An isomunchnone-based method for the synthesis of highly substituted 2(1H)-pyridones

Article abstract of DOI:10.1021/jo9911600

1-(Benzenesulfonyl-diazoacetyl)-pyrrolidin-2-one was prepared by a diazo transfer of 1-(benzenesulfonylacetyl)-pyrrolidin-2-one with p- acetamidobenzenesulfonyl azide and triethylamine. Treatment of the diazoimide with a catalytic quantity of rhodium(II) acetate resulted in the formation of an isomunchnone dipole, which underwent bimolecular trapping with various dipolarophiles in high yield. The initially formed cycloadducts were not isolable or observed, as they all readily underwent ring opening to give the 3-hydroxy-2(1H)-pyridone ring system. The 3-hydroxy-2(1H)pyridones were readily converted to the corresponding triflates, which function as suitable substrates in various types of palladium-catalyzed cross-coupling reactions. Commercial tetrakis(triphenylphoshine)palladium was found to be a particularly effective catalyst for the cross-coupling with aryl, vinyl, and acetylenic partners. An application of the method to the synthesis of the indolizidine alkaloid (±)-ipalbidine was carried out in eight steps in 17% overall yield. The angiotensin-converting enzyme inhibitor (-)-A58365A was also synthesized by a process based on the [3 + 2]-cycloaddition reaction of a phenylsulfonyl substituted isomunchnone intermediate. The starting material for this process was prepared from L-pyroglutamic acid and involved using a diazo phenylsulfonyl substituted pyrrolidine imide. Treatment of the diazoimide with Rh₂(OAc)₄ in the presence of methyl vinyl ketone afforded a 3-hydroxy-2-pyridone derivative, which was subsequently converted to the ACE inhibitor in six additional steps.

Full text of DOI:10.1021/jo9911600

8648
J . Org. Chem. 1999, 64, 8648-8659
An Isom u1 n ch n on e-Ba sed Meth od for th e Syn th esis of High ly
Su bstitu ted 2(1H)-P yr id on es
Albert Padwa,* Scott M. Sheehan, and Christopher S. Straub
Department of Chemistry, Emory University, Atlanta, Georgia 30322
Received J uly 21, 1999
1-(Benzenesulfonyl-diazoacetyl)-pyrrolidin-2-one was prepared by a diazo transfer of 1-(benzene-
sulfonylacetyl)-pyrrolidin-2-one with p-acetamidobenzenesulfonyl azide and triethylamine. Treat-
ment of the diazoimide with a catalytic quantity of rhodium(II) acetate resulted in the formation
of an isomu¨nchnone dipole, which underwent bimolecular trapping with various dipolarophiles in
high yield. The initially formed cycloadducts were not isolable or observed, as they all readily
underwent ring opening to give the 3-hydroxy-2(1H)-pyridone ring system. The 3-hydroxy-2(1H)-
pyridones were readily converted to the corresponding triflates, which function as suitable substrates
in various types of palladium-catalyzed cross-coupling reactions. Commercial tetrakis(triphen-
ylphoshine)palladium was found to be a particularly effective catalyst for the cross-coupling with
aryl, vinyl, and acetylenic partners. An application of the method to the synthesis of the indolizidine
alkaloid (()-ipalbidine was carried out in eight steps in 17% overall yield. The angiotensin-converting
enzyme inhibitor (-)-A58365A was also synthesized by a process based on the [3 + 2]-cycloaddition
reaction of a phenylsulfonyl substituted isomu¨nchnone intermediate. The starting material for this
process was prepared from L-pyroglutamic acid and involved using a diazo phenylsulfonyl substituted
pyrrolidine imide. Treatment of the diazoimide with Rh2(OAc)4 in the presence of methyl vinyl
ketone afforded a 3-hydroxy-2-pyridone derivative, which was subsequently converted to the ACE
inhibitor in six additional steps.
Six-membered nitrogen heterocycles comprise the back-
active ingredients in drugs for the therapy of fibrotic
disease and have been evaluated as inhibitors of human
leukocyte elastase.11 The pyridone acids 1 and 2, which
bone of many biologically and structurally interesting
alkaloids.1,2 The 2(1H)-pyridone ring system is a valuable
building block in natural product synthesis, as it can act
as a common intermediate for the preparation of a wide
variety of piperidine, pyridine, quinolizidine, and in-
dolizidine alkaloids.3,4 This substructure is also found in
a large number of natural products such as camptoth-
ecin,5 elastase,6 and thrombin.7 N-Alkyl substituted py-
ridones are known to exhibit both antibacterial and
antifungal activity.8 4-Hydroxy-2(1H)-pyridones such as
pyridoxatin9 and huperzine A10 have become increasingly
important in the treatment of a variety of diseases.
N-Substituted 2-pyridones have also been utilized as
were obtained from the fermentation broth of the bacte-
rium Streptomyces chromofuscus in the Eli Lilly labora-
tories, were found to be ACE inhibitors at nanomolar
concentrations.12 This property makes them of potential
value as lead compounds for the design of drugs to lower
blood pressure.
(1) Rubiralta, M.; Giralt, E.; Diez, A. Piperidine: Structure, Prepara-
tion, Reactivity, and Synthetic Applications of Piperidine and its
Derivatives; Elsevier: Amsterdam, 1991.
Numerous methods for the preparation of substituted
2-pyridones have been reported in the literature.13 As far
back as 1892, Decker investigated the oxidation of
pyridinium salts to produce the corresponding 2-pyri-
dones using ferricyanide under basic conditions.14 This
(2) Strunz, G. M.; Findlay, J . A. The Alkaloids; Academic Press:
New York, 1985; Vol. 26, p 89. Southon, I. W., Buckingham, J .
Dictionary of Alkaloids; Chapman and Hall: London, 1989. Daly, J .
W. J . Nat. Prod. 1998, 61, 162.
(3) Scriven, E. F. V. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984;
Vol. 2.
(4) Elbein, A. D.; Molyneux, R. J . In Alkaloids: Chemical and
Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New York, 1981;
Vol. 5, pp 1-54.
(5) For total synthesis of camptothecin using substituted pyridones
as starting materials, see: Comins, D. L.; Hong, H.; Saha, J . K.;
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J ianhua, G. Tetrahedron Lett. 1994, 35, 5331. Curran, D. P.; Liu, H.
J . Am. Chem. Soc. 1992, 114, 5863.
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10.1021/jo9911600 CCC: $18.00 © 1999 American Chemical Society
Published on Web 10/22/1999

Isomu¨nchnone-Based Synthesis of 2(1H)-Pyridones
J . Org. Chem., Vol. 64, No. 23, 1999 8649
Sch em e 1
approach provides easy access to a variety of 2-pyridones
as long as the starting pyridinium salts are available.
Substituted 2-pyridones are generally prepared, however,
from acyclic starting materials that often incorporate a
Michael addition as the key synthetic step.15 The 2-py-
ridone ring system has also been synthesized through a
variety of cycloaddition16,17 and cyclization procedures.18
However, only a few methods of preparing 3-hydroxy-
2(1H)-pyridones have been reported,19 and they typically
involve harsh conditions that preclude the presence of
sensitive functional groups.20 In this paper, we describe
a new, general, and flexible entry to a variety of 3-hy-
droxy substituted 2-pyridones.21 The cornerstone of our
synthetic plan is the [3 + 2]-cycloaddition of a phenyl-
sulfonyl substituted isomu¨nchnone intermediate (i.e.,
4).22,23 Once the cycloaddition reaction occurs, the result-
ing adduct 5 undergoes ready ring opening to give the
desired pyridone 6 (Scheme 1).24 The versatility of our
strategy lies in the fact that, by appropriate selection of
the diazo precursor 3 and dipolarophile, various groups
can be introduced into the N-1 and C-4, C-5, C-6 posi-
tions. Moreover, substituents can be subsequently intro-
duced at C-3 by conversion of the hydroxyl functionality
to a triflate group,25 followed by a palladium-catalyzed
cross-coupling reaction.26 To highlight the method, the
above synthetic strategy was applied to the synthesis of
several indolizidine alkaloids. Among other examples,
this procedure was employed in an efficient synthesis of
(()-ipalbidine27 (7) and the angiotensin converting en-
zyme inhibitor (-)-A58365A (1) (Scheme 2).28
Sch em e 2
(13) J ones, G. In Comprehensive Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford,
1996; Vol. 5. Comins, D. L.; J ianhua, G. Tetrahedron Lett. 1994, 35,
2819. Sieburth, S. M.; Hiel, G.; Lin, C. H.; Kuan, D. P. J . Org. Chem.
1994, 59, 80. Schmidhauser, J . C.; Khouri, F. F. Tetrahedron Lett. 1993,
34, 6685. Sieburth, S. M.; Chen, J . L. J . Am. Chem. Soc. 1991, 113,
8163.
Resu lts a n d Discu ssion
The preparation of the requisite diazoimide 9 was
accomplished by a diazo transfer reaction29 of 1-[(benze-
nesulfonyl)acetyl]pyrrolidine-2-one with p-acetamidoben-
zenesulfonyl azide30 and triethylamine. Formation of the
isomu¨nchnone ring was achieved by the reaction of 9 with
Rh2(OAc)4 to give a rhodium carbenoid species that
undergoes an intramolecular cyclization onto the neigh-
boring carbonyl oxygen to form the mesoionic dipole 4.
Bimolecular trapping of the dipole with N-phenylmale-
imide or phenyl vinyl sulfone proceeded in 87% and 63%
yield, respectively (Scheme 3). The initially formed cy-
cloadducts (i.e., 5) were not isolable, as they readily
underwent ring opening to give the 3-hydroxy-2(1H)-
pyridones 12 and 14. As a consequence of its hydrolytic
reactivity, cycloadduct 12 was immediately reacted with
triisopropylsilyl chloride to give silyl ether 13. In a
similar fashion, 3-hydroxy pyridone 14 was allowed to
react with acetic anhydride, dimethyl sulfate, or N-phenyl
trifluoromethanesulfonamide31 to give the crystalline
derivatives 15-17 in high yield.
(14) Decker, H. Chem. Ber. 1892, 25, 443.
(15) Aggarwal, V.; Singh, G.; Ila, H.; J unjappa, H. Synthesis 1982,
214. Datta, A.; Ila, H.; J unjappa, H. J . Org. Chem. 1990, 55, 5589.
Chuit, C.; Corriu, R. J . P.; Perz, R.; Reye, C. Tetrahedron 1986, 42,
2293. Cainelli, G.; Panunzio, M.; Giacomini, D.; Simone, B. D.;
Camerini, R. Synthesis 1994, 805.
(16) Kappe, T.; Pocivalnik, D. Heterocycles 1983, 20, 1367. Tutonda,
M. G.; Vandenberghe, S. M.; Van Aken, K. J .; Hoornaert, G. J . J . Org.
Chem. 1992, 57, 2935. Gotthardt, H.; Flosbach, C. Chem. Ber. 1988,
121, 951.
(17) McKillop, A.; Boulton, A. J . In Comprehensive Heterocyclic
Chemistry; Boulton, A. J ., McKillop, A., Eds.; Pergamon: Oxford, 1984;
Vol. 2, p 67.
(18) Gurski Birchler, A.; Liu, F.; Liebeskind, L. S. J . Org. Chem.
1994, 59, 7737. Zhang, S.; Liebeskind, L. S. J . Org. Chem. 1999, 64,
4042.
(19) Molenda, J . J .; J ones, M. M.; J ohnston, D. S.; Walker, E. M.;
Cannon, D. J . J . Med. Chem. 1994, 37, 4363.
(20) Meislich, H. Chemistry of Heterocyclic Compounds; Interscience
Publishers: New York, 1962; Chapter 12, p 509. Tieckelmann, H.
Chemistry of Heterocyclic Compounds; Interscience Publishers: New
York, 1974; Chapter 12, p 597.
(21) For a preliminary report, see: Straub, C. S.; Padwa, A. Org.
Lett. 1999, 1, 83.
(22) Hamaguchi, M.; Ibata, T. Tetrahedron Lett. 1974, 4475. Hamagu-
chi, M.; Ibata, T. Chem. Lett. 1975, 499.
(27) Hart, N. K.; J ohns, S. R.; Lamberton, J . A. Aust. J . Chem. 1968,
21, 2579. Wick, A. E.; Bartlett, P. A.; Dolphin, D. Helv. Chim. Acta
1971, 54, 513.
(28) For some earlier syntheses, see: Fang, F. G.; Danishefsky, S.
J . Tetrahedron Lett. 1989, 30, 3621. Wong, P. L.; Moeller, K. D. J . Am.
Chem. Soc. 1993, 115, 11434. Clive, D. L. J .; Zhou, Y.; de Lima, D. P.
J . Chem. Soc., Chem. Comm. 1996, 1463. Clive, D. L. J .; Coltart, D.
M. Tetrahedron Lett. 1998, 39, 2519. Clive, D. L. J .; Coltart, D. M.;
Zhou, Y. J . Org. Chem. 1999, 64, 1447.
(23) Sheehan, S. M.; Padwa, A. J . Org. Chem. 1997, 62, 438. Marino,
J . P., J r.; Osterhout, M. H.; Padwa, A. J . Org. Chem. 1995, 60, 2704.
Padwa, A.; Hertzog, D. L.; Nadler, W. R. J . Org. Chem. 1994, 59, 7072.
Marino, J . P., J r.; Osterhout, M. H.; Price, A. T.; Semones, M. A.;
Padwa, A. J . Org. Chem. 1994, 59, 5518. Padwa, A.; Hertzog, D. L.;
Nadler, W. R.; Osterhout, M. H.; Price, A. T. J . Org. Chem. 1994, 59,
1418. Hertzog, D. L.; Austin, D. J .; Nadler, W. R.; Padwa, A.
Tetrahedron Lett. 1992, 33, 4731.
(24) Padwa, A. J . Chem. Soc., Chem. Commun. 1998, 1417.
(25) For a review on triflate chemistry, see: Ritter, K. Synthesis
1993, 735.
(26) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508. Scott,
W. J .; Stille, J . K. J . Am. Chem. Soc. 1986, 108, 3033.
(29) Regitz, M.; Hocker, J .; Leidhegener, A. Organic Syntheses; J ohn
Wiley: New York, 1973; Collect. Vol. 5, p 179.
(30) Baum, J . S.; Shook, D. A.; Davies, H. M. L.; Smith, H. D. Synth.
Commun. 1987, 17, 1709.
(31) McMurry, J . E.; Scott, W. J . Tetrahedron Lett.1983, 24, 979.

