimeric O-demethyl-
murrayafoline A.26
Keywords: Carbazoles; Palladium-catalyzed; Alkaloids.
* Corresponding author. Tel.: +1 3042933435; fax: +1 3042934904; e-mail:
bjorn.soderberg@mail.wvu.edu
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.08.100

10836
T. L. Scott et al. / Tetrahedron 62 (2006) 10835–10842
O
Pd(dba)2, dppp
1,10-phenanthroline
O
SnBu3
NO2
I
PdCl2(PhCN)2
+
CO (6 atm), DMF
97%
AsPh3, CuI
NMP, 87%
NO2
O
O
1) Pd/C, Ph2O, 230 °C
1,2,4-trimethylbenzene, 63%
2) Fremy's salt, 83%
N
H
N
H
O
Murrayaquinone-A
Scheme 1.
O
I
SnBu3
PPh3, I2
MeCN, Et3N
PdCl2(PhCN)2, AsPh3
CuI, NMP
+
NO2
O
O
1 (90%)
2
Pd(dba)2, dppp
1,10-Phenanthroline
CO (6 atm), DMF
N
H
NO2
3 (89%)
O
O
4 (76%)
Scheme 2.
Carbazolone 9 is a key intermediate in Desmaele and
d’Angelo’s synthesis of (+)-aspidospermidine (Scheme
3).11 The synthesis of this intermediate was realized in 35%
overall yield starting from cyclohexenone 6. It was antici-
pated that we could improve upon the synthesis of carbazo-
lone 9 using our methodology. Cyclohexenone 6 was
prepared by Desmaele and d’Angelo by a DDQ oxidation
of the trimethylsilylenol ether 5. In our hands, despite several
attempts, the procedure reported in the literature completely
failed to produce 6. However, a palladium-catalyzed Saegusa
oxidation27 of 5 furnished 6 in 57% yield. Iodide 7, prepared
by treatment of 6 with iodine and pyridine in tetrachloro-
methane,28 was coupled with 2 to afford 8 in good yield.
The palladium-catalyzed N-heteroannulation of 8 proceeded
smoothly to give carbazolone 9 in 75% yield. In comparison
with the previous route to this intermediate, carbazolone 9
was obtained in a 52% overall yield starting from 6.
intermediate toward the naturally occurring alkaloids
clausenol and clausenine,13 clausenamine A,12 and glycozo-
line.29 In the event, Stille-type cross-coupling of tributyl(5-
methoxy-2-nitrophenyl)stannane 10 with vinyl iodide 1 gave
the expected product 11 (Scheme 4). Palladium-catalyzed
annulation of 11 furnished the expected carbazolone 12.
For the carbazolones 4 and 12 discussed above, the regio-
selectivity of the reported Fischer indole syntheses leading
to the carbazolones does not pose a problem since only one
isomer can be formed. In contrast, reactions of 3-substituted
arylhydrazones frequently afford two regioisomeric prod-
ucts. For example, reaction of 13 has been described three
times in the literature by the same authors. In each case, 13
was treated with a mixture of acetic and hydrochloric acid
(at reflux) to afford 14 and 15 (Scheme 5). A detailed exper-
imental procedure was not found in either of the papers. The
yield of the isomers was not reported in the first paper,30 and
in the second paper the yield of 15 was reported to be 50%.21
In the third paper, compound 14 was isolated in 65.5% yield
The third example, 6-methoxy-3-methyl-2,3,4,9-tetrahydro-
1H-carbazol-1-one (12), has been used as an advanced
OTMS
O
O
CO2Me
I
CO2Me
CO2Me
Pd(OAc)2, O2
DMSO
PPh3, I2
CCl4, pyr
5
6 (57%)
7 (86%)
O
CO2Me
CO2Me
O
Pd(dba)2, dppp
2, PdCl2(PhCN)2
AsPh3, CuI, NMP
1,10-Phenanthroline
CO (6 atm), DMF
N
H
NO2
8 (79%)
9 (75%)
Scheme 3.

T. L. Scott et al. / Tetrahedron 62 (2006) 10835–10842
10837
MeO
MeO
SnBu3
NO2
MeO
1, PdCl2(PhCN)2
AsPh3, CuI, NMP
Pd(dba)2, dppp
1,10-Phenanthroline
CO (6 atm), DMF
N
H
O
NO2
11 (76%)
O
10
12 (78%)
Scheme 4.
