Cyclizations and cycloadditions of acetylenic sulfones on solid supports

Article abstract of DOI:10.1039/b512016k

Acetylenic sulfones attached to solid supports by means of ester linkers were employed in a variety of cyclization and cycloaddition reactions, followed by cleavage of the products from the resin by ester hydrolysis or reductive desulfonylation. The Royal

Full text of DOI:10.1039/b512016k

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Cyclizations and cycloadditions of acetylenic sulfones on solid
supports{
Thomas G. Back* and Huimin Zhai
Received (in Cambridge, UK) 24th August 2005, Accepted 2nd November 2005
First published as an Advance Article on the web 30th November 2005
DOI: 10.1039/b512016k
without the need to purify products at each stage. The preparation
of libraries of biologically, or otherwise interesting compounds can
be facilitated by conducting various combinations of reactions on
solid-supported starting materials. To date, for example, b-ben-
zoyloxyalkyl and c-hydroxyalkyl sulfones anchored to solid
supports have been employed in Julia–Lythgoe olefinations8a
and in the preparation of trisubstituted 2-pyridones,8b while
supported vinyl sulfones have been converted into libraries of
tetrahydro-b-carbolines9a or tertiary amines,9b and into peptides
used as probes of cysteine proteases.10 We now report the
preparation of the first acetylenic sulfones attached to solid
supports, along with several types of subsequent transformation
that illustrate their potential synthetic utility.
Acetylenic sulfones attached to solid supports by means of ester
linkers were employed in variety of cyclization and
a
cycloaddition reactions, followed by cleavage of the products
from the resin by ester hydrolysis or reductive desulfonylation.
The electron-withdrawing sulfone moiety1 activates adjacent
double and triple bonds2 toward conjugate additions, and
stabilizes the corresponding a-anions, which can then react with
various electrophiles. Thus, when conjugate addition and intra-
molecular a-alkylation3 or acylation4 are employed in tandem, a
sulfone-mediated cyclization protocol ensues. This approach has
been employed in the synthesis of several alkaloids and related
species.5 Vinyl and acetylenic sulfones also undergo a variety of
Diels–Alder and 1,3-dipolar cycloadditions.1,2 Finally, the sulfone
moiety can either be retained in the cyclized product, where it
serves as a useful functional group for further transformations, or
it can be cleaved by appropriate reductive desulfonylation
methods.6 These processes are illustrated in Scheme 1, where the
unsaturated sulfone functions as the synthetic equivalent of
hypothetical alkane and alkene dipole species.
Acetylenic sulfones can be easily prepared by the free radical
selenosulfonation of acetylenes, followed by selenoxide syn-
elimination (Scheme 2),11 as well as by other methods.2a
Our first approach to attaching an acetylenic sulfone to a
polymer support is shown in Scheme 3. The commercially
available
[4-(hydrazinosulfonyl)phenyl]propionyl
resin
1
(Novabiochem Inc.) was converted to selenosulfonate 2,12 followed
by free radical addition to 1-hexyne. Diphenyl diselenide was
added to the mixture to facilitate the chain transfer step of the
phenylseleno group to the intermediate b-sulfonylvinyl radical,
thereby affording 3. Selenoxide elimination then produced the
desired acetylenic sulfone 4, confirmed by a strong IR absorption
The immobilization of reagents and starting materials on solid
supports has become increasingly popular in organic synthesis.7
Advantages typically include simplified work-ups, cleaner reactions
and the possibility of conducting sequential transformations
at 2194 cm21 13
Unfortunately, several efforts to perform
.
cyclizations with 4 provided low yields of relatively impure
products when attempts were made to cleave the latter from the
support by reductive desulfonylation.
An alternative method was therefore developed, in which a
series of acetylenic sulfones were attached to the solid support
via an ester linker. Thus, the selenosulfonation of three
representative acetylenes with 6, which was in turn prepared from
sulfonhydrazide 5, afforded adducts 7a–7c. Esterification of resin
Scheme 1 Reactions of unsaturated sulfones.
Department of Chemistry, University of Calgary, Calgary, AB, Canada
T2N 1N4. E-mail: tgback@ucalgary.ca; Fax: (403) 289-9488;
Tel: (403) 220-6256
{ Electronic Supplementary Information (ESI) available: Procedures and
characterization data for products. See DOI: 10.1039/b512016k
Scheme 2 Preparation of acetylenic sulfones by selenosulfonation.
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326 | Chem. Commun., 2006, 326–328

