Synthesis of cyclic sulfones by ring-closing metathesis.

Article abstract of DOI:10.1021/ol017142y

A general and highly efficient synthesis of cyclic sulfones based on ring-closing metathesis has been developed. The synthetic utility of the resulting cyclic sulfones was demonstrated by their participation in stereoselective Diels-Alder reactions and transformation to cyclic dienes by the Ramberg-Baecklund reaction.

Full text of DOI:10.1021/ol017142y

ORGANIC
LETTERS
2002
Vol. 4, No. 3
427-430
Synthesis of Cyclic Sulfones by
Ring-Closing Metathesis
Qingwei Yao
Department of Chemistry and Biochemistry, The Michael Faraday Laboratories,
Northern Illinois UniVersity, DeKalb, Illinois 60115-2862
qyao@niu.edu
Received November 28, 2001
ABSTRACT
A general and highly efficient synthesis of cyclic sulfones based on ring-closing metathesis has been developed. The synthetic utility of the
resulting cyclic sulfones was demonstrated by their participation in stereoselective Diels−Alder reactions and transformation to cyclic dienes
by the Ramberg−Ba1cklund reaction.
Sulfones are a major class of organosulfur compounds1 that
have been extensively used as versatile intermediates in
organic synthesis.2 The importance of the sulfone functional
group in synthetic organic chemistry warrants significant
interest in the development of new methodologies related to
the introduction of the sulfone functionality into an organic
molecule as well as the further synthetic transformation of
the sulfone intermediate, and, when desirable and possible,
its eventual elimination from the target. Cyclic sulfones, in
particular, have unique synthetic utilities. For example,
substituted 3-sulfolenes are an excellent source of conjugated
dienes through SO2 extrusion and have been employed as
masked dienes for intramolecular Diels-Alder reactions in
numerous complex syntheses.3 Medium ring cyclic sulfones
can be used as precursors for the construction of cyclic
olefins4 by the well-established Ramberg-Ba¨cklund reac-
tion.5,6 Cyclic sulfones have also been investigated as the
key subunit and scaffold for the construction of biologically
active molecules such as protease and â-lactamase inhibi-
tors.7,8
Although a plethora of methods for the synthesis of cyclic
sulfones exists in the literature,1,2 a generally applicable and
highly efficient approach to the synthesis of cyclic sulfones
of various ring sizes and different substitution patterns is
still highly desirable. The majority of existing methodologies
for the synthesis of cyclic sulfones involve the construction
of the corresponding cyclic sulfides from appropriately
(4) (a) MaGee, D. I.; Beck, E. J. J. Org. Chem. 2000, 65, 8367. (b)
Vedejs, E.; Singer, S. P. J. Org. Chem. 1978, 43, 4884. (c) McAllister, G.
D.; Taylor, R. J. K. Tetrahedron Lett. 2001, 42, 1197. (d) Cere`, V.; Peri F.;
Pollicino, S. Tetrahedron Lett. 1997, 38, 7797. (e) Cere`, V.; Mantovani,
G.; Peri, F.; Pollicino, S.; Rici, A. Tetrahedron 2000, 56, 1225.
(5) Ramberg, L.; Ba¨cklund, B. ArkiV. Kemi. Mineral. Geol. 1940, 13A,
No. 27; Chem. Abstr. 1940, 34, 4725.
(6) Selected reviews on Ramberg-Ba¨cklund rearrangement: (a) Paquette,
L. A.; Org. React. 1977, 25, 1. (b) Paquette, L. A. Acc. Chem. Res. 1968,
1, 209. (c) Clough, J. M. In ComprehensiVe Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol 6, Chapter 3. (d) See
ref 2, Chapter 7.
(1) Schank, K. In The Chemistry of Sulphones and Sulphoxides; Patai,
S., Rappoport, Z., Stirling, C., Eds.; John Wiley & Sons: New York, 1988.
(2) Simpkins, N. S. Sulphones in Organic Synthesis; Pergamon: Oxford,
1993.
(3) For an excellent review, see: (a) Leonard, J.; Hague, A. B.; Knight,
J. A. In Organosulfur Chemistry; Page, P., Ed., Academic Press: San Diego,
1998; Volume 2, Chapter 6. For recent examples, see: (b) Shing, T. K.;
Tang, Y. J. Chem. Soc., Perkin Trans. 1 1994, 1625. (c) Leonard, J.; Hague,
A. B.; Jones, M. F. Tetrahedron Lett. 1997, 38, 3071.
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Y.; Swaminathan, S.; Bischofberger, N.; Chen, M. S.; Cherrington, J. M.;
Xiong, S. F.; Griffin, L.; Cundy, K. C.; Lee, A.; Yu, B.; Gulnik, S.; Erickson,
J. W. J. Med. Chem. 1996, 39, 3431. (b) Ghosh, A. K.; Thompson, W. J.;
Munson, P. M.; Liu, W.; Huff, J. R. Bioorg. Med. Chem. Lett. 1995, 5, 83,
and references therein.
(8) (a) Richter, H. G. GF.; Angehrn, P.; Hubschwerlen, C.; Kania, M.;
Page, M. G. P.; Specklin, J.-L.; Winkler, F. K. J. Med. Chem. 1996, 39,
3712. (b) Buynak, J. D.; Vogeti, L.; Chen, H. Org. Lett. 2001, 3, 2953.
10.1021/ol017142y CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/04/2002