OMe
X
HOAc
HCl
N
N
+
Me
O
MeO
N
H
N
H
H
X
X
13 (X=O)
16 (X=H2)
14 (X=O, 50%)
17 (X=H2, 54%)
15 (X=O, 7%)
18 (X=H2, 6%)
Scheme 5.
using identical reaction conditions and times with no men-
tioning of 15.8 We decided to repeat the reaction but were
unable to obtain 15 as the major product using the reaction
conditions described. In our hands an approximately 7:1 mix-
ture of 14 and 15 was obtained in 57% yield. A similar result
was reported by Chakravarty et al. from a Fischer indole
synthesis of the corresponding 4-methylcyclohexane hydra-
zone derivative 16 in place of 13.10 In this case, a 9:1 mixture
(60% yield) of the 3-methyl-7-methoxy- and 3-methyl-
5-methoxy-tetrahydrocarbazoles 17 and 18 was obtained,
respectively. Wolff–Kishner–Huang–Minlon reduction21 of
Stille-type cross-coupling of 19 with 1 under standard
reaction conditions produced 20 in excellent yield. The
reductive cyclization of 20 also proceeded smoothly afford-
ing the carbazolone 14.
5-Methoxy-3-methyl-3,4-dihydrocarbazol-1(2H)-one (15)
has previously been used as an intermediate in a synthesis
of 5-methoxy-3-methylcarbazole; a structure initially named
glycozolicine.21 However, the structure of glycozolicine was
later shown not to be 5-methoxy-3-methylcarbazole based
on extensive NMR data and synthesis.10 A second com-
pound, glycoborine was identified as 5-methoxy-3-methyl-
carbazole. It should be noted that the true structure of the
glycozolicine is still unknown.
1
14 gave the expected compound 17, having identical H
NMR chemical shifts compared to reported data.10
In contrast to the Fischer indole synthesis, the palladium-
catalyzed N-heteroannulation is inherently regiospecific
and both 14 and 15 can be obtained in good overall yield.
7-Methoxy-3-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one
(14), has been used as an advanced intermediate toward the
naturally occurring alkaloids koenigenine-quinone A,8 mur-
rayafoline B and murrayaquinone B,16 and pyrrayaquinones
A and B.6 The formal synthesis of these compounds using
the palladium-catalyzed methodology was carried out in
the same manner as described above for murrayaquinone
A. Organostannane 1931 was first prepared starting from
commercially available 1-iodo-4-methoxy-2-nitrobenzene
and hexabutylditin using Kosugi’s procedure (Scheme 6).32
For the synthesis of 15, a novel tin coupling partner was
required. Initially, hexabutylditin was used to prepare
6-methoxy-2-nitrophenyl tributylstannane from 1-iodo-
2-methoxy-6-nitrobenzene. However, the reaction was
sluggish and a complex mixture of products was obtained.
Turning to hexamethylditin solved this problem and 21 was
obtained in 49% yield. The ensuing Stille coupling, afford-
ing 22, and annulation proceeded uneventfully to give carba-
zolone 15. The significant lower yield of products 21 and 22
compared to the previous examples is probably a reflection
of the hindered nature of the substrates. The annulation, in
contrast, gave a quantitative yield of product (Scheme 7).
SnBu3
I
PdCl2(PPh3)2, PPh3
1, PdCl2(PhCN)2
MeO
Sn2Bu6, Toluene
AsPh3, CuI, NMP
NO2
MeO
MeO
NO2
NO2
O
20 (97%)
19 (77%)
Pd(dba) , dppp
2
MeO
1,10-Phenanthroline
CO (6 atm), DMF
N
H
O
14 (89%)
Scheme 6.

10838
T. L. Scott et al. / Tetrahedron 62 (2006) 10835–10842
OMe
OMe
OMe
SnMe3
I
1, PdCl (PhCN)
Pd(dba) , PPh
2
2
2
3
AsPh , CuI, NMP
3
Sn Me , Toluene
NO2
2
6
NO2
NO
O
2
21 (49%)
22 (71%)
OMe
Pd(dba)2, dppp
1,10-Phenanthroline
CO (6 atm), DMF
N
H
O
15 (quantitative)
Scheme 7.
O
O
SnMe3
NO2
O
O
1, PdCl2(PhCN)2
Pd(dba)2, dppp
AsPh3, CuI, NMP
1,10-Phenanthroline
CO (6 atm), DMF
NO2
O
23
24 (91%)
O
O
O
O
N
H
N
H
O
25 (quantitative)
Clausenalene
Scheme 8.