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Scheme 5 Preparation of ester-linked acetylenic sulfones on solid
supports from a sulfonhydrazide.
A third approach consisted of introducing the selenosulfonate
moiety to the resin via the sulfonhydrazide 10,13 as shown in
Scheme 5, followed by addition to the appropriate acetylene and
selenoxide elimination. This method has the advantage that
a single polymer-supported selenosulfonate can be used to
generate an array of supported acetylenic sulfones 9, making it
more attractive for the eventual production of libraries of
cyclization products when used in conjunction with subsequent
transformations (vide infra).
Scheme 3 Conversion of a sulfonhydrazide to an acetylenic sulfone on a
solid support.
814 with 7a–7c produced the desired products 9a–9c, respectively.
Desilylation of 9c afforded the corresponding terminal acetylene
9d (Scheme 4).13
Resins 9a, 9b and 9d were then subjected to a variety of
illustrative cyclization and cycloaddition reactions with chloro-
amines 1115 and 12,16 cyclopentadiene (13) and nitrile N-oxide
14.17 The results are summarized in Scheme 6.
Cyclization via conjugate addition of chloroamines 11 and 12,
followed by base-mediated intramolecular alkylation and cleavage
from the resin with lithium hydroxide afforded 15 and 17,
respectively. The Diels–Alder reactions of the supported acetylenic
sulfones with 13 and their dipolar cycloadditions with 14 were also
successful, affording cycloadducts 19 and 21, respectively, after
similar cleavage from the support. Alternatively, enamine reduc-
tion with sodium cyanoborohydride, followed by reductive
cleavage from the support with 5% sodium amalgam, afforded
the corresponding desulfonylated products 16 and 18. Similarly,
reductive desulfonylation of the cycloadduct obtained from 13 and
9b afforded 20b, while that of the cycloadduct derived from nitrile
oxide 14 and 9b was accompanied by N–O cleavage to provide
Scheme 4 Preparation of acetylenic sulfones on solid supports using an
ester linker.
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Notes and references
1 For a general review of sulfones, see: N. S. Simpkins, in Sulfones in
Organic Synthesis, Pergamon Press, Oxford, 1993.
2 (a) For a review of acetylenic and allenic sulfones, see: T. G. Back,
Tetrahedron, 2001, 57, 5263; (b) For vinyl sulfones, see: N. S.
Simpkins, Tetrahedron, 1990, 46, 6951; (c) For dienyl sulfones, see:
J.-E. Ba¨ckvall, R. Chinchilla, C. Na´jera and M. Yus, Chem. Rev., 1998,
98, 2291.
3 (a) T. G. Back and K. Nakajima, Org. Lett., 1999, 1, 261; (b) T. G. Back
and K. Nakajima, J. Org. Chem., 2000, 65, 4543.
4 (a) T. G. Back and K. Nakajima, J. Org. Chem., 1998, 63, 6566; (b)
T. G. Back, M. Parvez and J. E. Wulff, J. Org. Chem., 2003, 68, 2223;
(c) T. G. Back, M. D. Hamilton, V. J. J. Lim and M. Parvez, J. Org.
Chem., 2005, 70, 967.
5 These include (2)-pumiliotoxin C,4a indolizidines (2)-167B, (2)-209D,
(2)-209B and (2)-207A,3b alkaloids from the medicinal plant Ruta
chalepensis,4b (-)-lasubine II4c and (¡)-myrtine4c.
6 C. Na´jera and M. Yus, Tetrahedron, 1999, 55, 10547.
7 For selected recent reviews, see: Solid-Phase Organic Syntheses, ed.
A. W. Czarnik, Wiley, New York, 2001, vol. 1; F. Z. Do¨rwald, Organic
Synthesis on Solid Phase: Supports, Linkers, Reactions, Wiley-VCH,
Weinheim, 2nd edn, 2002; S. E. Booth, C. M. Dreef-Tromp, P. H.
