1,3-Dipolar cycloaddition chemistry for the preparation of novel indolizinone-based compounds

Article abstract of DOI:10.1021/jo0511492

Starting from methyl 5-oxo-6-trifluoromethanesulfonyloxy-1,2,3,5- tetrahydroindolizine-8-carboxylate, obtained by a Rh(II)-catalyzed 1,3-dipolar cycloaddition reaction of 1-(2-benzenesulfonyl-2-diazoacetyl)pyrrolidin-2-one and methyl acrylate, several indolo- and furano-fused indolizinones were efficiently prepared. In the first case, a palladium-mediated C-N coupling of the triflate with a variety of substituted anilines provided the desired methyl 5-oxo-6-(arylamino)-1,2,3,5-tetrahydroindolizine-8-carboxylates in high yield. Methyl 6-(2-bromophenylamino)-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylate as well as its decarboxylated analogue, 6-(2-bromophenylamino)-2,3-dihydro-1H- indolizin-5-one, were synthesized in excellent yield and were found to undergo an intramolecular Heck cyclization to give 1,2,3,6-tetrahydroindolizino[6,7-b] indol-5-ones. To prepare furano-fused indolizinones, methyl 6-hydroxy-5-oxo-1,2, 3,5-tetrahydroindolizine-8-carboxylate was etherified with different allyl halides, and the resultant allyl ethers were subjected to a thermal Claisen rearrangement to give the corresponding methyl 7-allyl-6-hydroxy-5-oxo-1,2,3,4- tetrahydroindolizine-8-carboxylates. Cyclization under Wacker oxidation conditions afforded methyl 2-methyl-8-oxo-5,6,7,8-tetrahydro-1-oxa-7a-aza-s- indacene-4-carboxylates in near-quantitative yield.

Full text of DOI:10.1021/jo0511492

1,3-Dipolar Cycloaddition Chemistry for the Preparation of Novel
Indolizinone-Based Compounds
Edwin M. Mmutlane, Joel M. Harris, and Albert Padwa*
Department of Chemistry, Emory University, Atlanta, Georgia 30322
chemap@emory.edu
Received June 8, 2005
Starting from methyl 5-oxo-6-trifluoromethanesulfonyloxy-1,2,3,5-tetrahydroindolizine-8-carboxyl-
ate, obtained by a Rh(II)-catalyzed 1,3-dipolar cycloaddition reaction of 1-(2-benzenesulfonyl-2-
diazoacetyl)pyrrolidin-2-one and methyl acrylate, several indolo- and furano-fused indolizinones
were efficiently prepared. In the first case, a palladium-mediated C-N coupling of the triflate with
a variety of substituted anilines provided the desired methyl 5-oxo-6-(arylamino)-1,2,3,5-tetrahy-
droindolizine-8-carboxylates in high yield. Methyl 6-(2-bromophenylamino)-5-oxo-1,2,3,5-tetrahy-
droindolizine-8-carboxylate as well as its decarboxylated analogue, 6-(2-bromophenylamino)-2,3-
dihydro-1H-indolizin-5-one, were synthesized in excellent yield and were found to undergo an
intramolecular Heck cyclization to give 1,2,3,6-tetrahydroindolizino[6,7-b]indol-5-ones. To prepare
furano-fused indolizinones, methyl 6-hydroxy-5-oxo-1,2,3,5-tetrahydroindolizine-8-carboxylate was
etherified with different allyl halides, and the resultant allyl ethers were subjected to a thermal
Claisen rearrangement to give the corresponding methyl 7-allyl-6-hydroxy-5-oxo-1,2,3,4-tetrahy-
droindolizine-8-carboxylates. Cyclization under Wacker oxidation conditions afforded methyl
2-methyl-8-oxo-5,6,7,8-tetrahydro-1-oxa-7a-aza-s-indacene-4-carboxylates in near-quantitative yield.
Introduction
Indolizidine alkaloids are ubiquitous in nature and
have been isolated from the entire spectrum of the
animate world: monerans to higher plants and animals.
The azabicyclic nucleus forms the main framework of
what are commonly called “simple” indolizidine alkaloids.
As can be gleaned from the select examples in Figure 1,
these can be relatively simple structures such as ipalbi-
dine 1 or polysubstituted and stereochemically challeng-
ing ones such as cyclizidine 4.
Ipalbidine 1 was isolated from the crushed seeds of
Ipomoea alba1 as well as from purple moonflower, Calo-
nyction muricatum.2 The heteroatom-substituted slafra-
mine 2, bearing two additional stereogenic centers, is the
FIGURE 1. Some simple indolizidine alkaloids from natural
sources.
neurotoxin derived from Rhizoctonia leguminicola,3
a
fungus that infects ruminant fodder, especially red clover,
and causes profuse salivation, anorexia, diarrhea, and
even death among sheep, horses, and cattle.4 The trihy-
droxylated swainsonine 3 was isolated from Rhizoctonia
leguminicola5 and has also been found in a variety of
(1) .Gourley, J. M.; Heacock, R. A.; McInnes, A. G.; Nikolin, B.;
Smith, D. G. J. Chem Soc., Chem. Commun. 1969, 709.
(2) Wang, Y.-M.; Li, X.-J.; Wang, Y.-W.; Gu, J.-K.; Zhou, H. Chin.
Trad. Herbal Drugs 2002, 33, 111; Chem. Abstr. 2003, 138, 86507.
(3) (a) Rainey, D. P.; Smalley, E. B.; Crump, M. H.; Strong, F. M.
Nature 1965, 205, 203. (b) Aust, S. D.; Broquist, H. P. Nature 1965,
205, 204.
(4) Broquist, H. P.; Snyder, J. J. In Microbial Toxins; Kadis, S.,
Ciegler, A., Ajl, S. J., Eds.; Academic Press: New York, 1971; Vol. 7,
pp 319-333.
(5) Guengerich, F. P.; DiMari, S. J.; Broquist, H. P. J. Am. Chem.
Soc. 1973, 95, 2055.
10.1021/jo0511492 CCC: $30.25 © 2005 American Chemical Society
Published on Web 08/13/2005
J. Org. Chem. 2005, 70, 8055-8063
8055

Mmutlane et al.
several water-soluble derivatives of camptothecin, equally
potent but with minimal side effects, are prescription
drugs.16 The alkaloid strychnofoline 7, on the other hand,
represents a fascinating combination of a spiroindolizi-
dine-oxoindole core with a â-carboline (9H-pyrido[3,4-
b]indole) pendant. The â-carboline is another ring com-
bination that forms the core of numerous natural products,
many of them biologically active. Isolated from the leaves
of Strychnos usambarensis,17 strychnofoline displays an-
timitotic activity against cultures of mouse melanoma
and Ehrlich tumor cells.18 The first total synthesis of this
challenging molecule, as a racemate, has recently been
reported.19
The potent biological activity of indolizidine and in-
dolizidine-containing alkaloids, coupled with their chal-
lenging molecular architecture, continues to make them
tantalizing and formidable targets for synthesis. Over the
years, a vast array of methods, both general and target-
specific, have been developed which are now conventional
tools for the synthesis of indolizidine alkaloids. These
synthetic approaches, together with the isolation, bio-
synthesis, and pharmacological activities of indolizidine
alkaloids, are outlined in a series of comprehensive
annual reviews.20
Our research group has previously demonstrated that
the indolizidine ring system can be efficiently assembled
in a few steps using the Rh(II)-catalyzed [3 + 2] dipolar
cycloaddition of 1-(2-benzenesulfonyl-2-diazoacetyl)pyr-
rolidin-2-one (8) and an appropriately substituted dipo-
larophile 9 (Scheme 1).21 The resultant pyridone 10
represents a very versatile synthon. As depicted in
Scheme 2, hydrogenation of the pyridinone ring and
subsequent functional group interconversions could pro-
vide access to a variety of “simple” indolizidine alkaloids
and others containing the indolizidine core. The C-8
substituent (R ) CO2Me) allows for substitution/decar-
boxylation to give a hydrogen substituent or further
oxidation under Baeyer-Villiger conditions (R ) COMe).
On the other hand, the C-6 hydroxyl substituent, pro-
tected as a triflate, allows for an assortment of cross-
coupling possibilities: either Kumada,22 Negishi,23 Stille,24
FIGURE 2. Some related indolizidine structures.
higher plants.6 It is a potent toxin that inhibits man-
nosidase II, one of the enzymes required in N-linked
glycoprotein processing, thereby inducing a condition
similar to the genetic disease mannosidosis.7 As a result,
swainsonine is used clinically as an antimetastatic agent.
Because of its ability to disrupt cellular recognition, it
has been found to inhibit the association of Trypanosoma
cruzi,8 the causative agent of Chagas’ disease. The
unique, polyfunctionalized cyclizidine 4 was isolated from
a soil bacterium, a Streptomyces species NCB 11649. This
natural product shows nonselective immunostimulatory
properties, and its secondary monoacetate has the same
effect as some â-blocking drugs,9 causing a reduction in
beat frequency of cultured heart cells.10 Last in the
selection is pumiliotoxin 307A (5), an example of an
indolizidine alkaloid obtained from kingdom animalia,
and it, together with several other neurotoxins, was
isolated from South American poison-dart frogs (Den-
drobatidae).11
The indolizidine core or various unsaturated versions
thereof are also embedded in a vast number of alkaloids
that are not classified as indolizidine-based. An example
is the antineoplastic agent camptothecin 6 (Figure 2), a
monoterpenoid indole alkaloid first isolated from the
Chinese tree Camptotheca acuminata.12 Because of its
antitumor activity, camptothecin received a great deal
of attention from synthetic chemists, but eventually this
scrutiny declined due to the severe side effects observed
during clinical trials, associated with its low solubility
in water.13 It was only after Hsiang and co-workers
elucidated the mechanism of action of camptothecin14
that synthetic activity was reinvigorated.15 Nowadays,
(6) (a) Colegate, S. M.; Dorling, P. R.; Huxtable, C. R. Aust. J. Chem.
1979, 32, 2257. (b) Molyneux, R. J.; James, L. F. Science 1982, 216,
190. (c) Medeiros, R. M. T.; Barbosa, R. C.; Riet-Correa, F.; Lima, E.