1
As a final example, a synthesis of the antibacterial carbazole
clausenalene, isolated from the stem bark of Clausena
heptaphylla was pursued.9 Clausenalene is the first reported
methylenedioxy carbazole alkaloid isolated from a plant
source. The known arylstannane 23 was coupled with 1 to
give 24 (Scheme 8). Reductive N-heteroannulation of 24
gave tetrahydrocarbazolone 25, which has been previously
used to prepare clausenalene via a Wolff–Kishner reduction
and aromatization.
internal standards. H–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 parenthe-
ses where, relative to CDCl3, (ꢀ) denotes CH3 or CH and (+)
denotes CH2 or C.
Toluene, pyridine, hexanes, acetonitrile, and ethyl acetate
were distilled from calcium hydride. Chemicals prepared ac-
cording to literature procedures have been footnoted first
time used; all other reagents were obtained from commercial
sources and used as received. All reactions were performed
under an argon or nitrogen atmosphere in oven-dried glass-
ware unless otherwise stated. Solvents were removed from
reaction mixtures and products on a rotary evaporator at
water aspirator pressure or by bulb-to-bulb distillation under
reduced pressure. Chromatography was performed on silica
gel 60 (35–75 mm, VWR). Melting points were determined
on a MelTemp and are uncorrected. High resolution mass
spectra (HRMS) were performed at University of California,
Riverside Mass Spectrometry Center. Elemental analyses
were performed in the Department of Chemical Engineer-
ing, College of Engineering and Mineral Resources, West
Virginia University.
3. Conclusion
In conclusion, we have successfully applied a sequential
Stille-type cross-coupling reaction followed by a palla-
dium-catalyzed reductive N-heteroannulation to the synthe-
sis of six tetrahydrocarbazolones. The products are late
intermediates in the synthesis of a number of naturally
occurring carbazole alkaloids.
4. Experimental
4.1. General procedures
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
4.1.1. 3-Iodo-5-methyl-2-cyclohexen-1-one (1). To a solu-
tion of triphenylphosphine (4.75 g, 18.1 mmol) in aceto-
nitrile (80 mL) was added iodine (4.53 g, 17.8 mmol). The
reaction mixture was stirred for 2 h. Triethylamine (2.60 mL,
1
to Me4Si (0.0 ppm, H and 13C) or CDCl3 (77.0 ppm, 13C)

T. L. Scott et al. / Tetrahedron 62 (2006) 10835–10842
10839
18.5 mmol) was added slowly, followed by 5-methyl-1,3-
cyclohexanedione (2.04 g, 16.2 mmol). The reaction mixture
was stirred for 14 d at ambient temperature. The solvent was
evaporated and the crude product was purified by chromato-
graphy (hexanes/EtOAc, 95:5) to give 1 (3.44 g, 14.6 mmol,
was extracted with hexanes (3ꢂ50 mL). The organic phases
were combined, dried (MgSO4), filtered, and the solvents
were removed by bulb-to-bulb distillation under reduced
pressure. To a portion of the crude silylenol ether 5 (1.94 g,
6.82 mmol) in DMSO (50 mL) was added Pd(OAc)2
(159 mg, 0.708 mmol). The flask containing the reaction mix-
ture was flushed with oxygen and was kept under oxygen
(1 atm, balloon) while being heated at 40 ꢁC (72 h). Addi-
tional Pd(OAc)2 (95.6 mg, 0.426 mmol) was added to the
reaction mixture and the reaction was heated at 60 ꢁC
(24 h). The reaction mixturewas cooled and diluted with ethyl
acetate (200 mL). The mixture was washed with water
(3ꢂ50 mL), dried (MgSO4), filtered, and concentrated under
reduced pressure. The crude product was purified by chro-
matography (hexanes/EtOAc, 7:3) to give 6 (820 mg,
3.90 mmol, 57%) as a colorless oil. Spectral data (1H NMR)
are in complete accordance with the literature values.11
90%) as a faint yellow oil. IR (neat): 2956, 1676, 1592 cmꢀ1
;
1H NMR (270 MHz): d 1.07 (dd, J¼6.5, 1.8 Hz, 3H), 2.10
(ddd, J¼12.1, 11.7, 3.6 Hz, 1H), 2.24–2.40 (m, 1H), 2.46–
2.65 (m, 2H), 2.95–3.06 (m, 1H), 6.77–6.82 (m, 1H);
13C NMR (67.5 MHz): d 19.9 (ꢀ), 30.9 (+), 44.0 (ꢀ), 47.6
(ꢀ), 125.7 (+), 139.4 (ꢀ), 194.3 (+); HRMS (EI) calcd
for C7H9IO (M+): 235.9698, found: 235.9696; Anal. Calcd
for C7H9IO: C, 35.62; H, 3.84. Found: C, 35.65; H, 4.01.
