Straightforward synthesis of strained α,β-epoxysulfones via epoxidation of vinylsulfones using N-methylmorpholine N-oxide as epoxidizing reagent

Article abstract of DOI:10.1055/s-2007-984496

An efficient, stereoselective route to the α,β-epoxysulfones using N-methylmorpholine N-oxide (NMO) as epoxidizing reagent is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-984496

1948
LETTER
Straightforward Synthesis of Strained a,b-Epoxysulfones via Epoxidation of
Vinylsulfones Using N-Methylmorpholine N-Oxide as Epoxidizing Reagent
S
ynthesis of Stra
o
a
,
b
-Epo
c
xysulfones
í
via Ep
o
oxidation of
V
inyls
R
ulfones incón, Ana Aljarilla, María Criado, Joaquín Plumet*
Departamento de Química Orgánica I, Facultad de Química, Universidad Complutense, 28040 Madrid, Spain
E-mail: plumety@quim.ucm.es
Received 19 April 2007
Dedicated to Prof. José Luís García Ruano, Universidad Autónoma de Madrid
On the other hand, although epoxysulfones are versatile
Abstract: An efficient, stereoselective route to the a,b-epoxy-
sulfones using N-methylmorpholine N-oxide (NMO) as epoxidizing
reagent is described.
synthons, particularly in the presence of nucleophilic
reagents,8 the chemistry of strained a,b-epoxysulfones
such as 2 and 3 (Figure 2) remains almost unexplored9 de-
spite the rich functionality present in these compounds.
Key words: vinylsulfone, a,b-epoxysulfone, N-methylmorpholine
N-oxide, epoxidation
Usually these epoxysulfones have been synthesized by the
nucleophilic epoxidation of a,b-unsaturated sulfones with
t-BuOOLi, among other epoxidizing reagents.10
The oxa- and azanorbornenic vinylsulfones 1 (Figure 1)
are useful intermediates for the synthesis of substituted
cyclohexane and cyclohexene derivatives via regio- and
stereocontrolled ring-opening reactions.1
X
O
X
O
SO2Ar
SO2Ar
ArO2S
X
2a X = O
2b NR
2c CH2
3a X = O
3b NR
R2
1
X = O, NR
Figure 2
Figure 1
In the search for an alternative method, we speculate that
if the Michael addition described in Scheme 1 could be
carried out using a nucleophilic oxygen atom attached to
a good leaving group, the elimination step may occur on
this leaving group, thereby leaving the bicyclic skeleton
intact and allowing for the synthesis of epoxysulfones
such as 2 and 3 (Scheme 2).
In particular, the nucleophilic (Michael) addition of
organometallic reagents followed by b-elimination of the
resulting arylsulfonyl-stabilized carbanion occurs with
concomitant bridge opening2 (Scheme 1) due to the
strained character of the bicyclic system.
ArO2S
ArO2S
R1M
X
X
ArO2S
ArO2S
(Michael)
R2
R2
LG-O
R1
X
X
O
1
LG
β-elimination
ArO2S
R2
SO2Ar
R1
XM
X
O
Scheme 1
2, 3
This methodology has become a key step for the synthesis
of compounds such as 7-deoxypancratistatin,3 several
carbasugars,4 analogues of a ring of vitamin D3,5 poly-
propionate (stereotetrads) fragments6 and analogues of
conduramines.7
Scheme 2
Assuming the exo attack of the nucleophilic reagent on the
bicyclic system,11 the exo stereochemistry of the oxirane
functionality (endo-sulfone) remains secure. In this con-
text an amine oxide constitutes an excellent candidate for
testing this assumption.12 In this way, vinylsulfones 4–8
(Figure 3) were prepared13 and treated with N-methyl-
SYNLETT 2007, No. 12, pp 1948–1950
2
4
.0
7
.2
0
0
7
Advanced online publication: 25.06.2007
DOI: 10.1055/s-2007-984496; Art ID: G12807ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Strained a,b-Epoxysulfones via Epoxidation of Vinylsulfones
1949
ArO2S
References and Notes
ArO2S
X
X
(1) (a) Review: Arjona, O.; Plumet, J. Curr. Org. Chem. 2002,
6, 571. For other comprehensive reviews on the synthetic
applications of oxa- and azanorbornene derivatives, see:
(b) Vogel, P.; Cossy, J.; Plumet, J.; Arjona, O. Tetrahedron
1999, 55, 13521. (c) Vogel, P. Curr. Org. Chem. 2000, 65,
455. (d) Arjona, O.; Csáky, A. G.; Plumet, J. Eur. J. Org.
