Novel palladium-catalyzed synthesis of 1,2-dihydro-4(3H)-carbazolones

Article abstract of DOI:10.1016/S0040-4039(02)00072-2

Two sequential palladium-catalyzed reactions are the key steps in a novel synthetic route to carbazolones, an intermolecular Stille coupling followed by a recently developed palladium-catalyzed reductive N-heteroannulation. A number of functionalized 1,2-dihydro-4(3H)-carbazolones were prepared using this sequence.

Full text of DOI:10.1016/S0040-4039(02)00072-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1621–1624
Novel palladium-catalyzed synthesis of
1,2-dihydro-4(3H)-carbazolones
Tricia L. Scott and Bjo¨rn C. G. So¨derberg*
Department of Chemistry, West Virginia University, Morgantown, WV 26506-6045, USA
Received 30 November 2001; revised 3 January 2002; accepted 4 January 2002
Abstract—Two sequential palladium-catalyzed reactions are the key steps in a novel synthetic route to carbazolones, an
intermolecular Stille coupling followed by a recently developed palladium-catalyzed reductive N-heteroannulation. A number of
functionalized 1,2-dihydro-4(3H)-carbazolones were prepared using this sequence. © 2002 Elsevier Science Ltd. All rights
reserved.
Carbazolones have been used as intermediates in total
synthesis of a variety of naturally occurring carbazole
alkaloids for example, pyrayaquinones A and B, mur-
rayaquinone A, koeniginequinone A,1 and murrayafo-
line A.2 In addition, the synthetic drug ondansetron
(Fig. 1) is a potent 5HT3 receptor agonist used for the
prevention of nausea caused by chemotherapy and
radiation treatment of cancer patients.
system via two consecutive palladium-catalyzed reac-
tions, a Stille coupling followed by the reductive N-het-
eroannulation. Thus, in our initial synthetic sequence,
2-iodo-2-cyclohexenone (2)5 was reacted with 2-(tri-n-
butylstannyl)-1-nitrobenzene (1)6 in the presence of
bis(benzonitrile)palladium dichloride (PdCl2(PhCN)2, 5
mol%), triphenylarsine (AsPh3, 10 mol%), and copper
iodide (10 mol%) in N-methylpyrrolidinone (NMP) to
give the expected coupling product 3 in good isolated
yield. Attempted N-heteroannulation of 3 using palla-
dium diacetate (6 mol%), triphenylphosphine (24
mol%), and carbon monoxide (4 atm) in acetonitrile at
70°C, reaction conditions previously employed for the
preparation of a large variety of indoles, surprisingly
gave only recovered starting material. Palladium–
phenanthroline complexes have been shown to be par-
ticularly active catalysts for the reductive carbonylation
of nitrobenzenes to give isocyanates.7 Thus, using
somewhat modified conditions, palladium bis(dibenzyli-
deneacetone) (Pd(dba)2, 6 mol%), 1,3-bis(diphenylphos-
phino)propane (dppp, 12 mol%), 1,10-phenanthroline
(12 mol%), and CO (6 atm) in dimethylformamide
(DMF) at 80°C, the expected 1,2-dihydro-4(3H)-carba-
zolone 4 was obtained in good isolated yield (Scheme
1). In later reactions, 1,10-phenanthroline dihydrate
was used with no apparent detrimental effect. In the
absence of the diphosphine, a somewhat lower yield of
product was observed. Thus, all reactions discuss herein
were performed with both ligands present.
A variety of methods have been utilized to obtain
carbazolones. One of the most common methods used
is the Fischer indole synthesis. For example, the parent
system, 1,2-dihydrocarbazol-4(3H)-one, was prepared
in 51% yield by reaction of phenylhydrazine with 1,3-
cyclohexanedione followed by treatment of the hydra-
zone with sulfuric acid.3 Drawbacks of this
methodology are the highly acidic reaction conditions
and the formation of regioisomeric products using
unsymmetrical substrates.
We have recently developed a relatively mild and very
efficient palladium-catalyzed route to substituted
indoles via a reductive N-heteroannulation of function-
alized 2-nitrostyrenes.4 Based on these results, we envi-
sioned a short and novel route to the carbazole ring
The polarity of the coupling reagents can readily be
switched, i.e. using an arylhalide and a 2-trialkyltin
substituted enone. The required tin compound was
prepared by reaction of the vinylbromoketal 58 with 2
equiv. of t-butyllithium followed by addition of tri-n-
Figure 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00072-2