4.1.2. 3-(2-Nitrophenyl)-5-methyl-2-cyclohexen-1-one
(3). A solution of 1 (1.00 g, 4.24 mmol), tributyl(2-nitro-
phenyl)stannane (2)32 (2.10 g, 5.10 mmol), PdCl2(PhCN)2
(81 mg, 0.21 mmol), AsPh3 (130 mg, 0.42 mmol), and CuI
(81 mg, 0.42 mmol) in N-methylpyrrolidinone (NMP)
(8.4 mL) was heated at 80 ꢁC for 48 h. The reaction was
diluted with benzene (100 mL) and washed with NH4OH
(10%, aq, 3ꢂ30 mL) and H2O (2ꢂ30 mL). The organic
phase was dried (MgSO4), filtered, and the solvents were
removed by bulb-to-bulb distillation under reduced pressure.
The crude product was purified by chromatography
(hexanes) to give 3 (873 mg, 3.78 mmol, 89%) as a pale
yellow solid. Mp 62–64.5 ꢁC; IR (neat): 2956, 1669, 1525,
4.1.5. Methyl (S)-1-ethyl-2-oxo-3-iodo-3-cyclohexenone-
1-propanoate (7). To a solution of 6 (508 mg, 2.42 mmol)
in 10 mL of 1:1 CCl4/pyridine cooled to 0 ꢁC was added
drop wise a solution of iodine (1.26 g, 4.96 mmol) dissolved
in 10 mL of 1:1 CCl4/pyridine with stirring. The reaction
mixture was allowed to warm to ambient temperature over-
night. The reaction 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 concen-
trated under reduced pressure. The crude product was puri-
fied by chromatography (hexanes/EtOAc, 8:2) to give 7
(698 mg, 2.08 mmol, 86%) as a pale yellow oil. IR (neat):
1346 cmꢀ1
;
1H NMR (600 MHz): d 1.13 (d, J¼6.6 Hz,
3H), 2.20 (dd, J¼16.2, 12.6 Hz, 1H), 2.34 (ddd, J¼18.6,
11.4, 2.4 Hz, 1H), 2.44–2.54 (overlapping s and m, 2H),
2.59 (dd, J¼16.8, 4.2 Hz, 1H), 5.98 (d, J¼2.4 Hz, 1H),
7.30 (dd, J¼7.8, 1.2 Hz, 1H), 7.55 (dt, J¼8.4, 1.8 Hz, 1H),
7.67 (dt, J¼7.2, 1.2 Hz, 1H), 8.10 (dd, J¼8.1, 1.2 Hz, 1H);
13C NMR (150 MHz): d 21.0 (+), 30.8 (+), 38.8 (ꢀ), 45.5
(ꢀ), 124.9 (+), 127.2 (+), 129.5 (+), 129.7 (+), 133.8 (+),
136.5 (ꢀ), 146.6 (-), 159.8 (ꢀ), 199.1 (ꢀ); HRMS (DEI)
calcd for C13H13NO3 (MH+): 232.0974, found: 232.0974;
Anal. Calcd for C13H13NO3: C, 67.52; H, 5.67; N, 6.06.
Found: C, 68.13; H, 6.01; N, 5.79.
3450, 2944, 1732, 1679 cmꢀ1
;
1H NMR (270 MHz):
d 0.83 (t, J¼7.5 Hz, 3H), 1.49–1.71 (m, 2H), 1.80–2.01
(m, 4H), 2.11–2.36 (m, 2H), 2.43–2.50 (m, 2H), 7.64
(t, J¼4.1 Hz, 1H); 13C NMR (67.5 MHz): d 7.9 (ꢀ), 26.8
(+), 28.5 (+), 28.5 (+), 30.0 (+), 47.7 (+), 51.4 (ꢀ), 103.4
(+), 157.3 (ꢀ), 173.5 (+), 195.3 (+); HRMS (DEI) calcd
for C12H17IO3 (MH+): 336.0222, found: 336.0210; Anal.
Calcd for C13H13NO3: C, 42.87; H, 5.10. Found: C, 42.87;
H, 5.38.
4.1.3. 2,3,4,9-Tetrahydro-3-methyl-1H-carbazol-1-one
(4).15 5-Methyl-3-(2-nitrophenyl)-2-cyclohexenone (3)
(133 mg, 0.575 mmol), Pd(dba)2 (19.9 mg, 0.0346 mmol),
dppp (14.3 mg, 0.0347 mmol), 1,10-phenanthroline mono-
hydrate (13.7 mg, 0.0691 mmol), and DMF (6 mL) were
placed into a pressure tube fitted with a pressure head. The
tube was flushed three times with CO and the reaction was
heated and stirred at 80 ꢁC under CO (6 atm, 72 h). The
reaction mixture was filtered through Celite and the solvent
was removed by bulb-to-bulb distillation under reduced
pressure. The crude product was purified by chromatography
(hexanes/EtOAc, 7:3) to give 4 (88 mg, 0.44 mmol, 77%) as
a white powder. Mp 193–195 ꢁC (lit.32 197 ꢁC).