F.; Tabosa, I. M.; de Barros, S. S.; Gardner, D. R.; Molyneux, R. J.
Toxicon. 2003, 41, 933.
(7) For a review, see: Elbein, A. D.; Molyneux, R. J. In Compre-
hensive Natural Products Chemistry; Barton, D. H. R., Nakanishi, K.,
Eds.; Elsevier: Oxford, 1999; Vol. 3, pp 129-160.
(8) Villalta, F.; Kierszenbaum, F. Mol. Biochem. Parasitol. 1985, 16,
1.
(9) Freer, A. A.; Gardner, D.; Greatbanks, D.; Poyser, J. P.; Sim, G.
A. J. Chem. Soc., Chem. Commun. 1982, 1161.
(10) Leeper, F. J.; Shaw, S. E.; Satish, P. Can. J. Chem. 1994, 72,
131.
(11) (a) Daly, J. W.; Brown, G. B.; Mensah-Dwumah, M.; Myers, C.
W. Toxicon, 1978, 16, 163. (b) Witkop, B.; Go¨ssinger, E. In The
Alkaloids: Chemistry and Pharmacology; Brossi, A., Ed.; Academic
Press: New York, 1983; Vol. 21, pp 139-253.
(12) Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.; McPhail,
A. T.; Sim, G. A. J. Am. Chem. Soc. 1966, 88, 3888.
(13) (a) Schultz, A. G. Chem. Rev. 1973, 73, 385. (b) Wall, M. E.;
Wani, M. C. In Heterocyclic Compounds: Monoterpenoid Indole
Alkaloids; Saxton, J. E., Ed.; John Wiley and Sons: Chichester, 1994;
Vol. 25, Part 4, pp 689-713.
(14) Hsiang, Y. H.; Hertzberg, R. P.; Hecht, S. M.; Liu, L. F. J. Biol.
Chem. 1985, 260, 14873.
(15) For a succinct account of the latest approaches to camptothecin
synthesis,see: Nguyen, T.; Wicki, M. A.; Snieckus, V. J. Org. Chem.
2004, 69, 7816.
(16) Challener, C. A., Ed. Chiral Drugs; Gower Publishing: Alder-
shot, 2001; pp 318-338.
(17) Angenot, L. Plant Med. Phytother. 1978, 12, 123.
(18) Bassleer, R.; Depauw-Gillet, M. C.; Massart, B.; Marnette, J.-
M.; Wiliquet, P.; Caprase, M.; Angenot, L. Planta Med. 1982, 45, 123.
(19) Lerchner, A.; Carreira, E. M.; J. Am. Chem. Soc. 2002, 124,
14826.
(20) (a) Michael, J. P. Nat. Prod. Rep. 2004, 21, 625. (b) Michael, J.
P. Nat. Prod. Rep. 2003, 20, 458. (c) Michael, J. P. Nat. Prod. Rep.
2001, 18, 520. (d) Michael, J. P. Nat. Prod. Rep. 2000, 17, 579. (e)
Michael, J. P. Nat. Prod. Rep. 1999, 16, 675. (f) Michael, J. P. Nat.
Prod. Rep. 1998, 15, 571. (g) Michael, J. P. Nat. Prod. Rep. 1997, 14,
619. (h) Michael, J. P. Nat. Prod. Rep. 1997, 14, 21. (i) Michael, J. P.
Nat. Prod. Rep. 1995, 12, 535. (j) Michael, J. P. Nat. Prod. Rep. 1994,
11, 639. (k) Michael, J. P. Nat. Prod. Rep. 1994, 11, 17. (l) Michael, J.
P. Nat. Prod. Rep. 1993, 10, 51. (m) Michael, J. P. Nat. Prod. Rep.
1991, 8, 553. (n) Michael, J. P. Nat. Prod. Rep. 1990, 7, 485. (o) Michael,
J. P. Nat. Prod. Rep. 1989, 6, 523. (p) Grundon, M. F. Nat. Prod. Rep.
1987, 4, 415. (q) Howard, A. S.; Michael, J. P. In The Alkaloids:
Chemistry and Pharmacology; Brossi, A., Ed.; Academic Press: New
York, 1986; Vol. 28, pp 183-308.
(21) Sheehan, S. M.; Padwa, A. J. Org. Chem. 1997, 62, 438.
(22) . Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi, M.; Fujioka,
A.; Kodma, S.-I.; Nakajima, I.; Minato, A.; Kumada, M. Bull. Chem.
Soc. Jpn. 1976, 49, 1958.
(23) (a) Negishi, E.-I. Acc. Chem. Res. 1982, 15, 340. (b) Erdik, E.
Tetrahedron 1992, 48, 9577. (c) Negishi, E.-I. In Handbook of Orga-
nopalladium Chemistry for Organic Synthesis; Negishi, E.-I., Ed.; John
Wiley and Sons: New York, 2002; Vol. 1, pp 229-247.
8056 J. Org. Chem., Vol. 70, No. 20, 2005

Preparation of Novel Indolizinone-Based Compounds
SCHEME 1. Rhodium(II)-Catalyzed [3 + 2]-
Cycloaddition
SCHEME 3. Palladium(0)-Catalyzed
Cross-Coupling
SCHEME 2. Use of Pyridone Triflate for
Cross-Coupling Chemistry
derivatives that we have since prepared owing to the
versatility of compound 10.
Results and Discussion
or Suzuki-Miyaura25 C-C couplings as well as Buch-
wald-Hartwig C-N/S/O coupling.26 We have demon-
strated some of these possibilities in the past through
the syntheses of (()-ipalbidine,21 the angiotensin convert-
ing enzyme inhibitor (-)-A58365A,27 (() septicine,28 and
a variety of other novel indolizidine-based compounds.
The use of 10 as a key intermediate in total synthesis
has also been demonstrated recently by Greene and co-
workers in a synthesis of the antiviral agent mappicine
ketone, one of the alkaloids isolated together with camp-
tothecin from the Indian plant Nothapodytes foetida.29
We had previously reported our preliminary studies
dealing with the conversion of 10, via a triflate, to
â-carbolinones.30 The current paper aims at providing the
full details of this endeavor and also reports on additional
As depicted in Scheme 3, the Rh(II)-catalyzed 1,3-
dipolar cycloaddition reaction of 8 with two different
dipolarophiles 9 gave the requisite pyridones 10 and 12
(Scheme 3). Treatment of 10 (R ) CO2Me) with hot
hydrobromic acid afforded the decarboxylated product 11,
which was then converted to the trifluoromethane-
sulfonate 13 by reaction with N-phenyltrifluoromethane-
sulfonimide.31 Using this triflate, we explored C-N cross-
coupling reactions which could allow access to novel
heterocycles. In the first instance, we carried out the
reaction with aniline and employed 0.1 molar equiv of
9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (xant-
phos) as the ligand, 0.05 molar equiv of palladium(II)
acetate, and 1.5 molar equiv of cesium carbonate as the
base in toluene, under reflux for 6 h. Under these
conditions, 6-phenylamino-2,3-dihydro-1H-indolizin-5-one
(16a) (R ) H) was obtained in 62% isolated yield. Using
Pd2(dba)3 as the palladium source afforded a marginally
improved 65% yield of product but at a much shorter
reaction time of 1.5 h. The use of a microwave reactor
further abridged the reaction time to a mere 20 min at
25 W. To further improve the yield, we tried a variety of
different ligands [2,2′-bis(diphenylphosphino)-1,1′-bi-
naphthalene [(()-BINAP], (t-Bu)3P, 1,1′-bis(diphenylphos-
phino)ferrocene (DPPF), 2-(dicyclohexylphosphino)biphe-
nyl], but in all cases, the reaction resulted in much lower
yields if it proceeded at all. Using a microwave reactor,
(24) (a) Farina, V.; Krishnamurphy, V.; Scott, W. J. Org. React. 1997,
50, 1. (b) Kosugi, M.; Fugami, K. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-I., Ed.; John Wiley and
Sons: New York, 2002, Vol. 1, pp 263-283.
(25) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (b) Li,
J. J. Alkaloids: Chem. Biol. Persp. 1999, 14, 437. (c) Suzuki, A. In
Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E.-I., Ed.; John Wiley and Sons: New York, 2002; Vol. 1, pp
249-262.
(26) (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805. (b) Hartwig, J. F. Acc. Chem. Res. 1998, 31,
852. (c) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046.
(27) Straub, C. S.; Padwa, A. Org. Lett. 1999, 1, 83.
(28) Padwa, A.; Sheehan, S. M.; Straub, C. S. J. Org. Chem. 1999,
64, 8648.
(29) (a) Raolji, G. B.; Garcon, S.; Greene, A. E.; Kanazawa, A. Angew.
Chem., Int. Ed. 2003, 42, 5059. (b) see also Anderson, R. J.; Raolji, G.
B.; Kanazawa, A.; Greene, A. E. Org. Lett. 2005, 7, 2989.
(30) Padwa, A.; Harris, J. A. Org. Lett. 2003, 5, 4195.
(31) Hendrickson, J. B.; Bergeron, R. Tetrahedron Lett. 1973, 4607.
J. Org. Chem, Vol. 70, No. 20, 2005 8057

Mmutlane et al.
SCHEME 4. Intramolecular Heck Reaction
SCHEME 6. Williamson Etherification/Claisen
Rearrangement Sequence
SCHEME 5. An Attempt To Cyclize Using Oxygen
and Sulfur Nucleophiles
the recovery of hydroxypyridone 10 and in some cases
the starting material triflate 14. With the oxygen sub-
stituent proving rather impervious to substitution, we
attempted to use 10 as the oxygen donor and couple it
with a variety of bromo- and iodoarenes. However, all of
our attempts were unsuccessful and only resulted in the
quantitative recovery of starting material. Still another
attempt to circumvent the inertness of the substrate
involved conversion of the triflate group of 14 to a
bromide or iodide, which we thought could better permit
oxidative insertion and subsequent coupling. In the
simplest case, aryl triflates activated toward substitution
with electron-withdrawing groups at the ortho and/or
para position can be converted to the corresponding
halide by reaction with tetrabutylammonium bromide37
or sodium iodide38 at elevated temperatures. However,
all of our efforts to carry out a related reaction using
substrate 14 and allowing it to react with sodium iodide
were unsuccessful. Thus, we employed an indirect route
which entailed conversion to the trimethylstannane
under palladium catalysis, followed by displacement with
elemental bromine.39 Unfortunately, this attempt also
failed to produce any of the desired bromide, and we
decided instead to investigate several other transforma-
tions to which 14 could be subjected.