8650 J . Org. Chem., Vol. 64, No. 23, 1999
Padwa et al.
Sch em e 3
Sch em e 5
of the sulfonyl-substituted center (i.e., C3 (0.30)) in the
LUMO. It is well-known that the Câ-coefficient of the
HOMO of enol ethers is larger than the CR-coefficient,34
and consequently pyridone 22 is predicted to be the major
regioisomer formed.
Sch em e 4
Compound 18, derived from the Rh(II)-catalyzed reac-
tion of 9 with methyl acrylate, was easily decarboxylated
by heating with 48% HBr at 135 °C for 12 h. This reaction
resulted in the formation of the unsubstituted 3-hydroxy
pyridone 23 in 91% yield (Scheme 5). At this juncture,
we decided to examine the chemical behavior of 23 with
various reagents because we were interested in introduc-
ing carbon-based substituents onto the pyridone ring for
eventual indolizidine alkaloid synthesis. The presence of
a 3-hydroxy substituent on the pyridone ring allows for
an element of diversity, and this functionality can be used
as a site for further modification. Our initial studies were
designed to evaluate the reactivity of 23 with several
electrophilic reagents. The Mannich reaction of 23 with
the iminium ion derived from formaldehyde and piperi-
dine gave the 4-substituted pyridone 24 (63%) after
conversion to the corresponding triflate. In contrast,
exposure of 23 to bromine in glacial acetic acid followed
by triflation afforded the 5-bromo substituted triflate 25
in 71% overall yield.
The synthetic potential of vinyl triflates has been well
established over the past decade,25 and these compounds
have been shown to be suitable substrates in various
types of coupling reactions, including Stille couplings26
and Heck reactions.35 In contrast to the numerous
examples of cross-coupling reactions with simple vinyl
triflates, there were no examples of similar reactions with
pyridone-derived triflates when we initiated work in this
area.36 To test the feasibility of the palladium-catalyzed
cross-coupling reaction of this new class of triflates,37 we
subjected the easily available phenylsulfonyl and car-
bomethoxy substituted triflates 17 and 19 to various
organometallic reagents in the presence of a Pd(0)
catalyst (Scheme 6). Reaction of 17 with tributylphenyltin
Several types of dipolarophiles were examined to
establish the scope and generality of the process. The
tandem cyclization-cycloaddition-ring opening sequence
using diazoimide 9 proceeded smoothly with methyl
acrylate, methyl vinyl ketone, and isobutyl vinyl ether
(Scheme 4). In all cases the initially formed isomu¨nch-
none dipole was trapped by the added dipolarophile, and
good yields of the expected 3-hydroxy pyridones were
obtained. Compounds 18 and 20 were readily converted
to the corresponding triflates 19 and 21. The Rh(II)-
catalyzed reaction of 9 with isobutyl vinyl ether (vide
infra) also proved to be a highly efficient process leading
to 3-hydroxy pyridone 22, which was isolated as a
crystalline solid, mp 167-168 °C. The regiochemical
crossover in product formation when an electron-rich
dipolarophile is used is understandable on the basis of
FMO theory.32 The HOMO of the mesoionic dipole is the
dominant MO when electron-deficient olefins are used,
whereas the LUMO of the dipole is the controlling
molecular orbital with electron-rich dipolarophiles.33 The
frontier orbital coefficients at the reacting centers of the
isomu¨nchnone dipole were calculated by using the QCPE
AMPAC program with the AM1 Hamiltonian. The MO
calculations indicate that the atomic coefficient at the
amide carbonyl center (i.e., C5) is larger (0.69) than that
(34) Houk, K. N.; Sims, J .; Duke, R. E.; Strozier, R. W.; George, J .
K. J . Am. Chem. Soc. 1973, 95, 7287.
(35) De Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994,
33, 2379.
(36) Since this project was initiated in our laboratory, several
examples of pyridones bearing a triflate group in the 3- or 4-position
of the heteroaromatic ring have been reported to undergo palladium-
catalyzed cross-coupling reactions. Fu, J . M.; Chen, Y.; Castelhano,
A. L. Synlett 1998, 1408. Collins, I.; Castro, J . L. Tetrahedron Lett.
1999, 40, 4069. Nadin, A.; Harrison, T. Tetrahedron Lett. 1999, 40,
4073.
(32) Fleming, I. Frontier Orbitals and Organic Chemical Reactions;
Wiley-Interscience: New York, 1976.
(37) For
a review on organometallic coupling reactions of enol
(33) Osterhout, M. H.; Nadler, W. R.; Padwa, A. Synthesis 1994,
123.
triflates, see: Scott, W. J .; McMurry, J . E. Acc. Chem. Res. 1988, 21,
47.

Isomu¨nchnone-Based Synthesis of 2(1H)-Pyridones
J . Org. Chem., Vol. 64, No. 23, 1999 8651
Sch em e 6
Sch em e 7
in the presence of lithium chloride (3 equiv) and tetrakis-
(triphenylphosphine)palladium(0) (0.05 equiv) gave the
phenyl-substituted pyridone 26 in 85% yield. Raney
nickel reduction of 26 furnished the desulfonylated
pyridone 27 in 97% yield. Conversion of the triflate group
present in 17 or 19 into the unsubstituted 2-pyridone 28
or 32 was achieved via a palladium(0)-catalyzed formate
reduction38 in 92% yield. Stille coupling of 17 with
vinyltributyltin afforded pyridone 29 in 78% yield. (Tri-
methylsilyl)acetylene also underwent palladium-cata-
lyzed coupling with triflate 17 to provide acetylene 30 in
91% yield. Likewise, we successfully reduced and coupled
the carbomethoxy substituted triflate 19 with phenyl and
vinyltin reagents to give pyridones 31 and 33 in high
yield. We found that the Diels-Alder reaction of 33 with
N-phenylmaleimide at 110 °C afforded, after 4 h, cy-
cloadduct 34 in 92% yield. Compound 34 is the result of
offers versatile access to many functionalized targets.39
As a continuation of our studies dealing with the chem-
istry of pyridone triflates, we questioned whether sub-
strates such as the 5-bromo substituted pyridone triflate
25 could also undergo C-C bond formation in a sequen-
tial manner and thereby provide access to a variety of
aryl and acetylenic pyridones. We discovered that when
25 was treated with an excess of the organometallic
coupling partner in the presence of a Pd(0) catalyst, the
bis-substituted pyridones 36 and 38 were formed in good
yield. We expected that pyridone 25 might exhibit regi-
oselectivity in its reactions with coupling partners and
that the triflate portion of the molecule would be more
reactive than the bromide toward cross-coupling. It was
anticipated that 25 would react with 1 equiv of an
organometallic agent to first give a 3-substituted 5-bromo
pyridone (i.e., 37 or 39) as the major product of the
reaction. Indeed, a single bromo substituted pyridone
(i.e., 37 or 39) was produced when 1 equiv of the
organometallic reagent was used or when the coupling
reaction was carried out for shorter periods of time
(Scheme 7). Further reaction of 37 (or 39) with an
additional equivalent of the organometallic species gave
the 3,5-bispyridone 36 (or 38) in high yield. Conversion
of 25 into the 5-bromo substituted pyridone 40 could also
be achieved via a palladium(0)-catalyzed formate reduc-
tion in 86% yield.
addition of the dienophile to the pyridone “3,4-double
bond/ 3-vinyl group” diene system. The transient [4 +
2]-adduct undergoes tautomerization to 34 either during
the course of the thermolysis or upon purification by silica
gel chromatography.
Another example of the synthetic usefulness of the
pyridone triflate intermediate involves a palladium(0)
catalyzed Heck reaction of 19 with methyl acrylate to
generate the propenoate ester 35 in 96% isolated yield.
Ap p lica tion of th e Meth od Tow a r d th e Syn th esis
of In d olizid in e Alk a loid s. Given the success in forming
a variety of substituted 5,6-fused pyridones from the [3
+ 2]-cycloaddition of phenylsulfonyl substituted iso-
mu¨nchnones, it seemed to us that this approach could
well prove to be adaptable to the synthesis of a host of
indolizidine alkaloids. The indolizidine skeleton com-
prises the backbone of a number of biologically and
The sequential cross-coupling of organometallic species
with dihalides or bis(enoltriflates) in Stille-type chemistry
(39) For some examples of sequential cross-coupling, see: Moniatte,
M.; Eckhardt, M.; Brickmann, K.; Bruckner, R.; Suffert, J . Tetrahedron
Lett. 1994, 35, 1965. Chan, H. W.; Chan, P. C.; Liu, J . H.; Wong, H.
M. C. J . Chem. Soc., Chem. Commun. 1997, 1515.
(38) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 25,
4821.

8652 J . Org. Chem., Vol. 64, No. 23, 1999
Padwa et al.
Sch em e 8
Sch em e 10
Sch em e 9a
by Stille coupling with tributyl(4-methoxyphenyl)tin,44
gave the aryl substituted 2-pyridone 46 in 72% yield.
Desulfonylation of 46 was effected using Raney nickel
to give pyridone 47 in 90% yield. Heating a sample of 47
in 48% HBr afforded phenol 48 in 97% yield. Reduction
of 48 with alane (LiAlH4, AlCl3) gave (()-ipalbidine 7 in
eight steps in 17% overall yield.
The indolizidine alkaloid septicine (52) has been iso-
lated from Ficus septica, a plant belonging to the Mora-
ceae family, and is considered to be a biogenetic precursor
to the phenanthroizidine alkaloid, tylophorine.45,46 Our
approach to this indolizidine alkaloid called for the
preparation of bistriflate 50 followed by its sequential
cross-coupling with the appropriate organometallic re-
agent. Pyridone 22, prepared from the Rh(II)-catalyzed
reaction of diazoimide 9 with isobutyl vinyl ether (see
Scheme 4), was treated with BBr3 to cleave the ether
bond. The transient diol 49 was allowed to react with
N-phenyl trifluoromethanesulfonamide in the presence
of triethylamine to give the bistriflate 50 in 68% yield
as a crystalline solid. The Pd(0)-catalyzed aryl zinc
coupling of 50 provided the diaryl-substituted pyridone
51 in 64% yield (Scheme 10). The above sequence
constitutes a formal synthesis of (()-septicine (52), based
on the successful reduction of 51 to 52 by Moore and co-
workers.47
a
Reagents: (a) (TfO)2NPh, NEt3; (b) MeOC6H4SnBu3, Pd-
(PPh3)4, LiCl; (c) Ra-Ni, EtOH (65 °C); (d) 48% HBr, reflux; and
(e) LiAlH4, AlCl3.
structurally interesting molecules isolated from diverse
natural sources.40 δ-Coniceine (43) was chosen as our
initial target because its rather trivial structure41 would
allow us to easily test the basic principles of our method.
The starting material for the synthesis of 43 was triflate
19, which on Pd(0)-formate reduction gave pyridone 32
in 85% yield. After a sample of 32 was heated with 48%
HBr at 135 °C, the decarboxylated pyridone 41 was
formed in 96% yield. This compound was then catalyti-
cally hydrogenated to 42 (89%), which was further
reduced with LAH to give δ-coniceine (43) (80%), com-
parable to authentic material (Scheme 8).42
The successful synthesis of δ-coniceine by the iso-
mu¨nchnone route prompted us to use a similar methodol-
ogy for the preparation of (()-ipalbidine (7).43 A short
synthesis of this alkaloid was carried out as depicted in
Scheme 9. Reaction of R-diazoimide 9 with cis-1-(phenyl-
sulfonyl)-1-propene and a catalytic quantity of Rh2OAc4
in benzene at 80 °C provided the expected 3-hydroxy-
2(1H)-pyridone 44 in 51% isolated yield. Conversion of
44 to the corresponding vinyl triflate 45 (86%), followed
(43) For some alternate syntheses of (()-ipalbidine, see: Danishef-
sky, S. J .; Vogel, C. J . Org. Chem. 1986, 51, 3915. Iida, H.; Watanabe,
Y.; Kibayashi, C. J . Chem. Soc., Perkin Trans. 1 1985, 261. Cragg, J .
E.; Hedges, S. H.; Herbert, R. B. Tetrahedron Lett. 1981, 22, 2127.
Howard, A. S.; Gerrans, G. C.; Michnel, J . P. J . Org. Chem. 1980, 45,
1713. Hedges, S. H.; Herbert, R. B. J . Chem. Res., Synop. 1979, 1, 413.
Stevens, R. V.; Luh, Y. Tetrahedron Lett. 1977, 979. Govindachari, T.
R.; Sidhaye, A. R.; Viswanathan, N. Tetrahedron 1970, 26, 3829.
(44) Stille, J . K.; Echavarren, A. M.; Williams, R. M.; Hendrix, J .
A. Organic Synthesis; Overman, L. E., Ed.; Wiley and Sons: New York,
1993; Vol. 71, p 97.
(45) Gellert, E. In Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; J ohn Wiley & Sons: New York, 1987; Vol. 5, p
55. Suffness, M.; Cordell, G. A. In The Alkaloids; Brossi, A., Ed.;
Academic Press: Orlando, FL, 1985; Vol. 25, Chapter 1, pp 3-355.
(46) Syntheses of (()-septicine: Govindachari, T. R.; Viswanathan,
N. Tetrahedron 1970, 26, 715. Iwashita, T.; Suzuki, M.; Kusumi, T.;
Kakisawa, H. Chem. Lett. 1980, 383. Cragg, J . E.; Herbert, R. B.;
J ackson, F. B.; Moody, C. J .; Nicolson, I. T. J . Chem. Soc., Perkin Trans.
1 1982, 2477. Iida, H.; Watanabe, Y.; Tanaka, M.; Kibayashi, C. J .
Org. Chem. 1984, 49, 2412. Comins, D. L.; Morgan, L. A. Tetrahedron
Lett. 1991, 32, 5919. Comins, D. L.; Chen, X.; Morgan, L. A. J . Org.
Chem. 1997, 62, 7435. Ciufolini, M. A.; Roschangar, F. J . Am. Chem.
Soc. 1996, 118, 12082.
(40) Howard, A. S.; Michael, J . P. In The Alkaloids. Chemistry and
Pharmacology; Brossi, A., Ed.; Academic Press: New York, 1986; Vol.
28, Chapter 3, pp 235-246.
(41) Pizzorno, M. T.; Albonico, S. M. J . Org. Chem. 1977, 42, 909.
Stevens, R. V.; Luh, Y.; Sheu, J . T. Tetrahedron Lett. 1976, 3799.
Khatri, N. A.; Schmitthenner, H. F.; Shringarpure, J .; Weinreb, S. M.
J . Am. Chem. Soc. 1981, 103, 6387.
(42) Takahata, H.; Takamatsu, T.; Yamazaki, T. J . Org. Chem. 1989,
54, 4812.