4.1.6. Methyl (S)-1-ethyl-2-oxo-3-(2-nitrophenyl)-3-
cyclohexenone-1-propanoate (8). Reaction of 7 (250 mg,
0.744 mmol), tributyl(2-nitrophenyl)stannane (2) (369 mg,
0.895 mmol), PdCl2(PhCN)2 (14.9 mg, 0.0388 mmol),
AsPh3
(23.1 mg,
0.0754 mmol),
CuI
(14.5 mg,
0.0761 mmol), and NMP (1.4 mL), as described for 3
(80 ꢁC, 40 h), gave after workup and chromatography
(hexanes/EtOAc, in sequence 9:1 and 8:2) 8 (196 mg,
0.591 mmol, 79%) as a yellow oil. IR (neat): 3446, 2939,
1736, 1669, 1526, 1353 cmꢀ1
;
1H NMR (600 MHz):
d 0.87 (t, J¼7.2 Hz, 3H), 1.54–1.66 (m, 1H), 1.68–1.80
(m, 1H), 1.86–2.08 (m, 4H), 2.29 (t, J¼8.4 Hz, 2H), 2.59
(q, J¼4.2 Hz, 2H), 3.64 (s, 3H), 6.93 (t, J¼4.2 Hz, 1H),
7.23 (dd, J¼7.8, 1.2 Hz, 1H), 7.46 (dt, J¼7.8, 1.2 Hz, 1H),
7.58 (dt, J¼7.2, 1.2 Hz, 1H), 7.98 (dd, J¼7.8, 1.2 Hz,
1H); 13C NMR (150 MHz): d 7.9 (+), 22.8 (ꢀ), 26.3 (ꢀ),
28.5 (ꢀ), 28.6 (ꢀ), 30.2 (ꢀ), 46.9 (ꢀ), 51.5 (+), 123.9 (+),
128.6 (+), 131.9 (+), 132.3 (+), 133.0 (ꢀ), 138.2 (ꢀ),
145.3 (+), 148.8 (ꢀ), 174.2 (ꢀ), 199.5 (ꢀ); HRMS (DEI)
calcd for C18H21NO5 (MH+): 332.1498, found: 332.1512;
Anal. Calcd for C18H21NO5: C, 65.24; H, 6.39; N, 4.23.
Found: C, 65.32; H, 7.05; N, 3.86.
4.1.4. Methyl (S)-1-ethyl-2-oxo-3-cyclohexene-1-propa-
noate (6).11 To a solution of methyl (S)-1-ethyl-2-oxo-cyclo-
hexane-1-propanoate (5) (3.25 g, 15.3 mmol) in DMF
(23 mL) was added triethylamine (11.3 mL, 80.4 mmol).
Chlorotrimethylsilane (5.93 mL, 46.4 mmol) was added
dropwise and the reaction mixture was heated (100 ꢁC, 3 d).
The reaction was allowed to cool to ambient temperature,
diluted with hexanes (50 mL), and poured into cold water
(50 mL). The layers were separated and the aqueous portion

10840
T. L. Scott et al. / Tetrahedron 62 (2006) 10835–10842
4.1.7. Methyl (S)-[3-ethyl-4-oxo-2,3,4,9-tetrahydro-1H-
carbazol-3-yl]propanoate (9).11 Reaction of 8 (184 mg,
0.555 mmol), Pd(dba)2 (19.5 mg, 0.0339 mmol), dppp
(14.0 mg, 0.0339 mmol), and 1,10-phenanthroline monohy-
drate (13.5 mg, 0.0681 mmol) in DMF (5 mL), as described
for 4 (80 ꢁC, 6 atm CO, 20 h), gave after workup and chroma-
tography(hexanes/EtOAc,insequence8:2and1:1)andrecrys-
tallization (hexanes/EtOAc, 2:1) 9 (126 mg, 0.421 mmol,
75%) as a white solid. Mp 126–126.5 ꢁC (lit.11 125–126 ꢁC).
