Dichloroketene-induced cyclizations of vinyl sulfilimines: Application of the method in the synthesis of (±)-desoxyeseroline

Article abstract of DOI:10.1021/jo051550o

The reactions of several aryl-, furanyl-, and vinyl-substituted sulfilimines with dichloroketene proceeded at 25 °C to yield thioalkyl-substituted γ-lactams. The overall process involves nucleophilic addition of the nitrogen atom of the sulfilimine onto the highly electrophilic dichloroketene to first generate a zwitterionic intermediate. A subsequent [3,3]-sigmatropic rearrangement is followed by intramolecular trapping of the Pummerer cation by the amido anion to furnish the observed γ-lactam product. Incorporation of donor groups on the aromatic ring of the sulfonyl functionality had little effect when aryl-substituted sulfilimines were used but exhibited a major effect on the efficiency of the reaction with furanyl-substituted systems. The placement of an electron donor group (i.e., OMe) on the sulfonyl aryl group enhances the nucleophilicity of the amido anion contained within the sulfonium ion intermediate and facilitates the rate of the 3,3-sigmatropic rearrangement. Styryl-substituted sulfilimines cyclize in a stereospecific manner and produce a 3:2-mixture of γ-lactams and the isomeric imino-lactone system. The heavily functionalized γ-lactams are easily converted to a variety of nitrogen containing substrates. The vinyl sulfilimine cyclization method was applied to the total synthesis of the Calabar alkaloid (±)-desoxyeseroline.

Full text of DOI:10.1021/jo051550o

Dichloroketene-Induced Cyclizations of Vinyl Sulfilimines:
Application of the Method in the Synthesis of (()-Desoxyeseroline
Albert Padwa,* Shinji Nara, and Qiu Wang
Department of Chemistry, Emory University, Atlanta, Georgia 30322
chemap@emory.edu
Received July 26, 2005
The reactions of several aryl-, furanyl-, and vinyl-substituted sulfilimines with dichloroketene
proceeded at 25 °C to yield thioalkyl-substituted γ-lactams. The overall process involves nucleophilic
addition of the nitrogen atom of the sulfilimine onto the highly electrophilic dichloroketene to first
generate a zwitterionic intermediate. A subsequent [3,3]-sigmatropic rearrangement is followed
by intramolecular trapping of the Pummerer cation by the amido anion to furnish the observed
γ-lactam product. Incorporation of donor groups on the aromatic ring of the sulfonyl functionality
had little effect when aryl-substituted sulfilimines were used but exhibited a major effect on the
efficiency of the reaction with furanyl-substituted systems. The placement of an electron donor
group (i.e., OMe) on the sulfonyl aryl group enhances the nucleophilicity of the amido anion
contained within the sulfonium ion intermediate and facilitates the rate of the 3,3-sigmatropic
rearrangement. Styryl-substituted sulfilimines cyclize in a stereospecific manner and produce a
3:2-mixture of γ-lactams and the isomeric imino-lactone system. The heavily functionalized γ-lactams
are easily converted to a variety of nitrogen containing substrates. The vinyl sulfilimine cyclization
method was applied to the total synthesis of the Calabar alkaloid (()-desoxyeseroline.
Introduction
transformations are useful for the synthesis of drugs and
sulfur-substituted natural products.5-7 The Pummerer
reaction of sulfoxides has established itself as an ex-
tremely useful method for the preparation of R-substi-
tuted sulfides.8 The reaction has been widely studied and
has received considerable attention as a valuable syn-
thetic process. Pummerer thionium ions are generally
formed by treating a sulfoxide bearing an R-hydrogen
with acetic anhydride.9 Currently, Pummerer-based trans-
formations are finding widespread application in carbo
and heterocyclic synthesis by reaction of the initially
generated thionium ion with internally disposed nucleo-
philes.10
Sulfur-carbon ylides represent important reagents in
organic synthesis, particularly in reactions involving
intramolecular rearrangement and intermolecular attack
on substrates bearing an electrophilic carbon.1 The
reaction of a sulfonium ylide with carbonyl compounds
to give epoxides has proven to be an important synthetic
method.2 In addition, sigmatropic rearrangements of
sulfonium ylides constitute a powerful synthetic tool for
regio-, stereo-, and enantioselective C-C bond formation.3
Sulfoxides have also been extensively studied because of
their varied reactivity as a functional group for trans-
formations into a variety of sulfur compounds.4 These
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(1) Clark, J. S. In Nitrogen, Oxygen and Sulfur Ylides Chemistry. A
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10.1021/jo051550o CCC: $30.25 © 2005 American Chemical Society
Published on Web 09/21/2005
8538
J. Org. Chem. 2005, 70, 8538-8549

Cyclizations of Vinyl Sulfilimines
SCHEME 1. Additive Pummerer Reaction
FIGURE 1. A comparison of some sulfur ylides.
SCHEME 2. Marino Vinyl Sulfoxide Protocol
The additive Pummerer reaction11-18 represents one of
the more interesting variants of the Pummerer process
and occurs when a nucleophile displaces the acyloxy
leaving group of a vinylsulfonium ion through an SN2′
mechanism producing a saturated â-functionalized thion-
ium species (3) (Scheme 1). Trapping with a second
nucleophilic agent affords a product (4) formally derived
by the sequential attack of two nucleophiles on an R,â-
dication. This sequence of reactions has been utilized by
a number of research groups for the formation of carbon-
heteroatom and carbon-carbon bonds.17-20
The Marino group developed a novel variation of the
additive Pummerer reaction that produces γ-butyrolac-
tones by the reaction of dichloroketene with vinyl sul-
foxides.21 In general, the oxygen of a vinyl sulfoxide such
as 5 first attacks dichloroketene to produce in situ the
salt 6 (Scheme 2). The resulting enolate anion present
in 6 then undergoes a 3,3-sigmatropic rearrangement to
provide thionium ion intermediate 7. Finally, the result-
ing carboxylate anion adds to the neighboring thionium
ion to furnish butyrolactone 8, which retains the geom-
etry of the starting olefin.
As part of our continuing program designed to explore
the use of thionium ions for heterocyclic synthesis,22 we
became interested in developing some comparable addi-
tive Pummerer chemistry using sulfur-nitrogen ylides
(sulfilimines). Consideration of the relative electronega-
tivities of the atoms involved in this particular sulfur
ylide leads to the prediction that the chemical behavior
of sulfilimines should be intermediate between those of
sulfonium ylides and sulfoxides (Figure 1). The properties
of sulfilimines23 are known to be similar to those exhib-
ited by sulfoximines,24 but the sulfilimines are more
reactive, just as sulfonium ylides are more reactive than
the corresponding oxosulfonium ylides.1-3 To demonstrate
that vinyl sulfilimines can be induced to undergo the
additive Pummerer reaction,25,26 we decided to examine
their reactions with dichloroketene with the intention of
using the resulting γ-lactams for alkaloid synthesis.
(10) Bur, S. K.; Padwa, A. Chem. Rev. 2004, 104, 2401.
(11) Rea´monn, L. S. S.; O’Sullivan, W. I. J. Chem. Soc., Chem.
Commun. 1976, 642.
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Commun. 1985, 542.
Results and Discussion
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1990, 31, 6441. (b) Craig, D.; Daniels, K.; MacKenzie, A. R. Tetrahedron
Lett. 1991, 32, 6973.
Because oxindoles represent an important substructure
associated with many biologically active natural prod-
ucts,27 we thought that it might be possible to synthesize
this heterocyclic ring system by treating an aryl sulfil-
imine such as 12 with dichloroketene as outlined in
Scheme 3, Path B. Although various methods are avail-
(15) King, R. R. J. Org. Chem. 1980, 45, 5347.
(16) Kosugi, H.; Uda, H.; Yamagiwa, S. J. Chem. Soc., Chem.
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Chem. Soc., Perkin Trans. 1 1979, 570.
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Y. Chem. Pharm. Bull. 1987, 35, 562. (b) Brichard, M.-H.; Janousek,
Z.; Mere´nyi, R.; Viehe, H. G. Tetrahedron Lett. 1992, 33, 2511. (c) Iwata,
C.; Maezaki, N.; Kurumada, T.; Fukuyama, H.; Sugiyama, K.; Iman-
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Kurumada, T.; Maezaki, N.; Sugiyama, K.; Iwata, C. J. Chem. Soc.,
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A.; Kanna, H.; Uda, H. J. Chem. Soc., Perkin Trans. 1 1989, 935.
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Marino, J. P.; Laborde, E.; Paley, R. S. J. Am. Chem. Soc. 1988, 110,
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P.; Fernandez de la Pradilla, R.; Laborde, E. Synthesis 1987, 1088. (f)
Marino, J. P.; Fernandez de la Pradilla, R. Tetrahedron Lett. 1985,
26, 5381. (g) Marino, J. P.; Kim, M.-W.; Lawrence, R. J. Org. Chem.
1989, 54, 1782. (h) Marino, J. P.; Bogdan, S.; Kimura, K. J. Am. Chem.
Soc. 1992, 114, 5566. (i) Marino, J. P.; Rubio, M. B.; Cao, G.; de Dios,
A. J. Am. Chem. Soc. 2002, 124, 13398.
(22) For some leading references, see: Padwa, A.; Danca, M. D.;
Hardcastle, K. I.; McClure, M. S. J. Org. Chem. 2003, 68, 929.
(23) (a) Taylor, P. C. Sulfur Rep. 1999, 21, 241. (b) Oae, S.;
Furukawa, N. Sulfilimines and Related Derivatives; ACS Monograph
179; American Chemical Society: Washington, DC, 1983. (c) Ruano,
J. L. G.; Alemparte, C.; Clemente, F. R.; Gutie´rrez, L. G.; Gordillo, R.;
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D. H. R., Ollis, W. D., Eds.; Pergamon: New York, 1979; Vol. 3, Chapter
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Chem. 1999, 64, 1699. (b) Goehring, R. R.; Sachdeva, Y. P.; Pisipati,
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Soc., Perkin Trans. 1 1997, 2405.
J. Org. Chem, Vol. 70, No. 21, 2005 8539