functionalized precursors that often require tedious multistep
manipulations, followed by oxidation of the sulfides to
sulfones. In this Letter, we describe a novel and versatile
strategy for the synthesis of cyclic sulfones based on the
ring-closing metathesis (RCM) of acyclic sulfones which can
be readily prepared from alkenyl alcohols and alkenyl halides
through standard functional group transformations (vide
infra), as outlined in Scheme 1.
RCM of substrates containing a sulfonamide group has been
well documented15 and the cross metathesis of both allyl and
vinyl sulfones has recently been described independently by
the groups of Grubbs16 and Grela,17 the RCM of sulfone
dienes remains rare and there is only one isolated example
of the formation of a six-membered cyclic sulfone in the
literature.18 The possibility of an internal Ru-sulfonyl oxygen
ligation was recently proposed by Paquette et al. in their
study on the macrocyclization of bicyclic sulfones.19 Ad-
ditionally, the compatibility of sulfones with Ru carbene
catalysts has previously been demonstrated by Fu¨rstner.20
We set out to examine the RCM of diallyl sulfone 3a as
a test substrate (Scheme 2). Treatment of 3a with 2 mol %
Scheme 1. RCM Approach to Cyclic Sulfones
Scheme 2
The rapidly emerging olefin metathesis reaction has found
many spectacular applications in organic synthesis.9 In
particular, the RCM of R,æ-dienes mediated by Grubbs’
ruthenium-based catalysts 110 and 211 (Figure 1) has evolved
of 121 in CH2Cl2 (0.05 M) at reflux gave cleanly 3-sulfolene
4a, which was isolated in 95% yield after chromatography.
A number of structurally diverse sulfonyl dienes (3b-3i)
were then prepared and their RCM performed with the results
listed in Table 1.22 The diene substrates23 were conveniently
prepared, as illustrated by the synthesis of 3b in Scheme 3,
Figure 1. Grubbs Ru catalysts.
Scheme 3. Representative Procedures for the Synthesis of
Acyclic Sulfones
into a powerful tool for the construction of carbo- and
heterocyclic compounds.9,12 The excellent functional group
tolerance of 1 and 2 has allowed them to be widely applied
to the synthesis of oxygen-, nitrogen-, and phosphorus-
containing cyclic molecules. However, the application of
RCM to the synthesis of sulfur-containing heterocycles
remains very limited. Thus, both (Cy3P)2(Cl)2Ru(dCH-
CHdCPh2)13 and 1 were shown to be either unreactive or
of low reactivity toward the RCM of R,æ-dienes containing
a sulfide moiety,14 possibly due to the poisoning of the
ruthenium catalyst by the sulfide functionality. Although the
by a general and high-yielding protocol. This involved the
Mitsunobu reaction of an alkenyl alcohol with thioacetic acid
(9) Leading reviews on olefin metathesis: (a) Schuster M.; Blechert, S.
Angew. Chem., Int. Ed. Engl. 1997, 36, 2036. (b) Fu¨rstner, A. Top.
Organomet. Chem. 1998, 1, 1. (c) Armstrong, S. K. J. Chem. Soc., Perkin
Trans. 1 1998, 371. (d) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54,
4413. (e) Pandit, U. K.; Overleeft, H. S.; Borer, B. C.; Biera¨ugel, H. Eur.
J. Org. Chem. 1999, 959. (f) Phillips, A. J.; Abell, A. D. Aldrichimica Acta
1999, 32, 75. (g) Fu¨rstner, A. Angew. Chem., Int. Ed. 2000, 39, 3012. (h)
Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
(10) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996,
119, 100.
(11) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953. For a related catalyst with similar reactivity, see: (b) Scholl, M.;
Trnka, T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron Lett. 1999, 40,
2247. (c) Huang, J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. F. J. Am.
Chem. Soc. 1999, 121, 2674.
(14) (a) Armstrong, S. K.; Christie, B. A. Tetrahedron Lett. 1996, 37,
9373. (b) Barrett, A. G. M.; Baugh, S. P. D.; Gibson, V. C.; Giles, M. R.;
Marshall, E. L.; Procopiou, P. A. Chem. Commun. 1997, 155. (c) Shon,
Y.-S.; Lee, T. R. Tetrahedron Lett. 1997, 38, 1283. (d) Fu¨rstner, A.; Seidel,
G.; Kindler, N. Tetrahedron. 1999, 55, 8255.
(15) For the synthesis of cyclic sulfonamides, see: (a) Hanson, P. R.;
Probst, D. A.; Robinson, R. E.; Yau, M. Tetrahedron Lett. 1999, 40, 4761.
For RCM involving unsaturated sulfonamides as substates, see: (b) Visser,
M. S.; Heron, N. M.; Didiuk, M. T.; Sagal, J. F.; Hoveyda, A. H. J. Am.
Chem. Soc. 1996, 118, 4291. (c) Fu¨rstner, A.; Picquet, M.; Bruneau, C.;
Dixneuf, P. H. Chem. Commun. 1998, 1315. (d) Cerezo, S.; Corte´s, J.;
Moreno-Man˜as, M.; Pleixats, R.; Roglans, A. Tetrahedron 1998, 54, 14869.
(e) Paquette, L. A.; Leit, S. M. J. Am. Chem. Soc. 1999, 121, 8126. (f)
Yao, Q. Angew. Chem., Int. Ed. 2000, 39, 3896.
(12) Yet, L. Chem. ReV. 2000, 100, 2963.
(13) Nguyen, S. T.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1993,
115, 9858.
(16) Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751.
428
Org. Lett., Vol. 4, No. 3, 2002