19 (445 mg, 1.01 mmol), PdCl2(PhCN)2 (17.2 mg,
0.0448 mmol), AsPh3 (27.1 mg, 0.0885 mmol), CuI
(17.8 mg, 0.0935 mmol), and NMP (2 mL), as described
for 3 (80 ꢁC, 2 d), gave after workup and chromatography
(hexanes/EtOAc, in sequence 9:1 and 8:2) 20 (222 mg,
0.850 mmol, 97%) as a yellow solid. Mp 45–47 ꢁC;
IR (neat): 2953, 1666, 1531, 1350 cmꢀ1
;
1H NMR
(600 MHz): d 1.12 (d, J¼6.6 Hz, 3H), 2.18 (dd, J¼16.2,
12.0 Hz, 1H), 2.30 (ddd, J¼18.0, 10.8, 2.4 Hz, 1H), 2.38–
2.50 (m, 2H), 2.56 (dd, J¼17.4, 4.8 Hz, 1H), 3.91 (s, 3H),
5.95 (d, J¼2.4 Hz, 1H), 7.19 (dd, J¼8.4, 2.4 Hz, 1H), 7.22
(d, J¼9.0 Hz, 1H), 7.58 (d, J¼3.0 Hz, 1H); 13C NMR
(150 MHz): d 20.9 (+), 30.6 (+), 38.8 (ꢀ), 45.4 (ꢀ), 55.9
(+), 109.7 (+), 119.8 (+), 127.2 (+), 128.5 (+), 130.6 (ꢀ),
147.3 (ꢀ), 159.8 (ꢀ), 160.0 (ꢀ), 199.2 (ꢀ); HRMS (DEI)
calcd for C14H15NO4 (MH+): 262.1080, found: 262.1078;
Anal. Calcd for C14H15NO4: C, 64.36; H, 5.79. Found: C,
64.08; H, 6.04.
4.1.8. 3-(5-Methoxy-2-nitrophenyl)-5-methyl-2-cyclo-
hexen-1-one (11). Reaction of 1 (619 mg, 2.62 mmol),
tributyl(5-methoxy-2-nitrophenyl)stannane (10)33 (1.29 g,
2.92 mmol), PdCl2(PhCN)2 (50.2 mg, 0.131 mmol), AsPh3
(80.2 mg, 0.262 mmol), and CuI (50.0 mg, 0.262 mmol) in
NMP (2 mL), as described for 3 (80 ꢁC, 6 atm CO, 20 h),
gave after workup and chromatography (hexanes/EtOAc,
8:2) 11 (577 mg, 2.21 mmol, 76%) as a yellow solid. Mp
124–126 ꢁC; IR (neat): 3462, 2959, 2252, 1663, 912 cmꢀ1
;
1H NMR (600 MHz): d 1.13 (d, J¼6.6 Hz, 3H), 2.20 (dd,
J¼16.2, 12.0 Hz, 1H), 2.31 (ddd, J¼18.0, 10.8, 3.0 Hz,
1H), 2.44–2.55 (overlapping dd and m, 2H), 2.58 (ddd,
J¼16.2, 4.2, 1.8 Hz, 1H), 3.92 (s, 3H), 5.96 (d, J¼2.4 Hz,
1H), 6.71 (d, J¼2.4 Hz, 1H), 6.97 (dd, J¼9.0, 3.0 Hz, 1H),
8.18 (dd, J¼9.0, 1.2 Hz, 1H); 13C NMR (150 MHz):
d 21.1 (+), 30.8 (+), 38.9 (ꢀ), 45.5 (ꢀ), 56.1 (+), 114.0
(+), 114.6 (+), 126.6 (+), 127.7 (+), 139.2 (+), 139.3 (+),
160.8 (ꢀ), 163.7 (ꢀ), 199.3 (ꢀ); Anal. Calcd for
C14H15NO4: C, 64.36; H, 5.79. Found: C, 64.56; H, 6.27.
4.1.12. 2,3,4,9-Tetrahydro-7-methoxy-3-methyl-1H-car-
bazol-1-one (14).8 Reaction of 20 (73.6 mg, 0.282 mmol),
Pd(dba)2
(9.7 mg,
0.017 mmol),
dppp
(6.9 mg,
0.017 mmol), 1,10-phenanthroline monohydrate (6.7 mg,
0.034 mmol), and DMF (5 mL), as described for 4 (80–
90 ꢁC, 6 atm CO, 3 d), gave after workup and chromato-
graphy (hexanes/EtOAc, 7:3) 14 (57.7 mg, 0.252 mmol,
89%) as a white solid. Mp 206–209 ꢁC (lit.12 200–203 ꢁC).
