A New β-Carbolinone Synthesis Using a Rh(II)-Promoted [3 + 2]-Cycloaddition and Pd(0) Cross-Coupling/Heck Cyclization Chemistry

Article abstract of DOI:10.1021/ol0356338

(Equation presented) A short and efficient synthesis of the β-carbolinone ring system was achieved using a rhodium(II)-catalyzed [3 + 2]-cycloaddition, a Pd(0)-catalyzed C-N amination reaction, and a subsequent intramolecular Heck reaction as the key synthetic steps.

Full text of DOI:10.1021/ol0356338

ORGANIC
LETTERS
2003
Vol. 5, No. 22
4195-4197
A New â-Carbolinone Synthesis Using a
Rh(II)-Promoted [3 + 2]-Cycloaddition
and Pd(0) Cross-Coupling/Heck
Cyclization Chemistry
Joel M. Harris† and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received August 27, 2003
ABSTRACT
A short and efficient synthesis of the â-carbolinone ring system was achieved using a rhodium(II)-catalyzed [3 + 2]-cycloaddition, a Pd(0)-
catalyzed C−N amination reaction, and a subsequent intramolecular Heck reaction as the key synthetic steps.
The 1,2-dihydropyrido[3,4-b]indol-1-one (i.e., â-carbolinone)
nucleus occurs in many natural products,1 and several of these
compounds show significant biological activity.2 One of the
metabolites isolated from the sponge genus F. reticulata was
identified as secofascaplysin (1) and represents the first
naturally occurring â-carbolinone.3 Many â-carbolinone
derivatives have been found to exhibit affinity for the
benzodiazepine receptor,4 show antileukemic properties,5 and
function as useful central nervous system depressants.6 A
novel series of human leukocyte elastase (HLE) inhibitors
containing the â-carbolinone ring system has also been
reported, and these compounds have been used as potential
therapy agents in disease states.7 The â-carbolinone ring can
serve as a highly efficient peptidiomimetic and shows
significant in vitro potency and selectivity for HLE.7
† NIH Postdoctoral Fellow, Grant No. GM 64027-1.
(1) (a) Larsen, L. K.; Moore, R. E.; Patterson, G. M. L. J. Nat. Prod.
1994, 57, 419. (b) Roll, D. M.; Ireland, C. M.; Lu, H. S. M.; Clardy, J. J.
Org. Chem. 1988, 53, 3276. (c) Beccalli, E. M.; Broggini, G.; Marchesini,
A.; Rossi, E. Tetrahedron 2002, 58, 6673.
(2) (a) Kardono, L. B.; Angerhofer, C. K.; Tsauri, S.; Padmawinata, K.;
Pezzuto, J. M.; Kinghorn, A. D. J. Nat. Prod. 1991, 54, 1360. (b) Doyle,
T. W.; Balitz, D. M.; Grulich, R. E.; Nettleton, D. E.; Gould, S. J.; Tann,
C.; Moews, A. E. Tetrahedron Lett. 1981, 22, 4594.
(3) Jimenez, C.; Quinoa, e.; Adamczereski, M.; Hunter, L. M.; Crews,
P. J. Org. Chem. 1991, 56, 3403.
(4) (a) Braestrup, C.; Nielsen, H. M.; Petersen, E. N.; Jepsen, L. H.
Biochem. Pharmacol. 1984, 33, 859. (b) Lippke, K. P.; Schunack, W. G.;
Wenning, W.; Mu¨ller, W. E. J. Med. Chem. 1983, 26, 499.
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54, 1068. (b) Kobayashi, J.; Cheng, J.; Ohta, T.; Nozol, S.; Ohizumi, Y.;
Sasaki, T. J. Org. Chem. 1990, 55, 3666. (c) Hagen, T. J.; Narayanan, K.;
Names, J.; Cook, J. M. J. Org. Chem. 1989, 54, 2170.
Since the biological properties of these heterocycles have
spurred considerable preparative efforts,8 the development
of new synthetic methods for the construction of novel
â-carbolinone ring systems remains an attractive research
(6) Evanno, Y.; Sevrin, M.; Maloizel, C.; Legallondec, O.; George, P.
(Synthelabo S. A. Patent No. WO 9815552, 1998; Chem. Abstr. 128,
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B.; Williams, J. J. Med. Chem. 1995, 38, 86.
10.1021/ol0356338 CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/02/2003