Padwa et al.
SCHEME 3. Methods To Synthesize Oxindoles
SCHEME 4. Reaction of Aryl Sulfiliminines with
Dichloroketene
amounts of methyl phenyl sulfide and amide 22 (Scheme
4).37 Amide 22 is presumably derived by C-N cleavage
of the N-sulfonyl lactam 15 in competition with mercap-
tan elimination, which leads to oxindole 21 (Scheme 3,
Path B). Similar results were obtained using aryl-
substituted sulfilimines 18-20 with the oxindole (i.e.,
23-25) being formed in low yield (ca. 15-20%). Changing
the substituent group on both aromatic rings to the more
electron-donating methoxy group on the aryl sulfilimine
(i.e., X ) OMe (19) and Ar ) p-OMeC6H4 (20)) had only
a minimal effect on the yield of oxindole formation (13-
19%). Apparently, the key rate-determining step of the
process (i.e., 13 f 14) possesses a relatively high activa-
tion energy as a consequence of the disruption of aroma-
ticity. To minimize this difficulty, we opted to study the
reaction of the more reactive naphthyl-substituted sul-
filimine 26 with dichloroketene. In contrast to the results
obtained with sulfilimine 17, the cyclization reaction of
26 proceeded in 56% yield and furnished 27 as the only
detectable product that could be isolated from the crude
reaction mixture.
Next, we turned our attention to the related reaction
of several benzofuranyl-, indolyl-, and 2-furanyl-substi-
tuted sulfilimines. The results we obtained showed that
these cyclizations also proceeded at rt in THF and
furnished novel γ-lactams in good yield. Thus, the reac-
tion of benzofuranyl (28)- and indolyl-substituted (29)
sulfilimines with dichloroketene furnished the cyclized
lactams 30 and 31 in 52% and 78% yield, respectively
(Scheme 5). When the 2-furanyl-substituted sulfilimines
32 and 33 were used as the starting substrates, dihy-
drofuranyl γ-lactams 34 and 35 were formed in 58% and
40% yield, respectively. Interestingly, all of the γ-lactams
that were isolated were unexpectedly robust and did not
undergo loss of mercaptan even under somewhat forcing
conditions (i.e., heat, acid).
able for the preparation of oxindoles,28-34 their synthesis
is often limited by the availability of starting materials.
The method reported by Gassman and co-workers,35
which proceeds from a substituted aniline and ethyl
(methylthio)acetate via chlorination of the sulfide and
subsequent treatment with an arylamine and base, is one
of the most generally useful methods in terms of scope,
starting material availability, brevity, and reproducibility
(Scheme 3, Path A). We reasoned that by simply switch-
ing the sulfur and nitrogen positions, it might be possible
to use vinyl sulfilimines to prepare oxindoles according
to the sequence outlined in Scheme 3, Path B. Thus, we
expected that the reaction of arylsulfilimine of type 12
with dichloroketene would first afford zwitterion 13
where the nitrogen and sulfur atoms were interchanged
relative to the analogous Gassman intermediate 10. A
subsequent [3,3]-sigmatropic rearrangement would then
deliver the Pummerer-thionium ion intermediate 14.
Cyclization to 15 and loss of the mercaptan should yield
the desired oxindole 16. We first examined the reaction
of phenyl sulfilimine 17 with dichloroketene36 in THF at
25 °C, which afforded oxindole 21 together with varying
(28) Sundberg, R. J. Indoles; Academic Press: London, 1996; pp
152-154.
(29) (a) Cabri, W.; Candiani, I.; Colombo, M.; Franzoi, L.; Bedeschi,
A. Tetrahedron Lett. 1995, 36, 949. (b) Jones, K.; Wilkinson, J.; Ewin,
R. Tetrahedron Lett. 1994, 35, 7673. (c) Jones, K.; McCarthy, C.
Tetrahedron Lett. 1989, 30, 2657. (d) Bowman, W. R.; Heaney, H.;
Jordan, B. M. Tetrahedron Lett. 1988, 29, 6657.
(30) (a) Mori, M.; Ban, Y. Tetrahedron Lett. 1976, 17, 1807. (b)
Hennessy, E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 12084.
(31) (a) Kametani, T.; Ohsawa, T.; Ihara, M. Heterocycles 1980, 14,
277. (b) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402. (c)
Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem. 1998,
63, 6546.
(32) (a) Beckett, A. H.; Daisley, R. W.; Walker, J. Tetrahedron 1968,
24, 6093. (b) Sumpter, W. C. Chem. Rev. 1945, 37, 443.
(33) (a) Hardegger, E.; Corrodi, H. Helv. Chim. Acta 1956, 39, 514.
(b) Romeo, A.; Corrodi, H.; Hardegger, E. Helv. Chim. Acta 1955, 38,
463.
In contrast to the results noted with aryl sulfilimines
17-20, where the incorporation of donor groups on the
aromatic ring of the sulfonyl functionality had little effect,
the situation was quite different with furanyl sulfilimines
36-39. When sulfilimine 36 (R2 ) p-NO2C6H4) was
treated with dichloroketene, no discernible quantities of
(36) (a) Brady, W. T.; Liddell, H. G.; Vaughn, W. L. J. Org. Chem.
1966, 31, 626. (b) Krepski, L. R.; Hassner, A. J. Org. Chem. 1978, 43,
2879.
(37) For some earlier examples of the reaction of ketenes with
sulfilimines, see: (a) Abou-Gharbia, M.; Ketcha, D. M.; Zacharias, D.
E.; Swern, D. J. Org. Chem. 1985, 50, 2224. (b) Tomimatsu, Y.; Satoh,
K.; Sakamoto, M. Heterocycles 1977, 8, 109.
(34) Crestini, C.; Saladino, R. Synth. Commun. 1994, 24, 2835.
(35) (a) Gassman, P. G.; Gruetzmacher, G.; van Bergen, T. J. J. Am.
Chem. Soc. 1974, 96, 5512. (b) Gassman, P. G.; van Bergen, T. J. J.
Am. Chem. Soc. 1974, 96, 5508. (c) Gassman, P. G.; van Bergen, T. J.;
Gruetzmacher, G. J. Am. Chem. Soc. 1973, 95, 6508.
8540 J. Org. Chem., Vol. 70, No. 21, 2005

Cyclizations of Vinyl Sulfilimines
noted in their 1H and 13C NMR properties. In particular,
the vicinal trans coupling constant for N-tosyl lactams
54 and 55 exhibits a value of J ) 8.4 Hz, whereas the
related coupling for 57 and 58 has a value of J ) 10.8
Hz (600 MHz in CDCl3). The formation of a mixture of
products is really not so surprising because both com-
pounds are generated by either N- or O-alkylation39 of
the sulfonium ion 60 by the adjacent N-tosyl stabilized
amido anion formed by the 3,3-sigmatropic rearrange-
ment of 59 (Scheme 8). The complete stereospecificity of
the cyclization process is undoubtedly related to the
highly ordered transition state of the 3,3-sigmatropic
rearrangement. The resulting Pummerer intermediate
60 is rapidly trapped by the amido anion before C-C
bond rotation can occur. What is so surprising, however,
is that the formation of a mixture of isomeric γ-lactams
and imino-lactones only occurs with these styryl-substi-
tuted sulfilimines. In no other case were we able to detect
any of the less stable imino-lactone structure in the crude
reaction mixture.40 For example, the reaction of cyclic
sulfilimines of type 61-63 with dichloroketene only
afforded the N-tosyl γ-lactams 64-66 (Scheme 9).
As part of an effort to further broaden the utility of
this cyclization protocol, we decided to carry out some
simple chemical manipulations of these highly function-
alized γ-lactams to probe their usefulness for the syn-
thesis of various nitrogen containing substrates. It was
anticipated that lactam 47, derived from the reaction of
dichloroketene with S-ethyl-S-ethenyl-N-(toluene-4-sul-
fonyl)sulfilimine, could be used to prepare a variety of
substituted pyrrolidine derivatives. Indeed, the reaction
of 47 with zinc in the presence HOAc and TMEDA cleanly
led to the dechlorinated lactam 67 in 88% yield. Oxida-
tion of 67 with mCPBA followed by treatment with tert-
butyldimethylsilyl trifluoromethane-sulfonate (Scheme
10) provided pyrrole 68 in 86% yield. This activated
pyrrole corresponds to an attractive intermediate for the
eventual synthesis of several pyrrolidine alkaloids (vide
infra). N-(p-Toluenesulfonyl)pyrrolidine 69 was obtained
in 83% yield when lactam 67 was reduced with BH3‚THF.
We also subjected 47 to reduction with BH3‚THF and
found that carbinolamide 70 was cleanly formed in 84%
yield. Reduction of 47 with NaBH4 followed by further
reaction with zinc/HOAc furnished the 1,4-amino alcohol
71 in 81% yield.
SCHEME 5. Reaction of Heteroaryl Sulfilimines
with Dichloroketene
SCHEME 6. Reaction of Furanyl Sulfilimines with
Dichloroketene
lactam 40 were detected in the crude reaction mixture.
On the other hand, the reaction of sulfilimine 39 (R2 )
p-OMeC6H4), which contains an electron-donor group on
the aromatic ring, with dichloroketene furnished γ-lac-
tam 43 in 72% yield (Scheme 6). The less activated
sulfilimines 37 (R2 ) C6H5) and 38 (R2 ) p-MeC6H4)
afforded the expected γ-lactams but in 20% and 51%
yield, respectively. Clearly, the overall efficiency of the
furanyl-substituted sulfilimine cyclization is highly de-
pendent on the nature of the substituent group attached
to the sulfonyl aromatic ring. An electron donor group
on R2 (i.e., 39) enhances the nucleophilicity of the amido
anion contained within the sulfonium intermediate (13),
thereby facilitating the rate of the 3,3-sigmatropic rear-
rangement, which we assume corresponds to the rate-
determining step in the overall process.
To further explore the scope and generality of the
method, we carried out a series of reactions using a
variety of vinyl-substituted sulfilimines as outlined in
Schemes 7 and 9. The reaction of dichloroketene with
acyclic sulfilimines 44-46 proceeded smoothly to give the
expected γ-lactams 47-49 in 60-68% yield as the only
isolable products. Most interestingly, when the styryl-
substituted sulfilimines 50-52 were treated with dichlo-
roketene under identical experimental conditions, a 3:2
mixture of two isomeric compounds was obtained in ca.
75% yield. Separation of the mixture of products by silica
gel chromatography afforded pure samples of both the
expected N-tosyl γ-lactams 53-55 together with the
isomeric imino-lactones 56-58. The carbonyl stretching
frequency of the N-tosyl γ-lactam system appeared at
1765 cm-1, whereas the lactone N-tosylimine showed an
The reactivity of γ-lactam 34, which contains a fused
dihydrofuran ring as part of its skeleton, was also
investigated. Smooth dechlorination occurred when 34
was treated with zinc affording the novel heterocycle 72
in 84% yield (Scheme 11). The loss of the thioethyl group
proved to be more difficult than originally anticipated.
All of our attempts to induce the elimination of ethyl
mercaptan from 34 with various thiophilic reagents
failed. When treated with trifluoroacetic acid at 100 °C,
34 was smoothly converted into furan 73 in 71% yield
by preferential elimination of the N-(p-toluenesulfonyl)
group. However, by first oxidizing the thio group with
mCPBA and then treating the resulting sulfone with
IR absorption at 1662 cm-1 38
Similar results were
.
(39) Trost, B. M.; Sudhakar, A. R. J. Am. Chem. Soc. 1987, 109,
3792.
(40) The reason a mixture of products is obtained with the styryl
sulfilimines and not with the other systems examined is not obvious
to us, and further studies are needed before this lack of regioselectivity
can be completely understood.
reported by Marino and Zou.26 Some significant spectral
differences between the two isomeric products were also
(38) Fritschi, S.; Vasella, A. Helv. Chim. Acta 1991, 74, 2024.
J. Org. Chem, Vol. 70, No. 21, 2005 8541

Padwa et al.
SCHEME 7. Reaction of Styryl Sulfilimines with Dichloroketene
SCHEME 8. Mechanism of Sulfiliminine Reaction
SCHEME 11. Chemical Transformations of
Compound 34
desoxyeseroline (79) using our methodology to create the
hexahydro[2,3-b]indole framework of the target. The
pyrrolidinoindoline ring system containing a carbon
substituent at the C-3a site is a widely distributed
structural framework that has been obtained from a
diverse array of natural sources.41 Physostigmine was
isolated initially from the seeds of the African Calabar
bean Physostigma venenosum42 and is known to be a
potent reversible inhibitor of acetyl and butyrylcholines-
terase and is employed to treat glaucoma.43 More re-
cently, analogues of physostigmine (75) (Figure 2) have
shown promise in the treatment of Alzheimer’s disease.44
The unique structural array and the interesting biological
activities displayed by this class of compounds have made
them attractive synthetic targets. As a result, many
innovative methodologies toward the core hexahydro-
pyrrolo[2,3-b]indole skeleton have been developed.45 Dur-
ing the course of our work with sulfilimines, we were
intrigued by the possibility of utilizing these ketene
cyclizations for the synthesis of the Calabar alkaloids.
As was mentioned earlier, pyrrolo[2,3-b]indole 31 was
easily prepared in 78% yield by treating the readily
available indole 29 with dichloroketene. Subjecting this
compound to zinc with acetic acid and TMDEA in ethanol
at reflux followed by treatment with formic acid furnished
SCHEME 9. Reaction of Cycloalkenyl Sulfilimines
with Dichloroketene
SCHEME 10. Chemical Reductions of Compound
47
(41) (a) Hino, T.; Nakagawa, M. Alkaloids 1988, 34, 1. (b) Anthoni,
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York, 1999; Vol. 13, pp 163-236.
(42) For recent reviews of physostigmine, see: (a) Takano, S.;
Ogasawara, K. Alkaloids 1989, 36, 225. (b) Triggle, D. J.; Mitchell, J.
M.; Filler, R. CNS Drug Rev. 1998, 4, 87.
(43) (a) Sneader, W. Drug News Perspect. 1999, 12, 433. (b) Giaco-
bini, E. Neurochem. Int. 1998, 32, 413.
trimethylaluminum, it was possible to introduce a methyl
substituent on the carbon atom adjacent to the two
heteroatoms (i.e., formation of 74).
In an effort to more fully explore and exploit the
sulfilimine/dichloroketene cyclization chemistry, we de-
cided to pursue a synthesis of the Calabar alkaloid (()-
(44) (a) Greig, N. H.; Pei, X.-F.; Soncrant, T. T.; Ingram, D. K.;
Brossi, A. Med. Res. Rev. 1995, 15, 3. (b) Sano, N.; Bell, K.; Marder,
K.; Stricks, L.; Stern, Y.; Mayeux, R. Clin. Neuropharmacol. 1993, 16,
61.
(45) For some leading references, see: Zhang, T. Y.; Zhang, H.
Tetrahedron Lett. 2002, 43, 1363.
8542 J. Org. Chem., Vol. 70, No. 21, 2005

