One-pot synthesis of (Z)-β-sulfonyl enoates from ethyl propiolate

Article abstract of DOI:10.1016/j.tetlet.2012.08.051

β-Sulfonyl enoates may be synthesized through a one-pot two-step sequence from ethyl propiolate with good to excellent selectivity for the Z isomer. Trialkylamines catalyze thioconjugate additions of aryl thiols, and alkoxides catalyze the addition of ali

Full text of DOI:10.1016/j.tetlet.2012.08.051

Tetrahedron Letters 53 (2012) 5763–5765
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot synthesis of (Z)-b-sulfonyl enoates from ethyl propiolate
⇑
C. Wade Downey , Smaranda Craciun, Ana M. Neferu, Christina A. Vivelo, Carly J. Mueller,
Brian C. Southall, Stephanie Corsi, Eric W. Etchill, Ryan J. Sault
Department of Chemistry, University of Richmond, Richmond, VA 23173, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Available online 19 August 2012
b-Sulfonyl enoates may be synthesized through a one-pot two-step sequence from ethyl propiolate with
good to excellent selectivity for the Z isomer. Trialkylamines catalyze thioconjugate additions of aryl thi-
ols, and alkoxides catalyze the addition of aliphatic thiols. Addition of meta-chloroperbenzoic acid
(mCPBA) and LiClO4 to the reaction mixture provides rapid access to the sulfonyl enoates. Yields of the
pure Z isomer range from 51–90%.
Keywords:
Conjugate addition
Sulfide oxidation
One-pot reactions
Enoate
Ó 2012 Elsevier Ltd. All rights reserved.
Ynoate
Dienophile
Ethyl propiolate
Thiol
Conjugate additions to enoate acceptors are staple reactions in
the field of organic synthesis,1 but conjugate addition reactions
of ynoates are undervalued. As part of our development of a
one-pot synthesis of chiral esters from ynoates,2 we required a
convenient and rapid synthesis of geometrically enriched b-sulfo-
nyl enoates.3 We now report the realization of this goal: a one-
pot two-step thioconjugate addition-oxidation reaction of ethyl
propiolate with various thiols and meta-chloroperbenzoic acid
(mCPBA) in the presence of LiClO4. These convenient electrophiles
should find use as building blocks for a variety of scenarios.
Thiols are known to react reliably with ethyl propiolate, provid-
ing a predominance of either the E or the Z enoate product depend-
ing upon the reaction conditions.4 Because our ultimate goal is the
development of one-pot methodology, the thioconjugate addition
step in our laboratory was subject to the additional requirement
of taking place under reaction conditions very similar to those that
would be employed in the oxidation step. Accordingly, we con-
ducted our own optimization study for the base-catalyzed conju-
gate addition of various thiols to ethyl propiolate.4
solvent. Toluene, THF, and Et2O were all clearly inferior to CH2Cl2,
with none providing a selectivity of 4:1 or higher.
Encouraged by the optimization of the conjugate addition of
p-toluenethiol, we set out to determine the reaction scope. Table
2 summarizes our results. Electron-rich aromatic thiols performed
best, as illustrated by entries 1–3. Electron-poor aromatic thiols
were capable nucleophiles, but selectivity suffered slightly.
Because the geometric selectivity of the conjugate addition is
determined by the protonation of the allenolate intermediate, the
less acidic electron-rich thiols may be more selective acids.
Table 1
Optimization of thioconjugate addition
As illustrated in Table 1, we examined a variety of amine bases
and organic solvents in the conjugate addition of p-toluenethiol to
ethyl propiolate. When the reaction was performed in CH2Cl2 at
ꢀ78 °C, selectivity and conversion as measured by 1H NMR spec-
troscopy were uniformly high. We chose i-Pr2NEt as the amine
base for further study because of the high conversion observed.
Geometric selectivity was easily controlled through choice of
Entry
R3N
Solvent
Z:Ea
Conva (%)
1
2
3
4
5
6
2,6-lutidine
Et3N
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
i-Pr2NEt
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
THF
12:1
10:1
11:1
3.3:1
2.6:1
2.4:1
90
92
100
100
90
Et2O
100
Bold values are the optimized reaction conditions that were used for further
experiments; they are the most important data in the table.
⇑
Corresponding author. Tel.: +1 804 484 1557; fax: +1 804 287 1897.
E-mail address: wdowney@richmond.edu (C.W. Downey).
a
Determined by 1H NMR spectroscopy of unpurified reaction mixture.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.051

