β-Acyloxysulfonyl tethers for intramolecular Diels-Alder cycloaddition reactions

Article abstract of DOI:10.1021/ol050930t

(Chemical Equation Presented) β-Hydroxy sulfone-based tethers were employed for the first time to achieve thermally mediated intramolecular Diels-Alder cycloaddition. The reactions proceeded with complete regioselectivity and high (10/1) to complete endo/

Full text of DOI:10.1021/ol050930t

ORGANIC
LETTERS
2005
Vol. 7, No. 15
3203-3206
â
-Acyloxysulfonyl Tethers for
Intramolecular Diels
Reactions
−Alder Cycloaddition
Nataliya Chumachenko,*,† Paul Sampson,*,† Allen D. Hunter,‡ and Matthias Zeller‡
Department of Chemistry, Kent State UniVersity, Kent, Ohio 44242, and
Department of Chemistry, Youngstown State UniVersity, One UniVersity Plaza,
Youngstown, Ohio 44555
psampson@kent.edu
Received April 26, 2005
ABSTRACT
â
-Hydroxy sulfone-based tethers were employed for the first time to achieve thermally mediated intramolecular Diels−Alder cycloaddition. The
reactions proceeded with complete regioselectivity and high (10/1) to complete endo/exo-selectivity and resulted in the preferential formation
of one of the two possible endo-cycloadducts. The yields and stereoselectivities were proportional to the bulk of the R1 substituent on the
â
-acyloxysulfonyl tether.
It is known that temporary tethers can be used to control
the regio- and stereoselectivity in Diels-Alder cycloaddition
reactions.1 However, to the best of our knowledge, only two
types of tethers based on sulfur-containing functional groups
have been reported, involving the use of sulfonate esters2
and sulfonamides.3 On the other hand, the intermolecular
Diels-Alder reactivity of sulfonyl-substituted dienes and
dienophiles has been studied. 1-Sulfonyl-1,3-dienes (the data
are scarce and restricted to cyclic dienes)4-6 and 2-sulfonyl-
1,3-dienes7-13 are prone to self-dimerization4,8-10 through
Diels-Alder reactions. They also undergo highly regiose-
lective cycloaddition with electron-rich5,9-11 dienophiles and
less regioselective reactions with electron-deficient6,9,10,12,13
(6) Miller, J. A.; Ullah, G. M. J. Chem. Res. (Miniprint) 1988, 2737.
(7) Synthesis of 2-sulfonyl-1,3-dienes: (a) Andell, O. S.; Ba¨ckvall, J.-
E. Tetrahedron Lett. 1985, 26, 4555. (b) Ba¨ckvall, J.-E.; Juntunen, S. K.;
Andell, O. S. Org. Synth. 1990, 68, 148. (c) Ba¨ckvall, J.-E.; Na´jera, C.;
Yus, M. Tetrahedron Lett. 1988, 29, 1445. See also refs 8-10, 12, and 13.
(8) (a) Chou, T.-S.; Hung, S. C.; Tso, H.-H. J. Org. Chem. 1987, 52,
3394. (b) Hoffmann, H. M. R.; Weichert, A.; Slawin, A. M. Z.; Williams,
D. J. Tetrahedron 1990, 46, 5591.
† Kent State University.
‡ Youngstown State University (X-ray crystallography).
(1) Gauthier, D. R.; Zandi, K. S.; Shea, K. J. Tetrahedron 1998, 54,
2289.
(9) (a) Inomata, K.; Kinoshita, H.; Takemoto, H.; Murata, Y.; Kotake,
H. Bull. Chem. Soc. Jpn. 1978, 51, 3341. (b) Chou, T.-S.; Hung, S.-C. J.
Org. Chem. 1988, 53, 3020.
(2) (a) Metz, P.; Fleischer, M.; Fro¨hlich, R. Tetrahedron 1995, 51, 711.
(b) Plietker, B.; Seng, D.; Fro¨hlich, R.; Metz, P. Tetrahedron 2000, 56,
873-879.