Isomu¨nchnone-Based Synthesis of 2(1H)-Pyridones
J . Org. Chem., Vol. 64, No. 23, 1999 8653
Sch em e 11a
The next step involved the trifluoroperacetic acid induced
Baeyer-Villiger oxidation of 59 to give acetate 60 in 96%
yield. Compound 60 underwent transesterification and
acetate cleavage to produce the dibenzyl ester 61 (98%,
[R]25D -146 °, (CH2Cl2, c 0.39)) when subjected to heating
with Otera’s catalyst in the presence of benzyl alcohol/
toluene.48 Catalytic hydrogenation (Pd/C) of 61 in metha-
nol has already been reported to give A58365A (1) in 96%
yield.28 Thus, the formal synthesis of 1 in 11 steps in
32.6% overall yield starting from L-pyroglutamic acid has
been achieved. This synthesis further underscores the
flexibility provided by the [3 + 2]-cycloaddition reaction
of phenylsulfonyl isomu¨nchnones.
In summary, we have shown that a range of highly
substituted 2(1H)-pyridones can be rapidly and conver-
gently assembled using the (i) [3 + 2]-cycloaddition of
phenylsulfonyl-substituted isomu¨nchnone intermediates
and (ii) conversion of the resulting 3-hydroxy-2(1H)-
pyridones into the corresponding triflates, which function
as suitable substrates in various types of palladium-
catalyzed cross-coupling reactions. This methodology
allows the synthesis of highly substituted pyridones,
which would be difficult to obtain through other methods.
Further utilization of this sequence for the stereocon-
trolled synthesis of several indolizidine alkaloids is under
current investigation.
a
Reagents: (a) MeOH, Dowex; (b) PhSCH2COCl (9), benzene,
80 °C; (c) Oxone, MeOH, 25 °C; (d) p-CH3CONHC6H4SO2N3, NEt3;
(e) Rh2(OAc)4, CH2dCHCOCH3, benzene, 80 °C; and (f) (TfO)2NPh,
NEt3, 25 °C.
Sch em e 12a
Exp er im en ta l Section
Melting points are uncorrected. Mass spectra were deter-
mined at an ionizing voltage of 70 eV. Unless otherwise noted,
all reactions were performed in flame-dried glassware under
an atmosphere of dry argon. Solutions were evaporated under
reduced pressure with a rotary evaporator ,and the residue
was chromatographed on a silica gel column using an ethyl
acetate/hexane mixture as the eluent unless specified other-
wise. All solids were recrystallized from ethyl acetate/hexane
for analytical data.
1-(P h en ylsu lfon yla cetyl)p yr r olid in -2-on e. To a solution
containing 4.2 g (21 mmol) of phenylsulfonyl acetic acid in 20
mL of benzene was added 5.5 mL (63 mmol) of oxalyl chloride
that contained 2 drops of DMF. The solution was allowed to
stir for 2 h at 25 °C, and the excess oxalyl chloride was
removed under reduced pressure. The crude acid chloride was
taken up in 10 mL of benzene and was cannulated into a
solution containing 1.3 mL (17 mmol) of 2-pyrrolidinone in 5
mL of benzene. The mixture was heated at reflux for 8 h,
concentrated under reduced pressure, taken up in CH2Cl2,
washed once with a saturated NaHCO3 solution, and then with
brine. The combined organic extracts were dried over MgSO4
and concentrated under reduced pressure. The resulting
residue was subjected to flash silica gel chromatography to
give 4.3 g (91%) of 1-(phenylsulfonylacetyl)pyrrolidin-2-one as
a white solid: mp 99-100 °C; IR (CH2Cl2) 1737, 1695, and
1332 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.02 (m, 2H), 2.58 (t,
2H, J ) 7.5 Hz), 3.82 (t, 2H, J ) 7.5 Hz), 4.25 (s, 2H), 7.20-
7.31 (m, 3H), and 7.42-7.45 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 16.1, 32.6, 45.1, 60.1, 127.8, 128.6, 133.6, 138.8, 161.0,
and 175.0. Anal. Calcd for C12H13NO4S: C, 53.92; H, 4.90; N,
5.24. Found: C, 54.04; H, 4.91; N, 5.23.
1-(P h en ylsu lfon yld ia zoa cetyl)p yr r olid in -2-on e (9). To
a solution of 5.3 g (20 mmol) of the above imide in 20 mL of
acetonitrile at 0 °C was added 6.7 mL (48 mmol) of triethyl-
amine. The solution was allowed to stir at 0 °C for 20 min,
after which time 5.7 g (24 mmol) of p-acetamidophenylsulfonyl
azide30 was added in one portion. The solution was allowed to
warm to 25 °C and was stirred at room temperature for 14 h.
The solvent was removed under reduced pressure, and the
residue was taken up in CH2Cl2. The solution was filtered, and
the mother liquor was concentrated to dryness under reduced
a
Reagents: (g) CH2dCHCO2Me, Pd(PPh3)2Cl2, NEt3; (h) H2, Pd/
C, CHCl3; (i) H2O2, CF3CO2H, 25 °C; (j) PhCH2OH, toluene, Otera’s
catalyst, 120 °C; and (k) H2, Pd/C, MeOH.
We also applied the above method to the synthesis of
the ACE inhibitor (-)-A58365A (1). The four-step conver-
sion of commercially available L-pyroglutamic acid 53 to
the isomu¨nchnone precursor 57 was carried out using
conventional chemistry. Esterification of 53 with metha-
nol in the presence of Dowex ion-exchange resin gave
methyl ester 54 in 98% yield. Treatment of 54 with
(phenylthio)acetyl chloride in benzene afforded 5-oxo-1-
(2-phenylthioacetyl)-pyrrolidine-2-carboxylate (55) in 87%
yield. Oxidation of 55 with Oxone furnished sulfone 56
(67%), which was converted to diazoimide 57 using
established diazotization procedures29 in 91% yield. Reac-
tion of 57 with methyl vinyl ketone and a catalytic
quantity of Rh2(OAc)4 in benzene at 80 °C provided the
expected 3-hydroxy-2(1H)-pyridone 10 in 86% isolated
yield (Scheme 11). The hydroxy-substituted pyridone 10
was easily converted to the corresponding triflate 58
(94%) by treatment with N-phenyl trifluoromethane-
sulfonamide and triethylamine.31 A Heck reaction of 58
with methyl acrylate in the presence of Pd(PPh3)Cl2 at
25 °C in acetonitrile gave the prop-2-enoate derivative
11 in 86% yield (Scheme 12). Catalytic hydrogenation of
11 proceeded in quantitative yield to afford pyridone 59.
(47) Verxa, B. R.; Yang, K.; Moore, H. W. Tetrahedron 1994, 50,
6173.
(48) Otera, J .; Yano, T.; Kawabata, A.; Nozaki, H. Tetrahedron Lett.
1986, 27, 2383.