substituted 3-hydroxy-2(1H)-pyridone 6. It was envisaged
that the C3-hydroxyl group present in 6 could be transformed
to an amino group (i.e., 7) by a palladium-catalyzed
amination reaction of its corresponding triflate. Finally, a
subsequent Pd(0)-promoted Heck reaction would furnish the
desired â-carbolinone ring system 8 as outlined in Scheme
1.
Scheme 1
To investigate the potential of this strategy, diazoimide 2
(R ) H) was chosen as the starting substrate. Formation of
the isomu¨nchnone dipole was achieved by reaction of 2 with
Rh2(OAc)4 to first give the rhodium carbenoid species that
undergoes a subsequent intramolecular cyclization onto the
neighboring carbonyl oxygen. Bimolecular trapping of the
dipole with either methyl acrylate or phenyl vinyl sulfone
gave pyridones 9 and 11 in 86% and 85% yield, respectively.
Pyridone 9 was easily decarboxylated by heating with 48%
HBr at 135 °C for 12 h to furnish the unsubstituted pyridone
10 in 90% yield. All three 2(1H)-pyridones (9-11) were
readily converted to the corresponding triflates (12-14) using
N-phenyl trifluoromethanesulfonamide and triethylamine in
high yield (Scheme 2).13,14
area. Most of the described syntheses of â-carbolinones use
a 2-carboxyindole-3-acetic acid as the starting material9 or
are based on the Fischer indole reaction of 3-formyl-2-
pyrrolidinone derivatives with aryl hydrazines.10 We envis-
aged a conceptually new approach to these heterocycles
based upon our recently reported synthesis of 2(1H)-
pyridones via the [3 + 2]-cycloaddition reactions of iso-
mu¨nchnones derived from the Rh(II)-catalyzed reaction of
R-diazoimido sulfones.11 Herein, we report the scope and
generality of this methodology and document its usefulness
in the preparation of variously substituted â-carbolinones.
Our laboratory has been involved in the utilization of the
Rh(II)-catalyzed cyclization/cycloaddition cascade of diazo-
substituted carbonyl compounds for the synthesis of complex
azapolycyclic ring systems.12 Among other examples, this
procedure was employed in an efficient synthesis of (()-
ipalbidine (3) and the angiotensin inhibitor (-)-A58365A
(4) (Scheme 1).13 The versatility of this strategy lies in the
fact that by appropriate selection of the diazo precursor and
dipolarophile, various groups can be introduced into the N-1
and C-4, C-5, C-6 positions. The cornerstone of the cascade
sequence involves the ready ring-opening reaction of the
initially formed isomu¨nchnone cycloadduct 5 to give a
Scheme 2
C-N cross-coupling of aryl halides and triflates with
amines has been the subject of intense studies in recent years,
primarily by the groups of Buchwald15 and Hartwig.16
Application of this methodology to various heteroaromatic
compounds is still a relatively unexplored process. We
initially investigated the cross-coupling of pyridone 13 and
aniline. The amination reaction proceeded quite well using
5 mol % Pd(OAc)2, 10 mol % Xantphos, and 1.5 equiv of
Cs2CO3 in refluxing toluene for 6 h (method A) to give
6-phenylamino-2,3-dihydro-1H-indolizin-5-one (15) in 62%
isolated yield. The use of Pd2(dba)3 (method B) gave a
(8) (a) Misztal, S.; Beilecka, Z.; Mokkrosz, J. L. J. Chem. Soc., Perkin
Trans. 1 1991, 1871. (b) Malnyk, P.; Ducrot, P.; Thal, C. Tetrahedron 1993,
49, 8589. (c) Rodriguez, J. G.; Gil-Lopetegui, P. J. Heterocycl. Chem. 1993,
30, 373. (d) Tietze, L. F.; Wichmann, J. Angew. Chem., Int. Ed. Engl. 1992,
31, 1079.
(9) Mashelkar, U. C.; Thakur, P. A.; Walavalkar, K. V. Indian J.
Heterocycl. Chem. 1992, 1, 201.
(10) Tokmakov, G. P.; Grandberg, I. I. Khim. Geterotsik Soedin. 1980,
3, 331.
(11) Padwa, A.; Straub, C. S. Org. Lett. 1999, 1, 83.
(12) (a) Sheehan, S. M.; Padwa, A. J. Org. Chem. 1997, 62, 438. (b)
Marino, J. P., Jr.; Osterhout, M. H.; Padwa, A. J. Org. Chem. 1995, 60,
2704. (c) Padwa, A.; Hertzog, D. L.; Nadler, W. R. J. Org. Chem. 1994,
59, 7072.
(14) McMurry, J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979.
(15) (a) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653. (b) Yin, J.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 6043. (c) Yin, J.; Buchwald, S. L. Org.
Lett. 2000, 2, 1101. (d) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.;
Buchwald, S. L. J. Org. Chem. 2000, 65, 1158. (e) Wolfe, J. P.; Buchwald,
S. L. J. Org. Chem. 1997, 62, 1264. (f) Ahman, J.; Buchwald, S. L.
Tetrahedron Lett. 1997, 38, 6363.
(16) (a) Hooper, M. W.; Masaru, U.; Hartwig, J. F. J. Org. Chem. 2003,
68, 2861. (b) Alcazar-Roman, L. M.; Hartwig, J. F. Organometallics 2002,
21, 491. (c) Alcazar-Roman, L. M.; Hartwig, J. F.; Rheingold, A. L.; Liable-
Sands, L. M.; Guzei, I. A. J. Am. Chem. Soc. 2000, 122, 4618. (d) Hartwig,
J. F. Angew. Chem., Int. Ed. 1998, 37, 2046. (e) Louie, J.; Driver, M. S.;
Hamannn, B. C.; Hartwig, J. F. J. Org. Chem. 1997, 62, 1268.
(13) Padwa, A.; Sheehan, S. M.; Straub, C. S. J. Org. Chem. 1999, 64,
8648.
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Org. Lett., Vol. 5, No. 22, 2003