At this stage of our studies, we recognized that hy-
droxypyridone 10 allows for a classical Williamson
etherification with allyl halides and the resulting ethers
can then undergo a subsequent Claisen rearrangement.
While Claisen rearrangements in the phenyl and naph-
thyl versions are commonly utilized in synthesis,40 the
pyridine and quinoline versions have rarely been re-
ported.29,41 Considering the paucity of such examples, we
proceeded with the synthesis of the allyl ethers and
subjected them to the Claisen rearrangement (Scheme
6). Reaction of 10 with allyl bromide in the presence of
potassium carbonate in acetone under reflux for 18 h gave
the requisite ether 29 in near-quantitative yield. Several
related ethers were prepared analogously using the
appropriate allylic chloride (crotyl, methallyl, and cin-
namyl chloride) under Finkelstein conditions with sodium
iodide.42 The subsequent Claisen rearrangement was
carried out in boiling DMF and required careful monitor-
ing. We found that the best yields were obtained by
we employed a variety of substituted anilines, both
electron-poor and electron-rich, and found that all of
these aromatic amines underwent smooth coupling to
give the requisite products 16-25 (R ) H) in high yield.
Methyl 5-oxo-6-trifluoromethanesulfonyloxy-1,2,3,5-
tetrahydroindolizine-8-carboxylate 14 as well as 8-ben-
zenesulfonyl-5-oxo-1,2,3,5-tetrahydroindolizin-6-yl tri-
fluoromethanesulfonate 15 were also found to readily
undergo amination to afford the expected amination
products (R ) CO2Me and R ) SO2Ph), although yields
were varied in the case of 15. We envisaged compounds
22a (R ) H) and 22b (R ) CO2Me) as immediate
precursors to the â-carbolinone unit found in many
natural products (vide supra) and for that reason sub-
jected them to an intramolecular Heck reaction32 by
treatment with a catalytic amount of [Pd(PPh3)4] and a
slight excess of cesium carbonate in dioxane at 110 °C.
This resulted in the formation of the desired â-carboli-
nones 26 and 27 in 65% yield, respectively (Scheme 4).
Emboldened by these positive results, we proceeded to
investigate C-S and C-O coupling as outlined in Scheme
5, with the ultimate aim of producing furan and thiophene
analogues of 27. Diaryl thioethers have been previously
prepared by the base-induced reaction of benzene thiols
with appropriately substituted aryl triflates via an SN-
Ar mechanism.33 We attempted to carry out a related
coupling reaction with substrate 14 using Buchwald-
Hartwig methodology. Unfortunately, all of our efforts
to effect a C-O and C-S couplings and obtain compounds
of general structure 28 have thus far been unsuccessful
(Scheme 5). The reaction of 14 with several phenols and
thiophenols employing various ligand/Pd and base com-
binations (biphenyl-2-yl-di-tert-butylphosphane,34 DP-
PF,35 (()-BINAP,36 and (R)-(S)-JOSIPHOS) led only to
(32) (a) Heck, R. F. Org. React. 1982, 27, 345. (b) Beletskaya, I. P.;
Cheprakov, A. V. Chem. Rev. 2000, 100, 3009. (c) Link, T. J. Org. React.
2002, 60, 157.
(33) Winn, M.; Reilly, E. B.; Liu, G.; Huth, J. R.; Jae, H.-S.; Freeman,
J.; Pei, Z.; Xin, Z.; Lynch, J.; Kester, J.; von Geldern, T. W.; Leitza, S.;
DeVries, P.; Dickinson, R.; Mussatto, D.; Okasinski, G. F. J. Med.
Chem. 2001, 44, 4393.
(34) (a) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi,
J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369. (b) Willis,
M. C.; Taylor, D.; Gillmore, A. T. Chem. Commun. 2003, 2222.
(35) Mann, G.; Hartwig, J. F. Tetrahedron Lett. 1997, 38, 8005.
(36) Zheng, N.; McWilliams, J. C.; Fleitz, F. J.; Armstrong, J. D.,
III; Volante, R. P. J. Org. Chem. 1998, 63, 9606.
(37) Katritzky, A. R.; Li, J.; Stevens, C. V.; Ager, D. J. Org. Prep.
Proc. Int. 1994, 26, 439.
(38) McClure, K. F.; Danishefsky, S. J. J. Am. Chem. Soc. 1993, 115,
6094.
(39) Paquette, L. A.; Gao, Z.; Ni, Z.; Smith, G. F. J. Am. Chem. Soc.
1998, 120, 2543.
(40) (a) Tarbel, D. S. Org. React. 1944, 2, 1. (b) Rhoads, S. J.; Raulins,
N. R. Org. React. 1975, 22, 1. (c) Blechert, S. Synthesis 1989, 71.
(41) Thyagarajan, B. S. Adv. Heterocycl. Chem. 1967, 8, pp 143-
163. See also ref 29 and references therein.
8058 J. Org. Chem., Vol. 70, No. 20, 2005

Preparation of Novel Indolizinone-Based Compounds
SCHEME 7. Wacker-Type Oxidation
process giving furans or via a 6-endo-trig cyclization to
give chromenes. The intramolecular Wacker oxidation
has since found wide application in heterocyclic chemis-
try, and a variety of structures including isochromenes,
pyrans, and lactones have been prepared in this man-
ner.49 The synthesis of indoles has also been achieved in
what has since become known as the Hegedus indole
synthesis.51 While the syntheses of indolizines annulated
to thiophene, benzothiophene, benzene, and furan rings
have been reported before,52 our application of the
intramolecular Wacker oxidation provides simple and
rapid access to poly-substituted furans from a fully
assembled indolizine core. Although a literature search
revealed several instances in which a heteroarene-arene
biaryl axis has been generated by means other than
transition-metal-mediated biaryl coupling,53 the forma-
tion of methyl 2-methyl-8-oxo-3-phenyl-5,6,7,8-tetrahy-
dro-1-oxa-7a-aza-s-indacene-4-carboxylate 39 provides
the only other example in which this has been ac-
complished from o-phenallylphenol.54
In conclusion, using the Buchwald-Hartwig C-N
coupling regimen followed by an intramolecular Heck
reaction, the â-carbolinone core structure present in a
variety of alkaloids was efficiently prepared from 5-oxo-
1,2,3,5-tetrahydroindolizine-6-trifluoromethanesulfon-
ate precursors. Allylation of methyl 6-hydroxy-5-oxo-
1,2,3,5-tetrahydroindolizine-8-carboxylate gave the corres-
ponding ethers which subsequently underwent thermal
Claisen rearrangement to afford the C-allyl products in
high yields. Cyclization of the latter under Wacker
oxidation conditions gave novel polysubstituted furans
fused onto an indolizinone core.
immersing the solution of the allyl ether in a minimal
volume of DMF in an oil bath preheated to 160 °C. In
this way, the requisite C-allyl products 33-36 were
obtained in a matter of minutes in high yield.
The presence of the C-allyl substituent allows for
functional group interconversions en route to different
targets. For instance, rearrangement-internalization
under transition metal43 or t-BuOK catalysis,44 followed
by oxidative cleavage using ozone45 or under Lemieux-
Johnson conditions,46 could provide a carbonyl substitu-
ent. Even more importantly, when in close proximity to
a heteroatom, a C-allyl substituent offers an ideal op-
portunity for heterocycle ring construction under transi-
tion-metal catalysis.47 In most cases, this has been
achieved via an intramolecular Wacker oxidation48 with
the nucleophile being the proximal heteroatom in the
substrate. Indeed, we found that when compounds 33-
36 were treated with PdCl2 and CuCl2 as the co-oxidant
in aqueous DMF under an oxygen atmosphere, the
polysubstituted furans 37-39 were formed in near-
quantitative yield (Scheme 7).
The reaction of alkenes with a catalytic amount of
palladium is known to generate π-complexes, and the
reaction of the latter with alcohols was reported as early
as 1960.49 In 1969, Lloyd and Luberoff investigated the
acetalization of various alkenes with alcohols under
Wacker oxidation conditions.50 Intramolecular reactions
were studied later on, and depending on the catalyst
system used, cyclization can proceed by a 5-exo-trig
Experimental Section
General Procedure for Pd-Catalyzed Couplings of
Pyridone Triflates and Anilines/Amide/Carbamate. A
flame-dried, 10 mL, round-bottom flask was charged with tris-
(dibenzylideneacetone)dipalladium(0) (0.005 mmol, 2.5 mol %),
xantphos (0.02 mmol, 10 mol %), pyridone 11, 14, or 15 (0.18
mmol), and Cs2CO3 (0.27 mmol). The solid reactants were
dissolved in 5 mL of dioxane, and the appropriate aniline
derivative (0.27 mmol) was added to the flask. The flask was
capped with a condensor and kept under an atmosphere of
argon. The mixture was heated at 100 °C for 1-2 h or until
the starting triflate had been completely consumed as judged
by TLC. The solution was cooled to room temperature, diluted
with ethyl acetate, filtered through a pad of Celite, and
concentrated under reduced pressure. The crude material was
purified by silica gel chromatography on silica gel to give the
corresponding 6-(N-arylamino)-2,3-dihydro-1H-indolizin-5-one.
6-Phenylamino-2,3-dihydro-1H-indolizin-5-one (16a).
Recrystallization from hexane gave a cream-colored solid
(65%): mp 166-168 °C; IR (thin film) 1645, 1596, 1560, 1497,
(42) (a) Finkelstein, H. Chem. Ber. 1910, 43, 1528. (b) Kowalczyk,
J. J. In Encyclopedia of Reagents for Organic Synthesis; Paquette, L.
A., Ed.; John Wiley and Sons: Chichester, 1995; Vol. 7, pp 4587-4591.
(43) (a) Ni catalysts: Wang, X.; Woo, K. J. Mol. Catal. A: Chem.
