New application of the Pummerer reaction of imidosulfoxides for the generation of mesoionic dipoles

Full text of DOI:10.1021/jo961986r

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74
J . Org. Chem. 1997, 62, 774-775
Communications
New Ap p lica tion of th e P u m m er er
Rea ction of Im id osu lfoxid es for th e
Gen er a tion of Mesoion ic Dip oles†
Sch em e 1
J effrey T. Kuethe and Albert Padwa*
Department of Chemistry, Emory University,
Atlanta, Georgia 30322
Received October 23, 1996
Sch em e 2
R-Acyl thionium ions generated from R-acyl sulfoxides
under Pummerer conditions are powerful electrophiles,
reacting efficiently with a variety of nucleophilic species.1
Bimolecular addition of these types of cations to carbon-
carbon double bonds is well known.3 In the realm of
natural product synthesis, most success has been achieved
-3
using intramolecular Friedel-Crafts cyclization of the
Pummerer thionium ion intermediate.4
-12
Recent pub-
lications from these laboratories have described the
internal trapping of the Pummerer thionium ion by
adjacent carbonyl groups as a method for generating
reactive dienes for subsequent use in Diels-Alder chem-
istry.13 The combination of a sequence of individually
powerful methods often has a value significantly greater
than the sum of the individual reactions and is of current
1
4
interest to the synthetic organic community.
In the
context of our studies dealing with the tandem chemistry
of thionium ions, we have discovered that the Pummerer
Imidosulfoxide 7 was easily prepared from 2-piperidone
in two steps (85%) by heating the lactam with (ethyl-
sulfenyl)acetyl chloride (6),17 followed by sodium perio-
date oxidation. Slow addition of 7 to a refluxing mixture
of toluene, acetic anhydride (10 equiv), N-phenylmale-
imide (1.3 equiv), and p-toluenesulfonic acid (1 mol %)
led to the formation of cycloadduct 9 in 75% yield. An
analogous process occurred using maleic anhydride as the
trapping agent to afford cycloadduct 10 in 69% yield. The
isolation of these compounds supports the intermediacy
of dipole 8, formed by thionium ion cyclization followed
by a subsequent deprotonation (Scheme 2).
The ability of imidosulfoxides to undergo intramolecu-
lar dipolar cycloaddition leading to complex nitrogen
polyheterocycles was demonstrated by exposure of 11 to
acetic anhydride in refluxing toluene to provide 12 in 61%
isolated yield (Scheme 3). Two additional examples that
illustrate the scope and variety of systems that can be
employed in this cyclization-deprotonation-cycloaddi-
tion sequence are outlined below. Exposure of 13 to the
standard Pummerer conditions afforded acetoxypyridone
reaction can also be utilized for generating mesoionic
dipoles15 of type 2 (Scheme 1). Herein we report details
of this new reaction and provide an application of the
process to the formal synthesis of lupinine (4) and
anagyrine (5), two members of the lupinine family of
alkaloids.16
†
Dedicated to my research mentor, Cheves Walling, on the occasion
of his 80th birthday.
(
1) DeLucchi, O.; Miotti, U.; Modena, G. Organic Reactions; Paquette,
L. A., Ed.; J ohn Wiley: New York, 1991; Chapter 3, pp 157-184.
2) Grierson, D. S.; Husson, H. P. in Comprehensive Organic
Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, 1991; Vol. 6, pp 909-
47.
3) Kennedy, M.; McKervey, M. A. in Comprehensive Organic
Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, 1991; Vol. 7, pp 193-
16.
4) Magnus, P. D.; Gallagher, T.; Brown, P.; Huffman, J . C. J . Am.
(
9
(
2
(
Chem. Soc. 1984, 106, 2105. Magnus, P.; Giles, M.; Bonnert, R.;
J ohnson, G.; McQuire, C.; Deluca, M.; Merrit, A.; Kim, C., S.; Vicker,
N. J . Am. Chem. Soc. 1993, 115, 8116.
(
5) Oikawa, Y.; Yonemitsu, O. J . Org. Chem. 1976, 41, 1118.
(6) Ishibashi, H.; Sato, T.; Takahashi, M.; Hayashi, M.; Ikeda, M.
Heterocycles 1988, 27, 2787.
1
5 in 52% yield. The initially formed cycloadduct 14 was
(
(
7) Hunter, R.; Simon, C. D. Tetrahedron Lett. 1986, 27, 1385.
8) Torisawa, Y.; Satoh, A.; Ikegami, S. Tetrahedron Lett. 1988, 29,
not isolated as it readily underwent oxybridge cleavage,
presumably promoted by the nitrogen atom lone pair.
Subsequent reaction of a transient 5-hydroxypyridone
intermediate with additional acetic anhydride furnished
1
729.
(
(
(
(
9) Stamos, I. K. Tetrahedron Lett. 1985, 26, 2787.
10) Oikawa, Y.; Yonemitsu, O. Tetrahedron 1974, 30, 2653.
11) Mander, L. N.; Mundill, P. H. C. Synthesis 1981, 620.
12) Craig, D.; Daniels, K.; MacKenzie, A. R. Tetrahedron 1992, 48,
1
5. In a related fashion, imidosulfoxide 16 produced a
7
803.
13) Cochran, J . E.; Padwa, A. Tetrahedron Lett. 1995, 36, 3495.
mixture of cycloadduct 17 (29%) and pyridone 18 (41%),
thereby demonstrating that a tethered alkene attached
to the sulfoxide can also be used in these Pummerer-
induced cycloadditions. Further heating of 17 in toluene
with a trace of p-toluenesulfonic acid resulted in dehy-
dration to form pyridone 18 in quantitative yield.
Our interest in establishing imidosulfoxide 7 as a
useful building block for indolizidine alkaloid synthesis
(
Cochran, J . E.; Padwa, A. J . Org. Chem. 1995, 60, 3938. Padwa, A.;
Cochran, J . E.; Kappe, C. O. J . Org. Chem. 1996, 61, 3706. Padwa, A.;
Kappe, C. O.; Reger, T. S. J . Org. Chem. 1996, 61, 4888. Kappe, C. O.;
Padwa, A. J . Org. Chem. 1996, 61, 6166.
(14) Ho, T. L. Tandem Organic Reactions; Wiley: New York, 1992.
Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131.
Wender, P. A., Ed. Frontiers in Organic Synthesis. Chem. Rev. 1996,
9
6, 1-600.
15) For some methods to generate mesoionic dipoles of type 2, see:
Osterhout, M. H.; Nadler, W. R.; Padwa, A. Synthesis 1994, 123.
16) Introduction to Alkaloids. A Biogenetic Approach; Cordell, G.
A., Ed.; J ohn Wiley & Sons, Inc.: New York, 1981; pp 154-195.
(
(
(17) Mooradian, A.; Cavallito, C. J .; Bergman, A. J .; Lawson, E. J .;
Suter, C. M. J . Am. Chem. Soc. 1949, 71, 3372.
S0022-3263(96)01986-X CCC: $14.00 © 1997 American Chemical Society