5764
C. W. Downey et al. / Tetrahedron Letters 53 (2012) 5763–5765
Table 2
of a one-pot reaction wherein a second synthetic step occurs
in situ, while the Z:E ratio is maximized.
Scope of amine-catalyzed thioconjugate addition
Aliphatic thiols proved to be more challenging substrates.
Nonetheless, 1 h at ꢀ78 °C proved sufficient to achieve a very high
yield (Table 2, entry 7) with acceptable geometric selectivity (4:1
Z:E) when benzyl mercaptan was used as the nucleophile. The elec-
tronically analogous 2-furanmethanethiol behaved very similarly
(entry 8), but purely aliphatic thiols did not perform consistently
well under amine-catalyzed conditions (entries 9 and 10). Reso-
nance donation of the sulfur lone pairs in the product to the conju-
gated enoate system, presumably a much more significant factor in
the S-alkyl case than for S-aryl analogs, may explain the relatively
low geometric selectivity. Indeed, we have observed the slow
equilibration of neat S-alkyl b-thioenoates from the Z isomer to
an E/Z mixture overnight even at 5 °C, providing further impetus
for the development of a one-pot reaction process to immediately
convert these products into more elaborated synthons.
Fortunately, replacement of the amine catalyst with more basic
alkoxides provided a convenient solution for aliphatic thiols.
Transesterification and geometric equilibration occurred when
NaOMe was employed as base, but the sterically hindered KOt-
Bu proved to be very effective. Addition of tetrabutylammonium
bromide (TBABr) to the reaction mixture rendered the reaction
homogeneous and allowed the reactions to proceed at 0 °C with
Entry
1
RSH
Product
Z:Ea,b
Yieldc (%)
94
1a
3.9:1(12:1)
2
3
4
1b
1c
1d
3.0:1(10:1)
15:1(16:1)
6:1(6:1)
93
95
97
5
6
1e
1f
9:1(9:1)
86
91
4.2:1(11:1)
7
8
1g
1h
3.4:1(4.2:1)
3.3:1(8:1)
96
91
Table 4
Scope of amine-catalyzed one-pot thioconjugate addition-oxidations
9
1i
1j
4.2:1(6:1)
2.9:1(5:1)
67d
59e
10
Determined by 1H NMR spectroscopy.
Values in parentheses show the Z:E ratio prior to purification on silica gel.
Isolated yield of a mixture of Z and E isomers for reaction performed on 2 mmol
a
b
c
Entry
1
RSH
Product
Z:Ea
Yield of Zb (%)
71c
scale.
d
Reaction performed at 0 °C.
Reaction performed at ambient temperature.
2a
12:1
e
2
3
4
2b
2c
2d
8:1
81d
90
Although selectivity generally favored the Z isomer, geometric pur-
ity degraded during chromatography, sometimes dramatically.
This observation emphasizes the importance of the development
10:1
10:1
Table 3
70
Scope of alkoxide-catalyzed thioconjugate additions
5
6
2e
2f
3:1
51e
84
10:1
Entry
1
RSH
Product
Z:Ea,b
Yieldc (%)
90
7
8
2g
2h
5:1
—
64
1i
4.2:1(4.7:1)
decomp.
2
3
1j
2.7:1(3.5:1)
4.0:1(4.1:1)
81
88
Determined by 1H NMR spectroscopy.
Isolated yield of Z isomer for reaction performed on 2 mmol scale.
0.5 equiv LiClO4 used.
0.5 equiv LiClO4 used.
Modified reaction conditions: 1,2-dichloroethane used as solvent; second step
a
b
c
1k
Determined by 1H NMR spectroscopy.
Values in parentheses show the Z:E ratio prior to purification on silica gel.
Isolated yield of a mixture of Z and E isomers for reaction performed on 2 mmol
a
b
c
d
e
scale.
at 83 °C.