Table 1. Formation of Cyclic Sulfones by Ring-Closing Metathesis Catalyzed by Grubbs Catalysts 1 and 2
a All RCM reactions were carried out in CH2Cl2 at reflux with substrate concentration and reaction time as indicated. b Refers to isolated, pure products.
c Diene 3d was prepared according to the literature in footnote 24. d Diene 3i was prepared from ring-opening of allyl glycidyl ether by allyl mercaptan,
silylation of the resulting alcohol, and subsequent oxidation with mCPBA, see the Supporting Information.
(Ph3P, DIAD in THF), subsequent one-step conversion of
the thiolester to the sulfide24 by in situ cleavage of the
thiolester by KOH in MeOH, direct alkylation of the resulting
thiolate with an alkenyl halide, and oxidation of the resulting
sulfide with mCPBA to give the required sulfone.
As shown in Table 1, the new method can be applied to
the synthesis of a variety of 3-sulfolenes. Formation of the
2-substituted 3-sulfolene 4b proceeded smoothly with catalyst
1 (entry 2), but the cyclization of substrates containing a
gem-disubstituted alkene (entries 3 and 4) required the more
reactive catalyst 2.11,21 Nevertheless, the tri- and tetrasub-
stituted cyclic olefins 4c and 4d were formed in essentially
(17) Grela, K.; Bieniek, M. Tetrahedron Lett. 2001, 38, 6425.
(18) Miller, J. F.; Termin, A.; Koch, K.; Piscopio, A. D. J. Org. Chem.
1998, 63, 3158.
(19) Paquette, L. A.; Fabris, F.; Tae, J.; Gallucci, J. C.; Hofferberth, J.
E. Am. Chem. Soc. 2000, 122, 3391.
(20) (a) Fu¨rstner, A.; Gastner, T.; Weintritt, H. J. Org. Chem. 1999, 64,
2361. (b) Fu¨rstner, A.; Ackermann, L. Chem. Commun. 1999, 95.
(21) Catalysts 1 and 2 were purchased from Strem Chemicals, Inc.
(22) A representative procedure for the RCM is provided in the
Supporting Information.
(23) The known compound 3d was prepared according to ref 24.
(24) Cao, X.-P.; Chan, T. L.; Chou, H.-F.; Tu, J. Chem. Commun. 1995,
1297.
Org. Lett., Vol. 4, No. 3, 2002
429