Cyclizations of Vinyl Sulfilimines
mixture was stirred at rt for 20 min, filtered through a Celite
column into an aqueous NaHCO3 solution, and washed with
EtOAc. The combined organic layer was washed with brine,
dried over MgSO4, and concentrated under reduced pressure.
The residue was purified by silica gel flash chromatography
to give 0.051 g (13%) of 21 as a clear oil: IR (neat) 1773, 1464,
1377, and 1180 cm-1 1H NMR (CDCl3, 400 MHz) δ 2.44 (s,
;
3H), 7.30 (td, 1H, J ) 8.0 and 0.8 Hz), 7.36 (d, 2H, J ) 8.0
Hz), 7.48 (td, 1H, J ) 8.0 and 0.8 Hz), 7.63 (dd, 1H, J ) 8.0
and 0.8 Hz), 7.92 (d, 1H, J ) 8.0 Hz), and 7.98 (d, 2H, J ) 8.0
Hz); 13C NMR (CDCl3, 100 MHz) δ 22.0, 73.9, 114.5, 125.5,
126.5, 128.3, 128.5, 130.3, 132.8, 134.2, 136.6, 146.8, and 166.5.
A second fraction isolated from the chromatographic column
contained 0.089 g (22%) of a yellow oil whose structure was
assigned as N-[2,2-dichloro-2-(2-methyl-sulfanylphenyl)acetyl]-
4-toluenesulfonamide (22): IR (neat) 1667, 1431, 1190, 1086,
FIGURE 2. Representatiave hexahydropyrrolo[2,3-b]indole
alkaloids with a quaternary center at C-3a.
SCHEME 12. Synthesis of (()-Desoxyeseroline
1
and 660 cm-1; H NMR (DMSO-d6, 600 MHz) δ 2.36 (s, 3H),
2.40 (s, 3H), 7.22 (t, 1H, J ) 7.5 Hz), 7.40 (d, 2H, J ) 7.8 Hz),
7.44 (d, 1H, J ) 7.5 Hz), 7.49 (d, 1H, J ) 7.5 Hz), 7.60 (t, 1H,
J ) 7.5 Hz), and 7.80 (d, 2H J ) 7.8 Hz); 13C NMR (DMSO-d6,
150 MHz) δ 15.1, 21.1, 96.6, 123.9, 125.9, 127.3, 128.9, 129.2,
133.1, 133.9, 141.7, 143.5, and 168.7.
In addition to compounds 21 and 22, 0.021 g (17%) of methyl
phenyl sulfide was obtained as a colorless oil: 1H NMR (CDCl3,
300 MHz) δ 2.40 (s, 3H), 7.05 (m, 1H), 7.20-7.33 (m, 4H).
3,3-Dichloro-5-methyl-1-(toluene-4-sulfonyl)-1,3-dihy-
droindol-2-one (23). To a mixture of 0.25 g (0.81 mmol) of
sulfilimine 1849 and 1.0 g of Zn-Cu in 4.0 mL of THF was
slowly added 0.45 mL (4.1 mmol) of trichloroacetyl chloride
in 5.0 mL of THF at 0 °C. The reaction mixture was stirred at
rt for 20 min, filtered through Celite into a saturated aqueous
NaHCO3 solution, and washed with EtOAc. After the organic
layer was separated, the aqueous layer was washed twice with
EtOAc. The combined organic layer was washed with brine,
dried over MgSO4, and concentrated under reduced pressure.
The residue was purified by flash silica gel chromatography
to give 0.034 g (13%) of 23 as a white solid: mp 105-107 °C;
82 in 72% overall yield (Scheme 12). Removal of the
N-tosyl group by reduction with sodium naphthalinide
afforded 83 in 81% yield. Further reaction of 83 with
sodium hydride/methyl iodide gave 84 in 87% yield.
Reduction of 84 with BH3‚THF furnished desoxyeseroline
(79)46 in 80% yield, which had previously been converted
to physostigmine by Fuji and co-workers.47
In conclusion, we have disclosed a new and efficient
method for the synthesis of highly functionalized γ-lac-
tams. The overall process involves reaction of a vinyl-
substituted sulfilimine with the highly electrophilic
dichloroketene to first generate a zwitterionic intermedi-
ate. A subsequent [3,3]-sigmatropic rearrangement is
followed by intramolecular trapping of the Pummerer
cation by the amido anion to furnish the observed
γ-lactam products. The heavily functionalized lactams are
easily converted to a variety of nitrogen containing
substrates. The vinyl sulfilimine cyclization method has
been applied to the total synthesis of (()-desoxyeseroline.
This approach should also serve as a general method for
access to other Calabar alkaloids and for preparing
libraries of structurally diverse pyrrolo[2,3-b]indoles that
may exhibit interesting biological activities.
1
IR (neat) 1777, 1484, 1192, and 1180 cm-1; H NMR (CDCl3,
400 MHz) δ 2.37 (s, 3H), 2.42 (s, 3H), 7.25 (dd, 1H, J ) 8.4
and 0.8 Hz), 7.33 (d, 2H, J ) 8.4 Hz), 7.42 (d, 1H, J ) 0.8 Hz),
7.77 (d, 1H, J ) 8.4 Hz), and 7.95 (d, 2H, J ) 8.4 Hz); 13C
NMR (CDCl3, 100 MHz) δ 21.2, 22.1, 74.2, 114.3, 125.8, 128.2,
128.3, 130.3, 133.4, 134.2, 134.3, 136.7, 146.7, and 166.7. Anal.
Calcd for C16H13Cl2NO3S: C, 51.90; H, 3.54; N, 3.78. Found:
C, 52.15; H, 3.53; N, 3.70.
3,3-Dichloro-5-methoxy-1-(toluene-4-sulfonyl)-1,3-di-
hydroindol-2-one (24). To a solution containing 1.0 mL (7.1
mmol) of 1-methoxy-4-methylsulfanyl-benzene in 20 mL of
EtOH was added 2.0 g (7.1 mmol) of chloramine-T trihydrate.
The mixture was stirred at rt for 1 h and concentrated under
reduced pressure. The residue was purified by silica gel
chromatography to give 1.7 g (74%) of sulfilimine 19 as a white
solid: IR (neat) 1634, 1498, 1175, and 1139 cm-1 1H NMR
;
(CDCl3, 400 MHz) δ 2.30 (s, 3H), 2.77 (s, 3H), 3.78 (s, 3H),
6.91 (d, 2H, J ) 8.8 Hz), 7.10 (d, 2H, J ) 8.0 Hz), 7.56 (d, 2H,
J ) 8.8 Hz), and 7.65 (d, 2H, J ) 8.0 Hz); 13C NMR (CDCl3,
100 MHz) δ 21.5, 39.2, 55.8, 115.5, 126.3, 126.5, 128.1, 129.3,
141.4, 141.7, and 163.1.
Experimental Section
3,3-Dichloro-1-(toluene-4-sulfonyl)-1,3-dihydroindol-2-
one (21). To a mixture of 0.3 g (1.1 mmol) of sulfilimine 1748
and 0.65 g of Zn-Cu in 20 mL of THF was slowly added 0.44
mL (4.0 mmol) of trichloroacetyl chloride at 0 °C. The reaction
To a mixture of 0.2 g (0.6 mmol) of sulfilimine 19 and 0.79
g of Zn-Cu in 30 mL of THF was slowly added 0.35 mL (3.1
mmol) of trichloroacetyl chloride at 0 °C. The reaction mixture
was stirred at rt for 20 min, filtered through Celite into a
saturated aqueous NaHCO3 solution, and washed with EtOAc.
After the organic layer was separated, the aqueous layer was
washed with EtOAc. The combined organic layer was washed
with brine, dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by flash silica gel chroma-
tography to give 0.035 g (15%) of 24 as a clear oil: IR (neat)
1775, 1487, 1191, and 671 cm-1; 1H NMR (CDCl3, 400 MHz) δ
2.43 (s, 3H), 2.84 (s, 3H), 6.99 (dd, 1H, J ) 9.2 and 2.8 Hz),
(46) (a) Santos, P. F.; Almeida, P. S.; Lobo, A. M.; Prabhakar, S.
Heterocycles 2001, 55, 1029. (b) Tsuji, R.; Nakagawa, M.; Nishida, A.
Heterocycles 2002, 58, 587. (c) Santos, P. F.; Lobo, A. M.; Prabhakar,
S. Tetrahedron Lett. 1995, 36, 8099. (d) The chemical shifts of
compound 79 were in complete agreement with the recorded values:
Smith, R.; Livinghouse, T. Tetrahedron 1985, 41, 3559. (e) Wijnberg,
J. B. P. A.; Speckamp, W. N. Tetrahedron 1978, 34, 2399. (f) Nakagawa,
M.; Kawahara, M. Org. Lett. 2000, 2, 953.
(47) Node, M.; Itoh, A.; Masaki, Y.; Fuji, K. Heterocycles 1991, 32,
1705.
(48) Johnson, C. R.; Mori, K.; Nakanishi, A. J. Org. Chem. 1979,
44, 2065.
(49) Marzinzik, A. L.; Sharpless, K. B. J. Org. Chem. 2001, 66, 594.
J. Org. Chem, Vol. 70, No. 21, 2005 8543