Chem. 2002, 611. (e) Medel, R.; Plumet, J. In Targets in
Heterocyclic Systems, Vol. 8; Attanasi, O. A.; Spinelli, D.,
Eds.; Società Chimica Italiana, 2004, 162–186. (f) Ishikura,
M.; Katagiri, N. Recent Res. Dev. Org. Chem. 2004, 8, 197.
(g) Robina, I.; Vogel, P. Synthesis 2005, 675. (h) Vogel, P.
In The Organic Chemistry of Sugars; Levy, D. E.; Fugedi,
P., Eds.; Taylor and Francis Group/CRC Press: Boca Ratón,
2006, Chap. 13, 629–725.
Ar = p-MeC6H4
4 X = O
5 X = NBoc
6 X = CH2
7 X = O
8 X = NBoc
Figure 3
Table 1 Synthesis of Oxa- and Azanorbornenic Epoxysulfones by
Reaction of Oxa- and Azanorbornenic Vinylsulfones with NMO14
Entry Starting material Epoxysulfone
Isolated yield (%)
1
2
3
4
5
4 (X = O)
2a
2b
2c
3a
3b
76
88
50
65
95
(2) Arjona, O.; de Dios, A.; de la Pradilla, R. F.; Plumet, J.;
Viso, A. J. Org. Chem. 1994, 59, 3906.
5 (X = NBoc)
6 (X = CH2)
7 (X = O)
(3) Arjona, O.; León, M. L.; Plumet, J. Org. Lett. 2000, 2, 3683.
(4) (a) Arjona, O.; Borrallo, C.; Iradier, F.; Medel, R.
Tetrahedron Lett. 1998, 39, 1977. (b) Arjona, O.; Iradier,
F.; Medel, R.; Plumet, J. Tetrahedron: Asymmetry 1999, 10,
3431. (c) Arjona, O.; Lorenzo, G.; Medel, R.; Plumet, J.
Tetrahedron Lett. 2001, 42, 7041.
8 (X = NBoc)
(5) Arjona, O.; Iradier, F.; Plumet, J.; Martínez-Alcázar, M. P.;
Hernández-Cano, F.; Fonseca, I. Tetrahedron Lett. 1998, 39,
8335.
(6) Arjona, O.; Menchaca, R.; Plumet, J. J. Org. Chem. 2001,
66, 2400.
morpholine N-oxide (NMO) in CH2Cl2 at r.t. for 24 hours,
affording the expected epoxysulfones 2a–c and 3a,b in
convenient yields (Table 1).
(7) Leung-Toung, R.; Liu, Y.; Muchowski, J. M.; Wu, Y. L.
J. Org. Chem. 1998, 63, 3235.
It is worth mentioning that:
(8) (a) Simpkins, N. L. In Sulfones in Organic Synthesis,
Tetrahedron Organic Chemistry Series; Pergamon Press:
Oxford, 1993. For some more recent references, see:
(b) Diez, D.; Beneitez, M. T.; Marcos, I. S.; Garrido, N. M.;
Basabe, P.; Sanz, F.; Broughton, H. B.; Urones, J. G. Org.
Lett. 2003, 5, 4361. (c) Diez, D.; Beneitez, M. T.; Gil, M. J.;
Moro, R. F.; Marcos, I. S.; Garrido, N. M.; Basabe, P.;
Urones, J. G. Synthesis 2005, 565.
a) The success of the reaction is strongly dependent on the
nature of the amine oxide used. Thus, whereas pyridine N-
oxide did not react with compounds 4–8, the reactivity of
trimethylamine N-oxide (TMAO) was similar to NMO.
For instance, compound 4, upon reaction with TMAO
(CH2Cl2, r.t., 24 h), gave the epoxysulfone 2a in 35%
isolated yield.
(9) For some synthetically useful transformations of this kind of
compound, see: (a) Arjona, O.; Menchaca, R.; Plumet, J.
Tetrahedron 2000, 56, 3901. (b) Hodgson, D. M.; Maxwell,
C. R.; Wisedate, R.; Matthews, I. R.; Carpenter, K. J.;
Dickenson, A. H.; Wonnacott, S. J. Chem. Soc., Perkin
Trans. 1 2001, 3150.
b) Only the strained vinylsulfones reacted under the de-
scribed conditions giving the expected epoxysulfones.
Compounds such as phenylvinylsulfone or cyclohexenyl-
sulfone were recovered unchanged after reaction with
NMO even under reflux of CH2Cl2.