8654 J . Org. Chem., Vol. 64, No. 23, 1999
Padwa et al.
pressure. The residue was subjected to flash silica gel chro-
matography to give 5.0 g (85%) of 9 as a yellow solid: mp 124-
125 °C; IR (CH2Cl2) 2128, 1740, and 1655 cm-1; 1H NMR (300
MHz, CDCl3) δ 2.03 (m, 2H), 2.54 (t, 2H, J ) 7.5 Hz), 3.73 (t,
2H, J ) 7.5 Hz), 7.51-7.62 (m, 3H), and 8.04-8.07 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 17.7, 32.7, 46.2, 128.2, 129.0,
133.9, 141.5, 157.6, 174.2. Anal. Calcd for C12H11N3O4S: C,
49.14; H, 3.78; N, 14.34. Found: C, 49.07; H, 3.61; N, 14.19.
2-P h en yl-4-tr iisopr opylsilan yloxy-7,8-dih ydr o-6H-2,5a -
d ia za -a s-in d a cen e-1,3,5-tr ion e (13). A solution containing
0.1 g (0.3 mmol) of diazoimide 9, 0.09 g (0.5 mmol) of
N-phenylmaleimide, and 2 mg of rhodium(II) acetate in 5 mL
of benzene was heated at reflux for 12 h. The solvent was
removed under reduced pressure, and the brown residue was
dissolved in 5 mL of CH2Cl2. To this mixture was added 0.2
mL (0.7 mmol) of triisopropylsilyl chloride, the solution was
cooled to 0 °C, and 0.1 mL (0.7 mmol) of triethylamine was
added. The reaction mixture was stirred at 25 °C for 1 h,
quenched with water, and extracted with CH2Cl2. The organic
layer was washed with brine and dried over Na2SO4. The
organic extracts were filtered and concentrated under reduced
pressure. The crude residue was subjected to flash silica gel
chromatography to give 0.13 g (87%) of 13 as a clear oil: IR
tion containing 0.1 g (0.3 mmol) of 14 in 2 mL of CH2Cl2 at 0
°C was added 0.05 mL of triethylamine. The mixture was
allowed to stir for 20 min, after which time 0.1 g (0.3 mmol)
of N-phenyl trifluoromethanesulfonamide was added in one
portion. The reaction mixture was allowed to warm to room
temperature, stirred for an additional 6 h, quenched with
water, and extracted with CH2Cl2. The organic layer was
washed with brine and dried over Na2SO4. The organic extracts
were filtered and concentrated under reduced pressure. The
crude residue was subjected to flash silica gel chromatography
to give 0.1 g (70%) of 17 as a white solid: mp 196-197 °C; IR
(CH2Cl2) 1674, 1424, 1211, and 1151 cm-1; 1H NMR (300 MHz,
CDCl3) δ 2.25-2.37 (m, 2H), 3.47 (t, 2H, J ) 7.9 Hz), 4.21 (t,
2H, J ) 7.5 Hz), 7.56-7.69 (m, 3H), and 7.86-7.90 (m, 3H);
13C NMR (75 MHz, CDCl3) δ 20.8, 32.6, 50.2, 114.0, 118.5 [q,
1J (13C-19F) ) 320 Hz], 127.0, 129.5, 129.7, 133.9, 137.1, 140.9,
154.9, and 155.2. Anal. Calcd for C15H12F3NO6S2: C, 42.55;
H, 2.86; N, 3.31. Found: C, 42.60; H, 2.89; N, 3.27.
6-H yd r oxy-5-oxo-1,2,3,5-t et r a h yd r oin d olizin e-8-ca r -
boxylic Acid Meth yl Ester (18). A solution containing 1.0 g
(3.4 mmol) of diazoimide 9, 1.5 mL (17 mmol) of methyl
acrylate, and 2 mg of rhodium(II) acetate in 35 mL of benzene
was heated at reflux for 14 h. The solvent was removed under
reduced pressure, and the residue was subjected to flash silica
gel chromatography to give 0.61 g (86%) of 18 as a white
solid: mp 194-195 °C; IR (neat) 1713, 1640, 1609, and 1216
1
(neat) 1715, 1669, 1645, and 1353 cm-1; H NMR (300 MHz,
CDCl3) δ 1.13 (d, 18H, J ) 7.5 Hz), 1.42-1.49 (m, 3H), 2.32-
2.38 (m, 2H), 3.44 (t, 2H, J ) 7.8 Hz), 4.18 (t, 2H, J ) 7.5 Hz),
and 7.35-7.48 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 14.2, 18.0,
21.8, 29.9, 49.1, 102.6, 118.4, 126.1, 127.9, 128.1, 129.0, 129.1,
131.8, 134.2, 142.9, 148.0, and 160.0; HRMS calcd for
1
cm-1; H NMR (300 MHz, CDCl3) δ 2.22-2.30 (m, 2H), 3.48
(t, 2H, J ) 7.8 Hz), 3.85 (s, 3H), 4.21 (t, 2H, J ) 7.5 Hz), 6.40
(brs, 1H), and 7.37 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 21.4,
32.7, 49.1, 51.8, 105.7, 115.0, 143.7, 146.9, and 165.3. Anal.
Calcd for C10H11NO4: C, 57.40; H, 5.30; N, 6.70. Found: C,
57.51; H, 5.28; N, 6.74.
C
25H32N2O4 424.2362, found 424.2358.
5-Oxo-8-(ph en ylsu lfon yl)-1,2,3-tr ih ydr oin dolizin -6-yl Ac-
eta te (15). A solution of 0.9 g (3.1 mmol) of diazoimide 9, 0.7
g (4.0 mmol) of phenyl vinyl sulfone, and 2 mg of rhodium(II)
acetate in 30 mL of benzene was heated at reflux for 14 h.
The mixture was cooled, and the solvent was removed under
reduced pressure. The crude residue was subjected to flash
silica gel chromatography to give 0.57 g (63%) of 8-phenylsul-
fonyl-6-hydroxy-2,3-dihydro-1H-indolizin-5-one (14) as a labile
oil, which was immediately used in the next step: 1H NMR
(300 MHz, CDCl3) δ 2.20-2.28 (m, 2H), 3.44 (t, 2H, J ) 7.8
Hz), 4.15 (t, 2H, J ) 7.5), 6.40 (s, 1H), 7.27 (s, 1H), 7.54-7.61
(m, 3H), 7.87 (s, 1H), and 7.90 (s, 1H).
Meth yl 5-Oxo-6-((tr iflu or om eth yl)su lfon yloxy)-1,2,3-
tr ih yd r oin d olizin e-8-ca r boxyla te (19). To a solution con-
taining 2.0 g (9.5 mmol) of pyridone 18 in 20 mL of CH2Cl2 at
0 °C was slowly added 2.6 mL (19 mmol) of triethylamine. The
mixture was allowed to stir for 20 min at 0 °C, after which
time 5.1 g (14 mmol) of N-phenyl trifluoromethanesulfonamide
was added in one portion. The mixture was stirred at room
temperature for 6 h, quenched with water, and extracted with
CH2Cl2. The organic layer was washed with brine and dried
over Na2SO4. The organic extracts were filtered and concen-
trated under reduced pressure. The crude residue was sub-
jected to flash silica gel chromatography to give 3.2 g (98%) of
19 as a white solid: mp 102-103 °C; IR (CH2Cl2) 1715, 1669,
1645, and 1353 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.26-2.37
(m, 2H), 3.60 (t, 2H, J ) 7.9 Hz), 3.88 (s, 3H), 4.26 (t, 2H, J )
7.6 Hz), and 7.92 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 20.7,
To a solution of 0.1 g (0.3 mmol) of pyridone 14 and 0.1 mL
(1.0 mmol) of acetic anhydride in 3 mL of CH2Cl2 at 0 °C was
added 0.05 mL (0.4 mmol) of triethylamine. The mixture was
stirred at room temperature for 2 h and concentrated under
reduced pressure, and the crude residue was subjected to flash
silica gel chromatography to give 0.11 g (96%) of 15 as a white
crystalline solid: mp 166-167 °C; IR (CH2Cl2) 1773, 1666, and
1
33.7, 49.9, 52.1, 103.4, 118.6 [q, J (13C-19F) ) 320 Hz], 131.1,
1
1190 cm-1; H NMR (300 MHz, CDCl3) δ 2.19-2.30 (m, 2H),
136.6, 155.7, 157.5, and 163.8. Anal. Calcd for C11H10F3NO6S:
C, 38.71; H, 2.96; N, 4.11. Found: C, 38.56; H, 2.97; N, 4.21.
8-Acetyl-6-h ydr oxy-2,3-dih ydr o-1H-in dolizin -5-on e (20).
A solution containing 1.0 g (3.4 mmol) of diazoimide 9, 1.0 mL
(12 mmol) of methyl vinyl ketone, and 2 mg of rhodium(II)
acetate in 30 mL of benzene was heated at reflux for 5 h. The
solvent was removed under reduced pressure, and the crude
residue was taken up in ethyl acetate and filtered to give 0.34
g (52%) of 20 as a clear oil: IR (neat) 1677, 1619, and 1605
2.33 (s, 3H), 3.43 (t, 2H, J ) 7.8 Hz), 4.15 (t, 2H, J ) 7.8 Hz),
7.50-7.65 (m, 4H), 7.86 (s, 1H), and 7.89 (s, 1H); 13C NMR
(75 MHz, CDCl3) δ 20.4, 21.0, 32.3, 49.7, 114.1, 127.0, 127.7,
129.5, 133.5, 138.9, 141.5, 152.0, 156.1, 168.1. Anal. Calcd for
C
16H15NO5S: C, 57.65; H, 4.54; N, 4.20. Found: C, 57.59; H,
4.57; N, 4.13.
8-P h en ylsu lfon yl-6-m eth oxy-2,3-d ih yd r o-1H-in d olizin -
5-on e (16). To a solution of 0.4 g (1.4 mmol) of pyridone 14 in
3 mL of dimethyl sulfate at room temperature was added a
20% solution of KOH in methanol until the solution remained
basic. The mixture was quenched with water and extracted
with CH2Cl2. The organic layer was washed with brine and
dried over Na2SO4. The organic extracts were filtered and
concentrated under reduced pressure. The crude residue was
subjected to flash silica gel chromatography to give 0.3 g (73%)
of 16 as a white crystalline solid: mp 167-168 °C; IR (CH2-
cm-1 1H NMR (400 MHz, CDCl3) δ 2.27 (pent, 2H, J ) 7.6
;
Hz), 2.48 (s, 3H), 3.48 (t, 2H, J ) 7.6 Hz), 4.03 (brs, 1H), 4.19
(t, 2H, J ) 7.6 Hz), and 7.32 (s, 1H); 13C NMR (75 MHz, CDCl3)
δ 21.2, 28.0, 33.1, 48.9, 113.5, 116.1, 143.7, 147.0, 157.8, and
196.2. Anal. Calcd for C10H11NO3: C, 62.17; H, 5.74; N, 7.25.
Found: C, 62.26; H, 5.83; N, 7.19.
Tr iflu or om eth a n esu lfon ic Acid 8-Acetyl-5-oxo-1,2,3,5-
tetr a h yd r oin d olizin -6-yl Ester (21). To a solution contain-
ing 0.26 g (1.4 mmol) of pyridone 20 and 0.7 g (2.0 mmol) of
N-phenyl trifluoromethanesulfonamide in 10 mL of CH2Cl2 at
0 °C was slowly added 0.3 mL (2.0 mmol) of triethylamine.
The mixture was stirred at room temperature for 16 h, the
solvent was removed under reduced pressure, and the crude
residue was subjected to flash silica gel chromatography to
give 0.4 g (85%) of 21 as a white solid: mp 129-131 °C; IR
(Nujol) 1695, 1661, and 1607 cm-1; 1H NMR (400 MHz, CDCl3)
δ 2.31 (tt, 2H, J ) 8.0 and 7.6 Hz), 2.48 (s, 3H), 3.61 (t, 2H, J
Cl2) 1652, 1405, 1250, and 1152 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 2.12-2.25 (m, 2H), 3.37 (t, 2H, J ) 7.8 Hz), 3.87 (s,
3H), 4.14 (t, 2H, J ) 7.5 Hz), 7.09 (s, 1H), 7.52-7.62 (m, 3H),
7.86 (s, 1H), 7.89 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 21.0,
31.5, 49.2, 56.3, 110.4, 113.8, 126.6, 128.0, 133.1, 141.5, 145.4,
147.3, and 156.6. Anal. Calcd for C15H15NO4S: C, 59.00; H,
4.95; N, 4.59. Found: C, 59.07; H, 4.90; N, 4.51.
Tr iflu or om eth a n esu lfon ic Acid 8-P h en ylsu lfon yl-5-
oxo-1,2,3,5-tetr a h yd r oin d olizin -6-yl Ester (17). To a solu-

Isomu¨nchnone-Based Synthesis of 2(1H)-Pyridones
J . Org. Chem., Vol. 64, No. 23, 1999 8655
) 8.0 Hz), 4.25 (t, 2H, J ) 7.6 Hz), and 7.82 (s, 1H); 13C NMR
(75 MHz, CDCl3) δ 21.0, 28.1, 34.5, 49.9, 111.4, 118.8 [q,
1J (13C-19F) ) 320 Hz], 131.2, 136.5, 155.6, 157.5, and 193.5.
Anal. Calcd for C11H10F3NO5S: C, 40.62; H, 3.10; N, 4.31.
Found: C, 40.65; H, 3.15; N, 4.24.
was added 1.8 mL (13 mmol) of triethylamine. The mixture
was allowed to stir for 20 min, after which time 4.6 g (13 mmol)
of N-phenyl trifluoromethanesulfonamide was added in one
portion. The mixture was allowed to warm to room tempera-
ture, stirred for an additional 6 h, quenched with water, and
extracted with CH2Cl2. The organic layer was washed with
brine and dried over Na2SO4. The organic extracts were filtered
and concentrated under reduced pressure. The crude residue
was subjected to flash silica gel chromatography to give 2.4 g
(71%) of 25 as a white solid: mp 104-105 °C; IR (CH2Cl2) 1656,
1455, and 1200 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.30-2.36
(m, 2H), 3.16 (t, 2H, J ) 7.6 Hz), 4.32 (t, 2H, J ) 7.4 Hz), and
7.45 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 21.0, 33.4, 51.2,
90.4, 118.6 [q, 1J (13C-19F) ) 319 Hz], 134.2, 137.8, 149.9, and
154.7. Anal. Calcd for C9H7F3NO4S: C, 29.92; H, 1.95; N, 3.88.
Found: C, 30.02; H, 1.98; N, 3.83.
6-Hydr oxy-7-(2-m eth ylpr opoxy)-2,3-dih ydr o-1H-in doliz-
in -5-on e (22). A solution containing 3.0 g (10.2 mmol) of
diazoimide 9, 4.2 g (41 mmol) of isobutyl vinyl ether, and 2
mg of rhodium(II) acetate in 60 mL of benzene was heated at
reflux for 20 h. The solvent was removed under reduced
pressure, and the crude residue was taken up in CH2Cl2 and
filtered to give 0.8 g (34%) of 22. The filtrate was concentrated
and subjected to flash silica gel chromatography to give an
additional 0.7 g (30%) of 22 as a white solid: mp 167-168 °C;
IR (KBr) 1661, 1584, and 1551 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 1.01 (d, 6H, J ) 6.8 Hz), 2.05-2.15 (m, 1H), 2.17-
2.24 (m, 2H), 3.02 (t, 2H, J ) 7.6 Hz), 3.86 (d, 2H, J ) 6.8
8-P h en ylsu lfon yl-6-p h en yl-2,3-d ih yd r o-1H-in d olizin -5-
on e (26). To a solution containing 0.5 g (1.2 mmol) of triflate
17 in 10 mL of THF was added 0.5 mL (1.5 mmol) of
tributylphenyltin. The solution was cannulated into a flask
that contained 0.03 g of Pd(PPh3)4 and 0.15 g of LiCl (3.6 mmol)
in 10 mL of THF. The mixture was heated at reflux for 17 h,
the solvent was removed under reduced pressure, and the
residue was subjected to flash silica gel chromatography. The
major fraction isolated was taken up in 10 mL of CH2Cl2,
poured into a saturated KF solution, and allowed to stir at
room temperature for 5 h. The organic phase was separated,
filtered through a pad of Celite, and concentrated under
reduced pressure to give 0.34 g (86%) of 26 as a white solid:
Hz), 4.15 (t, 2H, J ) 7.6), 6.03 (s, 1H), and 6.19 (brs, 1H); 13
C
NMR (75 MHz, CDCl3) δ 19.3, 22.3, 28.6, 31.2, 48.7, 76.2, 93.9,
130.6, 139.5, 149.0, and 157.8. Anal. Calcd for C12H17NO3: C,
64.55; H, 7.67; N, 6.27. Found: C, 64.37; H, 7.79; N, 6.12.
6-Hyd r oxy-1,2,3-tr ih yd r oin d olizin -5-on e (23). A solution
containing 0.6 g (2.9 mmol) of pyridone 18 in 5 mL of a 48%
HBr solution was heated at 135 °C for 12 h. The mixture was
concentrated to dryness under reduced pressure, and the
resulting residue was taken up in CHCl3 and washed with
water. The organic layer was washed with brine and dried over
Na2SO4. The organic extracts were filtered and concentrated
under reduced pressure. The crude residue was subjected to
flash silica gel chromatography to give 0.4 g (91%) of 23 as a
white solid: mp 168-169 °C; IR (CH2Cl2) 3400, 1643, and 1584
1
mp 195-196 °C; IR (CH2Cl2) 1648, 1548, and 1154 cm-1; H
NMR (300 MHz, CDCl3) δ 2.21-2.30 (m, 2H), 3.50 (t, 2H, J )
7.8 Hz), 4.19 (t, 2H, J ) 7.5 Hz), 7.35-7.44 (m, 3H), 7.51-
7.61 (m, 3H), 7.67-7.70 (m, 2H), 7.89 (s, 1H), 7.92 (s, 1H), and
7.99 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 20.7, 32.7, 49.8,
115.7, 126.9, 128.2, 128.3, 128.4, 129.1, 129.4, 133.3, 135.1,
135.6, 141.9, 153.5, and 160.2. Anal. Calcd for C20H17NO3S:
C, 68.36; H, 4.88; N, 3.99. Found: C, 68.20; H, 4.87; N, 3.95.
6-P h en yl-1,2,3-tr ih yd r oin d olizin -5-on e (27). To a solu-
tion containing 0.2 g (0.6 mmol) of pyridone 26 in 6 mL of
ethanol was added an excess of Raney nickel. The mixture was
heated at reflux for 5 h, cooled to room temperature, filtered
through a pad of Celite, quenched with water, and extracted
with CH2Cl2. The organic layer was washed with brine and
dried over Na2SO4. The organic extracts were filtered and
concentrated under reduced pressure. The crude residue was
subjected to flash silica gel chromatography to give 0.12 g
(97%) of 27 as a white solid: mp 133-134 °C; IR (CH2Cl2) 1642,
1584, and 1445 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.18-2.32
(m, 2H), 3.13 (t, 2H, J ) 7.5 Hz), 4.22 (t, 2H, J ) 7.4 Hz), 6.21
(d, 1H, J ) 7.2 Hz), 7.30 (d, 1H, J ) 7.2 Hz), 7.36-7.41 (m,
2H), 7.49 (d, 1H, J ) 6.9 Hz), and 7.69-7.72 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 21.5, 31.8, 49.1, 101.2, 127.2, 128.0, 128.1,
1
cm-1; H NMR (300 MHz, CDCl3) δ 2.19-2.28 (m, 2H), 3.03
(t, 2H, J ) 7.5 Hz), 4.18 (t, 2H, J ) 7.5 Hz), 6.08 (d, 1H, J )
7.5 Hz), and 6.83 (d, 1H, J ) 7.5 Hz); 13C NMR (75 MHz,
CDCl3) δ 22.3, 30.6, 48.6, 101.1, 115.6, 139.1, 144.6, and 157.3.
Anal. Calcd for C8H9NO2: C, 63.55; H, 6.00; N, 9.27. Found:
C, 63.64; H, 5.94; N, 9.25.
7-(P ip er id ylm et h yl)-6-((t r iflu r om et h yl)su lfon yloxy)-
1,2,3-tr ih yd r oin d olizin -5-on e (24). To a solution containing
1 mL (13 mmol) of 37% formaldehyde in 2 mL of ethanol at 0
°C was added 1.6 mL (16 mmol) of piperidine. The solution
was stirred at room temperature for 1.5 h and slowly added
to a solution of 0.2 g (1.3 mmol) of pyridone 23 in 5 mL of
ethanol. The mixture was allowed to stir at room temperature
for 1 h, and the solvent was removed under reduced pressure.
The residue was dissolved in CH2Cl2 and washed once with a
saturated NaHCO3 solution and again with brine. The com-
bined organic extracts were dried over MgSO4 and concen-
trated under reduced pressure to afford 0.3 g of a brown foam,
which was taken up in 8 mL of CH2Cl2 and cooled to 0 °C. To
this solution was added 0.25 mL (1.8 mmol) of triethylamine
followed by 0.65 g (1.8 mmol) of N-phenyl trifluoromethane-
sulfonamide. The mixture was stirred at room temperature
for 18 h, quenched with water, and extracted with CH2Cl2. The
organic layer was washed with brine and dried over Na2SO4.
The organic extracts were filtered and concentrated under
reduced pressure. The crude residue was subjected to flash
silica gel chromatography to give 0.31 g (63%) of 24 as a white
128.5, 136.9, 138.3, 149.6, and 160.7. Anal. Calcd for C14H13
-
NO: C, 79.59; H, 6.20; N, 6.63. Found: C, 79.38; H, 6.26; N,
6.54.
8-P h en ylsu lfon yl-2,3-d ih yd r o-1H-in d olizin -5-on e (28).
To a solution containing 0.15 g (0.3 mmol) of triflate 17 in 2
mL of DMF was added 0.1 mL (0.9 mmol) of triethylamine
and 5 mg of Pd(OAc)2(PPh3)2. To this mixture was added 24
µL (0.6 mmol) of 96% formic acid. The solution was stirred at
60 °C for 1 h, cooled to 0 °C, quenched with water, and
extracted with ethyl acetate. The organic layer was washed
with brine and dried over Na2SO4. The organic extracts were
filtered and concentrated under reduced pressure. The crude
residue was subjected to flash silica gel chromatography to
give 0.08 g (92%) of 28 as a colorless solid: mp 174-175 °C;
solid: mp 94-95 °C; IR (CH2Cl2) 1673, 1616, and 1417 cm-1
;
1H NMR (300 MHz, CDCl3) δ 1.47 (brs, 2H) 1.59-1.66 (m, 4H)
2.13-2.19 (m, 2H), 2.49 (brs, 4H), 2.97 (t, 2H, J ) 7.8 Hz),
3.48 (s, 2H), 4.15 (t, 2H, J ) 7.2 Hz), and 5.83 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 21.8, 23.9, 25.9, 31.6, 49.3, 54.7,
56.4, 100.3, 117.0, 118.6 [q, 1J (13C-19F) ) 320 Hz], 120.2, 135.7,
144.3, 149.0, and 155.5. Anal. Calcd for C15H19F3N2O4S: C,
47.36; H, 5.04; N, 7.37; Found: C, 47.50; H, 5.11; N, 7.28.
8-Br om o-6-((tr iflu or om eth yl)su lfon yloxy)-1,2,3-tr ih y-
d r oin d olizin -5-on e (25). To a solution containing 1.4 g (9.2
mmol) of pyridone 23 in 30 mL of glacial acetic acid was added
0.6 mL (11 mmol) of bromine. The solution was stirred at room
temperature for 1 h, diluted with water, and extracted with
CHCl3. The organic layer was washed with brine and dried
over Na2SO4. The organic extracts were filtered and concen-
trated under reduced pressure. The crude residue was taken
up in 30 mL of CH2Cl2 and cooled to 0 °C. To this solution
1
IR (CH2Cl2) 1660, 1320, and 1162 cm-1; H NMR (300 MHz,
CDCl3) δ 2.17 (m, 2H), 3.41 (t, 2H, J ) 7.8 Hz), 4.07 (t, 2H, J
) 7.5 Hz), 6.44 (d, 1H, J ) 9.6 Hz), 7.52-7.63 (m, 3H), and
7.81-7.89 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 20.4, 32.7,
49.3, 115.6, 117.6, 126.9, 129.4, 133.3, 138.2, 141.7, 155.0, and
161.2. Anal. Calcd for C14H13NO3S: C, 61.07; H, 4.76; N, 5.09.
Found: C, 61.07; H, 4.78; N, 5.06.
8-P h en ylsu lfon yl-6-vin yl-2,3-d ih yd r o-1H -in d olizin -5-
on e (29). To a solution containing 0.2 g (0.4 mmol) of triflate