1998, 130, 171. Bricout, H.; Mortreux, A.; Monflier, E. J. Organomet.
Chem. 1998, 553, 469. Jolly, P. W. In Comprehensive Organometallic
Chemistry; Wilkinson, G., Ed.; Pergamon Press: Oxford, 1982; Vol .8,
pp 615-647. (b) Ir catalysts: Leigh, G. J.; Richards, R. L. In
Comprehensive Organometallic Chemistry; Wilkinson, G., Ed.; Perga-
mon Press: Oxford, 1982; Vol. 5, pp 541-628. (c) Palladium cata-
lysts: Negishi, E.-I. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E.-I., Ed.; John Wiley and Sons: New York,
2002; Vol. 2, pp 2783-2789. (d) Ru catalysts: Bennet, M. A. In
Comprehensive Organometallic Chemistry; Wilkinson, G., Ed.; Perga-
mon Press: Oxford, 1982; Vol. 4, pp 931-965.
(44) (a) Pearson, D. E.; Buehler, C. A. Chem. Rev. 1974, 74, 45. (b)
Caine, D. In Encyclopedia of Reagents for Organic Synthesis; Paquette,
L. A., Ed.; John Wiley and Sons: Chichester, 1995; Vol. 6, pp 4189-
4195.
1
1235, and 1143 cm-1; H NMR (600 MHz, CDCl3) δ 2.20 (m,
2H), 3.03 (t, 2H, J ) 7.2 Hz), 4.20 (t, 2H, J ) 7.2 Hz), 6.06 (d,
(45) Fieser, L. F.; Fieser, M. Reagents For Organic Synthesis; John
Wiley and Sons: New York, 1967; Vol. 1, pp 773-777.
(51) Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988, 27, 1113.
(52) Szemes, F.; Kadlekova´, K.; Marchaln, S.; Bobokova´, M.; Dalla,
V.; Da¨ıch, A. Tetrahedron: Asymmetry 2004, 15, 1763 and references
therein.
(53) For the synthesis of 3-arylbenzofurans, see: (a) Katritzky, A.
R.; Ji, Y.; Fang, Y.; Prakash, I. J. Org. Chem. 2001, 66, 5613. (b)
Nicolaou, K. C.; Snyder, S. A.; Bigot, A.; Pfefferkorn, J. A. Angew.
Chem., Int. Ed. 2000, 39, 1093. (c) Habermann, J.; Ley, S. V.; Smits,
R. J. Chem. Soc., Perkin Trans. 1 1999, 2421.
(54) For other examples, see: (a) Joshi, S. C.; Trivedi, K. N. Monatsh.
Chem. 1992, 123, 557. (b) Fuerst, D. E.; Stoltz, B. M.; Wood, J. L. Org.
Lett. 2000, 2, 3521.
(46) Wee, A. G.; Liu, B. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; John Wiley and Sons: Chichester, 1995;
Vol. 7, pp 4616-4620.
(47) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104, 2285.
(48) Henry, P. M. In Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E.-I., Ed.; John Wiley and Sons: New York,
2002; Vol. 2, pp 2119-2159.
(49) Hosokawa, T.; Murahashi, S.-I. In Handbook of Organopalla-
dium Chemistry for Organic Synthesis; Negishi, E.-I., Ed.; John Wiley
and Sons: New York, 2002; Vol. 2, pp 2169 and references therein.
(50) Lloyd, W. G.; Luberoff, B. J. J Org. Chem. 1969, 34, 3949.
J. Org. Chem, Vol. 70, No. 20, 2005 8059

Mmutlane et al.
1H, J ) 7.2 Hz), 6.86 (brs, 1H), 6.95 (t, 1H, J ) 7.8 Hz), 7.11
(d, 1H, J ) 7.2 Hz), 7.15 (d, 2H, J ) 7.8 Hz), and 7.29 (t, 2H,
J ) 7.8 Hz); 13C NMR (150 MHz, CDCl3) δ 22.2, 30.7, 48.8,
100.9, 111.9, 118.7, 121.4, 129.2, 131.9, 137.4, 141.7, and 157.3;
FAB HRMS calcd for [(C14H14N2O) + Li]+ 233.1266, found
233.1273.
C14H13BrN2O: C, 55.10; H, 4.29; N, 9.18. Found: C, 55.05; H,
4.27; N, 8.98.
6-Benzylamino-2,3-dihydro-1H-indolizin-5-one (23a)
was obtained as a pale yellow oil (65%): IR (thin film) 1646,
1
1590, 1485, 1453, 1379, and 1223 cm-1; H NMR (600 MHz,
CDCl3) δ 2.15 (m, 2H), 2.96 (t, 2H, J ) 7.2 Hz), 4.14 (t, 2H, J
) 7.2 Hz), 4.32 (s, 2H), 5.25 (brs, 1H), 5.98 (d, 1H, J ) 7.2
Hz), 6.15 (d, 1H, J ) 7.2 Hz), and 7.24-7.38 (m, 5H); 13C NMR
(150 MHz, CDCl3) δ 22.4, 30.5, 47.7, 48.5, 101.4, 108.5, 127.1,
127.2, 128.5, 135.0, 136.5, 138.8, and 156.8; FAB HRMS calcd
for [(C15H16N2O) + Li]+ 247.1423, found 247.1412.
6-(4-Methoxyphenylamino)-2,3-dihydro-1H-indolizin-
5-one (17a). Recrystallization from hexane gave a tan solid
(70%): mp 148-150 °C; IR (KBr) 1645, 1596, 1581, 1440, 1233,
1
1179, and 1030 cm-1; H NMR (600 MHz, CDCl3) δ 2.18 (m,
2H), 3.00 (t, 2H, J ) 7.2 Hz), 3.79 (s, 3H), 4.18 (t, 2H, J ) 7.2
Hz), 6.02 (d, 1H, J ) 7.8 Hz), 6.60 (brs, 1H), 6.84 (d, 1H, J )
7.8 Hz), 6.86 (d, 2H, J ) 9.0 Hz), and 7.10 (d, 2H, J ) 9.0 Hz);
13C NMR (150 MHz, CDCl3) δ 22.3, 30.6, 48.7, 55.5, 101.0,
110.0, 114.6, 122.2, 133.5, 134.7, 136.4, 155.1, and 156.9. Anal.
Calcd for C15H16N2O2: C, 70.29; H, 6.29; N, 10.93. Found: C,
70.05; H, 6.29; N, 10.77.
N-(5-Oxo-1,2,3,5-tetrahydroindolizin-6-yl)benzamide
(24a). Recrystallization from hexane gave a white solid
(74%): mp 140-142 °C; IR (KBr) 1647, 1593, 1522, 1489, 1280,
1
1186, and 1031 cm-1; H NMR (400 MHz, CDCl3) δ 2.23 (m,
2H), 3.09 (t, 2H, J ) 7.2 Hz), 4.20 (t, 2H, J ) 7.2 Hz), 6.22 (d,
1H, J ) 7.6 Hz), 7.50 (m, 3H), 7.92 (m, 2H), 8.55 (d, 1H, J )
7.6 Hz), and 9.08 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ 21.9,
31.1, 49.1, 101.4, 123.3, 126.8, 127.1, 128.7, 131.8, 134.4, 142.7,
156.7, and 165.6. Anal. Calcd for C15H14N2O2: C, 70.85; H,
5.55; N, 11.02. Found: C, 70.62; H, 5.31; N, 11.27.
6-(4-Nitrophenylamino)-2,3-dihydro-1H-indolizin-5-
one (18a). Recrystallization from ethyl acetate gave a pale
yellow solid (76%): mp 238-240 °C; IR (KBr) 1643, 1582, 1558,
1471, 1365, and 1111 cm-1; 1H NMR (600 MHz, CDCl3) δ 2.24
(m, 2H), 3.09 (t, 2H, J ) 7.2 Hz), 4.21 (t, 2H, J ) 7.2 Hz), 6.18
(d, 1H, J ) 7.2 Hz), 7.11 (d, 2H, J ) 9.0 Hz), 7.32 (d, 1H, J )
7.2 Hz), 7.38 (brs, 1H), and 8.15 (d, 2H, J ) 9.0 Hz); 13C NMR
(150 MHz, CDCl3) δ 22.0, 31.1, 49.2, 100.6, 115.2, 118.0, 126.0,
128.8, 140.2, 141.4, 148.2, and 157.3. Anal. Calcd for C14H13-
N3O3: C, 61.99; H, 4.83; N, 15.49. Found: C, 61.62; H, 4.84;
N, 15.22.
Benzyl (5-oxo-1,2,3,5-tetrahydroindolizin-6-yl)-car-
bamate (25a) was obtained as a pale yellow oil (71%): IR (thin
film) 1716, 1647, 1581, 1533, 1448, 1362, 1211, and 1065 cm-1
;
1H NMR (400 MHz, CDCl3) δ 2.19 (m, 2H), 3.04 (t, 2H, J )
7.2 Hz), 4.15 (t, 2H, J ) 7.2 Hz), 5.19 (s, 2H), 6.14 (d, 1H, J )
7.2 Hz), 7.32-7.41 (m, 5H), 7.75 (brs, 1H), and 8.02 (d, 1H, J
) 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ 21.9, 31.1, 49.0, 66.9,
101.0, 121.1, 126.7, 128.1, 128.2, 128.5, 136.0, 141.7, 153.4,
and 156.2; FAB HRMS calcd for [(C16H16N2O3) + Li]+ 291.1232,
found 291.1318.
6-(3,5-Dimethoxyphenylamino)-2,3-dihydro-1H-indoliz-
in-5-one (19a) was obtained as a pale yellow oil (70%): IR
1
(thin film) 1646, 1600, 1519, 1441, 1194, and 1160 cm-1; H
NMR (600 MHz, CDCl3) δ 2.19 (m, 2H), 3.02 (t, 2H, J ) 7.2
Hz), 3.76 (s, 6H), 4.17 (t, 2H, J ) 7.2 Hz), 6.06 (d, 1H, J ) 7.8
Hz), 6.08 (s, 1H), 6.31 (s, 2H), 6.85 (brs, 1H), and 7.15 (d, 1H,
J ) 7.8 Hz); 13C NMR (150 MHz, CDCl3) δ 22.2, 30.7, 48.9,
55.2, 93.3, 96.8, 100.9, 113.2, 131.3, 137.7, 143.6, 157.1, and
161.4; FAB HRMS calcd for [(C16H18N2O3) +L i]+ 293.1477,
found 293.1478.