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T. L. Scott, B. C. G. So¨derberg / Tetrahedron Letters 43 (2002) 1621–1624
Scheme 1.
butyltin chloride. The crude reaction mixture was
stirred with HCl (10%, aq.) affording the deprotected
ketone 69 in high overall yield (Scheme 2). Palladium-
catalyzed cross coupling of 6 with 2-nitroiodobenzene
gave the expected cross coupling product 3 in 71%
yield.
yield of the reaction (entries 5 and 6). Similar results
were obtained in our previous studies of the forma-
tion of indoles by reductive N-heteroannulation.4
The mechanism of metal-catalyzed reductive N-het-
eroannulations of aromatic nitro compounds, in the
presence of CO, has been examined in some detail.
Watanabe, Cenini, and others have suggested the for-
mation of a metal bound nitrene intermediate formed
via sequential deoxygenations of the nitro group and
elimination of 2 equiv. of carbon dioxide.12,13 One
possible mechanism is presented in Scheme 3 for the
simpler 2-nitrostyrene substrate. Reaction of the
nitrogroup with palladium(0) and carbon monoxide
would give 19. Elimination of carbon dioxide to give
a metal bound nitrosamine 20 followed by insertion
of carbon monoxide would afford metallacyclobu-
tanone 21. A second elimination of carbon dioxide
produces the metal bound nitrene 22. Cyclization of
the metal bound nitrene to a six-membered metallacy-
cle 23, and reductive elimination followed by a [1,5]-
hydrogen shift would give the observed product and
regenerate the active palladium catalyst. A number of
partially deoxygenated, closely related, or isomeric
metallacyclo-pentanes, -butanes, and -propanes have
been isolated in support of the depicted mechanism.14
A ruthenium bound biphenylnitrene complex, related
to 22, has been characterized by X-ray diffraction.
Thermolysis of this complex gave carbazole, the
expected nitrene insertion product.15 Reduction of the
nitro group to an amino group followed by amino-
palladation and reductive-elimination, was recently
disproved as a major pathway.16
A number of additional examples of the cross cou-
pling–annulation sequence to 1,2-dihydro-4(3H)-car-
bazolones were examined, and the results thereof are
summarized in Table 1.10 A variety of substituted 2-
(2-nitrophenyl)-2-cycloalkenones (7–12) were prepared
as depicted in Schemes 1 and 2 via a palladium-cata-
lyzed Stille-type coupling of 1 or 6 with 2-iodo-2-
enones11 or aryl halides, respectively (Table 1). The
Stille couplings proceeded uneventfully; however,
lower yields of product were observed for the more
sterically hindered aryl bromides seen in entries 3 and
5. Some modifications of the reaction conditions were
required for the synthesis of compounds 9 and 11.
Although still moderate, the best yield of 9 was
obtained by replacing AsPh3 with 1,1%-bis-
(diphenylphosphino)ferrocene (dppf) as the ligand.
Compound 11 was prepared using PdCl2(PPh3)2 as
the catalyst in DMF (110°C) without added ligand. It
should be noted that, minor amounts (<10%) of
homocoupled dimers of 1 and 6 were seen in most
cases.
Palladium-catalyzed N-heteroannulation of 7–12 gave
the expected 2,3-fused indoles 13–18 in 61–89% iso-
lated yield (Table 1). The reactions were monitored
by TLC until all starting material had been consumed
(22–96 h). Five- and seven-membered rings were read-
ily fused to the indole skeleton (entries 1 and 2). The
annulation reaction is relatively unaffected by elec-
tron-withdrawing and electron-donating substituents
on the aromatic ring. As can be seen in entries 3 and
4, both ester and alkoxy groups work well. Sub-
stituents adjacent to the alkene or the nitro group of
the aromatic ring also do not appear to affect the
In summary, a novel route to tricyclic substituted 2,3-
fused indoles in general and carbazolones in particu-
lar has been developed. The scope and limitation of
this route together with applications thereof in total
synthesis are presently being examined in our labora-
tories.
Scheme 2.