(3) Brosius, A. D.; Overman, L. E.; Schwink, L. J. Am. Chem. Soc. 1999,
121, 700.
(10) Ba¨ckvall, J.-E.; Juntunen, S. K. J. Am. Chem. Soc. 1987, 109, 6396.
(11) (a) Ba¨ckvall, J.-E.; Plobeck, N. A.; Juntunen, S. K. Tetrahedron
Lett. 1989, 30, 2589. (b) Barnwell, N.; Beddoes, R. L.; Mitchell, M. B.;
Joule, J. A. Heterocycles 1994, 37, 175. (c) Ba¨ckvall, J.-E.; Rise, F.
Tetrahedron Lett. 1989, 30, 5347.
(4) (a) Hartke, K.; Gleim, H.-U. Liebigs Ann. Chem. 1976, 716. (b)
Hartke, K.; Jung, M. H.; Zerbe, H.; Ka¨mpchen, T. Arch. Pharm. (Weinheim,
Ger.) 1986, 319, 890. (c) Bridges, A. J.; Fischer, J. W. J. Chem. Soc., Perkin
Trans. 1 1983, 2359.
(5) (a) Posner, G. H.; Wettlaufer D. G. Tetrahedron Lett. 1986, 27, 667.
(b) Posner, G. H.; Switzer, C. J. Org. Chem. 1987, 52, 1642. (c) Posner,
G. H.; Kinter, C. M. J. Org. Chem. 1990, 55, 3967.
(12) (a) Cuvigny, T.; Du Penhoat, C. H.; Julia, M. Tetrahedron 1986,
42, 5329. (b) Chou, S.-S. P.; Chao, M.-H. J. Chin. Chem. Soc. 1996, 43,
53. (c) de la Pradilla, R. F.; Montero, C.; Viso, A. Chem. Commun. 1998,
409.
(13) (a) Chou, S.-S. P.; Sun, D.-J. J. Chem. Soc., Chem. Commun. 1988,
1176. (b) Back, T. G.; Lai, E. K. Y.; Muralidharan, K. R. J. Org. Chem.
1990, 55, 4595.
10.1021/ol050930t CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/24/2005

alkenes. If a 2-sulfonyl-1,3-diene bears an electron-donating
group at C-3, the regioselectivity of the cycloaddition with
R,â-unsaturated carbonyl compounds is increased in the
presence of Lewis acids.13 However, this is not the case for
nonsubstituted 2-sulfonyl butadienes.10 Connecting a sulfone-
bearing diene and an electron-deficient dienophile by a tether
bearing a stereogenic center might be expected not only to
improve the regioselectivity but also to cause the cycload-
dition to proceed in a diastereoselective manner. The
presence of a sulfone group in the final cycloadduct provides
various possibilities for further transformations. We have
begun to explore the potential utility of sulfone-based tethers
for cycloaddition reactions and present here our preliminary
results.14
produce the corresponding (Z)-â-hydroxy sulfones 7 and 8.
DMAP-mediated isomerization required longer times than
were employed for the preparation of sulfones 3 and 4 but
still provided quantitative yields of the corresponding (E)-
â-hydroxy sulfones 9 and 10 (Scheme 2).
Scheme 2
We considered the (Z)-butadienyl sulfinate anion, readily
available from butadiene sulfone (1),15 as an attractive
building block to prepare 1-sulfonyl-1,3-dienes. We found16
that Zn (Z)-sulfinate 2a, freshly prepared from the corre-
sponding Li (Z)-sulfinate in aqueous medium, reacted with
ethylene oxide or propylene oxide regioselectively to produce
the corresponding â-hydroxy sulfones as (E)-/(Z)-mixtures.
Isomerization to the (E)-stereoisomers occurred readily in
the presence of DMAP to give cleanly (E)-butadienyl
â-hydroxy sulfones 3 and 4 in 30% isolated yield from 1
(Scheme 1).