4.1.13. Trimethyl(2-methoxy-6-nitrophenyl)stannane
(21). To a solution of 1-iodo-2-methoxy-6-nitrobenzene34,35
(1.83 g, 6.56 mmol) in toluene (25 mL) was added hexa-
methylditin (2.36 g, 7.20 mmol), PdCl2(PPh3)2 (25 mg,
0.036 mmol), and PPh3 (34 mg, 0.13 mmol). The reaction
was heated at 80 ꢁC (2 d). The reaction mixture was diluted
with EtOAc (100 mL) and washed with NH4OH (10%, aq,
3ꢂ30 mL) and H2O (2ꢂ30 mL). The organic phase was
dried (MgSO4), filtered, and concentrated at reduced pres-
sure. The crude product was purified by chromatography
(hexanes) to give 21 (1.02 g, 3.23 mmol, 49%) as a yellꢀow1
4.1.9. 6-Methoxy-3-methyl-2,3,4,9-tetrahydro-1H-carba-
zol-1-one (12).12 Reaction of 11 (220 mg, 0.842 mmol),
Pd(dba)2 (29 mg, 0.055 mmol), dppp (21 mg, 0.051 mmol),
and 1,10-phenanthroline monohydrate (18 mg, 0.091 mmol)
in DMF (5 mL), as described for 4 (80–90 ꢁC, 6 atm, 36 h),
gave after workup and chromatography (hexanes/EtOAc,
8:2) 12 (151 mg, 0.659 mmol, 78%) as a faint yellow solid.
Mp 206–209 ꢁC (lit.12 mp 200–203 ꢁC).
4.1.10. Tributyl(4-methoxy-2-nitrophenyl)stannane (19).
To a solution of 1-iodo-4-methoxy-2-nitrobenzene (923 mg,
3.31 mmol) in toluene (6 mL) were added hexabutyl-
ditin (2.50 mL, 4.95 mmol), PdCl2(PPh3)2 (23.6 mg,
0.0336 mmol), and PPh3 (17.6 mg, 0.0671 mmol). The reac-
tion was heated at 80 ꢁC for 4 d. The reaction was diluted
with benzene (100 mL) and washed with NH4OH (10%, aq,
3ꢂ30 mL) and H2O (2ꢂ30 mL). The organic phase was dried
(MgSO4), filtered, and the solvents were removed under
reduced pressure. The crude product was purified by chroma-
tography (hexanes) to give 19 (1.13 g, 2.56 mmol, 77%) as
solid. Mp 49–52 ꢁC; IR (neat): 2956, 1528, 1344 cm
;
1H NMR (270 MHz): d 0.87 (t, J¼7.3 Hz, 3H), 1.10 (t,
J¼7.7 Hz, 2H), 1.30 (sextet, J¼4.0 Hz, 2H), 1.42–1.54 (m,
2H), 3.89 (s, 3H), 7.19 (dd, J¼8.1, 2.6 Hz, 1H), 7.54 (d,
J¼8.1 Hz, 1H), 7.85 (d, J¼4.3 Hz, 1H); 13C NMR
(67.5 MHz): d ꢀ5.7 (+), ꢀ4.33 (d, JC,Sn¼189.4 Hz), 55.8
(+), 114.1 (+), 116.2 (+), 127.6 (ꢀ), 130.5 (+), 155.6 (ꢀ),
164.9 (ꢀ); Anal. Calcd for C10H15NO3Sn: C, 38.02; H,
4.79. Found: C, 38.37; H, 5.14.
4.1.14. 3-(2-Methoxy-6-nitrophenyl)-5-methyl-2-cyclo-
hexen-1-one (22). Reaction of 1 (557 mg, 2.36 mmol), 21
(820 mg, 2.60 mmol), PdCl2(PhCN)2 (45 mg, 0.12 mmol),
AsPh3 (72.3 mg, 0.236 mmol), and CuI (50 mg,
0.26 mmol) in NMP (2 mL), as described for 3 (80 ꢁC,
48 h), gave after workup and chromatography (hexanes/
EtOAc, 8:2) 22 (437 mg, 1.67 mmol, 71%) as a yellow oil.
1
a yellow oil. IR (neat): 2956, 1528, 1344 cmꢀ1; H NMR
(270 MHz): d 0.87 (t, J¼7.3 Hz, 3H), 1.10 (t, J¼7.7 Hz,
2H), 1.30 (sextet, J¼4.0 Hz, 2H), 1.42–1.54 (m, 2H), 3.89
(s, 3H), 7.19 (dd, J¼8.1, 2.6 Hz, 1H), 7.54 (d, J¼8.1 Hz,
1H), 7.85 (d, J¼4.3 Hz, 1H); 13C NMR (67.5 MHz): d 10.8
(+), 13.6 (ꢀ), 27.3 (+), 29.0 (+), 55.5 (ꢀ), 108.8 (ꢀ), 120.6
(ꢀ), 130.0 (+), 138.0 (ꢀ), 154.5 (+), 160.5 (+); HRMS
(FAB) calcd for C19H33NO3Sn (Mꢀ): 443.1482, found:
443.1491; Anal. Calcd for C19H33NO3Sn: C, 51.71; H,
7.52; N, 3.17. Found: C, 50.31; H, 7.67; N, 3.02.