Padwa et al.
7.13 (d, 1H, J ) 2.8 Hz), 7.34 (d, 2H, J ) 8.4 Hz), 7.81 (d, 1H,
J ) 9.2 Hz), and 7.95 (d, 2H, J ) 8.4 Hz); 13C NMR (CDCl3,
100 MHz) δ 22.0, 56.1, 74.2, 110.4, 115.8, 118.7, 128.2, 129.4,
129.6, 130.3, 134.3, 146.7, 158.3, and 166.7.
EtOAc, and the combined organic layer was washed with brine,
dried over Na2SO4, and concentrated under reduced pressure.
The residue was purified by flash silica gel chromatography
to give 1.5 g (78%) of 31 as a white solid: mp 180-182 °C; IR
(neat) 1760, 1722, 1485, 1349, 1179, and 1081 cm-1; 1H NMR
(CDCl3, 400 MHz) δ 1.19 (t, 3H, J ) 7.6 Hz), 1.53 (s, 3H), 1.61
(s, 9H), 2.42 (s, 3H), 2.85 (dq, 1H, J ) 11.2 and 7.6 Hz), 3.49
(dq, 1H, J ) 11.2 and 7.6 Hz), 7.13 (td, 1H, J ) 7.6 and 0.8
Hz), 7.25-7.29 (m, 3H), 7.33 (td, 1H, J ) 7.6 and 0.8 Hz), 7.52
(d, 1H, J ) 7.6 Hz), and 8.15 (d, 2H, J ) 8.4 Hz); 13C NMR
(CDCl3, 100 MHz) δ 13.1, 17.7, 21.9, 27.4, 28.6, 65.0, 83.8, 86.1,
96.6, 117.8, 124.4, 124.5, 128.1, 129.4, 130.1, 130.2, 135.8,
142.4, 145.6, 150.2, and 165.1. Anal. Calcd for C25H28Cl2-
N2O5S2: C, 52.54; H, 4.94; N, 4.90. Found: C, 52.48; H, 4.81;
N, 5.00.
4,4-Dichloro-6a-ethylthio-6-(toluene-4-sulfonyl)-
3a,4,6,6a-tetrahydrofuro[2,3-b]-pyrrol-5-one (34). To a
mixture of 0.25 g (0.8 mmol) of sulfilimine 32 and 1.1 g of Zn-
Cu in 15 mL of THF was slowly added 0.5 mL (4.2 mmol) of
trichloroacetyl chloride at 0 °C. The reaction mixture was
stirred at rt for 20 min, filtered through Celite into a saturated
aqueous NaHCO3 solution, and washed with EtOAc. The
aqueous layer was washed with EtOAc, and the combined
organic layer was washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The residue was purified
by flash silica gel chromatography to give 0.2 g (58%) of 34 as
a white solid; mp 133-134 °C; IR (neat) 3114, 1762, 1618,
1377, and 907 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.34 (t, 3H,
J ) 7.2 Hz), 2.42 (s, 3H), 2.28 (dq, 1H, J ) 11.6 and 7.2 Hz),
2.90 (dq, 1H, J ) 11.6 and 7.2 Hz), 4.43 (t, 1H, J ) 2.4 Hz),
5.17 (dd, 1H, J ) 2.8 and 2.4 Hz), 6.40 (dd, 1H, J ) 2.8 and
2.4 Hz), 7.33 (d, 2H, J ) 8.0 Hz), and 8.01 (d, 2H, J ) 8.0 Hz);
13C NMR (CDCl3, 100 MHz) δ 13.9, 22.0, 25.9, 66.4, 80.3, 102.8,
106.1, 129.5, 129.7, 134.2, 146.3, 146.5, and 163.5. Anal. Calcd
for C15H15Cl2NO4S2: C, 44.12; H, 3.70; N, 3.43. Found: C,
44.07; H, 3.61; N, 3.36.
3,3-Dichloro-1-(4-methoxybenznesulfonyl)-1,3-dihy-
droindol-2-one (25). To the mixture of 0.1 g (0.3 mmol) of
sulfilimine 2050 and 0.21 g of Zn-Cu in 16 mL of THF was
slowly added 0.18 mL (1.6 mmol) of trichloroacetyl chloride
at 0 °C. The reaction mixture was stirred at rt for 35 min,
filtered through Celite into a saturated aqueous NaHCO3
solution, and washed with EtOAc. The aqueous layer was
washed twice with EtOAc, and the combined organic layer was
washed with brine, dried over MgSO4, and concentrated under
reduced pressure. The residue was purified by flash silica gel
chromatography to give 0.02 g (19%) of 25 as a clear oil: IR
(KBr) 1747, 1592, 1371, and 1164 cm-1; 1H NMR (CDCl3, 400
MHz) δ 3.88 (s, 3H), 7.01 (d, 2H, J ) 9.2 Hz), 7.28 (t, 1H, J )
7.6 Hz), 7.48 (td, J ) 7.6 and 1.2 Hz, 1H), 7.64 (dd, 1H, J )
7.6 and 1.2 Hz), 7.92 (d, 1H, J ) 7.6 Hz), and 8.04 (d, 2H, J )
9.2 Hz); 13C NMR (CDCl3, 100 MHz) δ 55.8, 114.3, 114.6, 125.3,
126.2, 128.2, 130.6, 132.6, 136.5, 164.9, and 166.4.
3,3-Dichloro-9b-ethylthio-1-(toluene-4-sulfonyl)-
1,3,3a,9b-tetrahydrobenzo-[g]indol-2-one (27). To a mix-
ture containing 0.1 g (0.3 mmol) of sulfilimine 26 and 0.15 g
of Zn-Cu in 14 mL of THF at 0 °C was slowly added 0.2 mL
(1.8 mmol) of trichloroacetyl chloride. After being stirred at rt
for 45 min, the reaction mixture was filtered and EtOAc was
added. The organic layer was washed with a saturated aqueous
NaHCO3 solution, brine, dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by flash
silica gel chromatography to give 0.074 g (56%) of 27 as a
colorless solid; mp 172-174 °C; IR (neat) 2927, 1754, 1372,
1223, 1176, 1049, 980, and 663 cm-1 1H NMR (CDCl3, 300
;
MHz) δ 0.91 (t, 3H, J ) 7.5 Hz), 1.94-2.05 (m, 1H), 2.48 (s,
3H), 2.75-2.86 (m, 1H), 3.28 (dd, 1H, J ) 6.0 and 1.2 Hz),
5.99 (dd, 1H, J ) 10.0 and 6.0 Hz), 6.88 (d, 1H, J ) 10.0 Hz),
7.17 (d, 1H, J ) 7.8 Hz), 7.30-7.40 (m, 4H), 7.98 (d, 1H, J )
7.8 Hz), and 8.24 (d, 2H, J ) 8.1 Hz); 13C NMR (CDCl3, 100
MHz) δ 13.1, 21.8, 27.2, 59.0, 78.4, 79.5, 117.7, 127.7, 127.9,
129.0, 129.2, 129.5, 129.9, 130.7, 131.0, 133.0, 134.8, 145.8,
and 164.7. Anal. Calcd for C21H19Cl2NO3S2: C, 53.85; H, 4.09;
N, 2.99. Found: C, 53.73; H, 4.07; N, 2.87.
3a-Acetoxymethyl-6a-butythio-4,4-dichloro-6-(toluene-
4-sulfonyl)-4,5,6,6a-tetrahydrofuro[2,3-b]pyrrol-5-one (35).
To a mixture of 0.1 g (0.25 mmol) of sulfilimine 33 and 0.07 g
of Zn-Cu in 13 mL of THF at 0 °C was added dropwise 0.1
mL (0.9 mmol) of trichloroacetyl chloride. After being stirred
at rt for 30 min, the reaction mixture was filtered and EtOAc
was added. The organic layer was washed with a saturated
aqueous NaHCO3 solution, brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified
by flash silica gel chromatography to provide 0.05 g (40%) of
35 as a pale yellow oil: IR (KBr) 1763, 1752, 1224, 1077, 1032,
3,3-Dichloro-8a-ethylthio-1-(toluene-4-sulfonyl)-
1,3,3a,8a-tetrahydro-2H-benzo-furo[2,3-b]pyrrol-2-one
(30). To a mixture of 0.3 g (0.9 mmol) of sulfilimine 28 and
0.28 g of Zn-Cu in 45 mL of THF at rt was slowly added 0.4
mL (3.5 mmol) of trichloroacetyl chloride. After being stirred
at rt for 45 min, the reaction mixture was filtered and EtOAc
was added. The organic layer was washed with a saturated
aqueous NaHCO3 solution, brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified
by flash silica gel chromatography to provide 0.2 g (52%) of
30 as a colorless solid: mp 126-128 °C; IR (KBr) 2968, 1757,
1
and 676 cm-1; H NMR (CDCl3, 300 MHz) δ 0.96 (t, 3H, J )
7.1 Hz), 1.41-1.54 (m, 2H), 1.61-1.75 (m, 2H), 2.09 (s, 3H),
2.45 (s, 3H), 3.01-3.18 (m, 2H), 4.53 (d, 1H, J ) 12.0 Hz),
4.86 (d, 1H, J ) 12.0 Hz), 5.23 (d, 1H, J ) 3.2 Hz), 6.41 (d,
1H, J ) 3.2 Hz), 7.34 (d, 2H, J ) 7.5 Hz), and 8.02 (d, 2H,
J ) 7.5 Hz); 13C NMR (CDCl3, 100 MHz) δ 13.6, 20.8, 21.8,
22.0, 31.3, 31.7, 63.6, 67.9, 82.3, 106.4, 107.5, 129.4, 129.5,
134.1, 145.6, 146.1, 163.5, and 170.2. HRMS Calcd for C20H24-
Cl2NO6S2 [M + H]+: 508.0417. Found: 508.0421.
1595, 1478, 1379, 1258, 1115, 983, and 749 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 1.30 (t, 3H, J ) 7.8 Hz), 2.42 (s, 3H), 2.75-
2.94 (m, 2H), 4.80 (s, 1H), 7.00 (d, 1H, J ) 7.5 Hz), 7.04 (t,
1H, J ) 7.5 Hz), 7.31 (d, 2H, J ) 7.8 Hz), 7.33 (t, 1H, J ) 7.5
6-(Benzenesulfonyl)-6a-(1-butylthio)-4,4-dichloro-
3a,4,6,6a-tetrahydrofuro-[2,3-b]pyrrol-5-one (41). To the
mixture of 0.1 g (0.3 mmol) of sulfilimine 37 and 0.2 g of Zn-
Cu in 15 mL of THF was slowly added 0.2 mL (1.6 mmol) of
trichloro-acetyl chloride at 0 °C. The reaction mixture was
stirred at rt for 20 min, filtered through Celite into a saturated
aqueous NaHCO3 solution, and washed with EtOAc. The
aqueous layer was washed twice with EtOAc. The combined
organic layer was washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The residue was purified
by flash silica gel chromatography to give 0.03 g (20%) of 41
as a pale yellow oil: IR (neat) 1764, 1385, 1229, 1190, 816
Hz), 7.48 (d, 1H, J ) 7.5 Hz), and 8.06 (d, 2H, J ) 7.8 Hz); 13
C
NMR (CDCl3, 150 MHz) δ 13.6, 21.8, 25.8, 65.6, 80.2, 106.5,
110.8, 121.2, 122.8, 128.0, 129.4, 129.5, 131.4, 133.9, 146.2,
157.5, and 163.2. Anal. Calcd for C19H17Cl2NO4S2: C, 49.78;
H, 3.74; N, 3.06. Found: C, 49.49; H, 3.78; N, 3.03.
tert-Butyl 3,3-Dichloro-8a-ethylthio-3a-methyl-2-oxo-
1-(toluene-4-sulfonyl)-2,3,3a,8a-tetrahydro-1H-pyrrolo-
[2,3-b]indole-8-carboxylate (31). To a mixture of 1.8 g (3.9
mmol) of sulfilimine 29 and 2.6 g of Zn-Cu in 200 mL of THF
was slowly added 1.7 mL (16 mmol) of trichloroacetyl chloride
at rt. The reaction mixture was stirred at 25 °C for 1 h, filtered
through Celite into a saturated aqueous NaHCO3 solution, and
washed with EtOAc. The aqueous layer was washed with
1
cm-1; H NMR (CDCl3, 400 MHz) δ 0.94 (t, 3H, J ) 7.2 Hz),
1.40-1.47 (m, 2H), 1.64-1.72 (m, 2H), 2.79 (dt, 1H, J ) 11.6
and 7.6 Hz), 2.88 (dt, 1H, J ) 11.6 and 7.6 Hz), 4.44 (t, 1H,
J ) 2.4 Hz), 5.18 (t, 1H, J ) 2.4 Hz), 6.41 (t, 1H, J ) 2.4 Hz),
(50) Ruff, K. F.; Kucshman, A. Tetrahedron Lett. 1972, 28, 4413.
8544 J. Org. Chem., Vol. 70, No. 21, 2005