The esterification of (E)-â-(dienesulfonyl) alcohols 3, 4,
9, and 10 with methacrylic acid (11) and acrylic acid (12)
proceeded in good yield using conventional DCC/DMAP
methods to afford the corresponding acrylate esters 14a-f,i
(Scheme 3, Table 1, method A). No alcohol decomposition
Scheme 1
Table 1. Esterification of (E)-â-(Dienylsulfonyl) Alcohols 3, 4,
9, and 10 to Afford Acrylate Esters 14a-i
product
R1
R2
methoda
yield (%)b
14a
14b
14c
14d
14e
14f
14g
14h
14i
H
Me
Me
Me
Me
H
A
A
A
A
A
A
A
B
A
85
93
81
50c
83
Me
Ph
t-Bu
Me
Ph
Me
Ph
H
As an alternative approach to â-hydroxy sulfone tethers,
we attempted to employ R-halo ketones as electrophiles to
trap the (Z)-butadienyl sulfinate anion. However, Zn, Li, or
K butadienyl sulfinates, freshly prepared from 1 in THF,
failed to react with R-bromo ketones, which were recovered
unreacted. Bouchez and Vogel reported17 that allyl or
â-carboxyalkyl sulfinate anions, produced in situ from the
corresponding silyl sulfinates, reacted with R-bromo esters
to generate the corresponding sulfones. To our delight, this
approach worked well for the reaction of (Z)-butadienyl silyl
sulfinate 2b with R-bromo ketones to furnish (Z)-â-oxo
sulfones 5 and 6, which were reduced in high yield to
H
81
Br
Br
H
28c
47c (59d)
85
a A: DCC, DMAP, CH2Cl2, rt. B: 2,4,6-Trichlorobenzoyl chloride, Et3N,
LiCl, THF, rt. b Isolated yields after purification by silica chromatography.
c Nonoptimized yields. d Based on consumed â-hydroxy sulfone.
was observed under the reaction conditions. Not surpris-
ingly,18 esterification using R-bromoacrylic acid (13) was
(14) Chumachenko, N.; Sampson, P. Abstracts of Papers, 228th National
Meeting of the American Chemical Society, Philadelphia, PA, August 22-
26, 2004; American Chemical Society: Washington, DC, 2004; ORGN 621.
(15) (a) Polunin, E. V.; Zaks, I. M.; Moiseenkov, A. M.; Semenovskii,
A. V. IzVestiya Akademii Nauk SSSR, Ser. Khim. 1979, 3, 641. (b) Krug,
R. C.; Rigney, J. A.; Tichelaar, G. R. J. Org. Chem. 1962, 27, 1305. (c)
Crumbie, R. L.; Ridley, D. D. Aust. J. Chem. 1981, 34, 1017.
(16) Chumachenko, N.; Sampson, P. Submitted.
(18) To the best of our knowledge, no examples of esterification of
R-bromoacrylic acid (13) using an alcohol have been reported. Esterification
to afford a phenyl ester (10% yield) was reported in one case: Schmidt,
A.; Bach, E.; Schollmeyer, E. Dyes Pigments 2003, 56, 27. Three esters of
13 have been prepared via carboxylate alkylation using (a) benzyl bromide
[Osborne, N. F. J. Chem. Soc., Perkin Trans. 1 1980, 150], (b) allyl bromide
[Bhat, L.; Steinig, A. G.; Appelbe, R.; de Meijere A,. Eur. J. Org. Chem.
2001, 9, 1673], and (c) epichlorohydrin [Mukhitdinova, N. A.; Khodzhaeva,
F.; Askarov, M. A. Dokl. Akad. Nauk UzSSR 1977, 39 (CA 87 134867)].
(17) Bouchez, L.; Vogel, P. Synthesis 2002, 225.