T. L. Scott, B. C. G. So¨derberg / Tetrahedron Letters 43 (2002) 1621–1624
Table 1. Stille cross coupling followed by N-heteroannulation
1623

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T. L. Scott, B. C. G. So¨derberg / Tetrahedron Letters 43 (2002) 1621–1624
Scheme 3.
Acknowledgements
8. Anderson, J. C.; Pearson, D. J. J. Chem. Soc., Chem.
Commun. 1998, 2023.
This work was supported by a research grant from the
National Institutes of Health (R01 GM57416). Copy
editing by Diana G. Duran is gratefully acknowledged.
9. For a previous synthesis, see: Adam, W.; Klug, P. Syn-
thesis 1994, 557.
10. 2-(6-Methyl-2-nitrophenyl)-2-cyclohexen-1-one (11): mp
79–80°C; IR 1671, 1520, 1356 cm−1; 1H NMR l 2.09–2.20
(m, 2H), 2.22 (s, 3H), 2.51 (q, J=5.7, 2H), 2.57–2.74 (m,
2H), 6.72 (t, J=4.2 Hz, 1H), 7.33 (t, J=7.8 Hz, 1H), 7.46
(d, J=7.5 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H); 13C NMR l
20.0, 22.5, 26.0, 38.2, 121.6, 127.9, 131.4, 134.4, 137.2,
138.3, 146.8, 149.4, 196.8; HRMS calcd for C13H13NO3:
231.0895; found: 231.0902.
11. Johnson, C. R.; Adams, J. P.; Braun, M. P.; Senanayake,
C. B. W. Tetrahedron Lett. 1992, 33, 919.
12. Akazome, M.; Kondo, T.; Watanabe, Y. J. Org. Chem.
1994, 59, 3375.
13. Cenini, C.; Ragaini, F. Catalytic Reductive Carbonylation
of Organic Nitro Compounds; Kluwer Academic: Dor-
drecht, Netherlands, 1997.
14. (a) Pizzotti, M.; Porta, F.; Cenini, S. J. Organomet.
Chem. 1987, 330, 265; (b) Gargulak, J. D.; Berry, A. J.;
Noirot, M. D.; Gladfelter, W. L. J. Am. Chem. Soc. 1992,
114, 8933.
15. Crotti, C.; Cenini, S.; Bassoli, A.; Rindone, B.; Demartin,
F. J. Mol. Catal. 1991, 70, 175.
16. Ragaini, F.; Sportiello, P.; Cenini, S. J. Organomet.
Chem. 1999, 577, 283.
References
1. For a review, see: Bouaziz, Z.; Nebois, P.; Poumaroux,
A.; Fillion, H. Heterocycles 2000, 52, 977.
2. Chakraborty, D. P.; Chowdhury, B. K. J. Org. Chem.
1968, 33, 1265.
3. Rodriguez, J.-G.; Temprano, F.; Esteban-Calderon, C.;
Martinez-Ripoll, M. J. Chem. Soc., Perkin Trans. 1 1989,
2117.
4. So¨derberg, B. C.; Chisnell, A. C.; O’Neil, S. N.; Shriver,
J. A. J. Org. Chem. 1999, 64, 9731.
5. (a) Boße, F.; Tunoori, A. R.; Niestroj, A. J.; Gronwald,
O.; Maier, M. E. Tetrahedron 1996, 52, 9485; (b) John-
son, C. R.; Adams, J. P.; Braun, M. P.; Senanayake, C.
B. W.; Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron
Lett. 1992, 33, 917.
6. Kosugi, M.; Ohya, T.; Migita, T. Bull. Chem. Soc. Jpn.
1983, 56, 3855.
7. Gallo, E.; Ragaini, S.; Cenini, S.; Demartin, F. J.
Organomet. Chem. 1999, 586, 190 and references cited
therein.