8656 J . Org. Chem., Vol. 64, No. 23, 1999
Padwa et al.
116.5, 140.0, 157.4, 161.9, and 165.0. Anal. Calcd for C10H11
NO3: C, 62.15; H, 5.74; N, 7.25. Found: C, 62.28; H, 5.72; N,
7.32.
17 in 10 mL of THF was added 0.1 mL (0.5 mmol) of
vinyltributyltin. The solution was cannulated into a flask
containing 9 mg of Pd(PPh3)4 and 0.05 g of LiCl (1.2 mmol) in
10 mL of THF. The resulting mixture was heated at reflux for
17 h and cooled to room temperature, and the solvent was
removed under reduced pressure. The residue was subjected
to flash silica gel chromatography, and the major fraction
isolated was taken up in 10 mL of CH2Cl2, poured into a
saturated KF solution, and allowed to stir for 5 h. The organic
phase was separated, filtered through a pad of Celite, and
concentrated under reduced pressure to give 0.09 g (78%) of
29 as a white solid: mp 137-138 °C; IR (CH2Cl2) 1655, 1540,
-
Met h yl 5-Oxo-6-vin yl-1,2,3-t r ih yd r oin d olizin e-8-ca r -
boxyla te (33). To a solution containing 1.0 g (3 mmol) of
triflate 19 in 15 mL of THF was added 1.1 mL (4 mmol) of
vinyltributyltin. The solution was cannulated into a flask
containing 0.07 g of Pd(PPh3)4 and 0.37 g of LiCl (9 mmol) in
15 mL of THF. The reaction mixture was heated at reflux for
17 h and cooled to room temperature, and the solvent was
removed under reduced pressure. The residue was subjected
to flash silica gel chromatography, and the major fraction
isolated was taken up in 10 mL of CH2Cl2, poured into a
saturated KF solution, and allowed to stir for 5 h. The organic
phase was separated, filtered through a pad of Celite, and
concentrated under reduced pressure to give 0.47 g (73%) of
33 as a white solid: mp 94-95 °C; IR (CH2Cl2) 1706, 1654,
1
and 1149 cm-1; H NMR (300 MHz, CDCl3) δ 2.17-2.27 (m,
2H), 3.44 (t, 2H, J ) 7.8 Hz), 4.15 (t, 2H, J ) 7.5 Hz), 5.41
(dd, 1H, J ) 11.2 and 1.0 Hz), 6.18 (dd, 1H, J ) 17.7 and 1.0
Hz), 6.73 (dd, 1H, J ) 11.7 and 11.3 Hz), 7.51-7.60 (m, 3H)
and 7.86-7.89 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 20.6, 32.5,
49.5, 115.5, 118.2, 126.0, 126.9, 129.4, 130.6, 133.3, 133.8,
141.8, 152.8, and 160.1. Anal. Calcd for C16H15NO3S: C, 63.77;
H, 5.02; N, 4.65. Found: C, 63.88; H, 5.09; N, 4.61.
1
1549, and 1206 cm-1; H NMR (300 MHz, CDCl3) δ 2.23 (tt,
2H, J ) 7.8 and 7.5 Hz), 3.54 (t, 2H, J ) 7.8 Hz), 3.86 (s, 3H),
4.20 (t, 2H, J ) 7.5 Hz), 5.35 (dd, 1H, J ) 11.4 and 1.2 Hz),
6.13 (dd, 1H, J ) 17.6 and 1.2 Hz), 6.76 (dd, 1H, J ) 17.6 and
11.4 Hz), and 7.97 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 20.6,
33.7, 49.3, 51.8, 105.3, 116.8, 124.8, 131.1, 136.1, 155.6, 160.8,
and 165.3. Anal. Calcd for C12H13NO3: C, 65.73; H, 5.98; N,
6.39. Found: C, 65.51; H, 5.95; N, 6.24.
8-P h en ylsu lfon yl-6-tr im eth ylsila n yleth yn yl-2,3-d ih y-
d r o-1H-in d olizin -5-on e (30). To a solution containing 0.08
g (0.03 mmol) of triphenyl phosphine in 6 mL of triethylamine
was added 8 mg of CuI followed by 6 mg of PdCl2(PPh3)2. To
this solution was added 0.1 mL (0.8 mmol) of (trimethylsilyl)-
acetylene in 6 mL of toluene followed by the addition of 0.2 g
(0.4 mmol) of triflate 17 in one portion. The mixture was
heated at 115 °C for 1 h, cooled to room temperature, poured
into ice water, extracted with CH2Cl2, washed with brine, and
dried over Na2SO4. The organic extracts were filtered and
concentrated under reduced pressure. The crude residue was
subjected to flash silica gel chromatography to give 0.14 g
(91%) of 30 as a light yellow oil: IR (neat) 1663, 1581, 1543,
Met h yl 4,11-Dia za -3,5,10-t r ioxo-4-p h en ylt et r a cyclo-
[7.7.0.02,6011,15]-h exa d eca -1(9),15(16)-d ien e-16-ca r b oxyl-
a te (34). To a stirred solution containing 0.2 g (0.9 mmol) of
vinyl pyridone 33 in 20 mL of toluene was added 0.8 g (4.6
mmol) of N-phenylmaleimide. The solution was heated at
reflux for 4 h, and the solvent was removed under reduced
pressure. The resulting residue was subjected to flash silica
gel chromatography to give 0.33 g (92%) of 34 as an yellow
solid: mp 184-185 °C; IR (neat) 1710, 1648, 1385 and 1362
cm-1; 1H NMR (300 MHz, CDCl3) δ 1.90-2.07 (m, 2H), 2.22-
2.33 (m, 1H), 3.16-3.30 (m, 3H), 3.33-3.51 (m, 2H), 3.67-
3.79 (m, 2H), 3.82-3.90 (m, 1H), 3.83 (s, 3H), 4.22 (dd, 1H, J
) 5.7 and 9.0 Hz), 7.08-7.11 (m, 2H), and 7.33-7.44 (m, 3H);
13C NMR (75 MHz, CDCl3) δ 21.1, 26.6, 33.4, 37.3, 38.3, 43.1,
46.9, 51.7, 100.7, 126.6, 128.8, 129.2, 131.6 (2), 136.8, 152.7,
158.8, 167.0, 175.9, and 177.9. Anal. Calcd for C22H20N2O5: C,
67.34; H, 5.14; N, 7.14. Found: C, 67.46; H, 5.31; N, 7.01.
Meth yl 3-(8-(Meth oxyca r bon yl)-5-oxo-1,2,3-tr ih yd r oin -
d olizin -6-yl)p r op -2-en oa te (35). To a solution containing 0.2
g (0.6 mmol) of triflate 19 in 2 mL of DMF were added 0.1 mL
(1.0 mmol) of methyl acrylate, 7 mg of Pd(PPh3)Cl2, and 0.2
mL (1.6 mmol) of triethylamine. The solution was stirred at
80 °C for 2 h, cooled to 0 °C, quenched with water, and
extracted with ethyl acetate. The organic layer was washed
with brine and dried over Na2SO4. The organic extracts were
filtered and concentrated under reduced pressure. The crude
residue was subjected to flash silica gel chromatography to
give 0.16 g (96%) of 35 as a white crystalline solid: mp 158-
159 °C; IR (CH2Cl2) 1709, 1645, and 1204 cm-1; 1H NMR (300
MHz, CDCl3) δ 2.22-2.31 (m, 2H), 3.59 (t, 2H, J ) 7.8 Hz),
3.79 (s, 3H), 3.87 (s, 3 H), 4.23 (t, 2H, J ) 7.8 Hz), 7.11 (d, 1H,
J ) 15.9 Hz), 7.61 (d, 1H, J ) 15.9 Hz), and 8.11 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 20.4, 34.0, 49.6, 51.5, 51.9, 105.6,
120.2, 121.6, 139.5, 141.7, 158.0, 160.1, 164.7, and 168.0. Anal.
Calcd for C14H15NO5: C, 60.63; H, 5.46; N, 5.05. Found: C,
60.49; H, 5.48; N, 4.99.
and 1151 cm-1 1H NMR (300 MHz, CDCl3) δ 0.26 (s, 9H),
;
2.16-2.27 (m, 2H), 3.44 (t, 2H, J ) 7.9 Hz), 4.13 (t, 2H, J )
7.5 Hz), 7.53-7.63 (m, 3H), 7.86-7.89 (m, 2H), and 8.07 (s,
1H); 13C NMR (75 MHz, CDCl3) δ -0.19, 20.4, 32.9, 49.9, 98.4,
101.4, 113.5, 115.7, 127.0, 129.5, 133.5, 141.4, 154.6, and 160.1;
HRMS calcd for C19H21NO3SSi: 371.1012, found 371.1011.
Meth yl-5-oxo-6-p h en yl-1,2,3-tr ih yd r oin d olizin e-8-ca r -
boxyla te (31). To a solution containing 0.6 g (1.7 mmol) of
triflate 19 in 8 mL of THF was added 0.7 mL (2.3 mmol) of
tributylphenyltin. The solution was cannulated into a flask
containing 0.06 g of Pd(PPh3)4 and 0.2 g of LiCl (2.7 mmol) in
8 mL of THF. The mixture was heated at reflux for 17 h, the
solvent was removed under reduced pressure, and the residue
was subjected to flash silica gel chromatography. The major
fraction isolated was taken up in 10 mL of CH2Cl2, poured into
a saturated KF solution, and allowed to stir at room temper-
ature for 5 h. The organic phase was separated, filtered
through a pad of Celite, and concentrated under reduced
pressure to give 0.39 g (81%) of 31 as a white crystalline
solid: mp 121-122 °C; IR (CH2Cl2) 1715, and 1645 cm-1; H
1
NMR (300 MHz, CDCl3) δ 2.20-2.31 (m, 2H), 3.57 (t, 2H, J )
7.9 Hz), 3.86 (s, 3H), 4.23 (t, 2H, J ) 7.4 Hz), 7.32-7.42 (m,
3H), 7.69-7.72 (m, 2H), and 8.08 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 20.6, 33.8, 49.6, 51.7, 105.4, 127.6, 127.8, 128.1, 128.4,
135.8, 137.9, 156.2, 160.8, and 165.3. Anal. Calcd for C16H15
-
NO3: C, 71.35; H, 5.62; N, 5.20. Found: C, 71.12; H, 5.71; N,
5.09. Treatment of 31 with 48% HBr afforded 27 in 78% yield.
Met h yl-5-oxo-1,2,3-t r ih yd r oin d olizin e-8-ca r b oxyla t e
(32). To a solution containing 0.3 g (0.9 mmol) of triflate 19 in
2 mL of DMF were added 0.4 mL (2.6 mmol) of triethylamine
and 13 mg of Pd(OAc)2(PPh3)2 followed by 0.07 mL (1.7 mmol)
of 96% formic acid. The solution was stirred at 60 °C for 1 h,
cooled to 0 °C, quenched with water, and extracted with ethyl
acetate. The organic layer was washed with brine and dried
over Na2SO4. The organic extracts were filtered and concen-
trated under reduced pressure. The crude residue was sub-
jected to flash silica gel chromatography to give 0.17 g (85%)
of 32 as a white crystalline solid: mp 136-137 °C; IR (CH2-
Cl2) 1730 and 1646 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.13-
2.21 (m, 2H), 3.47 (t, 2H, J ) 7.8 Hz), 3.87 (s, 3H), 4.09 (t, 2H,
J ) 7.8 Hz), 6.30 (d, 1H, J ) 9.6 Hz), and 7.81 (d, 1H, J ) 9.6
Hz); 13C NMR (75 MHz, CDCl3) δ 20.3, 33.7, 49.0, 51.6, 105.4,
6,8-Bis(tr im eth ylsilan yleth yn yl)-2,3-dih ydr o-1H-in doliz-
in -5-on e (36). To a solution of 0.02 g (0.08 mmol) of triphenyl
phosphine in 6 mL of triethylamine was added 0.02 g of CuI
followed by 15 mg of PdCl2(PPh3)2. To this solution was added
0.3 mL (2.2 mmol) of (trimethylsilyl)acetylene in 6 mL of
toluene followed by the addition of 0.2 g (0.6 mmol) of triflate
25 in one portion. The mixture was heated at 160 °C in a sealed
tube for 72 h, cooled to room temperature, poured into ice
water, extracted with CH2Cl2, washed with brine, and dried
over Na2SO4. The organic extracts were filtered and concen-
trated under reduced pressure. The crude residue was sub-
jected to flash silica gel chromatography to give 0.11 g (61%)
of 36 as a light yellow solid: mp 265-266 °C; IR (CH2Cl2) 1665,
1546, and 1150 cm-1 1H NMR (400 MHz, CDCl3) δ 0.20 (s,
;