3204
Org. Lett., Vol. 7, No. 15, 2005

Scheme 3
problematic. The best yield to date was achieved when
cycloadducts 16g,h underwent partial dehydrobromination
on exposure to silica to afford the corresponding dienes
18g,h. In the case of 16g, we were able to obtain a sample
of diastereomerically pure material from the silica column;
however, the dehydrobromination of 16h was too fast to
permit its isolation. The presence and relative amount of 16h,
as well as the exo-products 17b,c (derived from methacrylic
acid (11)) and 17g,h (derived from 2-bromoacrylic acid (13)),
were tentatively determined on the basis of the integration
alcohol 9 was treated with the mixed anhydride derived from
R-bromoacrylic acid (13) and 2,4,6-trichlorobenzoyl chloride
in the presence of LiCl and triethylamine (Scheme 3, Table
1, method B).
Thermally mediated intramolecular Diels-Alder cycload-
dition (IMDA) reaction of 14a-h (Scheme 3, Table 2)
1
of H4a in the H NMR of the crude reaction mixtures. The
Table 2. Diels-Alder Cycloaddition Reactions of 14a-h
absence of the formation of exo-products 17e,f in the Diels-
Alder cycloaddition of acrylate substrates 14e,f might have
been expected, while the high endo/exo-selectivity observed
for methacrylate substrates 14a-d, as well as bromoacrylate
substrates 14g,h, was a pleasant surprise. It is well-
documented that dienophiles derived from methacrylic acid
(11) give poor stereoselectivity in Diels-Alder reactions and
often show a proclivity to undergo exo-cycloaddition.19,20
The relative stereochemistry of the major endo-cycload-
ducts 15a,b,g and minor endo-cycloadduct 16g were con-
firmed by their X-ray crystal structures.21 The relative
stereochemistry of the remaining endo-cycloadducts was
T
time
(h)
ratio of
yield of 15a-h
entry compd (°C)
15/16/17/14a
(%)
1
2
3
4
5
6
7
8
9
14a
14b
14b
14c
14c
14d
14e
14f
130 29.5 100/- - -/33/20
128 32.5 100/25/12/22
42 of 15a + 17a
47 of 15b + 16b
36
49
49
65
140 41
138 28
145 50
138 47
130 43
127 43
115 21
127 21
100/25/12/- - -
100/25/10/20
100/25/10/- - -
100/4/12/- - -
100/30/- - -/- - - 54 + 18 of 16e
100/25/- - -/23
100/27/9/- - -b
100/12/8/- - -b
57 + 16 of 16f
58
63
14g
14h
10
1
established by NOE experiments and H NMR analysis.
a Determined from 1H NMR analysis of the crude reaction mixtures.
b Ratio can only be estimated because 16 and 17 are unstable.
We observed that increasing the bulk of the substituent
R1 on the tether backbone is beneficial for avoiding side
reactions during the IMDA reaction. The nonsubstituted
substrate 14i, derived from acrylic acid (12), failed to give
any intramolecular cycloaddition product and was completely
polymerized on heating (120 °C) in toluene. Large amounts
of polymerization byproducts were produced in IMDA
reactions of the other nonsubstituted (14a) and Me-
substituted (14b,e,g) substrates, while for Ph- (14c,f) and
t-Bu-substituted (14d) substrates, no significant tar formation
was observed during the IMDA reaction.
occurred with complete regioselectivity and high (10/1) to
complete endo/exo-selectivity (except when R1 ) H (14a))
and resulted in the preferential formation of one of the two
possible endo-cycloadducts. For substrates 14a-d, derived
from methacrylic acid (11), the major endo-cycloadducts
15a-d were separated as single diastereomers after crystal-
lization, while the minor exo-cycloadducts 17a,d and endo-
cycloadducts 16b-d were characterized by 1H and 13C NMR
analysis of the residual mother liquors. For cycloadditions
involving the substrates 14e,f, derived from acrylic acid (12),
both the major endo-cycloadducts 15e,f and the minor endo-
cycloadducts 16e,f were cleanly separated as single diaster-
eomers by column chromatography. For cycloadditions
involving substrates 14g,h, derived from 2-bromoacrylic acid
(13), the major endo-cycloadducts 15g,h were purified by
silica chromatography. Unfortunately, the minor endo-
(19) Saito, A.; Ito, H.; Taguchi, T. Org. Lett. 2002, 4, 4619.