Methyl 5-Oxo-6-phenylamino-1,2,3,5-tetrahydroindoliz-
ine-8-carboxylate (16b). Recrystallization from hexane gave
a white solid (75%): mp 170-172 °C; IR (KBr) 1708, 1632,
1
1590, 1435, 1382, 1181, and 1098 cm-1; H NMR (600 MHz,
CDCl3) δ 2.23 (m, 2H), 3.48 (t, 2H, J ) 7.2 Hz), 3.83 (s, 3H),
4.22 (t, 2H, J ) 7.2 Hz), 6.82 (s, 1H), 7.00 (d, 1H, J ) 7.2 Hz),
7.19 (d, 2H, J ) 7.8 Hz), 7.33 (t, 2H, J ) 8.4 Hz), and 7.62 (s,
1H); 13C NMR (150 MHz, CDCl3) δ 21.3, 32.8, 49.3, 51.7, 105.6,
110.5, 119.1, 122.0, 129.4, 131.5, 141.1, 144.8, 157.6, and 165.8.
Anal. Calcd for C16H16N2O5: C, 67.59; H, 5.67; N, 9.85.
Found: C, 67.19; H, 5.70; N, 9.64.
6-(2-Trifluoromethylphenylamino)-2,3-dihydro-1H-in-
dolizin-5-one (20a) was obtained as a pale yellow oil (73%):
IR (thin film) 1651, 1603, 1580, 1522, 1462, 1166, and 1041
1
cm-1; H NMR (600 MHz, CDCl3) δ 2.21 (m, 2H), 3.04 (t, 2H,
J ) 7.2 Hz), 4.20 (t, 2H, J ) 7.2 Hz), 6.07 (d, 1H, J ) 7.2 Hz),
7.00 (t, 1H, J ) 7.8 Hz), 7.07 (d, 1H, J ) 7.2 Hz), 7.14 (brs,
1H), 7.43 (t, 1H, J ) 7.8 Hz), 7.49 (d, 1H, J ) 7.8 Hz), and
7.59 (d, 1H, J ) 7.8 Hz); 13C NMR (150 MHz, CDCl3) δ 22.2,
30.9, 48.9, 100.5, 114.2, 120.2, 120.9, 124.3 (q, 1C, J ) 317.7
Hz), 127.0, 127.1, 131.1, 132.5, 139.1, 140.2, and 157.3; FAB
HRMS calcd for [(C15H13F3N2O)]+ 294.0980, found 294.0969.
Methyl 6-(4-methoxyphenylamino)-5-oxo-1,2,3,5-tet-
rahydroindolizine-8-carboxylate (17b) was obtained as a
pale yellow oil (40%): IR (KBr) 1701, 1636, 1602, 1592, 1440,
1
1375, and 1098 cm-1; H NMR (600 MHz, CDCl3) δ 2.22 (m,
2H), 3.45 (t, 2H, J ) 7.2 Hz), 3.80 (s, 6H), 4.22 (t, 2H, J ) 7.2
Hz), 6.57 (s, 1H), 6.90 (d, 2H, J ) 9.0 Hz), 7.13 (d, 2H, J ) 9.0
Hz), and 7.34 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 21.4, 32.7,
49.2, 51.7, 55.5, 105.8, 108.7, 114.7, 122.6, 134.0, 143.9, 155.5,
and 165.9; FAB HRMS calcd for [(C17H18N2O4) + Li]+ 321.1426,
found 321.1425.
Methyl 6-(4-Nitrophenylamino)-5-oxo-1,2,3,5-tetrahy-
droindolizine-8-carboxylate (18b). Recrystallization from
ethyl acetate gave a yellow solid (76%): mp 232-235 °C; IR
(KBr) 1719, 1637, 1596, 1485, 1328, 1268, and 1110 cm-1; 1H
NMR (600 MHz, CDCl3) δ 2.27 (m, 2H), 3.53 (t, 2H, J ) 7.2
Hz), 3.87 (s, 3H), 4.24 (t, 2H, J ) 7.2 Hz), 7.17 (d, 2H, J ) 9.0
Hz), 7.35 (s, 1H), 7.84 (s, 1H), and 8.17 (d, 2H, J ) 9.0 Hz);
13C NMR (150 MHz, CDCl3) δ 21.1, 33.1, 49.6, 52.0, 105.3,
115.7, 116.4, 126.0, 128.5, 140.7, 147.5, 148.1, 157.6, and 165.2.
Anal. Calcd for C16H15N3O5: C, 58.36; H, 4.59; N, 12.76.
Found: C, 58.49; H, 4.63; N, 12.85.
Methyl 6-(3,5-dimethoxyphenylamino)-5-oxo-1,2,3,5-
tetrahydroindolizine-8-carboxylate (19b) was obtained as
a pale yellow oil (67%): IR (thin film) 1711, 1638, 1598, 1377,
1216, 1098, and 1068 cm-1; 1H NMR (600 MHz, CDCl3) δ 2.24
(m, 2H), 3.49 (t, 2H, J ) 7.2 Hz), 3.79 (s, 6H), 3.83 (s, 3H),
4.22 (t, 2H, J ) 7.2 Hz), 6.13 (t, 1H, J ) 1.8 Hz), 6.35 (d, 2H,
J ) 1.8 Hz), 6.79 (s, 1H), and 7.68 (s, 1H); 13C NMR (150 MHz,
CDCl3) δ 21.3, 32.8, 49.3, 51.8, 55.3, 94.2, 97.3, 105.6, 111.8,
6-(Pyridin-2-ylamino)-2,3-dihydro-1H-indolizin-5-
one (21a). Recrystallization from hexane gave a white solid
(88%): mp 208-210 °C; IR (KBr) 1644, 1601, 1571, 1481, 1422,
1
1368, and 1157 cm-1; H NMR (600 MHz, CDCl3) δ 2.18 (m,
2H), 3.04 (t, 2H, J ) 7.2 Hz), 4.18 (t, 2H, J ) 7.2 Hz), 6.17 (d,
1H, J ) 7.2 Hz), 6.77 (dd, 1H, J ) 7.8 and 4.2 Hz), 6.74 (d,
1H, J ) 7.8 Hz), 7.47 (ddd, 1H, J ) 8.4, 7.8, and 1.8 Hz), 7.68
(brs, 1H), 8.23 (d, 1H, J ) 4.2 Hz), and 8.52 (d, 1H, J ) 7.8
Hz); 13C NMR (150 MHz, CDCl3) δ 22.1, 30.8, 49.0, 101.5,
111.7, 114.8, 118.2, 129.2, 137.0, 138.6, 147.4, 155.2, and 156.9.
Anal. Calcd for C13H13N3O: C, 68.71; H, 5.77; N, 18.49.
Found: C, 68.58; H, 5.82; N, 18.53.
6-(2-Bromophenylamino)-2,3-dihydro-1H-indolizin-5-
one (22a). Recrystallization from hexane gave a white solid
(80%): mp 125-127 °C; IR (KBr) 1649, 1586, 1519, 1440, 1365,
1275, 1181, and 1022 cm-1; 1H NMR (600 MHz, CDCl3) δ 2.21
(m, 2H), 3.04 (t, 2H, J ) 7.2 Hz), 4.21 (t, 2H, J ) 7.2 Hz), 6.08
(d, 1H, J ) 7.8 Hz), 6.79 (t, 1H, J ) 7.8 Hz), 7.10 (d, 1H, J )
7.8 Hz), 7.18 (brs, 1H), 7.23 (t, 1H, J ) 7.2 Hz), 7.37 (d, 1H, J
) 7.8 Hz), and 7.56 (d, 1H, J ) 7.8 Hz); 13C NMR (150 MHz,
CDCl3) δ 22.2, 30.9, 48.9, 100.6, 113.9, 114.5, 117.5, 121.9,
127.9, 130.9, 133.3, 138.8, 139.7, and 157.3. Anal. Calcd for
8060 J. Org. Chem., Vol. 70, No. 20, 2005

Preparation of Novel Indolizinone-Based Compounds
131.1, 143.0, 145.1, 157.6, 161.5, and 165.8; FAB HRMS calcd
8-Benzenesulfonyl-6-(3,5-dimethoxyphenylamino)-2,3-
dihydro-1H-indolizin-5-one (19c) was obtained as a pale
yellow oil (30%): IR (thin film) 1638, 1596, 1565, 1480, 1319,
for [(C18H20N2O5) + Li]+ 351.1532, found 351.1530.
Methyl 5-oxo-6-(2-trifluoromethylphenylamino)-1,2,3,5-
tetrahydroindoliz-ine-8-carboxylate (20b) was obtained as
a pale yellow oil (73%): IR (thin film) 1711, 1642, 1585, 1526,
1439, 1274, 1094, and 1035 cm-1; 1H NMR (600 MHz, CDCl3)
δ 2.25 (m, 2H), 3.50 (t, 2H, J ) 7.8 Hz), 3.82 (s, 3H), 4.24 (t,
2H, J ) 7.8 Hz), 7.08 (dd, 1H, J ) 8.4 and 6.6 Hz), 7.52 (m,
2H), 7.57 (s, 1H), and 7.63 (d, 1H, J ) 8.4 Hz); 13C NMR (150
MHz, CDCl3) δ 21.3, 33.0, 49.3, 51.8, 105.3, 112.4, 120.3, 121.8,
124.0 (q, 1C, J ) 336 Hz), 127.1, 127.2, 131.0, 132.8, 139.5,
146.2, 157.7, and 165.7; FAB HRMS calcd for [(C17H15N2O3F3)
+ Li]+ 359.1195, found 359.1191.