Isomu¨nchnone-Based Synthesis of 2(1H)-Pyridones
J . Org. Chem., Vol. 64, No. 23, 1999 8657
9H), 0.21 (s, 9H), 2.18-2.24 (m, 2H), 3.20 (t, 2H, J ) 8.0 Hz),
4.17 (t, 2H, J ) 7.8 Hz), and 7.59 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ -0.08, -0.10, 20.5, 32.4, 50.3, 97.2, 97.8, 99.3, 99.4,
concentrated under reduced pressure. The crude residue was
subjected to flash silica gel chromatography to give 0.05 g
(86%) of 40 as a colorless solid: mp 154-155 °C; IR (CH2Cl2)
1645, 1455, and 1200 cm-1; 1H NMR (300 MHz, CDCl3) δ 2.18-
2.29 (m, 2H), 3.12 (t, 2H, J ) 7.8 Hz), 4.23 (t, 2H, J ) 7.5 Hz),
6.33 (d, 1H, J ) 9.6 Hz), and 7.36 (d, 1H, J ) 9.6 Hz); 13C
NMR (100 MHz, CDCl3) δ 20.5, 33.3, 50.3, 94.0, 118,9, 142.9,
149.0, and 161.1. Anal. Calcd for C8H8NOBr: C, 45.07; H, 3.79;
N, 6.57. Found: C, 45.12; H, 3.74; N, 6.47.
99.5, 112.8, 145.7, 155.3, and 160.0. Anal. Calcd for C18H25
-
NOSi2: C, 66.03; H, 7.70; N, 4.28. Found: C, 66.04; H, 7.61;
N, 4.22.
8-Br om o-6-tr im eth ylsila n yleth yn yl-2,3-d ih yd r o-1H-in -
d olizin -5-on e (37). To a solution containing 0.02 g (0.08
mmol) of triphenyl phosphine in 6 mL of triethylamine was
added 0.2 g of CuI followed by 15 mg of PdCl2(PPh3)2. To this
mixture was added 0.1 mL (0.6 mmol) of (trimethylsilyl)-
acetylene in 6 mL of toluene followed by the addition of 0.2 g
(0.6 mmol) of triflate 25 in one portion. The reaction mixture
was heated at 115 °C for 72 h, cool to room temperature,
poured into ice water, extracted with CH2Cl2, washed with
brine, and dried over Na2SO4. The organic extracts were
filtered and concentrated under reduced pressure. The crude
residue was subjected to flash silica gel chromatography to
give 0.09 g (53%) of 37 as a light yellow foam: IR (CH2Cl2)
1664, 1544, and 1151 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.24
(s, 9H), 2.11-2.28 (m, 2H), 3.13 (t, 2H, J ) 7.9 Hz), 4.24 (t,
2H, J ) 7.5 Hz), and 7.62 (s, 1H); 13C NMR (75 MHz, CDCl3)
δ -0.19, 20.4, 32.9, 49.9, 98.4, 99.3, 101.4, 113.5, 144.6, 154.6,
and 160.1; HRMS calcd for C13H16NOBrSi: 309.0185, found
309.0181.
2,3-Dih yd r o-5(1H)-in d olizin on e (41). A solution of 0.15
g (0.8 mmol) of pyridone 32 in 6 mL of 48% HBr was heated
at 135 °C for 12 h. The reaction mixture was taken to dryness
under reduced pressure, and the resulting residue was taken
up in CH2Cl2 and washed with water. The organic layer was
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The crude residue was subjected to flash
silica gel chromatography to give 0.1 g (96%) of 2,3-dihydro-
5(1H)-indolizinone (41) as a pale yellow oil:49 IR (CH2Cl2) 1654,
1
1545, and 1149 cm-1; H NMR (300 MHz, CDCl3) δ 2.19 (m,
2H), 3.12 (t, 2H, J ) 7.8 Hz), 4.17 (t, 2H, J ) 7.5 Hz), 6.17 (d,
1H, J ) 8.1 Hz), 6.43 (d, 1H, J ) 8.5 Hz), and 7.30-7.35 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 21.5, 32.1, 48.8, 101.2, 117.9,
140.1, 150.5, and 163.1; HRMS calcd for C8H9NO 135.0684,
found 135.0680.
5-Oxoin d olizid in e (42). To a solution of 0.08 g (0.6 mmol)
of pyridone 41 in 7 mL of acetic acid was added a catalytic
amount of PtO2, and the reaction mixture was stirred under
a hydrogen atmosphere of 90 psi for 2 h. After filtration of the
catalyst, the solution was extracted with CH2Cl2 and washed
with water. The organic layer was washed with brine, dried
over Na2SO4, and concentrated under reduced pressure. The
crude residue was subjected to flash silica gel chromatography
to give 0.07 g (89%) of 5-oxoindolizidine (42) as a pale yellow
6,8-Bis(3,4-d im eth oxyp h en yl)-1,2,3-tr ih yd r oin d olizin e-
5-on e (38). To a solution of 0.3 mL (1.1 mmol) of bromovera-
trole in 4 mL of THF at -78 °C was added 1.3 mL (2.2 mmol)
of tert-butyllithium. The solution was stirred for 15 min at -78
°C, after which time 0.15 g (1.1 mmol) of zinc chloride was
added, and the mixture was allowed to warm to room tem-
perature over a period of 1 h. A 0.1 g (0.27 mmol) sample of
triflate 25 and 13 mg of Pd(PPh3)4 were added, and the mixture
was heated at reflux for 36 h. The reaction mixture was cooled
to room temperature, and the solvent was removed under
reduced pressure. The residue was subjected to flash silica gel
chromatography to give 0.07 g (62%) of 38 as a clear oil: IR
oil:42 IR (CH2Cl2) 1620 cm-1 1H NMR (300 MHz, CDCl3) δ
;
1.09-2.45 (m, 10H), 3.20-3.70 (m, 3H, J ) 7.8 Hz). Anal.
Calcd for C8H13NO: C, 69.02; H, 9.42; N, 10.07. Found: C,
68.91; H, 9.38; N, 10.04.
(CH2Cl2) 1630, 1502, and 1246 cm-1 1H NMR (400 MHz,
;
δ-Con icein e (43). A mixture of 0.05 g (0.36 mmol) of lactam
42 and 0.03 g (0.9 mmol) of lithium aluminum hydride in 5
mL of THF was heated at reflux for 15 h. After the mixture
cooled to 0 °C, water, 15% sodium hydroxide, and water were
successively added. The mixture was dried and filtered through
Celite. The filtrate was evaporated to give 43 (98%) as a
colorless oil (picrate mp 228-231 °C, lit.50 mp 224-228 °C).
8-P h en ylsu lfon yl-6-h yd r oxy-7-m eth yl-2,3-d ih yd r o-1H-
in d olizin -5-on e (44). A solution containing 1.75 g (6 mmol)
of diazoamide 9, 1.6 g (9 mmol) of cis-phenylsulfonyl-1-propene,
and 2 mg of rhodium(II) acetate in 60 mL of benzene was
heated at reflux for 12 h. The solvent was removed under
reduced pressure, and the residue was subjected to flash silica
gel chromatography to give 0.9 g (51%) of 44 as a white solid:
acetone-d6) δ 2.22-2.31 (m, 2H), 3.32 (t, 2H, J ) 7.8 Hz), 3.81
(s, 3H), 3.82 (s, 3H), 3.83 (s, 3H), 3.85 (s, 3H), 4.24 (t, 2H, J )
7.8 Hz), 6.85 (s, 1H), 6.93 (d, 1H, J ) 8.4 Hz), 7.01 (s, 1H),
7.08 (s, 1H), 7.33 (m, 1H), 7.47 (s, 1H), 7.73 (s, 1H); 13C NMR
(75 MHz, CDCl3) δ 21.7, 32.0, 49.3, 55.8, 55.9, 56.0 (2), 103.8,
110.8, 110.9, 112.9, 114.8, 121.5, 124.0, 126.1, 128.8, 132.7,
147.9, 148.3, 148.4 (2), 148.6, 150.2, and 161.8. Anal. Calcd
for C24H25NO5: C, 70.73; H, 6.19; N, 3.44. Found: C, 70.63;
H, 6.08; N, 3.27.
6-(3,4-Dim eth oxyph en yl)-8-br om o-1,2,3-tr ih ydr oin doliz-
in -5-on e (39). To a solution of 0.16 mL (0.06 mmol) of
bromoveratrole in 4 mL of THF at -78 °C was added 0.7 mL
(1.1 mmol) of tert-butyllithium. The solution was stirred for
15 min at -78 °C, after which time 0.15 g (1.1 mmol) of zinc
chloride was added, and the mixture was allowed to warm to
room temperature over a period of 1 h. A 0.1 g (0.27 mmol)
sample of triflate 25 and 13 mg of Pd(PPh3)4 were added, and
the reaction mixture was heated at reflux for 1 h. The mixture
was cooled to room temperature, and the solvent was removed
under reduced pressure. The residue was subjected to flash
silica gel chromatography to give 0.07 g (71%) of 39 as a white
mp 234-235 °C; IR (CH2Cl2) 3226, 1627, 1606, and 1151 cm-1
;
1H NMR (300 MHz, CDCl3) δ 2.19 (s, 3H), 2.22-2.32 (m, 2H),
3.76 (t, 2H, J ) 7.8 Hz), 4.22 (t, 2H, J ) 7.5 Hz), 6.81 (brs,
1H), 7.52-7.60 (m, 3H), 7.80 (s, 1H), and 7.83 (s, 1H); 13C NMR
(75 MHz, CDCl3) δ 12.5, 21.3, 33.5, 49.1, 116.1, 123.4, 126.5,
129.2, 133.1, 142.4, 142.5, 145.1, 148.6, and 156.5. Anal. Calcd
for C15H15NO3S: C, 59.00; H, 4.95; N, 4.58. Found: C, 58.94;
H, 4.95; N, 4.56.
solid: mp 92-93 °C; IR (CH2Cl2) 1645, 1455, and 1200 cm-1
;
Tr iflu or om eth a n esu lfon ic Acid 8-P h en ylsu lfon yl-7-
m eth yl-5-oxo-1,2,3,5-tetr a h yd r oin d olizin -6-yl Ester (45).
To a solution containing 0.6 g (1.9 mmol) of pyridone 44 in 20
mL of CH2Cl2 at 0 °C was added 0.7 mL (5 mmol) of
triethylamine. The solution was allowed to stir at 0 °C for 20
min, at which time 1.4 g (3.9 mmol) of N-phenyl trifluo-
romethanesulfonamide was added in one portion. The mixture
was allowed to warm to room temperature, stirred for 14 h,
quenched with water, and extracted with CH2Cl2. The organic
layer was washed with brine and dried over Na2SO4. The
organic extracts were filtered and concentrated under reduced
pressure. The crude residue was subjected to flash silica gel
1H NMR (300 MHz, CDCl3) δ 2.20-2.31 (m, 2H), 3.14 (t, 2H,
J ) 7.8 Hz), 3.90 (s, 3H), 3.93 (s, 3H), 4.29 (t, 2H, J ) 7.8 Hz),
6.82 (d, 1H, J ) 8.4 Hz), 7.19-7.22 (m, 1H), 7.43 (d, 1H, J )
2.1 Hz), 7.54 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 20.7, 33.1,
50.6, 55.9, 94.1, 110.8, 111.7, 120.8, 128.4, 129.6, 139.8, 147.3,
148.3, 148.8, 159.7. Anal. Calcd for C16H16NO3Br: C, 55.01;
H, 4.62; N, 4.01. Found: C, 55.12; H, 4.58; N, 3.94.
8-Br om o-1,2,3-tr ih yd r oin d olizin -5-on e (40). To a solu-
tion containing 0.1 g (0.3 mmol) of triflate 25 in 2 mL of DMF
were added 0.1 mL (0.8 mmol) of triethylamine and 4 mg of
Pd(PPh3)Cl2. To this solution was added 0.02 mL (0.6 mmol)
of 96% formic acid. The mixture was stirred at 60 °C for 15
min, cooled to 0 °C, quenched with water, and extracted with
ethyl acetate. The organic layer was washed with brine and
dried over Na2SO4. The organic extracts were filtered and
(49) Thomas, E. W. J . Org. Chem. 1986, 51, 2184.
(50) Luning, B.; Lundin, C. Acta Chem. Scand. 1967, 21, 2136.