(20) (a) Evans, D. A.; Chapman, K. T.; Bisaha, J. J. Am. Chem. Soc.
1988, 110, 1238. (b) Hayashi, Y.; Nakamura, M.; Nakao, S.; Inoue, T.;
Shoji, M. Angew. Chem., Int. Ed. 2002, 41, 4079.
(21) (a) Zeller, M.; Hunter, A. D.; Sampson, P.; Chumachenko, N. Acta
Crystallogr. 2004, E60, o731. (b) Zeller, M.; Hunter, A. D.; Sampson, P.;
Chumachenko, N. Acta Crystallogr. 2004, E60, o729. (c) Zeller, M.; Hunter,
A. D.; Sampson, P.; Chumachenko, N. Acta Crystallogr. 2004, E60, o727.
(d) Zeller, M.; Hunter, A. D.; Sampson, P.; Chumachenko, N. Acta
Crystallogr. 2004, E60, o724.
Org. Lett., Vol. 7, No. 15, 2005
3205

The endo-major (15)/endo-minor (16) diastereoselectivity
in IMDA reactions involving Me- (14b,e,g) and Ph-
substituted (14c,f) substrates was comparable (∼4/1), while
for t-Bu-substituted substrate 14d, the diastereoselectivity
was improved to ∼25/1.
endo/exo-Diastereoselectivity was significantly increased
(from 3/1 to 10/1) on introducing a substituent R1 (Me) in
place of a hydrogen atom on the tether backbone (Table 2,
compare entries 1 and 2). Interestingly, it remained the same
(∼9/1 to ∼14/1) on changing R1 from a relatively small Me
group to the larger Ph and t-Bu substituents (see Table 2,
entries 2-6, 9, and 10).
The cycloaddition of R-bromoacrylate substrates 14g,h
proceeded faster than for the analogous methacrylate (14b,c)
and acrylate substrates (14e,f) and required ∼10 °C lower
reaction temperatures.
Figure 1. Proposed transition state for Diels-Alder cycloaddition
of 14b-h.
lective formation of the corresponding endo-IMDA cycload-
ducts. Our current efforts are directed toward the synthesis
of enantiomerically pure cycloadducts and exploring their
synthetic utility. Our results along these lines will be reported
in due course.
Furthermore, the fact that the acrylate substrate 14i failed
to give any IMDA reaction products, while the corresponding
methacrylate derivative 14a was converted into IMDA
products in 42% yield, contradicts the conventional wisdom
that normal-electron demand Diels-Alder reactions of meth-
acrylate dienophiles are usually more difficult than for the
corresponding acrylate substrates.19,20
Acknowledgment. We thank Kent State University for
financial support and Yehor Novikov for valuable discus-
sions. M.Z. was supported by NSF Grant 0111511, and the
diffractometer was funded by NSF Grant 0087210, by Ohio
Board of Regents Grant CAP-491, and by Youngstown State
University.
We propose a transition state for the above cycloaddition
reactions (Figure 1) in which (i) steric interactions between
R1 and the carbonyl group and (ii) the stereoelectronically
preferred s-trans ester conformation19 are responsible for the
observed diastereoselectivity.
In conclusion, the linkage of 1-sulfonyl-1,3-butadiene and
various acrylate dienophiles by a two-carbon tether bearing
a large Ph or t-Bu substituent allowed efficient diastereose-
Supporting Information Available: Full experimental
procedures and spectroscopic data for compounds 3-10, 14-
17, and 18g, along with copies of 1H and 13C NMR spectra
of major cycloadducts 15a-h, minor cycloadducts 16e,f, and
mixtures 17a/15a and 16/15(b,c,g). This material is available
free of charge via the Internet at http://pubs.acs.org.
OL050930T
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Org. Lett., Vol. 7, No. 15, 2005