slightly higher yield of the coupled product and with a
significant decrease in reaction time (65%, 1.5 h). Other
ligands investigated included (()-BINAP, tri-tert-butylphos-
phine, DPPF, and 2-(dicyclohexylphosphino)biphenyl. How-
ever, with these ligands a much lower yield of the coupled
product was obtained or else no reaction occurred. The cross-
coupling reaction was also carried out using a microwave
reactor available from CEM at 25 W for 20 min which
afforded a 60% yield of the coupled product (method C).
Both electron-rich and electron-deficient anilines underwent
efficient coupling. 2-Aminopyridine was the most efficient
coupling partner giving rise to pyridone 20 in 88% yield.
The use of Pd2(dba)3 facilitated the coupling of benzylamine,
benzamide and benzyl carbamate in good yield. Similar
cross-couplings were also carried out with both the 5-car-
bomethoxy- (12) and 5-phenylsulfonyl-substituted (14) py-
ridones in good yield with a variety of amines.
Scheme 3
at 110 °C gave the desired â-carbolinones 26 and 27 in 65%
unoptimized yield (Scheme 3).
In summary, we have shown that the â-carbolinone ring
system can be rapidly assembled by (i) a Rh(II)-promoted
[3 + 2]-cycloaddition of a phenylsulfonyl-stabilized iso-
mu¨nchnone intermediate, (ii) conversion of the resulting
3-hydroxy-2(1H)-pyridone into the corresponding triflate, (iii)
a Pd(0)-catalyzed C-N amination reaction, and (iv) a Pd-
(0)-catalyzed intramolecular Heck reaction. Further utilization
of this methodology for the construction of â-carbolinone
natural products and bicyclic peptide mimics is under current
investigation and will be reported in due course.
With an efficient method available for the synthesis of
3-anilino-substituted 2(1H)-pyridones in hand, we set out to
prepare an o-bromo-substituted anilino derivative to use as
a precursor for the Heck cyclization17 as proposed in Scheme
1. The cross-coupling reaction of 2-bromoaniline with triflate
13 proceeded smoothly affording an excellent yield of the
required product 21 in 80% yield. Similar results were
obtained with the carbomethoxy-substituted pyridone-triflate
12. Construction of the â-carbolinone system was next
investigated using these readily available pyridones. Indeed,
it was found that treatment of both compounds 21 and 25
with 10 mol % Pd(PPh3)4 and 1.2 equiv of Cs2CO3 in dioxane
Acknowledgment. We appreciate the financial support
provided by the National Science Foundation (Grant No.
CHE-0132651) and the National Institutes of Health (GM
059384).
Supporting Information Available: Spectroscopic data
and experimental details for the preparation of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) (a) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989. (b)
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(c) Melpolder, J. B.; Heck, R. F. J. Org. Chem. 1976, 41, 265. Sakamoto,
T.; Nagano, T.; Kondo, Y.; Yamanaka, H. Synthesis 1990, 215.
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