8658 J . Org. Chem., Vol. 64, No. 23, 1999
Padwa et al.
chromatography to give 0.74 g (86%) of 45 as a white solid:
stirred overnight, and then cooled to -78 °C. The mixture was
quenched with 5 mL of methanol, and the solvent was removed
under reduced pressure. The resulting brown solid was used
directly in the next step. To a solution containing the above
diol and 2.5 g (6.9 mmol) of N-phenyl trifluoromethanesulfona-
mide in 20 mL of CH2Cl2 at 0 °C was added 1.0 mL (6.9 mmol)
of triethylamine. The reaction mixture was allowed to warm
to room temperature and stirred overnight, and the solvent
was removed under reduced pressure. The crude residue was
subjected to flash silica gel chromatography to give 0.5 g (68%)
of 50 as a white solid: mp 115-116 °C; IR (neat) 1681, 1625,
1573, 1425 and 1206 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.35
(tt, 2H, J ) 7.2 and 8.0 Hz), 3.22 (t, 2H, J ) 8.0 Hz), 4.25 (t,
2H, J ) 7.2 Hz), and 6.29 (s, 1H); 13C NMR (75 MHz, CDCl3)
δ 21.6, 32.5, 50.2, 94.8, 118.6 (q), 128.4, 149.5, 152.1, and 155.9.
Anal. Calcd for C10H7F6NO7S2: C, 27.85; H, 1.64; N, 3.25.
Found: C, 27.87; H, 1.67; N, 3.22.
mp 185-186 °C; IR (CH2Cl2) 1667, 1418, 1200, and 1154 cm-1
;
1H NMR (300 MHz, CDCl3) δ 2.20-2.39 (m, 5H), 3.83 (t, 2H,
J ) 7.8 Hz), 4.24 (t, 2H, J ) 7.5 Hz), 7.56-7.65 (m, 3H), 7.81
(s, 1H), and 7.84 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 14.1,
20.6, 34.6, 49.9, 114.2, 118.7 [q, J (13C-19F) ) 320 Hz], 126.5,
1
129.5, 133.7, 136.6, 141.0, 141.8, 154.6, and 155.3. Anal. Calcd
for C16H14 F3NO6S2: C, 43.93; H, 3.23; N, 3.20. Found: C,
43.93; H, 3.24; N, 3.16.
8-P h en ylsu lfon yl-6-(4-m et h oxyp h en yl)-7-m et h yl-2,3-
d ih yd r o-1H-in d olizin -5-on e (46). To a solution containing
0.4 g (0.9 mmol) of triflate 45 in 8 mL of N-methyl pyrrolidi-
none was added 0.47 g (1.2 mmol) of 4-methoxyphenyl tribu-
tyltin. The solution was cannulated into a flask containing 0.03
g of Pd(PPh3)4 and 0.11 g of LiCl (2.7 mmol) in 8 mL of
N-methyl pyrrolidinone. The resulting mixture was heated at
150 °C for 2 h, cooled to room temperature, quenched with
water, and extracted with ether. The combined organic ex-
tracts were poured into a saturated KF solution and allowed
to stir for 5 h at room temperature. The organic phase was
separated, filtered through a pad of Celite, and concentrated
under reduced pressure. The residue was subjected to flash
silica gel chromatography to give 0.26 g (72%) of 46 as a white
crystalline solid: mp 182-183 °C; IR (CH2Cl2) 1644, 1526, and
6,7-Bis(3,4-d im eth oxyp h en yl)-1,2,3-tr ih yd r oin d olizin -
5-on e (51). To a stirred solution containing 0.13 g (0.9 mmol)
of 4-bromoveratrole in 3 mL of THF at -75 °C was added 1.3
mL of tert-butyllithium (1.6 M solution in pentane). The
reaction mixture was stirred at -75 °C for 0.5 h, 1.9 mL of
ZnCl2 (0.8 M in THF) was added, and the mixture was allowed
to warm to 25 °C while stirring for 0.5 h. To this mixture was
added a solution of 0.1 g (0.2 mmol) of ditriflate 50 and 0.013
g (0.01 mmol) of Pd(PPh3)4 in 2 mL of THF. The reaction
mixture was heated at reflux for 20 h, quenched with water,
and extracted with EtOAc. The combined organic extracts were
washed with a saturated brine solution, dried over MgSO4,
concentrated under reduced pressure, and subjected to flash
silica gel chromatography. The major product eluted from the
column (0.06 g, 64%) was identified as 51 and was obtained
as a yellow solid: mp 193-195 °C; IR (neat) 1644, 1596, 1516,
1
1244 cm-1; H NMR (300 MHz, CDCl3) δ 2.07 (s, 3H), 2.23-
2.30 (m, 2H), 3.81 (s, 3H), 3.87 (t, 2H, J ) 7.8 Hz), 4.22 (t, 2H,
J ) 7.5 Hz), 6.90 (d, 2H, J ) 8.7 Hz) 7.03 (d, 2H, J ) 8.7 Hz),
7.50-7.62 (m, 3H), 7.83 (s, 1H), and 7.86 (s, 1H); 13C NMR
(75 MHz, CDCl3) δ 18.7, 20.5, 34.7, 49.5, 55.1, 113.7, 115.2,
126.2, 126.3, 128.2, 128.4, 129.0, 129.1, 131.0, 131.7, 131.8,
131.9, 132.9, 142.7, 145.0, 154.5, 158.8, and 160.4. Anal. Calcd
for C23H21NO4S: C, 66.81; H, 5.35; N, 3.54. Found: C, 67.04;
H, 5.58; N, 3.28.
1
6-(4-Meth oxyph en yl)-7-m eth yl-2,3-dih ydr o-1H-in dolizin -
5-on e (47). To a solution containing 0.2 g (0.50 mmol) of
pyridone 46 in 6 mL of ethanol was added an excess of Raney
nickel. The mixture was heated at reflux for 5 h, cooled to room
temperature, filtered through a pad of Celite, quenched with
water, and extracted with CH2Cl2. The organic layer was
washed with brine and dried over Na2SO4. The organic extracts
were filtered and concentrated under reduced pressure. The
crude residue was subjected to flash silica gel chromatography
to give 0.12 g (90%) of 47 as a white solid: mp 126-127 °C;
1258, and 1136 cm-1; H NMR (400 MHz, CDCl3) δ 2.25 (tt,
2H, J ) 7.6 and 7.2 Hz), 3.15 (t, 2H, J ) 7.6 Hz), 3.56 (s, 3H),
3.68 (s, 3H), 3.83 (s, 3H), 3.85 (s, 3H), 4.23 (t, 2H, J ) 7.2 Hz),
6.27 (s, 1H), 6.54 (s, 1H), and 6.72-6.76 (m, 5H); 13C NMR
(75 MHz, CDCl3) δ 21.7, 32.0, 49.3, 55.8, 55.9, 56.0 (2), 103.8,
110.8, 110.9, 112.9, 114.8, 121.5, 124.0, 126.1, 128.8, 132.7,
147.9, 148.3, 148.4 (2), 148.6, 150.2, and 161.8. Anal. Calcd
for C24H25NO5: C, 70.73; H, 6.19; N, 3.44. Found: C, 70.63;
H, 6.08; N, 3.27.
Meth yl 5-Oxo-1-(2-p h en ylth ioa cetyl)p yr r olid in e-2-ca r -
boxyla te (55). To a stirred solution containing 10.0 g (77
mmol) of L-pyroglutamic acid (53) in 200 mL of methanol was
added 0.8 g of Dowex 50WX2-200 ion-exchange resin. The
suspension was heated at reflux for 3 h and cooled to room
temperature, and the ion-exchange resin was filtered. The
filtrate was concentrated under reduced pressure to give
L-methyl pyroglutamate (54) as a light yellow oil, which was
used directly in the next step. An 11 g sample of 54 was
dissolved in 50 mL of benzene, and this solution was added
slowly to a stirred solution of phenylthioacetyl chloride in 100
mL of benzene. The mixture was heated at reflux for 24 h,
concentrated under reduced pressure, taken up in Et2O, and
washed once with a saturated NaHCO3 solution and then with
brine. The organic layer was dried over MgSO4 and concen-
trated under reduced pressure. The resulting residue was
subjected to flash silica gel chromatography to give 19.7 g
(87%) of 55 as an orange oil: IR (neat) 1745, 1688, and 1581
cm-1; 1H NMR (400 MHz, CDCl3) δ 2.08-2.15 (m, 1H), 2.30-
2.42 (m, 1H), 2.55-2.64 (m, 1H), 2.70-2.81 (m, 1H), 3.73 (s,
3H), 4.18 (d, 1H, J ) 15.4 Hz), 4.36 (d, 1H, J ) 15.4 Hz), 4.76
(dd, 1H, J ) 9.6 and 2.8 Hz), 7.19-7.23 (m, 1H), 7.26-7.31
(m, 2H), and 7.40-7.44 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
21.4, 31.7, 38.9, 52.7, 57.9, 126.8, 128.9, 130.2, 135.1, 169.2,
171.1, and 174.2. Anal. Calcd for C14H15NO4S: C, 57.32; H,
5.15; N, 4.77. Found: C, 57.06; H, 5.17; N, 4.68.
1
IR (CH2Cl2) 1646, 1586, and 1243 cm-1; H NMR (300 MHz,
CDCl3) δ 2.05 (s, 3H), 2.11-2.26 (m, 2H), 3.06 (t, 2H, J ) 7.8
Hz), 3.83 (s, 3H), 4.14 (t, 2H, J ) 7.5 Hz), 6.07 (s, 1H), 6.93 (d,
2H, J ) 8.7 Hz), and 7.18 (d, 2H, J ) 8.7 Hz); 13C NMR (75
MHz, CDCl3) δ 20.8, 21.4, 31.5, 48.8, 55.2, 104.0, 113.5, 127.4,
128.5, 131.3, 147.3, 147.5, 158.4, and 161.4. Anal. Calcd for
C
16H17NO2: C, 75.26; H, 6.72; N, 5.41. Found: C, 75.16; H,
6.79; N, 5.42.
6-(4-Hydr oxyph en yl)-7-m eth yl-2,3-dih ydr o-1H-in dolizin -
5-on e (48). A solution of 0.1 g (0.4 mmol) of 47 in 5 mL of
48% HBr was heated at 135 °C for 12 h. The reaction mixture
was taken to dryness under reduced pressure. The resulting
residue was taken up in CH2Cl2, washed with water and brine,
and dried over Na2SO4. The organic extracts were filtered and
concentrated under reduced pressure. The crude residue was
subjected to flash silica gel chromatography to give 0.09 g
(97%) of 6-(4-hydroxyphenyl)-7-methyl-2,3-dihydro-1H-indolizin-
5-one (48) as a white solid: mp 231-233 °C (lit.27 mp 232-
234 °C); IR (CH2Cl2) 3400-2400, 1645,1560, and 1510 cm-1
;
1H NMR (300 MHz, DMSO-d6) δ 1.97 (s, 3H), 2.08 (quint, 2H,
J ) 7.5 Hz), 3.03 (t, 2H, J ) 7.5 Hz), 3.96 (t, 2H, J ) 7.5 Hz),
6.10 (s, 1H), 6.78 (d, 2H, J ) 8.8 Hz), 6.95 (d, 2H, J ) 8.8 Hz),
and 9.29 (s, 1H, exchangeable). Anal. Calcd for C14H13NO2: C,
73.98; H, 5.77; N, 6.17. Found: C, 73.85; H, 5.71; N, 6.03.
A 0.05 g (mmol) sample of 48 was subjected to alane
reduction using the conditions described by Wick to give (()-
ipalbidine (7), mp 148-150 °C (lit27 mp 149-150 °C).
Meth yl 5-Oxo-1-(2-(p h en ylsu lfon yl)a cetyl)p yr r olid in e-
2-ca r boxyla te (56). To a stirred solution containing 19.0 g
(65 mmol) of 55 in 300 mL of methanol and 150 mL of water
at 0 °C was slowly added 200 g of OXONE. The suspension
was stirred at ambient temperature for 7 h and filtered, and
the combined organic layers were concentrated under reduced
pressure. The residue was dissolved in CHCl3, washed with
6,7-Bis(tr iflu or om eth yl)su lfon yloxy)-1,2,3-tr ih yd r oin -
d olizin -5-on e (50). To a stirred solution containing 0.4 g (1.7
mmol) of 6-hydroxy pyridone 22 in 20 mL of CH2Cl2 at -78
°C was slowly added 5.2 mL of BBr3 (1.0 M solution in CH2-
Cl2). The resulting solution was allowed to warm to 25 °C,