Methyl 5-Oxo-6-(pyridin-2-ylamino)-1,2,3,5-tetrahy-
droindolizine-8-carboxylate (21b). Recrystallization from
ethyl acetate gave a yellow solid (62%): mp 213-215 °C; IR
(KBr) 1707, 1635, 1602, 1523, 1378, 1195, and 1095 cm-1; 1H
NMR (600 MHz, CDCl3) δ 2.24 (m, 2H), 3.51 (t, 2H, J ) 7.8
Hz), 3.88 (s, 3H), 4.22 (t, 2H, J ) 7.8 Hz), 6.78 (m, 2H), 7.52
(ddd,1H, J ) 9.0 and 1.8 Hz), 7.59 (brs, 1H), 8.31 (d, 1H, J )
4.8 Hz), and 9.00 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 21.2,
29.7, 32.9, 49.4, 51.8, 106.0, 111.6, 115.3, 117.0, 128.7, 137.2,
146.1, 147.7, 154.8, 157.5, and 166.0. Anal. Calcd for
C15H15N3O3: C, 63.15; H, 5.30; N, 14.73. Found: C, 63.07; H,
5.22; N, 14.81.
1
1152, and 1069 cm-1; H NMR (600 MHz, CDCl3) δ 2.23 (m,
2H), 3.44 (t, 2H, J ) 7.2 Hz), 3.79 (s, 6H), 4.16 (t, 2H, J ) 7.2
Hz), 6.17 (s, 1H), 6.32 (s, 2H), 6.86 (s, 1H), 7.52 (t, 2H, J ) 7.2
Hz), 7.55 (s, 1H), 7.59 (t, 1H, J ) 7.2 Hz), and 7.88 (d, 2H, J
) 7.8 Hz); 13C NMR (150 MHz, CDCl3) δ 21.4, 31.6, 49.4, 55.3,
95.1, 97.6, 108.7, 116.2, 126.9, 129.3, 132.2, 133.2, 141.3, 141.9,
142.1, 157.0, and 161.6; FAB HRMS calcd for [(C22H22N2SO5)
+ Li]+ 433.1409, found 433.1411.
8-Benzenesulfonyl-6-(2-trifluoromethylphenylamino)-
2,3-dihydro-1H-indolizin-5-one (20c) was obtained as a pale
yellow oil (30%): IR (thin film) 1644, 1609, 1585, 1461, 1321,
1
1152, and 1036 cm-1; H NMR (600 MHz, CDCl3) δ 2.24 (m,
2H), 3.41 (t, 2H, J ) 7.2 Hz), 4.19 (t, 2H, J ) 7.2 Hz), 7.16 (m,
2H), 7.42 (s, 1H), 7.53 (m, 4H), 7.60 (t, 1H, J ) 7.8 Hz), 7.66
(d, 1H, J ) 7.8 Hz), and 7.84 (m, 2H); 13C NMR (150 MHz,
CDCl3) δ 21.4, 31.6, 49.4, 108.9, 115.8, 120.9, 121.6, 122.8,
124.0 (q, 1C, J ) 317.7 Hz), 126.9, 127.3, 129.4, 132.2, 133.0,
133.3, 138.7, 141.8, 142.6, and 157.0; FAB HRMS calcd for
[(C21H17N2SO3F3) + Li]+ 441.1072, found 441.1070.
8-Benzenesulfonyl-6-(pyridin-2-ylamino)-2,3-dihydro-
1H-indolizin-5-one (21c). Recrystallization from hexane gave
a white solid: mp 218-220 °C; IR (KBr) 1642, 1591, 1520,
1475, 1317, and 1150 cm-1; 1H NMR (600 MHz, CDCl3) δ 2.23
(m, 2H), 3.46 (t, 2H, J ) 7.2 Hz), 4.21 (t, 2H, J ) 7.2 Hz), 6.76
(d, 1H, J ) 9.0 Hz), 6.81 (dd, 1H, J ) 7.2 and 5.4 Hz), 7.52 (m,
3H), 7.58 (m, 1H), 7.63 (brs, 1H), 7.96 (d, 2H, J ) 7.8 Hz),
8.33 (dd, 1H, J ) 4.8 and 1.8 Hz), and 9.11 (s, 1H); 13C NMR
(150 MHz, CDCl3) δ 21.2, 31.7, 49.5, 111.7, 114.6, 115.8, 116.6,
127.1, 129.2, 129.7, 133.1, 137.2, 142.0, 142.3, 147.8, 154.4,
and 156.9. Anal. Calcd for C19H17N3SO3: C, 62.11; H, 4.66; N,
11.44. Found: C, 62.37; H, 4.75; N, 11.30.
Methyl 6-(2-Bromophenylamino)-5-oxo-1,2,3,5-tetrahy-
droindolizine-8-carboxylate (22b). Recrystallization from
hexane gave a white solid (80%): mp 134-136 °C; IR (KBr)
1
1709, 1639, 1522, 1413, 1269, and 1094 cm-1; H NMR (600
MHz, CDCl3) δ 2.25 (m, 2H), 3.49 (t, 2H, J ) 7.2 Hz), 3.84 (s,
3H), 4.24 (t, 2H, J ) 7.2 Hz), 6.85 (ddd, 1H, J ) 7.8, 7.2, and
1.8 Hz), 7.16 (brs, 1H), 7.30 (ddd, 1H, J ) 7.8, 7.2, and 1.8
Hz), 7.44 (dd, 1H, J ) 7.8 and 1.8 Hz), 7.58 (dd, 1H, J ) 8.4
and 1.8 Hz), and 7.62 (s, 1H); 13C NMR (150 MHz, CDCl3) δ
21.2, 32.9, 49.3, 51.8, 105.3, 112.2, 114.8, 118.1, 122.6, 128.2,
130.5, 133.3, 139.1, 146.0, 157.7, and 165.7. Anal. Calcd for
C16H15BrN2O3: C, 52.91; H, 4.16; N, 7.71. Found: C, 52.71;
H, 4.18; N, 7.54.
1,2,3,6-Tetrahydroindolizino[6,7-b]indol-5-one (26). A
flame-dried, 20 mL, heavy-walled Pyrex tube was charged with
Pd(PPh3)4 (0.03 g, 0.02 mmol, 10 mol %), pyridone 22a (0.07
g, 0.23 mmol), and Cs2CO3 (0.11 g, 0.34 mmol). The solid
reactants were dissolved in 4 mL of dioxane, and the tube was
sealed with a Teflon screw cap. The reaction was heated at
110 °C for 24 h in an oil bath. The reaction mixture was cooled
to room temperature, diluted with ethyl acetate, filtered
through a pad of Celite, and concentrated under reduced
pressure. The crude material was purified by silica gel chro-
matography on silica gel to give â-carbolinone 26 (0.03 g, 0.15
mmol) in 65% yield. Recrystallization from hexane gave a
white solid: mp 170-172 °C; IR (KBr) 1661, 1594, 1566, 1301,
8-Benzenesulfonyl-6-phenylamino-2,3-dihydro-1H-in-
dolizin-5-one (16c) was obtained as a pale yellow oil (50%):
IR (thin film) 1638, 1589, 1520, 1446, 1150, and 1072 cm-1
;
1H NMR (600 MHz, CDCl3) δ 2.23 (m, 2H), 3.42 (t, 2H, J )
7.2 Hz), 4.17 (t, 2H, J ) 7.2 Hz), 6.91 (brs, 1H), 7.06 (t, 1H, J
) 7.8 Hz), 7.16 (d, 2H, J ) 7.8 Hz), 7.36 (t, 2H, J ) 7.8 Hz),
7.49 (s, 1H), 7.55 (m, 3H), and 7.87 (d, 2H, J ) 8.4 Hz); 13C
NMR (150 MHz, CDCl3) δ 21.4, 31.5, 49.4, 107.3, 116.1, 119.4,
122.8, 126.9, 128.5, 129.3, 129.6, 132.5, 140.3, 141.1, 141.9,
and 157.1; FAB HRMS calcd for [(C20H18N2SO3) + Li]+
373.1198, found 373.1194.
and 1255 cm-1 1H NMR (600 MHz, CDCl3) δ 2.31 (m, 2H),
;
3.21 (t, 2H, J ) 7.2 Hz), 4.35 (t, 2H, J ) 7.2 Hz), 6.87 (s, 1H),
7.22 (t, 1H, J ) 7.8 Hz), 7.45 (t, 1H, J ) 7.2 Hz), 7.58 (d, 1H,
J ) 8.4 Hz), 7.92 (d, 1H, J ) 7.8 Hz), and 10.09 (brs, 1H); 13
C
8-Benzenesulfonyl-6-(4-methoxyphenylamino)-2,3-di-
hydro-1H-indolizin-5-one (17c) was obtained as a pale
yellow oil (65%): IR (thin film) 1636, 1599, 1306, 1151, and
1101 cm-1; 1H NMR (600 MHz, CDCl3) δ 2.21 (m, 2H), 3.39 (t,
2H, J ) 7.2 Hz), 3.83 (s, 3H), 4.16 (t, 2H, J ) 7.2 Hz), 6.68 (s,
1H), 6.92 (d, 1H, J ) 8.4 Hz), 7.11 (d, 2H, J ) 8.4 Hz), 7.23 (s,
1H), 7.51 (m, 2H), 7.58 (m, 2H), and 7.84 (d, 2H, J ) 7.2 Hz);
13C NMR (150 MHz, CDCl3) δ 21.5, 31.4, 49.3, 55.6, 105.7,
114.9, 116.3, 122.7, 126.9, 128.3, 129.2, 133.1, 134.1, 140.2,
142.0, 156.0, and 156.9; FAB HRMS calcd for [(C21H20N2SO4)
+ Li]+ 403.1304, found 403.1302.
8-Benzenesulfonyl-6-(4-nitrophenylamino)-2,3-dihydro-
1H-indolizin-5-one (18c) was obtained as a pale yellow oil
(63%): IR (thin film) 1637, 1593, 1562, 1479, 1321, 1301, and
1112 cm-1; 1H NMR (600 MHz, CDCl3) δ 2.27 (m, 2H), 3.47 (t,
2H, J ) 7.2 Hz), 4.20 (t, 2H, J ) 7.2 Hz), 7.17 (d, 2H, J ) 9.0
Hz), 7.35 (brs, 1H), 7.57 (t, 2H, J ) 7.8 Hz), 7.64 (t, 1H, J )
7.8 Hz), 7.90 (d, 2H, J ) 7.8 Hz), and 8.23 (d, 2H, J ) 9.0 Hz);
13C NMR (150 MHz, CDCl3) δ 21.2, 31.8, 49.7, 112.7, 116.0,
116.3, 126.1, 127.0, 129.5, 129.8, 133.5, 141.4, 141.6, 144.4,
146.6, and 157.0; FAB HRMS calcd for [(C20H17N3SO5) + Li]+
418.1049, found 418.1046.