IR (neat): 3456, 2957, 2250, 1668, 911, 726 cmꢀ1 1H
;
NMR (600 MHz): d 1.15 (d, J¼3.6 Hz, 3H), 2.15–2.30 (m,
1H), 2.40–2.65 (m, 4H), 3.89 (d, J¼3.0 Hz, 3H), 5.78 (s,
1H), 7.55 (d, J¼7.8 Hz, 1H), 7.21 (dd, J¼8.4, 1.2 Hz, 1H),
7.46 (dt, J¼8.4, 2.4 Hz, 1H); 13C NMR (150 MHz): d 20.8
(+), 30.1 (+), 37.9 (ꢀ), 45.4 (ꢀ), 56.3 (+), 115.3 (+), 124.7
(ꢀ), 127.2 (+), 129.4 (+), 147.9 (ꢀ), 156.4 (ꢀ), 156.8 (ꢀ),
4.1.11. 3-(4-Methoxy-2-nitrophenyl)-5-methyl-2-cyclo-
hexen-1-one (20). Reaction of 1 (208 mg, 0.881 mmol),

T. L. Scott et al. / Tetrahedron 62 (2006) 10835–10842
10841
198.9 (ꢀ); Anal. Calcd for C14H15NO4: C, 64.36; H, 5.79.
Supplementary data
Found: C, 64.44; H, 5.27.
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.08.100.
4.1.15. 5-Methoxy-3-methyl-2,3,4,9-tetrahydro-1H-car-
bazol-1-one (15).21 Reaction of 22 (57 mg, 0.22 mmol),
Pd(dba)2
(7.5 mg,
0.014 mmol),
dppp
(5.4 mg,
References and notes
0.013 mmol), and 1,10-phenanthroline monohydrate
(4.7 mg, 0.024 mmol) in DMF (4 mL), as described for 4
(80–90 ꢁC, 6 atm CO, 2 d), gave after workup and chroma-
tography (hexanes/EtOAc, 19:1), 15 (50 mg, 0.22 mmol,
100%) as a white solid. Mp 240–242 ꢁC (lit.21 mp
201 ꢁC); IR (neat): 3460, 2253, 1646, 1471, 1381, 1264,
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3H), 2.29 (ddd, J¼15.3, 11.4, 0.98 Hz, 1H), 2.45 (m, 1H),
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methyl(6-nitro-1,3-benzodioxol-5-yl)stannane (23)31 (160 mg,
0.485 mmol), PdCl2(PhCN)2 (8.5 mg, 0.022 mmol), AsPh3
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after workup and chromatography (hexanes then hexanes/
EtOAc, in sequence 19:1, 9:1, and 8:2), 24 (110 mg,
0.400 mmol, 91%) as a yellow solid. Mp 124–126 ꢁC; IR
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(neat): 3619, 2254, 1711, 911, 735 cmꢀ1
;
1H NMR
(600 MHz): d 1.12 (d, J¼6.0 Hz, 3H), 2.18 (dd, J¼16.8,
12.6 Hz, 1H), 2.28 (ddd, J¼17.4, 9.6, 2.4 Hz, 1H), 2.40–
2.54 (overlapping dd and m, 2H), 2.57 (dd, J¼16.2, 3.0 Hz,
1H), 5.92 (d, J¼1.8 Hz, 1H), 6.17 (s, 2H), 6.65 (s, 1H),
7.61 (s 1H); 13C NMR (150 MHz): d 21.0 (+), 30.8 (+),
39.0 (ꢀ), 45.5 (ꢀ), 103.4 (ꢀ), 105.7 (+), 108.6 (+), 126.9
(+), 133.4 (ꢀ), 140.5 (ꢀ), 148.1 (ꢀ), 152.2 (ꢀ), 160.6 (ꢀ),
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0.095 mmol), and 1,10-phenanthroline monohydrate
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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). NSF-EPSCoR (Grant
#1002165R) is gratefully acknowledged for the funding of
a 600 MHz Varian Inova NMR and the NMR facility in
the C. Eugene Bennett Department of Chemistry at West
Virginia University.

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