quantitative yield. It should be noted that the convenient
synthesis of 4c points to a general and highly efficient
approach to 2,4-dialkylated 3-sulfones which are known to
be difficult to synthesize by existing methods.25 Coupled with
cheleotropic ring opening, this synthesis provides a rapid
access to trans-1,3-disubstituted 1,3-dienes, as demonstrated
by the reaction sequence shown in Scheme 4. The bicyclic
with catalyst 1, whereas the formation of seven-, eight-, and
nine-membered cyclic sulfones (entries 7-9) required a
higher loading of the catalyst and the metathesis reaction to
be performed under dilute conditions and for a longer
reaction time. In all cases, however, the cyclized products
were isolated in good to excellent yields.
Cyclic sulfones have previously been shown to be excel-
lent precursors for the regiospecific construction of cyclic
olefins.4 As shown in Scheme 5, both 4g and 4h underwent
Scheme 4. Sequential RCM/Stereospecific SO2 Extrusion/
Diels-Alder Reaction for Synthesis of Bicyclic Compound 8
Scheme 5. Ramberg-Ba¨cklund Rearrangment of Cyclic
Sulfones
clean and high-yielding Ramberg-Ba¨cklund rearrangement
upon treatment with Br2CF2 in the presence of KOH
supported on alumina.26
In conclusion, a general and highly efficient synthesis of
cyclic sulfones has been developed and their synthetic utility
further demonstrated by SO2 extrusion to afford a conjugated
diene and by their transformation to cyclic dienes through
the Ramberg-Ba¨cklund reaction.
compound 8 was isolated as a single diastereomer in 93%
yield from 4c (directly used after the RCM of 3c as shown)
by a sequence of stereospecific SO2 extrusion and an endo-
selective Diels-Alder reaction.
We next examined the efficacy and generality of the
protocol for the formation of six-membered and larger cyclic
sulfones. As shown in Table 1, both the diene 3e (entry 5)
and the enyne 3f (entry 6) were found to cyclize uneventfully
Acknowledgment. This work was generously supported
by grants from the National Institutes of Health (GM63522)
and the Petroleum Research Fund, administered by the
American Chemical Society (36466-G1).
(25) It is well-known that alkylation of 3-substituted 3-sulfolene affords
only the 2,3-disubstituted derivative. For example: Shing, Y. K. M.; Tang,
Y. J. Chem. Soc., Perkin Trans. 1 1994, 1025. For a general discussion of
this aspect of sulfolene chemistry, see ref 2.
Supporting Information Available: Representative pro-
cedures for the synthesis of acyclic sulfone dienes and for
the RCM reaction; NMR (1H and 13C) and analytical data
for compounds 3b-i, 4b-i, 8, 10, and 11. This material is
available free of charge via the Internet at http://pubs.acs.org.
(26) Chan, T. L.; Fong, S.; Li, Y.; Man, T.-O.; Poon, C. D. Chem.
Commun. 1994, 1771.
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