NMR (150 MHz, CDCl3) δ 22.8, 31.1, 48.1, 95.7, 112.4, 119.8,
121.2, 122.2, 126.4 (2C), 126.8, 139.7, 140.2, and 159.5; FAB
HRMS calcd for [(C14H12N2O) + Li]+ 231.1110, found 231.1109.
Methyl 5-Oxo-2,3,5,6-tetrahydro-1H-indolizino[6,7-b]-
indole-11-carboxylate (27). A flame-dried, 20 mL, heavy-
walled Pyrex tube was charged with Pd(PPh3)4 (0.06 g, 0.05
mmol, 10 mol %), pyridone 22b (0.18 g, 0.5 mmol), and Cs2-
CO3 (0.24 g, 0.74 mmol). The solid reactants were dissolved
in 5 mL of dioxane, and the tube was sealed with a Teflon
screw cap. The reaction was heated at 110 °C for 24 h in an
oil bath. The reaction mixture was cooled to room temperature,
diluted with ethyl acetate, filtered through a pad of Celite,
and concentrated under reduced pressure. The crude material
was purified by silica gel chromatography on silica gel to give
â-carbolinone 27 (0.09 g, 0.3 mmol) in 65% yield. Recrystalli-
zation from hexane gave a white solid: mp 250 °C; IR (KBr)
1
1707, 1655, 1555, 1383, 1307, and 1143 cm-1; H NMR (400
MHz, DMSO-d6) δ 2.19 (m, 2H), 3.45 (t, 2H, J ) 7.2 Hz), 3.94
(s, 3H), 4.18 (t, 2H, J ) 7.2 Hz), 7.14 (ddd, 1H, J ) 8.4 and
2.4 Hz), 7.40 (ddd, 1H, J ) 8.4 and 2.4 Hz), 7.51 (d, 1H, J )
8.4 Hz), 8.35 (d, 1H, J ) 8.4 Hz), and 12.18 (brs, 1H); 13C NMR
J. Org. Chem, Vol. 70, No. 20, 2005 8061

Mmutlane et al.
(150 MHz, DMSO-d6) δ 21.5, 32.2, 49.4, 52.1, 102.1, 112.0,
113.1, 119.0, 120.1, 121.2, 125.3, 126.7, 140.0, 147.3, 154.0,
and 166.5; FAB HRMS Calcd for [(C16H14N2O3) + Li]+ 289.1164,
found 289.1151.
(dt, 1H, J ) 16.0 and 6.0 Hz), 6.65 (d, 1H, J ) 16.0), 7.16-
7.25 (m, 4H), and 7.32 (d, 2H, J ) 7.2 Hz); 13C NMR (100 MHz,
CDCl3) δ 20.8, 32.8, 49.1, 51.7, 69.6, 103.9, 115.2, 123.2, 126.4,
127.8, 128.3, 133.6, 136.0, 145.5, 148.6, 157.5, and 165.4;
HRMS calcd for C19H20NO4 [M + H]+ 326.1392, found 326.1383.
Methyl 6-Allyloxy-5-oxo-1,2,3,5-tetrahydroindolizidine-
8-carboxylate (29). To a solution containing 0.5 g (2.4 mmol)
of pyridone 10 in 50 mL of acetone were added 0.3 mL (3.6
mmol) of allyl bromide and 0.5 g (3.6 mmol) of potassium
carbonate, and the resultant mixture was heated at reflux
under nitrogen for 18 h. The mixture was allowed to cool to
room temperature and filtered through Celite, and the filtrate
was concentrated under reduced pressure. Purification of the
resultant residue by silica gel column chromatography gave
0.57 g (96%) of 29 as a colorless oil: IR (NaCl film) 2951, 1709,
1655, 1611, and 1214 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.19
(quint, 2H, J ) 7.5 Hz), 3.43 (t, 2H, J ) 7.5 Hz), 3.81 (s, 3H),
4.15 (t, 2H, J ) 7.4 Hz), 4.55 (d, 2H, J ) 5.1 Hz), 5.26 (brd,
1H, J ) 10.5 Hz), 5.38 (brd, 1H, J ) 17.1 Hz), 5.95-6.08 (m,
1H), and 7.19 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.0, 32.9,
49.1, 51.7, 69.8, 103.7, 115.1, 118.3, 132.3, 145.7, 148.6, 157.4,
and 165.4; HRMS calcd for C13H16NO4 [M + H]+ 250.1079,
found 250.1072.
Methyl 6-(But-2-enyloxy)-5-oxo-1,2,3,5-tetrahydroin-
dolizidine-8-carboxylate (30). To a solution containing 0.5
g (2.4 mmol) of pyridone 10 in 50 mL of acetone were added
0.35 mL (3.6 mmol) of crotyl chloride, 0.5 g (3.6 mmol) of
potassium carbonate, and 0.36 g (2.4 mmol) of sodium iodide,
and the resultant mixture was heated at reflux under nitrogen
for 18 h. The mixture was allowed to cool to room temperature
and filtered through Celite, and the filtrate was concentrated
under reduced pressure. Purification of the resultant residue
by silica gel chromatography gave 0.57 g (90%) of 30 as a
colorless oil: IR (NaCl film) 2949, 1709, 1658, 1612, and 1213
cm-1; 1H NMR (400 MHz, CDCl3) δ 1.69-1.73 (m, 3H), 2.14-
2.22 (m, 2H), 3.43 (t, 2H, J ) 7.8 Hz), 3.82 (s, 3H), 4.15 (t, 2H,
J ) 7.6 Hz), 4.46 (d, 1H, J ) 6.0 Hz), 4.62 (d, 1H, J ) 6.0 Hz),
5.64-5.75 (m, 1H), 5.78-5.85 (m, 1H), and 7.16 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 17.7, 21.1, 32.9, 49.1, 51.7, 69.7,
103.7, 114.7, 125.2, 131.2, 145.9, 148.3, 157.5, and 165.5;
HRMS calcd for C14H18NO4 [M + H]+ 264.1236, found 264.1228.
Methyl 6-(2-Methylallyloxy)-5-oxo-1,2,3,5-tetrahydroin-
dolizidine-8-carboxylate (31). To a solution containing 0.5
g (2.4 mmol) of pyridone 10 in 50 mL of acetone was added
0.35 mL (3.6 mmol) of methallyl chloride, 0.5 g (3.6 mmol) of
potassium carbonate, and 0.36 g (2.4 mmol) of sodium iodide,
and the resultant mixture was heated at reflux under nitrogen
for 18 h. The mixture was then allowed to cool to room
temperature and filtered through Celite, and the filtrate was
concentrated under reduced pressure. Purification of the
resultant residue by silica gel column chromatography gave
0.62 g (98%) of 31 as a colorless oil: IR (NaCl film) 2950, 1710,
1657, 1612, and 1214 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.78
(s, 3H), 2.18 (quint., 2H, J ) 7.7 Hz), 3.42 (t, 2H, J ) 7.6 Hz),
3.84 (s, 3H), 4.15 (t, 2H, J ) 7.6 Hz), 4.46 (s, 2H), 4.96 (brs,
1H), 5.06 (brs, 1H), and 7.47 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 19.2, 21.0, 32.9, 49.1, 51.7, 72.6, 103.7, 113.3, 115.3,
139.8, 145.8, 148.6, 157.4, and 165.4; HRMS calcd for C14H18-
NO4 [M + H]+ 264.1236, found 264.1228.
Methyl 5-Oxo-6-(3-phenylallyloxy)-1,2,3,5-tetrahydroin-
dolizidine-8-carboxylate (32). To a solution containing 0.5
g (2.4 mmol) of pyridone 10 in 50 mL of acetone was added
0.36 mL (2.6 mmol) of cinnamyl chloride, 0.36 g (2.6 mmol) of
potassium carbonate, and 0.36 g (2.4 mmol) of sodium iodide,
and the resultant mixture was heated at reflux under nitrogen
for 18 h. The mixture was then allowed to cool to room
temperature and filtered through Celite, and the filtrate was
concentrated under reduced pressure. Purification of the
resultant residue by silica gel column chromatography gave
0.74 g (95%) of 32 as a colorless oil: IR (NaCl film) 3025, 2950,
1708, 1652, 1610, and 1214 cm-1; 1H NMR (400 MHz, CDCl3)
δ 2.12 (quint., 2H, J ) 7.2 Hz), 3.36 (t, 2H, J ) 7.0 Hz), 3.80
(s, 3H), 4.10 (t, 2H, J ) 7.6 Hz), 4.68 (d, 2H, J ) 5.6 Hz), 6.37
Methyl 7-Allyl-6-hydroxy-5-oxo-1,2,3,5-tetrahydroin-
dolizine-8-carboxylate (33). A solution of 0.5 g of pyridone
29 in 2 mL of DMF was immersed in an oil bath that was
preheated to 160 °C and was stirred under a nitrogen
atmosphere. After heating for 1 h, the dark solution was cooled
to room temperature and was purified by silica gel column
chromatography followed by recrystallization from ethyl ac-
etate-hexane to give 0.35 g (70%) of 33 as white crystals: mp
100-101 °C; IR (NaCl film) 3278, 2950, 1714, 1635, 1597, and
1271 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.20 (quint., 2H, J )
7.6 Hz), 3.32 (t, 2H, J ) 7.8 Hz), 3.62 (dt, 2H, J ) 6.1 and 1.4
Hz), 3.82 (s, 3H), 4.19 (t, 2H, J ) 7.6 Hz), 5.00-5.06 (m, 2H),
5.85-5.95 (m, 1H), and 6.68 (brs, 1H); 13C NMR (100 MHz,
CDCl3) δ 21.4, 30.7, 32.9, 49.2, 51.7, 108.0, 115.7, 126.7, 135.1,
141.9, 144.4, 156.7, and 166.5. Anal. Calcd for C13H15NO4: C,
62.64; H, 6.07; N, 5.62. Found: C, 62.76; H, 5.97, N, 5.60.