Isomu¨nchnone-Based Synthesis of 2(1H)-Pyridones
J . Org. Chem., Vol. 64, No. 23, 1999 8659
water, dried over MgSO4, and concentrated under reduced
pressure to give a colorless oil. Trituration with Et2O gave 14.0
g (66%) of 56 as a white solid: mp 99-101 °C; IR (KBr) 1748,
1706, 1459 and 1341 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.09-
2.15 (m, 1H), 2.29-2.40 (m, 1H), 2.53-2.60 (m, 1H), 2.65-
2.73 (m, 1H), 3.75 (s, 3H), 4.62 (d, 1H, J ) 14.0 Hz), 4.75 (dd,
1H, J ) 9.6 and 2.4 Hz), 5.30 (d, 1H, J ) 14.0 Hz), 7.56-7.60
(m, 2H), 7.66-7.70 (m, 1H), and 7.96-7.98 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 21.3, 31.7, 53.0, 58.1, 60.7, 128.7, 129.3,
chromatography to give 0.14 g (86%) of 11 as a pale yellow
solid: mp 189-191 °C; IR (neat) 1748, 1704, 1682, 1653, 1588
1
and 1461 cm-1; H NMR (400 MHz, CDCl3) δ 2.33-2.40 (m,
1H), 2.47-2.62 (m, 1H), 2.52 (s, 3H), 3.50-3.60 (m, 1H), 3.71-
3.81 (m, 1H), 3.79 (s, 3H), 3.82 (s, 3H), 5.21 (dd, 1H, J ) 10.0
and 3.2 Hz), 7.15 (d, 1H, J ) 16.0 Hz), 7.57 (d, 1H, J ) 16.0
Hz) and 8.01 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 26.6, 28.9,
34.5, 52.8, 54.2, 62.9, 114.8, 122.1, 122.9, 140.2, 143.5, 158.9,
160.4, 169.1, 171.1, and 195.5. Anal. Calcd for C16H17NO6: C,
60.18; H, 5.37; N, 4.39. Found: C, 60.30; H, 5.42; N, 4.32.
134.3, 139.4, 161.7, 170.8, and 174.4. Anal. Calcd for C14H15
-
NO6S: C, 51.69; H, 4.65; N, 4.31. Found: C, 51.73; H, 4.66;
N, 4.32.
Met h yl 3-(8-Acet yl-3-(m et h oxyca r b on yl)-5-oxo-1,2,3-
tr ih yd r oin d olizin -6-yl)p r op a n oa te (59). To a solution con-
taining 0.35 g (1.1 mmol) of 11 in 20 mL of CHCl3 was added
0.07 g of 10% Pd/C. The mixture was hydrogenated at 50 psi
for 5 h, filtered through a bed of Celite, and concentrated under
reduced pressure. The residue was subjected to flash silica gel
chromatography to give 0.35 g (100%) of 59 as a white solid:
mp 115-116 °C; IR (Nujol) 1733, 1681, 1644, 1603, and 1463
cm-1; 1H NMR (400 MHz, CDCl3) δ 2.25-2.36 (m, 1H), 2.46-
2.58 (m, 1H), 2.47 (s, 3H), 2.68 (t, 2H, J ) 7.2 Hz), 2.81-2.91
(m, 2H), 3.41-3.58 (m, 1H), 3.60-3.71 (m, 1H), 3.66 (s, 3H),
3.80 (s, 3H), 5.12 (dd, 1H, J ) 10.0 and 3.6 Hz), and 7.77 (s,
1H); 13C NMR (75 MHz, CDCl3) δ 26.0, 26.2, 28.2, 32.5, 33.2,
51.8, 53.1, 61.7, 113.4, 128.0, 138.5, 155.4, 161.1, 170.5, 173.6,
and 195.2. Anal. Calcd for C16H19NO6: C, 59.81; H, 5.96; N,
4.36. Found: C, 59.72; H, 5.94; N, 4.30.
Met h yl 5-Oxo-1-(2-(p h en ylsu lfon yl)d ia zoa cet yl)p yr -
r olid in e-2-ca r boxyla te (57). To a stirred solution containing
4.0 g (12 mmol) of imide 56 in 75 mL of acetonitrile at 0 °C
was added 4.1 mL (30 mmol) of triethylamine. The solution
was allowed to stir at 0 °C for 20 min, and then 3.6 g (15 mmol)
of p-acetamidobenzenesulfonyl azide was added in one portion.
The solution was allowed to warm to 25 °C and was stirred at
room temperature for 18 h. The solvent was removed under
reduced pressure, and the resulting residue was taken up in
CH2Cl2. The solution was filtered, and the filtrate was
concentrated to dryness under reduced pressure. The residue
was subjected to flash silica gel chromatography to give 3.9 g
(91%) of 57 as a yellow solid: mp 108-109 °C; IR (Nujol) 2136,
1740, 1683, and 1461 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.04-
2.11 (m, 1H), 2.33-2.43 (m, 1H), 2.51-2.59 (m, 1H), 2.65-
2.74 (m, 1H), 3.71 (s, 3H), 4.70 (dd, 1H, J ) 8.8 and 4.4 Hz),
7.53-7.57 (m, 2H), 7.62-7.67 (m, 1H), and 8.04-8.06 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 22.2, 31.4, 52.9, 58.5, 128.2, 129.2,
134.1, 141.6, 157.7, 170.7, and 173.4. Anal. Calcd for
Meth yl 3-(8-Acetyloxy-3-(m eth oxycar bon yl)-5-oxo-1,2,3-
tr ih yd r o-in d oliz-in -6-yl) p r op a n oa te (60). To a stirred
solution containing 1.9 g (9.0 mmol) of trifluoroacetic acid in
8 mL of CH2Cl2 at 0 °C was added 0.3 g of 30% H2O2. The
reaction mixture was stirred at 0 °C for 0.5 h, and the solution
was slowly added to a stirred solution containing 0.2 g (0.6
mmol) of 59 in 10 mL of CH2Cl2 at 0 °C. The mixture was
allowed to warm to 25 °C and was stirred for an additional
4.5 h at room temperature. The mixture was slowly added to
10 mL of a saturated NaHCO3 solution, and the mixture was
extracted with CH2Cl2. The combined organic extracts were
dried over MgSO4, concentrated under reduced pressure, and
subjected to flash silica gel chromatography to give 0.2 g (96%)
of 60 as a light yellow oil: IR (neat) 1747, 1671, 1601, 1571,
C
14H13N3O6S: C, 47.86; H, 3.73; N, 11.96. Found: C, 47.96;
H, 3.79; N, 11.91.
Meth yl 8-Acetyl-6-h yd r oxy-5-oxo-1,2,3-tr ih yd r oin d oliz-
in e-3-ca r boxyla te (10). To a solution of 3.9 g (11 mmol) of
diazoimide 57 in 70 mL of benzene w343 added 2.5 g (37 mmol)
of methyl vinyl ketone and 2 mg of rhodium(II) acetate, and
the reaction mixture was heated at reflux for 20 h. The mixture
was allowed to cool to 25 °C, and the solvent was removed
under reduced pressure. The crude residue was subjected to
flash silica gel chromatography to give 2.4 g (86%) of 10 as a
beige solid: mp 124-126 °C; IR (Nujol) 1748, 1740, 1684, 1628
and 1438 cm-1 1H NMR (400 MHz, CDCl3) δ 2.27 (s, 3H),
;
2.28-2.34 (m, 1H), 2.47-2.58 (m, 1H), 2.63-2.67 (m, 2H),
2.74-2.90 (m, 2H), 2.92-3.00 (m, 1H), 3.02-3.11 (m, 1H), 3.65
(s, 3H), 3.80 (s, 3H), 5.10 (dd, 1H, J ) 9.2 and 3.6 Hz), and
7.13 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 20.8, 26.2, 26.6, 28.1,
32.4, 51.7, 53.0, 62.2, 128.4, 129.7, 135.0, 139.4, 160.1, 169.0,
170.5, and 173.6. Anal. Calcd for C16H19NO7: C, 56.97; H, 5.68;
N, 4.15. Found: C, 56.80; H, 5.72; N, 4.08.
1
and 1458 cm-1; H NMR (400 MHz, CDCl3) δ 2.35-2.42 (m,
1H), 2.47 (s, 3H), 2.50-2.61 (m, 1H), 3.37-3.46 (m, 1H), 3.59-
3.67 (m, 1H), 3.81 (s, 3H), 5.18 (dd, 1H, J ) 9.6 and 3.2 Hz),
6.79 (s, 1H), and 7.33 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
26.8, 28.4, 32.2, 53.2, 61.5, 113.6, 115.5, 143.9, 146.7, 157.6,
170.1, and 195.6. Anal. Calcd for C12H13NO5: C, 57.37; H, 5.22;
N, 5.58. Found: C, 57.35; H, 5.20; N, 5.50.
P h en ylm eth yl 3-(8-Hyd r oxy-5-oxo-3-(ben zyloxyca r bo-
n yl)-1,2,3-tr ih yd r oin d olizin -6-yl)p r op a n oa te (61). To a
stirred solution containing 0.15 g (0.4 mmol) of 60 in 5 mL of
toluene was added 1.0 g (9.1 mmol) of benzyl alcohol and 0.05
g (0.1 mmol) of Otera’s48 catalyst. The reaction mixture was
heated at reflux for 15 h, the solvent was removed under
reduced pressure, and the residue was subjected to flash silica
Meth yl 8-Acetyl-5-oxo-6-((tr iflu or om eth yl)su lfon yloxy)-
1,2,3-tr ih yd r oin d olizin e-3-ca r boxyla te (58). To a solution
containing 1.7 g (6.7 mmol) of the above 3-hydroxy-2(1H)-
pyridone 10 and 3.6 g (10.0 mmol) of N-phenyl trifluo-
romethanesulfonamide in 50 mL of CH2Cl2 at 0 °C was added
1.4 mL (10 mmol) of triethylamine. The reaction mixture was
allowed to warm to room temperature while stirring overnight.
The solvent was removed under reduced pressure, and the
crude residue was subjected to flash silica gel chromatography
to give 2.4 g (94%) of 58 as a white solid: mp 83-84 °C; IR
gel chromatography to give 0.2 g (98%) of 61: [R]25 -146 (c
D
0.39, CH2Cl2); IR (neat) 1740, 1675, 1546, 1409, 1285, and 1187
cm-1; 1H NMR (400 MHz, CDCl3) δ 2.19-2.24 (m, 1H), 2.36-
2.47 (m, 1H), 2.62-2.66 (m, 2H), 2.72-2.87 (m, 2H), 2.99-
3.08 (m, 2H), 5.06 (s, 2H), 5.12 (m, 1H), 5.12 (d, 1H, J ) 12.4
Hz), 5.22 (d, 1H, J ) 12.4 Hz), 6.53 (brs, 1H), 7.10 (s, 1H),
and 7.28-7.34 (m, 10H); 13C NMR (75 MHz, CDCl3) δ 26.2,
26.8, 27.4, 32.9, 62.3, 66.4, 67.6, 128.3 (2), 128.4, 128.6, 128.7,
128.8, 128.9, 132.5, 133.9, 134.8, 135.4, 136.2, 159.1, 170.2,
and 173.2.
1
(neat) 1752, 1686, 1667 and 1462 cm-1; H NMR (400 MHz,
CDCl3) δ 2.37-2.44 (m, 1H), 2.49 (s, 3H), 2.58-2.69 (m, 1H),
3.46-3.55 (m, 1H), 3.69-3.77 (m, 1H), 3.79 (s, 3H), 5.22 (dd,
1H, J ) 10.0 and 3.2 Hz), and 7.86 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 25.9, 28.0, 33.1, 53.1, 62.1, 111.5, 118.6 (q), 131.8,
136.5, 155.1, 157.3, 169.3, and 193.3. Anal. Calcd for C13H12F3-
NO7S: C, 40.74; H, 3.16; N, 3.65. Found: C, 40.80; H, 3.20;
N, 3.69.
Met h yl 3-(8-Acet yl-3-(m et h oxyca r b on yl)-5-oxo-1,2,3-
t r ih yd r oin d olizin -6-yl)p r op -2-en oa t e (11). To a solution
containing 0.015 g (0.2 mmol) of Pd(PPh3)2Cl2 in 5 mL of CH3-
CN at 25 °C was added a solution of 0.2 g (0.5 mmol) of triflate
58, 0.08 g (0.9 mmol) of methyl acrylate, and 0.2 mL (1.4 mmol)
of triethylamine in 2 mL of CH3CN. The reaction mixture was
heated at reflux for 3 h, and the solvent was removed under
reduced pressure. The residue was subjected to flash silica gel
Ack n ow led gm en t. We gratefully acknowledge the
National Institutes of Health (GM59384-20) for their
generous support of this work.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for new compounds lacking elemental analyses. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O9911600