Cyclizations of Vinyl Sulfilimines
7.54-7.58 (m, 3H), 7.68 (m, 1H), and 8.15-8.18 (m, 2H); 13C
NMR (CDCl3, 100 MHz) δ 13.6, 22.1, 30.7, 31.1, 66.5, 80.1,
102.6, 106.0, 128.9, 129.3, 134.8, 137.0, 146.4, and 163.4.
6a-Butylthio-4,4-dichloro-6-(toluene-4-sulfonyl)-3a,4,6,-
6a-tetrahydrofuro-[2,3-b]pyrrol-5-one (42). To a mixture
of 0.5 g (1.5 mmol) of sulfilimine 38 and 0.4 g of Zn-Cu in 75
mL of THF at 0 °C was slowly added 0.4 mL (3.1 mmol) of
trichloroacetyl chloride. After being stirred at 0 °C for 30 min,
the reaction mixture was filtered and EtOAc was added. The
organic layer was washed with a saturated aqueous NaHCO3
solution, brine, dried over Na2SO4, and concentrated under
reduced pressure. The residue was purified by flash silica gel
chromatography to provide 0.34 g (51%) of 42 as a pale yellow
was washed with EtOAc, and the combined organic layer was
washed with brine, dried over MgSO4, and concentrated under
reduced pressure. The residue was purified by flash silica gel
chromatography to give 0.085 g (61%) of 48 as a white solid:
mp 122-124 °C; IR (neat) 1760, 1374, 1173, and 663 cm-1; 1H
NMR (CDCl3, 400 MHz) δ 2.43 (s, 3H), 2.98 (dd, 1H, J ) 14.8
and 3.6 Hz), 3.26 (dd, 1H, J ) 14.8 and 7.2 Hz), 5.59 (dd, 1H,
J ) 7.2 and 3.6 Hz), 7.32-7.44 (m, 7H), and 8.12 (d, 2H, J )
8.4 Hz); 13C NMR (CDCl3, 100 MHz) δ 22.0, 48.5, 64.8, 78.7,
129.6, 129.7, 129.9, 130.0, 130.7, 134.1, 134.9, 146.6, and 163.8.
3,3-Dichloro-4,4,5-trimethyl-1-(toluene-4-sulfonyl)-5-
(phenylthio)pyrrolidin-2-one (49). To a mixture of 0.2 g
(0.57 mmol) of sulfimide 46 and 0.75 g of Zn-Cu in 20 mL of
THF at 0 °C was slowly added 0.32 mL (2.9 mmol) of
trichloroacetyl chloride in 9 mL of THF. After being stirred at
0 °C for 10 min, the reaction mixture was quenched with
NaHCO3 and the mixture was filtered and EtOAc was added.
The organic layer was washed with a saturated aqueous
NaHCO3 solution, brine, dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by flash
silica gel chromatography to provide 0.15 g (59%) of 49 as a
white solid: mp 113-115 °C; IR (KBr) 1754, 1368, 1263, 1176,
752, and 653 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.26 (s, 3H),
1.63 (s, 3H), 1.68 (s, 3H), 2.45 (s, 3H), 7.35 (d, 2H, J ) 8.4
Hz), 7.39-7.44 (m, 3H), 7.77 (dd, 2H, J ) 8.0 and 1.3 Hz),
and 8.18 (d, 2H, J ) 8.4 Hz); 13C NMR (CDCl3, 100 MHz) δ
19.9, 21.8, 24.0, 24.7, 54.1, 82.5, 88.4, 128.0, 129.3, 129.7, 130.0,
131.1, 134.4, 138.5, 145.7, and 164.4. Anal. Calcd for C20H21-
Cl2NO3S2: C, 52.40; H, 4.62; N, 3.06. Found: C, 52.27; H, 4.70;
N, 3.07.
1
oil: IR (neat) 1763, 1384, 1088, 1038, 965, and 750 cm-1; H
NMR (CDCl3, 300 MHz) δ 0.94 (t, 3H, J ) 9.8 Hz), 1.40-1.50
(m, 2H), 1.62-1.72 (m, 2H), 2.44 (s, 3H), 2.73-2.90 (m, 2H),
4.42 (t, 1H, J ) 3.2 Hz), 5.17 (t, 1H, J ) 3.2 Hz), 6.41 (t, 1H,
J ) 3.2 Hz), 7.34 (d, 2H, J ) 11.2 Hz), and 8.02 (d, 2H, J )
11.2 Hz); 13C NMR (CDCl3, 100 MHz) δ 13.6, 21.8, 22.1, 30.7,
31.1, 66.4, 80.2, 102.6, 106.0, 129.3, 129.5, 134.1, 146.1, 146.4,
and 163.3.
6a-(1-Butylthio)-4,4-dichloro-6-(4-methoxybenznesul-
fonyl)-3a,4,6,6a-tetrahydrofuro[2,3-b]pyrrol-5-one (43).
To the mixture of 0.1 g (0.29 mmol) of sulfilimine 39 and 0.19
g of Zn-Cu in 15 mL of THF was slowly added 0.16 mL (1.5
mmol) of trichloroacetyl chloride at 0 °C. The reaction mixture
was stirred at rt for 20 min, filtered through Celite into a
saturated aqueous NaHCO3 solution, and washed with EtOAc.
The aqueous layer was washed twice with EtOAc. The
combined organic layer was washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The residue
was purified by flash silica gel chromatography to give 0.09 g
(72%) of 43 as a pale yellow oil: IR (neat) 1772, 1358, 1264,
1164, 835 cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.94 (t, 3H, J )
7.2 Hz), 1.41-1.49 (m, 2H), 1.63-1.71 (m, 2H), 2.78 (dt, 1H,
J ) 11.6 and 7.6 Hz), 2.87 (dt, 1H, J ) 11.6 and 7.6 Hz), 3.88
(s, 3H), 4.43 (t, 1H, J ) 2.4 Hz), 5.18 (t, 1H, J ) 2.4 Hz), 6.41
(t, 1H, J ) 2.4 Hz), 6.99 (d, 2H, J ) 9.2 Hz), and 8.09 (d, 2H,
J ) 9.2 Hz); 13C NMR (CDCl3, 100 MHz) δ 13.6, 22.1, 30.7,
31.1, 55.7, 66.4, 80.3, 102.6, 105.9, 114.0, 128.2, 131.8, 146.4,
163.3, and 164.5.
(Z)-3,3-Dichloro-4-phenyl-5-phenylthio-1-(toluene-4-
sulfonyl)pyrrolidin-2-one (53). To a mixture of 0.05 g (0.13
mmol) of sulfilimine 50 and 0.17 g of Zn-Cu in 5 mL of THF
was slowly added 0.075 mL (0.66 mmol) of trichloroacetyl
chloride at 0 °C. The reaction mixture was stirred at rt for 20
min, filtered through Celite with a saturated aqueous NaHCO3
solution, and washed with EtOAc. The combined organic layer
was washed with brine, dried over MgSO4, and concentrated
under reduced pressure. The residue was purified by flash
silica gel chromatography to give 0.042 g (60%) of 53 as a
1
colorless oil: IR (neat) 1765, 1373, 1175, and 1088 cm-1; H
3,3-Dichloro-5-ethylthio-1-(toluene-4-sulfonyl)pyrroli-
din-2-one (47). To a mixture of 0.12 g (0.46 mmol) of
sulfilimine 44 and 0.6 g of Zn-Cu in 10 mL of THF was slowly
added 0.3 mL (2.3 mmol) of trichloroacetyl chloride at 0 °C.
The reaction mixture was stirred at rt for 20 min, filtered
through Celite into a cold saturated aqueous NaHCO3 solution,
and washed with EtOAc. After the organic layer was sepa-
rated, the aqueous layer was washed with EtOAc. The
combined organic layer was washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The residue
was purified by flash silica gel chromatography to give 0.11 g
(68%) of 47 as a white solid: mp 135-136 °C; IR (neat) 1756,
1371, 1172, 1068, and 960 cm-1; 1H NMR (CDCl3, 600 MHz) δ
1.30 (t, 3H, J ) 7.2 Hz), 2.45 (s, 3H), 2.89 (dq, 1H, J ) 12.0
and 7.2 Hz), 2.94 (dq, 1H, J ) 12.0 and 7.2 Hz), 3.02 (dd, 1H,
J ) 15.0 and 3.6 Hz), 3.39 (dd, 1H, J ) 15.0 and 7.2 Hz), 5.39
(dd, 1H, J ) 7.2 and 3.6 Hz), 7.36 (d, 2H, J ) 8.4 Hz), and
8.05 (d, 2H, J ) 8.4 Hz); 13C NMR (CDCl3, 150 MHz) δ 14.9,
22.0, 28.4, 50.8, 62.3, 78.7, 129.3, 129.9, 134.3, 146.4, and
163.8. Anal. Calcd for C13H15Cl2NO3S2: C, 42.39; H, 4.11; N,
3.80. Found: C, 42.41; H, 4.10; N, 3.81.
NMR (CDCl3, 600 MHz) δ 2.47 (s, 3H), 4.35 (d, 1H, J ) 6.0
Hz), 5.79 (d, 1H, J ) 6.0 Hz), 7.18-7.26 (m, 5H), 7.34-7.41
(m, 5H), 7.63 (d, 2H, J ) 7.2 Hz), and 8.15 (d, 2H, J ) 8.4
Hz); 13C NMR (CDCl3, 150 MHz) δ 22.1, 59.4, 72.7, 82.4, 128.7,
128.8, 129.3, 129.4, 130.0, 130.8, 130.9, 133.4, 134.0, 134.3,
146.6, and 163.6; HRMS Calcd for C23H20Cl2NO3S2 [M + H]+:
492.0256. Found: 492.0261.
1
The H NMR spectrum of the crude reaction mixture also
showed the presence of (Z)-N-(3,3-dichloro-4-phenyl-5-phenyl-
sulfanyl-dihydrofuran-2-ylidene)-4-methyl-benzenesulfona-
mide (56), which could be isolated with some difficulty from
the chromatographic separation as a colorless oil: IR (neat)
1660, 1338, 1162, and 1086 cm-1; 1H NMR (CDCl3, 600 MHz)
δ 2.45 (s, 3H), 4.21 (d, 1H, J ) 4.8 Hz), 6.42 (d, 1H, J ) 4.8
Hz), 6.91 (d, 2H, J ) 7.8 Hz), 7.28 (t, 2H, J ) 7.8 Hz), 7.35-
7.39 (m, 4H), 7.47-7.49 (m, 2H), and 7.96 (d, 2H, J ) 8.4 Hz).
(E)-3,3-Dichloro-4-phenyl-5-phenylthio-1-(toluene-4-
sulfonyl)pyrrolidin-2-one (54). To a mixture of 0.06 g (0.17
mmol) of sulfilimine 51 and 0.21 g of Zn-Cu in 5 mL of THF
was slowly added 0.09 mL (0.83 mmol) of trichloroacetyl
chloride at 0 °C. The reaction mixture was stirred at rt for 20
min, filtered through Celite with a saturated aqueous NaHCO3
solution, and washed with EtOAc. The combined organic layer
was washed with brine, dried over MgSO4, and concentrated
3,3-Dichloro-5-phenylthio-1-(toluene-4-sulfonyl)pyrro-
lidin-2-one (48). To a mixture of 0.1 g (0.34 mmol) of
sulfilimine 4551 and 0.7 g of Zn-Cu in 16 mL of THF was
slowly added 0.3 mL (2.8 mmol) of trichloroacetyl chloride in
2 mL of THF at 0 °C. The reaction mixture was stirred at 0
°C for 15 min, filtered through Celite with a saturated aqueous
NaHCO3 solution, and washed with EtOAc. The aqueous layer
1
under reduced pressure. The H NMR spectrum of the crude
reaction mixture showed the presence of 54 and 57 in a 3:2
ratio. The residue was purified by flash silica gel chromatog-
raphy to give 0.04 g (50%) of 54 as a colorless oil: IR (neat)
1764, 1375, 1173, and 1085 cm-1; 1H NMR (CDCl3, 600 MHz)
δ 2.47 (s, 3H), 3.54 (d, 1H, J ) 8.4 Hz), 5.66 (d, 1H, J ) 8.4
Hz), 7.03 (d, 2H, J ) 8.4 Hz), 7.21-7.26 (m, 4H), 7.34 (td, 1H,
(51) Rayner, C. P.; Clark, A. J.; Rooke, S. M.; Sparey, T. J.; Tayor,
P. C. J. Chem. Soc., Perkin Trans. 1 2000, 79.
J. Org. Chem, Vol. 70, No. 21, 2005 8545