H. Hermkens, J. A. P. A. de Man and H. C. J. Ottenheijm, in
Combinatorial Chemistry, ed. G. Jung, Wiley-VCH, Weinheim, 1999,
pp. 35–76; Handbook of Combinatorial Chemistry, ed. K. C. Nicolaou,
R. Hanko and W. Hartwig, Wiley-VCH, Weinheim, 2002, vol. 1–2;
S. V. Ley, I. R. Baxendale, R. N. Bream, P. S. Jackson, A. G. Leach,
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J. Chem. Soc., Perkin Trans. 1, 2000, 3815; S. J. Shuttleworth, S. M. Allin
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8 (a) J. N. P. D’herde and P. J. De Clercq, Tetrahedron Lett., 2003, 44,
6657; (b) W. Li, Y. Chen and Y. Lam, Tetrahedron Lett., 2004, 45, 6545.
9 (a) R. V. Connors, A. J. Zhang and S. J. Shuttleworth, Tetrahedron
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11 T. G. Back, S. Collins and R. G. Kerr, J. Org. Chem., 1983, 48, 3077;
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For a review, see: T. G. Back, in Organoselenium Chemistry – A
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1999, pp. 175–178.
Scheme 6 Cyclization and cycloadditions of acetylenic sulfones on solid
supports.
12 Selenosulfonates attached to a polystyrene support via their selenium
atoms have been recently reported: H. Qian and X. Huang, Tetrahedron
Lett., 2002, 43, 1059.
22b. Products 21 and 22 were obtained as single regioisomers. The
purities of the isolated products were typically >90%, and in many
cases >95% (NMR analysis), without further purification. The
exceptions were 15d, 17d and 22b, where the purities of the crude
products were ,90%, and the corresponding yields are reported
for products isolated by flash chromatography.
13 The loading in 4 and 9a was determined gravimetrically. The loading in
9b and 9d was determined by hydrolysis of the ester linkers with LiOH
and isolation of 1-[(para-hydroxymethyl)benzenesulfonyl]-2-phenyl-
ethyne and (para-hydroxymethyl)phenyl methyl sulfone (formed by
cleavage of the corresponding b-keto sulfone), respectively. The loading
of 8 was determined gravimetrically by conversion into the correspond-
ing cesium carboxylate. The loading of 10 was determined by elemental
analysis for nitrogen.
14 The supported carboxylic acid 8 was prepared from Merrifield resin by
the method of: X. Beebe, N. E. Schore and M. J. Kurth, J. Org. Chem.,
1995, 60, 4196. The esterification of 8 was performed by the general
method of: G. A. Morales, J. W. Corbett and W. F. DeGrado, J. Org.
Chem., 1998, 63, 1172.
In conclusion, we have demonstrated that acetylenic sulfones
can be anchored either directly, or via an ester linker, to
appropriate solid supports. The latter species then undergo a
variety of useful cyclization or cycloaddition reactions, and the
resulting products can be isolated by cleavage from the resin via
ester hydrolysis or reduction with sodium amalgam to afford the
corresponding sulfone-functionalized or desulfonylated products,
respectively.
15 J. Heider, M. Psiorz, A. Bomhard, N. Hauel, B. Narr, K. Noll, C. Lillie,
W. Kobinger and J. Daemmgen, Eur. Pat. EP 292840, 1988.
16 T. R. Norton, R. A. Seibert, A. A. Benson and F. W. Bergstrom, J. Am.
Chem. Soc., 1946, 68, 1572.
We thank Merck Frosst (Canada) Ltd. and the Natural Sciences
and Engineering Research Council of Canada for financial support.
17 C. Grundmann and R. Richter, J. Org. Chem., 1968, 33, 476.
328 | Chem. Commun., 2006, 326–328
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