A new synthesis of γ-lactams based on the reaction of vinyl sulfilimines with dichloroketene

Article abstract of DOI:10.1021/ol047453j

(Chemical Equation Presented) The reactions of several aryl-, furanyl-, and vinyl substituted sulfilimines with dichloroketene proceeded at 25°C to yield thioalkyl substituted γ-lactams which, in turn, were converted to a variety of nitrogen-containing substrates.

Full text of DOI:10.1021/ol047453j

ORGANIC
LETTERS
2005
Vol. 7, No. 5
839-841
A New Synthesis of
on the Reaction of Vinyl Sulfilimines
with Dichloroketene
γ-Lactams Based
Qiu Wang, Shinji Nara, and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received December 11, 2004
ABSTRACT
The reactions of several aryl-, furanyl-, and vinyl substituted sulfilimines with dichloroketene proceeded at 25
°
C to yield thioalkyl substituted
γ
-lactams which, in turn, were converted to a variety of nitrogen-containing substrates.
The oxindole moiety represents a key substructure associated
with many biologically active natural products and medicinal
entities.1 Various methods have been developed for the
construction of this ring system. Among the techniques
commonly used in their synthesis are derivatization of other
heterocycles,2 radical cyclizations,3 intramolecular Heck
reactions,4 arylation of amides5 and variants of the Friedel-
Crafts reaction (Stolle synthesis).6 Stolle syntheses, however,
are of limited scope because of the harshly acidic conditions
required, while many of the other methods require a
specifically functionalized precursor. Oxindole syntheses
based on the cyclization of o-aminophenylacetic acid deriva-
tives7 and reduction of isatins8 are also limited by the
availability of starting materials. The method reported by
Gassman and co-workers,9 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 1, path A).
In recent years, our research group has been involved in
a program whereby Pummerer chemistry has been used for
the synthesis of aza-heterocycles.10 It occurred to us that it
might be possible to modify the Gassman method by simply
switching the sulfur and nitrogen positions and that this might
constitute a new method to prepare oxindoles as outlined in
Path B of Scheme 1. Taking into account the earlier and
elegant studies by Marino and co-workers on the chemistry
of vinyl sulfoxides with dichloroketenes,11 we expected that
(1) (a) Lakshmaiah, G.; Kawabata, T.; Shang, M.; Fuji, K. J. Org. Chem.
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2nd ed.; Ojima, I., Ed.; Wiley: New York, 2000; Chapter 8G. (b) Mori,
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24, 6093. (b) Sumpter, W. C. Chem. ReV. 1945, 37, 443.
(8) Crestini, C.; Saladino, R. Synth. Commun. 1994, 24, 2835.
(9) (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.; Gruetzmacher, G.; van Bergen,
T. J. J. Am. Chem. Soc. 1973, 95, 6508.
(10) (a) Padwa, A.; Gunn, D. E. Jr.; Osterhout, M. H. Synthesis 1997,
1353. (b) Padwa, A.; Pure Appl. Chem. 2003, 75, 47. (c) Padwa, A.; Bur,
S. K.; Danca, D. M.; Ginn, J. D.; Lynch, S. M. Synlett 2002, 851. (d) Bur,
S. K.; Padwa, A. Chem. ReV. 2004, 104, 2401.
10.1021/ol047453j CCC: $30.25
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Scheme 1
Scheme 2
56% yield as the only detectable product isolated from the
crude reaction mixture.
Next, we turned our attention to the related reaction of
several 2-furanyl substituted sulfilimines (i.e., 15 and 16).
The results we obtained showed that these cyclizations also
proceeded at room temperature in THF and furnished the
novel dihydrofuranyl γ-lactams 17 and 18 in 58% and 40%
yield, respectively. With the related benzofuranyl (19) and
indolyl substituted (20) sulfilimines, good yields of the
cyclized lactams 21 and 22 (52% and 56%) were also
obtained (Scheme 3). Interestingly, all of the γ-lactams that
the reaction of an aryl sulfilimine such as 4 with a ketene
would first afford zwitterion 5 where the nitrogen and sulfur
atoms were switched relative to the analogous Gassman
intermediate 2. A subsequent [3,3]-sigmatropic rearrange-
ment would then deliver the Pummerer-thionium ion inter-
mediate 6. Cyclization and loss of the mercaptan should yield
the desired oxindole 8. In this communication, we give an
account of our efforts dealing with this unique cyclization
method for the synthesis of a variety of functionalized
γ-lactams.
Scheme 3
First, we examined the reaction of phenyl sulfilimine 9
with dichloroketene12 in THF at 25 °C which afforded
oxindole 10 (Scheme 2) together with varying amounts of
methyl phenyl sulfide (11) and amide 12.13 Similar results
were obtained using a variety of aryl substituted sulfilimines
(i.e., X ) Me, OMe) with oxindole 10 always being formed
in low yield (ca. 20%). Apparently, the key rate determining
step of the process (i.e., 5 f 6) possesses a relatively high
activation energy as a consequence of the disruption of
aromaticity. To minimize this difficulty, we opted to study
the reaction of the more reactive naphthyl substituted
sulfilimine 13 with dichloroketene. In contrast to the results
obtained with sulfilimine 9, the cyclization reaction of 13
proceeded in high yield and the somewhat labile γ-lactam
14 could be obtained after chromatographic purification in
were isolated were unexpectedly robust and did not undergo
loss of mercaptan, even under somewhat forcing conditions
(i.e., heat, acid). Compound 22 encompasses the key scaffold
found in the pyrroloindoline and bis-pyrroloindole alkaloids14
and its ready formation points out the potential use of this
method for target oriented synthesis.
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 Scheme 4. The reaction
(11) (a) Marino, J. P.; Perez, A. D. J. Am. Chem. Soc. 1984, 106, 7643.
(b) Marino, J. P.; Fernanadez de la Pradilla, R. F. Tetrahedron Lett. 1985,
26, 5381. (c) Marino, J. P.; Fernanadez de la Pradilla, R. F.; Laborde, E.,
Synthesis 1987, 1088. (d) Marino, J. P.; Kim, M.-W.; Lawrence, R. J. Org.
Chem. 1989, 54, 1782. (e) Marino, J. P.; Bogdan, S.; Kimura, K. J. Am.
Chem. Soc. 1992, 114, 5566. (f) Marino, J. P.; Rubio, M. B.; Cao, G.; de
Dios, A. J. Am. Chem. Soc. 2002, 124, 13398.
(12) (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.
(13) For some earlier examples of the reaction of ketenes with sulfil-
imines, 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.
(14) (a) Overman, L. E. Pure Appl. Chem. 1994, 66, 1423. (b) Holst, P.
B.; Anthoni, U.; Christophersen, C.; Nielsen, P. H. J. Nat. Prod. 1994, 57,
997. (c) Hayashi, H.; Furutsuka, K.; Shiono, Y. J. Nat. Prod. 1999, 62,
315.
840
Org. Lett., Vol. 7, No. 5, 2005