Padwa et al.
J ) 7.8 and 0.6 Hz), 7.38-7.43 (m, 5H), and 8.16 (d, 2H,
J ) 8.4 Hz); 13C NMR (CDCl3, 150 MHz) δ 22.0, 59.6, 67.4,
83.4, 128.9, 129.5, 129.6, 129.7, 130.0, 130.1, 134.6, 135.8,
146.5, and 163.7. HRMS Calcd for C23H20Cl2NO3S2 [M + H]+:
492.0256. Found: 492.0262.
The second fraction isolated from the chromatographic
column contained 0.02 g (27%) of (E)-N-(3,3-dichloro-4-phenyl-
5-phenylsulfanyl-dihydrofuran-2-ylidene)-4-methyl-benzene-
sulfonamide (57) as a colorless oil: IR (neat) 1662, 1336, 1164,
and 1090 cm-1; 1H NMR (CDCl3, 600 MHz) δ 2.43 (s, 3H), 3.64
(d, 1H, J ) 10.8 Hz), 6.11 (d, 1H, J ) 10.8 Hz), 7.25 (d, 2H,
J ) 7.8 Hz), 7.32 (d, 2H, J ) 8.4 Hz), 7.36-7.46 (m, 8H), and
7.93 (d, 2H, J ) 8.4 Hz); 13C NMR (CDCl3, 150 MHz) δ 21.9,
61.3, 65.3, 84.2, 128.0, 128.3, 128.7, 129.1, 129.7, 129.9, 130.0,
130.3, 135.1, 137.5, 144.4, and 164.6; HRMS Calcd for C23H20-
Cl2NO3S2 [M + H]+: 492.0256. Found: 492.0261.
(E)-3,3-Dichloro-4-(4-methoxy-phenyl)-5-phenylsulfan-
yl-1-(toluene-4-sulfonyl)-pyrrolidin-2-one (55). To a mix-
ture of 0.08 g (0.19 mmol) of sulfilimine 52 and 0.24 g of Zn-
Cu in 5 mL of THF was slowly added 0.11 mL (1.0 mmol) of
trichloroacetyl chloride at 0 °C. The reaction mixture was
stirred at rt for 20 min, filtered through Celite with a saturated
aqueous NaHCO3 solution, and washed with EtOAc. The
combined organic layers were washed with brine, dried over
MgSO4, and concentrated under reduced pressure. The 1H
NMR spectrum of the crude reaction mixture showed the
presence of 55 and 58 in a 3:2 ratio. The residue was purified
by flash silica gel chromatography to give 0.043 g (44%) of 55
filtered through Celite with a saturated aqueous NaHCO3
solution, and washed with EtOAc. The combined organic layer
was washed with brine, dried over MgSO4, and concentrated
under reduced pressure. The residue was purified by flash
silica gel chromatography to give 0.086 g (65%) of 65 as a white
solid: mp 176-177 °C; IR (neat) 1753, 1376, 1176, and 1083
cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.60-1.66 (m, 1H), 1.78-
1.91 (m, 4H), 2.01-2.05 (m, 1H), 2.27-2.36 (m, 2H), 2.44 (s,
3H), 3.00-3.07 (m, 1H), 7.26-7.29 (m, 4H), 7.33-7.37 (m, 3H),
and 8.10 (d, 2H, J ) 8.4 Hz); 13C NMR (CDCl3, 100 MHz) δ
20.5, 21.9, 22.0, 34.2, 48.6, 78.3, 84.9, 129.7, 129.8, 129.8, 129.9,
130.3, 134.6, 135.9, 146.1, and 164.0. Anal. Calcd for C21H21-
Cl2NO3S2: C, 53.62; H, 4.50; N, 2.98. Found: C, 53.37; H, 4.37;
N, 3.02.
3,3-Dichloro-3a-methyl-6a-phenylthio-1-(toluene-4-sul-
fonyl)hexahydro-cyclopenta[b]pyrrol-2-one (66). To a
mixture of 0.045 g (0.12 mmol) of sulfilimine 63 and 0.15 g of
Zn-Cu in 5 mL of THF was slowly added 0.05 mL (0.48 mmol)
of trichloroacetyl chloride at 0 °C. The reaction mixture was
stirred at rt for 20 min, filtered through Celite with a saturated
aqueous NaHCO3 solution, and washed with EtOAc. The
aqueous layer was washed with EtOAc, and the combined
organic layer was washed with brine, dried over MgSO4, and
concentrated under reduced pressure. The residue was purified
by flash silica gel chromatography to give 0.011 g (20%) of 66
as a colorless oil: IR (neat) 1758, 1369, and 1176 cm-1 1H
;
NMR (CDCl3, 400 MHz) δ 1.66 (s, 3H), 1.65-1.82 (m, 3H),
1.86-1.94 (m, 1H), 2.07-2.15 (m, 1H), 2.46 (s, 3H), 2.84-2.88
(m, 1H), 7.36 (d, 2 H, J ) 8.0 Hz), 7.38-7.44 (m, 3H), 7.82-
7.85 (m, 2H), and 8.21 (d, 2H, J ) 8.0 Hz); 13C NMR (CDCl3,
100 MHz) δ 18.3, 21.6, 21.8, 40.1, 41.3, 62.6, 89.6, 113.3, 127.7,
129.4, 129.5, 129.8, 130.2, 135.9, 137.9, 144.1, and 165.9.
as a colorless oil: IR (neat) 1764, 1516, 1174, and 1087 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 2.47 (s, 3H), 3.45 (d, 1H, J ) 8.4
Hz), 3.84 (s, 3H), 5.60 (d, 1H, J ) 8.4 Hz), 6.92 (d, 2H, J ) 8.4
Hz), 7.02 (d, 2H, J ) 7.2 Hz), 7.14 (d, 2H, J ) 8.4 Hz), 7.23 (t,
2H, J ) 7.2 Hz), 7.34 (t, 1H, J ) 7.2 Hz), 7.40 (d, 2H, J ) 8.4
Hz), and 8.16 (d, 2H, J ) 8.4 Hz); 13C NMR (CDCl3, 100 MHz)
δ 22.1, 55.5, 59.0, 67.5, 83.8, 114.4, 121.7, 128.9, 129.5, 129.6,
130.0, 130.1, 131.3, 134.6, 135.8, 146.4, 160.6, and 163.8.
5-Ethylthio-1-(toluene-4-sulfonyl)pyrrolidin-2-one (67).
To a mixture containing 0.05 g (0.14 mmol) of sulfide 47 and
0.17 g of Zn metal in 8 mL of EtOH was added 0.04 mL (0.7
mmol) of acetic acid and 0.1 mL (0.7 mmol) of TEMDA. The
mixture was stirred at rt for 1 h and was then filtered through
Celite. The solvent was removed under reduced pressure, and
the residue was dissolved in EtOAc and washed with water.
The organic layer was separated, dried over MgSO4, and
concentrated under reduced pressure. The residue was purified
by flash silica gel chromatography to give 0.034 g (88%) of 67
as a white solid: mp 114-116 °C; IR (neat) 1742, 1359, 1165,
1088, and 814 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.25 (t, 3H,
J ) 7.2 Hz), 2.14-2.20 (m, 1H), 2.37-2.43 (m, 1H), 2.42 (s,
3H), 2.52-2.75 (m, 4H), 5.49 (d, 1H, J ) 7.2 Hz), 7.30 (d, 2H,
J ) 8.0 Hz), and 8.02 (d, 2H, J ) 8.0 Hz); 13C NMR (CDCl3,
100 MHz) δ 14.6, 21.9, 25.6, 29.5, 31.1, 64.7, 129.2, 129.5,
135.5, 145.4, and 172.6. Anal. Calcd for C13H17NO3S2: C, 52.15;
H, 5.72; N, 4.68. Found: C, 52.30; H, 5.78; N, 4.66.
The second fraction isolated from the chromatographic
column contained 0.029 g (30%) of (E)-N-[3,3-dichloro-4-(4-
methoxy-phenyl)-5-phenylsulfanyl-dihydrofuran-2-ylidene ]-4-
methyl-benzenesulfonamide (58): IR (neat) 1662, 1516, 1163,
and 739 cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.44 (s, 3H), 3.59
(d, 1H, J ) 10.4 Hz), 3.84 (s, 3H), 6.06 (d, 1H, J ) 10.4 Hz),
6.96 (d, 2H, J ) 8.4 Hz), 7.18 (d, 2H, J ) 8.4 Hz), 7.33 (d, 2H,
J ) 8.4 Hz), 7.40-7.46 (m, 5H), 7.94 (d, 2H, J ) 8.4 Hz); 13C
NMR (CDCl3, 150 MHz) δ 21.9, 55.5, 60.8, 84.5, 93.3, 114.5,
120.3, 127.9, 128.3, 129.7, 129.8, 130.3, 131.1, 135.1, 137.5,
144.4, 160.8, and 164.8.
3,3-Dichloro-6a-phenylthio-1-(toluene-4-sulfonyl)-hexa-
hydrocyclopenta[b]-pyrrol-2-one (64). To a mixture of 0.05
g (0.15 mmol) of sulfilimine 61 and 0.18 g of Zn-Cu in 5 mL
of THF was slowly added 0.08 mL (0.72 mmol) of trichloro-
acetyl chloride at 0 °C. The reaction mixture was stirred at rt
for 20 min, filtered through Celite with a saturated aqueous
NaHCO3 solution, and washed with EtOAc. The organic layer
was washed with brine, dried over MgSO4, and concentrated
under reduced pressure. The residue was purified by flash
silica gel chromatography to give 0.04 g (63%) of 64 as a white
solid: mp 129-131 °C; IR (neat) 1755, 1374, 1175, and 1086
cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.00-2.04 (m, 2H), 2.10-
2.15 (m, 2H), 2.44 (s, 3H), 2.51 (ddd, 1H, J ) 14.0, 10.0, and
7.2 Hz), 2.66 (ddd, 1H, J ) 14.0, 7.2, and 3.6 Hz), 3.04 (t, 1H,
J ) 7.2 Hz), 7.21-7.29 (m, 4H), 7.33 (dt, 1H, J ) 7.2 and 1.6
2-(tert-Butyl-dimethylsilanyloxy)-1-(toluene-4-sulfonyl)-
1H-pyrrole (68). To a solution containing 0.06 g (0.2 mmol)
of sulfide 67 in 5 mL of CH2Cl2 was added 0.07 g (0.4 mmol)
of m-chloroperbenzoic acid at rt. The reaction mixture was
stirred for 2 h and was then quenched by a saturated aqueous
NaHCO3 solution. The organic layer was separated, washed
with a saturated aqueous NaHCO3 solution, and dried over
MgSO4. Concentration under reduced pressure followed by
flash silica gel chromatography provided 0.044 g (94%) of
1-(toluene-4-sulfonyl)-1,5-dihydropyrrol-2-one as a white solid:
1
IR (neat) 1716, 1357, 1169, and 799 cm-1; H NMR (CDCl3,
600 MHz) δ 2.43 (s, 3H), 4.50 (quint, 2H, J ) 1.8 Hz), 6.07
(dt, 1H, J ) 6.0 and 1.8 Hz), 7.24 (dt, 1H, J ) 6.0 and 1.8 Hz),
7.33 (d, 2H, J ) 7.8 Hz), and 7.95 (d, 2H, J ) 7.8 Hz); 13C
NMR (CDCl3, 150 MHz) δ 21.9, 52.5, 127.4, 128.2, 130.0, 135.5,
145.4, 146.7, and 168.5.
Hz), 7.36 (d, 2H, J ) 8.0 Hz), and 8.14 (d, 2H, J ) 8.0 Hz); 13
C
NMR (CDCl3, 100 MHz) δ 22.0, 25.9, 27.0, 41.5, 59.3, 83.5,
129.8, 129.9, 130.0, 130.3, 130.5, 134.3, 136.6, 146.3, and 164.9.
Anal. Calcd for C20H19Cl2NO3S2: C, 52.63; H, 4.20; N, 3.07.
Found: C, 52.66; H, 4.09; N, 3.19.
To a solution containing 0.04 g (0.17 mmol) of above
pyrrolinone in 2 mL of CH2Cl2 at rt was added 0.07 mL (0.5
mmol) of 2,6-lutidine and 0.04 mL (0.18 mmol) of TBSOTf. The
reaction mixture was stirred at rt for 15 min and was
concentrated under reduced pressure. The residue was purified
by flash silica gel chromatography to give 0.05 g (86%) of 68
3,3-Dichloro-7a-phenylthio-1-(toluene-4-sulfonyl)oc-
tahydroindol-2-one (65). To a mixture of 0.11 g (0.29 mmol)
of sulfilimine 62 and 0.37 g of Zn-Cu in 20 mL of THF was
slowly added 0.16 mL (1.5 mmol) of trichloroacetyl chloride
at 0 °C. The reaction mixture was stirred at rt for 20 min,
8546 J. Org. Chem., Vol. 70, No. 21, 2005