Methyl 6-Hydroxy-7-(1-methylallyl)-5-oxo-1,2,3,5-tet-
rahydroindolizidine-8-carboxylate (34). A solution of 0.5
g of pyridone 30 in 2 mL of DMF was immersed in an oil bath
that was preheated to 160 °C and was stirred under a nitrogen
atmosphere. After heating for 1 h, the dark solution was cooled
to room temperature and was purified by silica gel chroma-
tography followed by recrystallization from ethyl acetate-
hexane to give 0.4 g (84%) of 34 as white needles: mp 89-90
°C; IR (NaCl film) 3247, 2971, 1716, 1638, 1596, and 1274
1
cm-1; H NMR (400 MHz, CDCl3) δ 1.42 (d, 3H, J ) 7.2 Hz),
2.17 (quint, 2H, J ) 7.5 Hz), 3.11-3.26 (m, 2H), 3.81 (s, 3H),
3.81-3.87 (m, 1H), 4.16 (t, 2H, J ) 7.4 Hz), 5.00 (dt, 1H, J )
10.4 and 1.6 Hz), 5.04. (dt, 1H, J ) 17.2 and 1.6 Hz), 6.18 (ddd,
1H, J ) 17.2, 10.4 and 1.6 Hz), and 6.91 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 17.5, 21.6, 32.0, 37.5, 49.1, 51.8, 108.9,
113.9, 130.6, 140.2, 141.8, 141.9, 156.9, and 167.2. Anal. Calcd
for C14H17NO4: C, 63.87; H, 6.51; N, 5.32. Found: C, 63.99,
H, 6.50; N, 5.32.
Methyl 6-Hydroxy-7-(2-methylallyl)-5-oxo-1,2,3,5-tet-
rahydroindolizidine-8-carboxylate (35). A solution of 0.5
g of pyridone 31 in 2 mL of DMF was immersed in an oil bath
that was preheated to 160 °C and stirred under a nitrogen
atmosphere. After heating for 1 h, the dark solution was cooled
to room temperature and was purified by silica gel chroma-
tography followed by recrystallization from ethyl acetate-
hexane to give 0.42 g (84%) of 35 as a white solid: mp 124-
125 °C; IR (NaCl film) 3259, 1713, 1640, 1599, and 1273 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.74 (s, 3H), 2.18 (quint, 2H, J
) 7.6 Hz), 3.29 (t, 2H, J ) 7.6 Hz), 3.58 (s, 2H), 3.77 (s, 3H),
4.19 (t, 2H, J ) 7.4 Hz), 4.41 (brs, 1H), 4.69 (brs, 1H), and
7.02 (brs, 1H); 13C NMR (100 MHz, CDCl3) δ 21.4, 23.0, 32.7,
33.8, 49.1, 51.6, 108.3, 110.1, 126.5, 142.2, 143.4, 143.9, 156.7,
and 166.5. Anal. Calcd for C14H17NO4: C, 63.87; H, 6.51; N,
5.32. Found: C, 63.85; H, 6.56; N, 5.32.
Methyl 6-Hydroxy-5-oxo-7-(1-phenylallyl)-1,2,3,5-tet-
rahydroindolizidine-8-carboxylate (36). A solution of 0.2
g of pyridone 32 in 2 mL of DMF was immersed in an oil bath
that was preheated to 160 °C and stirred under a nitrogen
atmosphere. After heating for 1 h, the dark solution was cooled
to room temperature and was purified by silica gel column
chromatography followed by recrystallization from ethyl ac-
etate-hexane to give 0.16 g (80%) of 36 as cream white
crystals: mp 135-136 °C; IR (NaCl film) 3232, 2945, 1716,
1634, 1539, and 1270 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.20-
2.29 (m, 2H), 3.18-3.39 (m, 2H), 3.61 (s, 3H), 4.19-4.30 (m,
2H), 5.31-5.38 (m, 3H), 6.60 (ddd, 1H, J ) 17.2, 10.0 and 8.6
Hz), 6.88 (brs, 1H), and 7.21-7.39 (m, 5H); 13C NMR (100
MHz, CDCl3) δ 21.6, 32.3, 47.6, 49.2, 51.6, 108.6, 117.8, 126.0,
127.2, 128.0, 128.6, 137.1, 141.5, 142.3, 142.7, 156.9, and 166.8.
Anal. Calcd for C19H19NO4: C, 70.14; H, 5.89; N, 4.30. Found:
C, 70.26; H, 5.80; N, 4.25.
8062 J. Org. Chem., Vol. 70, No. 20, 2005

Preparation of Novel Indolizinone-Based Compounds
Methyl 2-Methyl-8-oxo-5,6,7,8-tetrahydro-1-oxa-7a-aza-
indacene-4-carboxylate (37). To a solution containing 0.3
g (1.2 mmol) of pyridone 33 in 6 mL of DMF at 25 °C was
added a solution containing 0.21 g (1.2 mmol) of copper(II)
chloride dihydrate in 4 mL of water followed by palladium(II)
chloride (0.021 g, 0.11 mmol), and the reaction mixture was
stirred at room temperature under an oxygen atmosphere for
12 h. The dark reaction mixture was poured into a separatory
funnel containing 100 mL of water and was extracted with
100 mL of ethyl acetate. The organic layer was dried over
MgSO4 and filtered through Celite, and the filtrate was
concentrated under reduced pressure. Purification of the
resultant white solid by silica gel column chromatography gave
0.29 g (97%) of 37 as a white solid which was purified further
by recrystallization from dichloromethane: mp 159-160 °C;
IR (NaCl film) 1710, 1672, 1566, and 1235 cm-1; 1H NMR (400
MHz, CDCl3) δ 2.23 (quint, 2H, J ) 7.7 Hz), 2.44 (s, 3H), 3.52
(t, 2H, J ) 7.8 Hz), 3.87 (s, 3H), 4.21 (t, 2H, J ) 7.4 Hz), and
6.72 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 14.1, 21.5, 33.3,
48.5, 51.5, 99.6, 105.4, 134.6, 140.5, 151.7, 152.8, 159.9, and
165.7. Anal. Calcd for C13H13NO4: C, 63.15; H, 5.30; N, 5.67.
Found: C, 63.34; H, 5.55; N, 5.44.
33.0, 48.4, 51.4, 101.4, 111.9, 133.2, 140.4, 150.0, 151.8, 156.4,
and 165.9; HRMS calcd for C14H16NO4 [M + H]+ 262.1079,
found 262.1074.
Methyl 2-Methyl-8-oxo-3-phenyl-5,6,7,8-tetrahydro-1-
oxa-7a-azaindacene-4-carboxylate (39). To a solution con-
taining 0.08 g (0.24 mmol) of 36 in 4 mL of DMF, stirred at
room temperature, was added a solution containing 0.042 g
(0.24 mmol) of copper(II) chloride dihydrate in 4 mL of water
followed by palladium(II) chloride (4.2 mg, 0.024 mmol), and
the reaction mixture was stirred at room temperature under
an oxygen atmosphere for 12 h. The dark reaction mixture was
poured into a separatory funnel containing 100 mL of water
and was extracted with 100 mL of ethyl acetate. The organic
layer was dried over MgSO4 and filtered through Celite, and
the filtrate was concentrated under reduced pressure. Purifi-
cation of the resultant dark oil silica gel column chromatog-
raphy gave 0.064 g (80%) of 39 as a colorless oil: IR (NaCl
film) 2955, 1711, 1670, 1562, and 1219 cm-1 1H NMR (400
;
MHz, CDCl3) δ 2.26 (quint., 2H, J ) 7.6 Hz), 2.40 (s, 3H), 2.93
(s, 3H) 3.42 (t, 2H, J ) 7.6 Hz), 4.28 (t, 2H, J ) 7.2 Hz), 7.19-
7.21 (m, 2H), 7.33-7.36 (m, 1H), and 7.41-7.44 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 12.8, 21.9, 32.3, 48.6, 50.6, 100.9,
119.0, 127.0, 127.1, 128.3, 128.7, 129.0, 134.0, 150.4, 157.2,
and 165.7; HRMS calcd for C19H18NO4 [M + H]+ 324.1236,
found 324.1230.
Methyl 2,3-Dimethyl-8-oxo-5,6,7,8-tetrahydro-1-oxa-7a-
azaindacene-4-carboxylate (38). To a solution containing
0.32 g (1.2 mmol) of pyridone 34 in 6 mL of DMF, stirred at
room temperature, was added a solution containing 0.21 g (1.2
mmol) of copper(II) chloride dihydrate in 4 mL of water
followed by palladium(II) chloride (0.021 g, 0.11 mmol), and
the reaction mixture was stirred at room temperature under
an oxygen atmosphere for 12 h. The dark reaction mixture was
poured into a separatory funnel containing 100 mL of water
and was extracted with 100 mL of ethyl acetate. The organic
layer was dried over MgSO4 and filtered through Celite and
the filtrate concentrated under reduced pressure. Purification
of the resultant solid by silica gel column chromatography gave
0.3 g (95%) of 38 as a white solid: mp 128-129 °C; IR (NaCl
Acknowledgment. We appreciate the financial sup-
port provided by the National Institutes of Health (GM
059384) and the National Science Foundation (CHE-
0450779). E.M.M. is grateful for a postdoctoral fellow-
ship from the National Research Foundation (NRF) of
South Africa.
Supporting Information Available: 1H and 13C NMR
data of various key compounds lacking CH,N analyses. This
material is available free of charge via the Internet at
http://pubs.acs.org.
film) 2980, 1708, 1669, 1556, and 1243 cm-1 1H NMR (400
;
MHz, CDCl3) δ 2.09 (s, 3H), 2.19 (quint, 2H, J ) 7.6 Hz), 2.37
(s, 3H), 3.39 (t, 2H, J ) 7.8 Hz), 3.85 (s, 3H), and 4.20 (t, 2H,
J ) 7.4 Hz); 13C NMR (100 MHz, CDCl3) δ 11.0, 12.2, 21.7,
JO0511492
J. Org. Chem, Vol. 70, No. 20, 2005 8063