Scheme 4
Scheme 6
pyrrolidine alkaloids. N-(p-Toluenesulfonyl)pyrrolidine 40
was obtained in 83% yield when lactam 38 was reduced with
BH3•THF. We also subjected 37 to reduction with BH3‚THF
and found that carbinolamide 41 was cleanly formed in 84%
yield. Reduction of 37 with NaBH4 followed by further
reaction with zinc/HOAc furnished the 1,4-amino alcohol
42 in 81% yield.
A structure-activity relationship using γ-lactam 17, which
contains a fused dihydrofuran ring as part of its skeleton,
was also investigated. Smooth dechlorination occurred when
17 was treated with zinc in acetic acid affording the novel
heterocycle 43 in 84% yield (Scheme 6). 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 17 with various thiophilic reagents
failed. When treated with trifluoroacetic acid at 100 °C, 17
was smoothly converted into furan 44 in 71% yield by
preferential elimination of the N-(p-toluenesulfonyl) group.
However, by first oxidizing the thio group with m-CPBA
and then treating the resulting sulfone with trimethylalumi-
num, it was possible to introduce a methyl substituent on
the carbon atom adjacent to the two heteroatoms (i.e.,
formation of 45).
In conclusion, we have disclosed a new and efficient
method for the synthesis of highly functionalized γ-lactams.
The overall process involves the reaction of a vinyl substi-
tuted sulfilimine with the highly electrophilic dichloroketene
to first generate a zwitterionic intermediate. A subsequent
[3,3]-sigmatropic rearrangement is followed by intramolecu-
lar trapping of the Pummerer cation by the amido anion to
furnish the observed γ-lactam products. The heavily func-
tionalized lactams are easily converted to a variety of nitrogen
containing substrates. We are currently exploring the gen-
erality of the rearrangement/cyclization process and its
application to alkaloid synthesis.
of dichloroketene with both acyclic (23-26) and cyclic (31-
33) sulfilimines proceeded smoothly to give the expected
γ-lactams in good yield. The reactions of dichloroketene with
Z-(24) and E-phenyl styryl sulfilimine (25) afforded different
diastereomeric lactams (i.e., 28 and 29) and parallel Marino’s
observations with the corresponding vinyl sulfoxides.15 The
complete stereospecificity of the cyclization process is
undoubtedly related to the highly ordered transition state of
the sigmatropic rearrangement. The resulting Pummerer
intermediate is rapidly trapped by the amido anion before
C-C bond rotation can occur.
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 functionalized γ-lac-
tams to probe their usefulness for the synthesis of various
nitrogen containing substrates. It was anticipated that lactam
37, derived from the reaction of dichloroketene with S-ethyl-
S-ethenyl-N-(toluene-4-sulfonyl)sulfilimine, could be used to
prepare a variety of substituted pyrrolidine derivatives.
Indeed, the reaction of 37 with zinc/HOAc cleanly led to
the dechlorinated lactam 38 in 88% yield. Oxidation of 38
with m-CPBA followed by treatment with tert-butyldimeth-
ylsilyl trifluoromethanesulfonate (Scheme 5) provided pyrrole
39 in 86% yield. This activated pyrrole corresponds to an
attractive intermediate for the eventual synthesis of several
Scheme 5
Acknowledgment. We appreciate the financial support
provided by the National Science Foundation (Grant CHE-
0132651). S.N. thanks the Kyowa Hakko Kogyo Co. for their
generous support of a research leave at Emory University.
Supporting Information Available: Spectroscopic data
and experimental details for the preparation of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL047453J
(15) Marino, J. P.; Neisser, M. J. Am. Chem. Soc. 1981, 103, 7687.
Org. Lett., Vol. 7, No. 5, 2005
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