Cyclizations of Vinyl Sulfilimines
as a clear oil: IR (neat) 1585, 1179, 1154, 843, and 672 cm-1
;
6a-Ethylthio-6-(toluene-4-sulfonyl)-3a,4,6,6a-tetrahy-
drofuro[2,3-b]pyrrol-5-one (72). To a mixure containing 0.16
g (0.39 mmol) of sulfide 34 and 0.5 g of Zn metal in 15 mL of
EtOH were added 0.12 mL (1.9 mmol) of acetic acid and 0.29
mL (1.9 mmol) of TEMDA. The mixture was stirred at rt for
1 h and was filtered through Celite. The solvent was removed
under reduced pressure, and the residue was dissolved in
EtOAc and washed with water. The organic layer was sepa-
rated, dried over MgSO4, and concentrated under reduced
pressure. Silica gel chromatography gave 0.11 g (84%) of 72
as a white solid: mp 129-131 °C; IR (neat) 1740, 1371, 1174,
and 1011 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.29 (t, 3H, J )
7.2 Hz), 2.39 (dd, 1H, J ) 17.6 and 2.4 Hz), 2.40 (s, 3H), 2.65
(dq, 1H, J ) 11.6 and 7.2 Hz), 2.76 (dd, 1H, J ) 17.6 and 9.2
Hz), 2.79 (dq, 1H, J ) 11.6 and 7.2 Hz), 3.80 (dq, 1H, J ) 9.2
and 2.4 Hz), 5.01 (t, 1H, J ) 2.4 Hz), 6.35 (t, 1H, J ) 2.4 Hz),
7.28 (d, 2H, J ) 8.4 Hz), and 7.99 (d, 2H, J ) 8.4 Hz); 13C
NMR (CDCl3, 100 MHz) δ 13.8, 21.9, 25.0, 35.4, 49.2, 105.6,
108.8, 129.3, 129.4, 135.6, 145.1, 145.4, and 171.3. Anal. Calcd
for C15H17NO4S2: C, 53.08; H, 5.05; N, 4.13. Found: C, 53.11;
H, 5.08; N, 4.11.
1H NMR (CDCl3, 600 MHz) δ 0.18 (s, 6H), 0.93 (s, 9H), 2.39
(s, 3H), 5.15 (dd, 1H, J ) 3.6 and 1.8 Hz), 5.98 (t, 1H, J ) 3.6
Hz), 6.78 (dd, 1H, J ) 3.6 and 1.8 Hz), 7.25 (d, 2H, J ) 8.4
Hz), and 7.71 (d, 2H, J ) 8.4 Hz); 13C NMR (CDCl3, 150 MHz)
δ -4.8, 18.4, 21.8, 25.8, 92.3, 109.7, 113.9, 127.5, 129.8, 136.6,
143.4, and 144.7.
1-(Toluene-4-sulfonyl)-pyrrolidine (69). To a solution
containing 0.03 g (0.1 mmol) of amide 67 in 2 mL of THF was
added 0.3 mL of BH3‚THF (1.0 M in THF) at 0 °C. The reaction
mixture was stirred for 20 h, quenched with MeOH, and
concentrated under reduced pressure. Purification by flash
silica gel chromatography gave 0.02 g (83%) of 69 as a white
solid:52 1H NMR (CDCl3, 600 MHz) δ 1.73-1.76 (m, 4H), 2.43
(s, 3H), 3.21-3.34 (m, 4H), 7.32 (d, 2H, J ) 7.8 Hz), and 7.72
(d, 2H, J ) 7.8 Hz); 13C NMR (CDCl3, 150 MHz) δ 21.7, 25.4,
48.1, 127.8, 130.0, 134.2, and 143.5. HRMS Calcd for C11H15-
NO2S [M + H]+: 226.0896. Found: 226.0898.
3,3-Dichloro-5-ethylthio-1-(toluene-4-sulfonyl)pyrroli-
din-2-ol (70). To a solution containing 0.1 g (0.3 mmol) of
sulfide 47 in 3 mL of THF at 0 °C was added 0.8 mL (0.8 mmol)
of BH3‚THF (1.0 M). The reaction mixture was stirred at rt
for 12 h and was then quenched with MeOH. The aqueous
layer was extracted with EtOAc, and the combined organic
layer was washed with brine, dried over MgSO4, and concen-
trated under reduced pressure. The residue was purified by
flash silica gel chromatography to give 0.084 g (84%) of 70 as
a white solid: mp 119-120 °C; IR (neat) 1343, 1165, and 1082
N-{2,2-Dichloro-2-[2-(ethylthio)furan-3-yl]-acetyl}-4-
toluenesulfonamide (73). A solution containing 0.02 g (0.05
mmol) of sulfide 34 and 0.1 mL of TFA in 1 mL of toluene was
sujected to microwave irradiation (200 W, 100 °C) for 30 min.
The resulting mixture was diluted with H2O and extracted
with EtOAc. The organic layer was washed with a saturated
aqueous NaHCO3, brine, dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by flash
silica gel chromatography to provide 0.014 g (71%) of amide
1
cm-1; H NMR (CDCl3, 400 MHz) δ 0.95 (t, 3H, J ) 7.2 Hz),
2.31 (dq, 1H, J ) 12.0 and 7.2 Hz), 2.41 (s, 3H), 2.49 (dq, 1H,
J ) 12.0 and 7.2 Hz), 2.87 (dd, 1H, J ) 14.0 and 9.2 Hz), 2.98
(dd, 1H, J ) 14.0 and 6.8 Hz), 3.60 (brs, 1H), 4.99 (dd, 1H,
J ) 9.2 and 6.8 Hz), 5.71 (s, 1H), 7.28 (d, 2H, J ) 8.0 Hz), and
7.87 (d, 2H, J ) 8.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 13.9,
21.8, 23.3, 49.3, 62.9, 86.2, 89.9, 128.0, 130.0, 137.3, and 144.2.
Anal. Calcd for C13H17Cl2NO3S2: C, 42.16; H, 4.63; N, 3.78.
Found: C, 42.20; H, 4.54; N, 3.83.
73 as a yellow oil: IR (neat) 1721, 1638, 1408, and 1192 cm-1
;
1H NMR (CDCl3, 400 MHz) δ 1.40 (t, 3H, J ) 7.2 Hz), 2.42 (s,
3H), 3.16 (q, 2H, J ) 7.2 Hz), 7.34 (d, 2H, J ) 8.0 Hz), 7.34 (d,
1H, J ) 2.0 Hz), 7.37 (d, 1H, J ) 2.0 Hz), and 7.98 (d, 2H,
J ) 8.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 15.0, 21.9, 25.2,
112.5, 116.4, 128.7, 129.9, 135.3, 143.4, 145.8, 158.5, 166.3,
and 176.2.
4,4-Dichloro-6a-methyl-6-(toluene-4-sulfonyl)-3a,4,6,6a-
tetrahydrofuro[2,3-b]pyrrol-5-one (74). To a solution con-
taining 0.04 g (0.10 mmol) of sulfide 34 in 3 mL of CH2Cl2 at
0 °C was added 0.085 g (0.5 mmol) of m-chloroperbenzoic acid.
After being stirred at rt for 32 h, the mixture was quenched
with H2O and extracted with EtOAc. The organic layer was
washed with a saturated aqueous NaHCO3, brine, and dried
over Na2SO4. Concentration under reduced pressure followed
by flash silica gel chromatography provided 0.03 g (70%) of
4,4-dichloro-6a-ethane-sulfonyl-6-(toluene-4-sulfonyl)-3a,4,6,6a-
tetrahydrofuro[2,3-b]pyrrol-5-one as a colorless oil: 1H NMR
(CDCl3, 400 MHz) δ 1.55 (t, 3H, J ) 7.6 Hz), 2.45 (s, 3H), 3.72
(dq, 1H, J ) 14.0 and 7.6 Hz), 3.84 (dq, 1H, J ) 14.0 and 7.6
Hz), 5.26 (t, 1H, J ) 2.8 Hz), 5.36 (t, 1H, J ) 2.8 Hz), 6.48 (t,
1H, J ) 2.8 Hz), 7.36 (d, 2H, J ) 8.0 Hz), and 8.07 (d, 2H,
J ) 8.0 Hz).
To a solution containing 0.02 g (0.05 mmol) of the above
sulfone in 2 mL of CH2Cl2 at rt was added 0.1 mL (0.2 mmol)
of AlMe3 (2.0 M in toluene). After being heated at reflux for
36 h, the reaction mixture was quenched with a 10% aqueous
solution of Rochelle salt and extracted with EtOAc. The organic
layer was washed with brine, dried over Na2SO4, and concen-
trated under reduced pressure. The residue was purified by
flash silica gel chromatography to provide 0.013 g (70%) of 74
as a white solid: mp 147-148 °C; IR (KBr) 1765, 1376, 1038,
977, 817, and 665 cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.27 (s,
3H), 2.44 (s, 3H), 3.97 (t, 1H, J ) 2.4 Hz), 5.01 (t, 1H, J ) 2.4
Hz), 6.22 (t, 1H, J ) 2.4 Hz), 7.32 (d, 2H, J ) 8.0 Hz), and
7.96 (d, 2H, J ) 8.0 Hz); 13C NMR (CDCl3, 100 MHz) δ 21.7,
24.7, 65.7, 80.9, 101.6, 102.0, 129.0, 129.5, 134.5, 145.8, 145.9,
and 163.7. Anal. Calcd for C14H13Cl2NO4S: C, 46.42; H, 3.62;
N, 3.87. Found: C, 46.54; H, 3.71; N, 3.90.
N-(4-Hydroxybutyl)-4-toluenesulfonamide (71). To a
solution containing 0.05 g (0.14 mmol) of sulfide 47 in 2 mL of
MeOH was added 0.026 g (0.67 mmol) of NaBH4. The reaction
mixture was stirred at rt for 20 min and quenched with water.
The aqueous layer was extracted with EtOAc, and the com-
bined organic layer was washed with brine, dried over MgSO4,
and concentrated under reduced pressure. Purification by flash
silica gel chromatography gave 0.037 g (92%) of N-(3,3-
dichloro-4-hydroxybutyl)-4-toluenesulfonamide as a white
solid: mp 108-109 °C; IR (neat) 1305, 1151, and 1048 cm-1
;
1H NMR (CDCl3, 600 MHz) δ 2.43 (s, 3H), 2.46 (t, 2H, J ) 7.2
Hz), 2.67 (t, 1H, J ) 7.2 Hz), 3.30 (q, 2H, J ) 7.2 Hz), 3.88 (d,
2H, J ) 7.2 Hz), 4.98 (t, 1H, J ) 7.2 Hz), 7.32 (d, 2H, J ) 8.4
Hz), and 7.75 (d, 2H, J ) 8.4 Hz); 13C NMR (CDCl3, 100 MHz)
δ 21.8, 39.7, 43.7, 72.3, 91.6, 127.3, 130.1, 136.7, and 144.0.
Anal. Calcd for C11H15Cl2NO3S: C, 42.32; H, 4.84; N, 4.49.
Found: C, 42.27; H, 4.79; N, 4.56.
To a mixture containing 0.03 g (0.1 mmol) of the above
amide and 0.12 g of Zn in 5 mL of EtOH were added 0.03 mL
(0.5 mmol) of acetic acid and 0.07 mL (0.5 mmol) of TEMDA.
The reaction mixture was stirred at rt for 1 h and was filtered
through Celite. The solvent was removed under reduced
pressure, and the residue was dissolved in EtOAc and washed
with water. The organic layer was separated, dried over
MgSO4, and concentrated under reduced pressure. The residue
was purified by flash silica gel chromatography to give 0.021
g (88%) of 71 as a colorless oil:53 1H NMR (CDCl3, 400 MHz) δ
1.64 (m, 1H), 1.70 (quint, 2H, J ) 6.0 Hz), 2.42 (s, 3H), 3.10
(q, 2H, J ) 6.0 Hz), 3.70-3.80 (m, 2H), 4.81-4.88 (m, 1H),
7.30 (d, 2H, J ) 8.0 Hz), and 7.73 (d, 2H, J ) 8.0 Hz).
3a-Methyl-2-oxo-1-(toluene-4-sulfonyl)-2,3,3a,8a-tet-
rahydro-1H-pyrrolo[2,3-b]indole-8-carbaldehyde (82). To
a mixture of 0.16 g (2.8 mmol) of 31, 0.8 mL (14 mmol) of
(52) Zhu, S.; Jin, G.; Xu, Y. Tetrahedron 2003, 59, 4389.
(53) Bailey, T. R.; Garigipati, R. S.; Morton, J. A.; Weinreb, S. M. J.
Am. Chem. Soc. 1984, 106, 3240.
J. Org. Chem, Vol. 70, No. 21, 2005 8547