(10) (a) Simpkins, N. L. In Sulfones in Organic Synthesis,
Tetrahedron Organic Chemistry Series; Pergamon Press:
Oxford, 1993, 55–58. (b) interestingly, epoxidation of
sulfone 14 with MCPBA (CH2Cl2, 20 °C, 4 h) provides the
exo-epoxide 15 without the formation of Baeyer–Villiger
oxidation product (Scheme 3). See: Prakash Rao, H. S.;
Murali, R.; Taticchi, A.; Scheeren, H. W. Eur. J. Org. Chem.
2001, 2869.
In summary, in this report a new, safe, and clean method
for the synthesis of strained epoxysulfones from the relat-
ed a,b-unsaturated sulfones has been described. Further
application of the procedure to other electron-deficient
strained alkenes is now under exploration.
Acknowledgment
O
O
Ministerio de Educación y Ciencia (Project CTQ2006-15279-C03-
01) is gratefully thanked for financial support. One of us (AA)
thanks Ministerio de Educación y Ciencia for a Grant.
O
O
O
PhO2S
SO2Ph
14
15
Scheme 3
(11) The exo selectivity in the nucleophilic additions and
cycloadditions of the bicyclo[2.2.1]heptene double bond is a
characteristic behavior of these compounds. For a
comprehensive discussion, see: Huisgen, R. Pure Appl.
Chem. 1981, 53, 171; see in particular p. 181 and following.
Synlett 2007, No. 12, 1948–1950 © Thieme Stuttgart · New York

1950
R. Rincón et al.
LETTER
(12) Four isolated cases regarding the epoxidation reaction of
a,b-unsaturated esters 16 with an amine oxide (NMO) to
give endo-epoxides 17 (Scheme 4) have been previously
described. See: Andres, C. J.; Spetseris, N.; Norton, J. R.;
Meyers, A. J. Tetrahedron Lett. 1995, 36, 1613.
concerning the application of the ‘tetrazine method’ to the
synthesis of bicyclic a,b-unsaturated sulfones. Full details of
the procedure will be reported in due course or upon
request. (e) For the generation of isobenzofuran, see:
Warrener, R. N. J. Am. Chem. Soc. 1971, 93, 2346. (f) For
the generation of N-Boc isoindole, see: Priestly, G. M.;
Warrener, R. N. Tetrahedron Lett. 1972, 4295.
R1
R1
O
O
O
O
O
1.5 equiv NMO
CH2Cl2
Py
OR2
N
OR2
N
Ph
N
N
N
N
Ph
O
O
X
X
16
17
Py
R1 = Ph, Me
R2 = Me, Bu, t-Bu
22 X = O
23 X = N-Boc
20 X = O
21 X = N-Boc
19
Scheme 4
SO2Tol
(13) Compounds 4 and 5 were synthesized by cycloaddition
reaction of p-toluenesulfonylacetylene with furan and N-Boc
pyrrole, respectively: (a) Compound 4: Arjona, O.; Iradier,
F.; Medel, R.; Plumet, J. Heterocycles 1999, 50, 653. (b)
Compound 5: Altenbach, H. J.; Blech, B.; Marco, J. A.;
Vogel, E. Angew. Chem., Int. Ed. Engl. 1982, 21, 778.
(c) See also: Chen, Z.; Trudell, M. L. Tetrahedron Lett.
1994, 35, 9649. (d) In the same fashion, cycloaddition of
cyclopentadiene and p-toluenesulfonylacetylene gave 6 in
99% isolated yield. Compound 7 (30% isolated yield) was
prepared by trapping of isobenzofuran 22 [generated by
reaction of 3,6-di(2¢-pyridyl)-5-tetrazine(19) with 1,4-
dihydro-1,4-endoxynaphthalene (20)] with p-toluene-
sulfonylacetylene (Scheme 5). Analogous generation and
trapping of N-Boc isoindole 23 gave compound 8 (62%).
To the best of over knowledge these are the first cases
SO2Tol
X
7 X = O, 30%
8 X = N-Boc, 62%
Scheme 5
(14) Typical Experimental Procedure: To a solution of
compounds 4–8 (0.43 mmol) in anhyd CH2Cl2 (6 mL), NMO
(0.86 mmol) was added in one portion under argon at 0 °C.
The mixture was allowed to react at r.t. during 24 h. After
this time the solvent was removed under reduced pressure
and the residual material was purified by column
chromatography (hexane–EtOAc, 4:1).
Synlett 2007, No. 12, 1948–1950 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.