Communications
J . Org. Chem., Vol. 62, No. 4, 1997 775
Sch em e 3
Sch em e 5a
a
Reagents: (a) BF3‚OEt2; (b) (TfO)2NPh; (c) 2-(tri-n-butylstan-
nyl)pyridine, Pd2(dba)3, TFP; (d) H2, PtO2; (e) NaOMe, MeOH.
As shown in Scheme 5, cycloadduct 19 may also be
used for a short synthesis of (()-anagyrine (5). Oxidation
of 19 with NaIO
which, when treated with BF
with N-phenyltrifluoromethanesulfonamide, gave tri-
4
/RuCl
3
furnished sulfone 23 (91%),
3
‚OEt followed by reaction
2
1
9
2
0
flate 24 in 80% overall yield. Stille cross-coupling of
4 with (tri-n-butylstannyl)pyridine provided 25 in 70%
yield. Catalytic hydrogenation of 25 over PtO followed
Sch em e 4
2
2
by a base-induced equilibration delivered 26 in 85%
isolated yield. The present sequence constitutes a formal
synthesis of (()-anagyrine, based on the successful
2
1
conversion of lactam 26 into 5 by Goldberg and Lipkin.
In conclusion, this study has demonstrated that the
Pummerer reaction of imidosulfoxides represents a highly
efficient method for the synthesis of azapolycyclic ring
systems. The further utilization of this tandem cycliza-
tion-deprotonation-cycloaddition sequence for the ste-
reocontrolled synthesis of other alkaloids is under current
investigation.
Ack n ow led gm en t. We gratefully acknowledge the
National Cancer Institute (CA-26750), DHEW, for gen-
erous support of this work. Use of the high-field NMR
spectrometer used in these studies was made possible
through equipment grants from the NIH and NSF.
prompted us to use the above methodology for the
preparation of (()-lupinine (4). A short synthesis of this
alkaloid was carried out as depicted in Scheme 4. The
Pummerer-induced reaction of 7 with methyl acrylate
gave rise mainly to cycloadduct 19 (61%) together with
lesser quantities of pyridone 20 (10%). Interestingly,
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the preparation of, as well as spectroscopic data for,
all new compounds (18 pages).
treatment of 19 with BF
3
‚OEt
2
furnished the ethylthio-
J O961986R
substituted pyridone 21 (62%), which upon Raney-nickel
reduction provided the desulfurated pyridone 22 (85%).
The preparation of 22 constitutes a formal synthesis of
(18) Boekelheide, V.; Lodge, J . P., J r. J . Am. Chem. Soc. 1951, 73,
3
681.
(19) McMurry, J . E.; Scott, W. J . Tetrahedron Lett. 1983, 24, 979.
20) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(
()-lupinine (4), as Boekelheide had previously reported
(
18
the conversion of 22 into 4.
(21) Goldberg, S. I.; Lipkin, A. H. J . Org. Chem. 1972, 37, 1823.