Padwa et al.
HOAc, and 1.9 mL (14 mmol) of TMEDA in 40 mL of EtOH
was added 3.7 g (5.6 mmol) of Zn at rt. After being stirred for
2 h at rt, the reaction mixture was filtered through Celite into
a saturated aqueous NaHCO3 solution and extracted with
EtOAc. The combined organic layer was washed with brine,
dried over Na2SO4, and concentrated under reduced pressure.
The residue was purified by silica gel flash column chroma-
tography to give 1.2 g (86%) of tert-butyl 8a-ethylthio-3a-
methyl-2-oxo-1-(toluene-4-sulfonyl)-2,3,3a,8a-tetrahydro-1H-
pyrrolo[2,3-b]-indole-8-carboxylate as a white solid: mp 163-
164 °C; IR (KBr) 1745, 1721, and 1597 cm-1; 1H NMR (CDCl3,
400 MHz) δ 1.19 (t, 3H, J ) 7.2 Hz), 1.69 (s, 9H), 2.34 (s, 3H),
2.49-2.57 (m, 1H), 2.67 (d, 1H, J ) 17.6 Hz), 2.75-2.83 (m,
1H), 2.81 (d, 1H, J ) 17.6 Hz), 6.90-7.03 (m, 2H), 7.14 (d,
2H, J ) 8.0 Hz), 7.22 (ddd, 1H, J ) 8.4, 6.4, and 2.4 Hz), 7.75
(d, 1H, J ) 8.4 Hz), and 7.80 (d, 2H, J ) 8.0 Hz); 13C NMR
(CDCl3, 100 MHz) δ 12.4, 21.6, 22.3, 25.9, 28.4, 42.1, 54.9, 83.6,
99.2, 117.5, 122.5, 123.9, 128.7, 128.9, 129.0, 135.3, 140.2,
144.8, 151.6, and 170.3.
17.6 Hz), 2.66 (rotamer A; d, J ) 17.6 Hz, 1H), 2.72 (rotamer
B; d, 1H, J ) 17.6 Hz), 2.80 (rotamer A; d, 1H, J ) 17.6 Hz),
5.48 (rotamer A; s, 1H), 5.59 (rotamer B; s, 1H), 6.73 (brs, 1H),
7.14-7.29 (rotamer B; m, 5H and rotamer A; m, 4H), 8.02
(rotamer A; d, 1H, J ) 8.4 Hz), 8.62 (rotamer A; s, 1H), and
8.96 (rotamer B; s, 1H); 13C NMR (CDCl3, 100 MHz) δ 26.6,
43.9, 46.11, 17.7, 109.6, 124.3, 125.5, 129.0, 137.3, 138.0, 158.2,
and 175.0. HRMS Calcd for C12H12N2O2 [M + H]+: 217.0972.
Found: 217.0971.
1,3a-Dimethyl-2-oxo-2,3,3a,8a-tetrahydro-1H-pyrrolo-
[2,3-b]indole-8-carbaldehyde (84). To a solution containing
0.04 g (0.2 mmol) of 83 in 1.0 mL of THF at 0 °C was added
8.0 mg (0.34 mmol) of NaH. The mixture was stirred for 30
min at 0 °C, then 0.02 mL (0.32 mmol) of MeI was added, and
the temperature was allowed to warm to rt with stirring over
5 h. The reaction mixture was quenched with a saturated
aqueous NH4Cl solution and was extracted with EtOAc. The
combined organic layer was washed with brine, dried over Na2-
SO4, and concentrated under reduced pressure. The residue
was purified by preparative thick layer chromatography to give
0.02 g (49%) of 84 as a colorless oil: IR (neat) 2961, 1686, and
To a mixture of 0.53 g (1.0 mmol) of the above compound,
0.6 mL (10 mmol) of HOAc, and 1.4 mL (10 mmol) of TMEDA
in 50 mL of EtOH was added 1.4 g (20 mmol) of Zn at rt. After
being heated for 3 h at reflux, the reaction mixture was allowed
to cool, filtered through Celite into a saturated aqueous
NaHCO3 solution, and extracted with EtOAc. The combined
organic layer was washed with brine, dried over Na2SO4, and
concentrated under reduced pressure. The residue was purified
by silica gel flash column chromatography to give 0.39 g (73%)
of tert-butyl 2-ethylthio-3-methyl-3-[2-oxo-2-(toluene-4-sulfon-
ylamino)-ethyl]-2,3-dihydroindole-1-carboxylate as a colorless
1
1596 cm-1; H NMR (CDCl3, 400 MHz) δ 1.49 (rotamer B; s,
3H), 1.52 (rotamer A; s, 3H), 2.69 (rotamer A and B; d, 1H,
J ) 17.2 Hz), 2.84 (rotamer B; d, 1H, J ) 17.2 Hz), 2.88
(rotamer B; s, 3H), 2.90 (rotamer A; d, 1H, J ) 17.2 Hz), 2.94
(rotamer B; s, 3H), 5.28 (rotamer A; s, 1H), 5.74 (rotamer B;
s, 1H), 7.16-7.32 (rotamer B; m, 5H, and rotamer A; m, 4H),
7.98 (rotamer A; d, 1H, J ) 8.0 Hz), 8.68 (rotamer A; s, 1H),
and 8.97 (rotamer B; s, 1H); 13C NMR (CDCl3, 100 MHz)
rotamer B: δ 25.9, 28.3, 43.4, 45.3, 81.4, 110.8, 117.6, 124.4,
125.9, 129.0, 138.3, 159.6, and 172.2. Rotamer A: δ 25.5, 26.7,
43.1, 45.9, 84.1, 110.8, 117.6, 123.2, 126.1, 129.0, 137.9, 159.0,
and 171.8. HRMS Calcd for C25H30N2O5S2 [M + H]+: 231.1128.
Found: 231.1127.
The second fraction isolated by preparative thick layer
chromatography contained 0.02 g (47%) of 1,3a-dimethyl-
3,3a,8,8a-tetrahydro-1H-pyrrolo[2,3-b]indol-2-one as a colorless
oil: IR (neat) 1686 and 1608 cm-1; 1H NMR (CDCl3, 400 MHz)
δ 1.45 (s, 3H), 2.61 (d, 1H, J ) 17.2 Hz), 2.81 (d, 1H, J ) 17.2
Hz), 2.84 (s, 3H), 4.60 (brs, 1H), 4.88 (s, 1H), 6.65 (d, 1H, J )
8.0 Hz), 6.82 (t, 1H, J ) 7.2 Hz), and 7.07-7.10 (m, 2H); 13C
NMR (CDCl3, 100 MHz) δ 26.2, 26.8, 44.2, 47.1, 84.4, 110.7,
120.4, 123.1, 128.5, 135.9, 146.9, and 172.7.
A solution containing 0.02 g (0.1 mmol) of the above NH-
lactam was taken up in 1.0 mL of HCO2H and was stirred at
rt for 4 h. The reaction mixture was concentrated under
reduced pressure. The resultant residue was dissolved in
EtOAc and was washed with a saturated aqueous NaHCO3
solution. The organic layers were then washed with brine,
dried over Na2SO4, and concentrated under reduced pressure.
The residue was precipitated from EtOAc/hexane to provide
0.02 g (87%) of 84.
1
oil: IR (neat) 1701, 1664, and 1597 cm-1; H NMR (CD3OD,
400 MHz) δ 1.15 (t, 3H, J ) 7.6 Hz), 1.44 (s, 3H), 1.55 (s, 9H),
2.24 (d, 1H, J ) 14.8 Hz), 2.30 (d, 1H, J ) 14.8 Hz), 2.45 (s,
3H), 2.45-2.60 (m, 2H), 5.67 (s, 1H), 6.92-7.01 (m, 2H), 7.17
(td, 1H, J ) 8.0 and 1.6 Hz), 7.39 (d, 2H, J ) 8.0 Hz), 7.55 (m,
1H), and 7.86 (d, 2H, J ) 8.0 Hz); 13C NMR (CD3OD, 100 MHz)
δ 15.8, 19.7, 21.8, 26.7, 28.8, 47.3, 75.4, 83.1, 117.2, 123.7,
124.7, 129.3, 129.4, 129.5, 130.7, 137.9, 138.8, 146.3, 153.7,
and 170.8.
A solution of 0.37 g (0.7 mmol) of the above compound in 20
mL of HCO2H was stirred at rt for 4 h. The reaction mixture
was concentrated under reduced pressure, and the resultant
residue was dissolved in EtOAc and washed with a saturated
aqueous NaHCO3 solution. The organic layer was washed with
brine, dried over Na2SO4, and concentrated under reduced
pressure. The residue was precipitated with EtOAc/hexane to
provide 0.24 g (88%) of 82 as a white solid: mp 228-229 °C;
IR (KBr) 2973, 1734, and 1684 cm-1 1H NMR (CDCl3, 400
;
MHz) δ 1.50 (s, 3H), 2.36 (s, 3H), 2.88 (s, 3H), 6.07 (s, 1H),
7.11-7.25 (m, 5H), 7.76 (d, 2H, J ) 8.4 Hz), 7.83 (d, 1H, J )
8.0 Hz), and 8.99 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 21.6,
24.6, 43.1, 46.8, 82.2, 117.7.6, 122.9, 126.1, 127.9, 129.3, 129.7,
135.1, 136.4, 137.7, 145.5, 162.0, and 170.5. HRMS Calcd for
C19H18N2O4S [M + H]+: 371.1060. Found: 371.1060.
Desoxyeseroline (79). To a mixture containing 0.03 g (0.12
mmol) of 84 in 1.5 mL of THF was added 0.6 mL (0.6 mmol)
of a 1.0 M solution of BH3‚THF complex in THF at rt. After
being heated at reflux for 2 h, the reaction mixture was allowed
to cool to rt and 2.0 mL of H2O was added. The mixture was
heated at reflux for another 1 h, cooled to rt, and extracted
with EtOAc. The combined organic layer was dried over Na2-
SO4 and was concentrated under reduced pressure. The
residue was purified by silica gel flash column chromatography
to give 0.02 g (76%) of 78 as a colorless oil:46 IR (neat) 1605
3a-Methyl-2-oxo-2,3,3a,8a-tetrahydro-1H-pyrrolo[2,3-
b]indole-8-carbaldehyde (83). To a solution containing 0.88
g (6.9 mmol) of naphthalene in 20 mL of THF was added 0.17
g (7.0 mmol) of sodium, and the mixture was stirred at rt for
45 min so as to produce sodium naphthalinide. The blue
solution was cooled to -78 °C, and then a solution of 0.25 g
(0.69 mmol) of 82 in 10 mL of THF was added. After being
stirred for 1 h, the reaction was quenched with a saturated
aqueous NH4Cl solution and was allowed to warm to rt. The
mixture was extracted with EtOAc, and the combined organic
layer was washed with brine, dried over Na2SO4, and concen-
trated under reduced pressure. The residue was purified by
silica gel flash column chromatography to give 0.12 g (81%) of
83 as a white solid: mp 163-164 ïC; IR (KBr) 3200, 1708,
and 1677 cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.54 (rotamer A;
s, 3H), 1.56 (rotamer B; s, 3H), 2.64 (rotamer B; d, 1H, J )
and 1491 cm-1 1H NMR (CDCl3, 400 MHz) δ 1.45 (s, 3H),
;
1.90-2.10 (m, 2H), 2.56 (s, 3H), 2.60-2.66 (m, 1H), 2.74-2.79
(m, 1H), 2.95 (s, 3H), 4.16 (s, 1H), 6.42 (d, 1H, J ) 7.6 Hz),
6.69 (t, 1H, J ) 7.6 Hz), 7.00 (d, 1H, J ) 7.6 Hz), and 7.10 (t,
1H, J ) 7.6 Hz); 13C NMR (CDCl3, 100 MHz) δ 27.3, 36.6, 38.2,
40.7, 52.7, 53.2, 97.3, 106.7, 117.7, 122.2, 127.8, 136.5, and
151.9.
8548 J. Org. Chem., Vol. 70, No. 21, 2005

Cyclizations of Vinyl Sulfilimines
Supporting Information Available: Full experimental
details and spectroscopic data for the preparation of all new
vinyl and aryl sulfilimines. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. We appreciate the financial sup-
port provided by the National Institutes of Health (GM
059384) and the National Science Foundation (grant
CHE-0450779). S.N. wishes to thank the Kyowa Hakko
Kogyo Co. for their generous support of a research leave
at Emory University.
JO051550O
J. Org. Chem, Vol. 70, No. 21, 2005 8549