C. W. Downey et al. / Tetrahedron Letters 53 (2012) 5763–5765
5765
Table 5
In order to demonstrate the reactivity of these b-sulfonyl eno-
ates, the Diels–Alder cycloaddition of cyclopentadiene to sulfone
2b was performed. In the presence of LiClO4 at room temperature
in CH2Cl2, complete conversion to the cycloadduct was observed
overnight (Eq. 1). Column chromatography provided the pure ma-
jor endo isomer in 82% yield.
Scope of alkoxide-catalyzed one-pot thioconjugate addition-oxidations
ð1Þ
Entry
1
RSH
Product
Z:Ea
Yield of Zb (%)
60
In conclusion, we have developed a one-pot two-step thioconju-
gate addition-oxidation reaction that rapidly generates (Z)-b-sulfo-
nyl enoates from ethyl propiolate. Reaction scope includes both
aryl and aliphatic thiols. The major Z isomer is easily purified by
column chromatography. Expansion of this reaction to include
3-substituted ynoates as well as further demonstrations of the
electrophilicity of these compounds is underway.
2i
3.5:1
2
3
2J
3.1:1
3.0:1
51
58
2k
a
Determined by 1H NMR spectroscopy.
Isolated yield of Z isomer for reaction performed on 2 mmol scale.
b
Acknowledgments
acceptable geometric selectivity. Under these modified reaction
conditions, both sterically encumbered secondary thiols (Table 3,
entry 1) and long-chain aliphatic thiols (entries 2 and 3) performed
well, providing high yields of the conjugate addition adducts.
In order to render these b-thioenoate products more useful as
synthetic building blocks, we sought to increase their electrophilic-
ity through conversion to sulfones in situ. Initial studies with puri-
fied thioether 1b showed the mCPBA was a promising oxidant,
readily providing the sulfone when 3 equiv of the oxidizing agent
were used.5
Unfortunately, residual catalytic base in the one-pot version of
the reaction led to significant byproduct formation and low yield
(15%) when the one-pot two-step thioconjugate addition-oxidation
sequence was attempted. In order to mitigate the effect any resid-
ual base might have on the oxidation step, LiClO4 was added as an
amine- or alkoxide-sequestering agent. Under these conditions,
yield increased dramatically and the amount of mCPBA could be re-
duced to 2.5 equiv.6
Donors of the American Chemical Society Petroleum Research
Fund and Thomas F. Jeffress and Kate Miller Jeffress Memorial
Trust are acknowledged for support of this research. C.A.V.
acknowledges the Howard Hughes Medical Institute for a summer
fellowship. S. Craciun acknowledges the Grainger Science Initiative
for a summer fellowship. B.C.S, R.J.S., and S. Craciun acknowledge
the University of Richmond School of Arts and Sciences for summer
fellowships. E.W.E and S. Corsi acknowledge the University of Rich-
mond Department of Chemistry for Puryear-Topham fellowships.
We are indebted to NSF (CHE-0541848) and the University of Cal-
ifornia-Riverside for mass spectral data.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.08.
051. These data include MOL files and InChiKeys of the most
important compounds described in this article.
As illustrated in Table 4, aryl thiols again proved to be superior
substrates in the presence of trialkylamine catalyst, although some
drop in yield was observed for halogenated arenes (entries 4 and 5).
Benzyl mercaptan also performed well, but the 2-furyl derivative
proved unstable under the oxidizing conditions. Gratifyingly, Z:E ra-
tios for the sulfone products are very similar to those observed for
the simple conjugate addition reactions, demonstrating that very
little geometric equilibration occurs under the one-pot two-step
reaction conditions. Indeed, geometric purity is generally higher
for the sulfones than for the analogous thioethers purified immedi-
ately after the thioconjugate addition step. Conveniently, the Z and E
isomers of the sulfones could be easily separated via column
chromatography.
Although benzyl mercaptan reacted efficiently under the
amine-catalyzed reaction conditions, the other aliphatic thiols
examined suffered significant decomposition. When i-Pr2NEt was
replaced with KOt-Bu, a successful one-pot two-step thioconjugate
addition-oxidation sequence was completed for cyclohexanethiol,
dodecanethiol, and octanethiol (Table 5), each of which provided
useful isolated yields of the Z isomer.
References and notes
1. For a review of conjugate addition reactions, see: (a) Alexakis, A.; Benhaim, C.
Eur. J. Org. Chem. 2002, 3221–3236; For recent examples of the conjugate
additions of thiol nucleophiles, see: (b) Abe, A. M. M.; Sauerland, S. J. K.;
Koskinen, A. M. P. J. Org. Chem. 2007, 72, 5411–5413; (c) Marigo, M.; Schulte, T.;
Franzén, J.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 15710; (d) Peng, A.;
Rosenblatt, R.; Nolin, K. Tetrahedron Lett. 2012, 53, 2712–2714.
2. See succeeding article in this journal
3. For a synthesis of some aryl thiol-derived sulfonyl enoates by a different route,
see: Chen, D.-D.; Hou, X.-L.; Dai, L.-X. J. Org. Chem. 2008, 73, 5578–5581.
4. For example, the Z-selective addition of 4-methylbenzenethiol to an ynoate in
the presence of Et3N is known: (a) Maezaki, N.; Yagi, S.; Yoshigami, R.; Maeda, J.;
Suzuki, T.; Ohsawa, S.; Tsukamoto, K.; Tanaka, T. J. Org. Chem. 2003, 68, 5550–
5558; For an example of an E-selective reaction in the presence of Et3N, see: (b)
Nishida, A.; Shibasaki, M.; Ikegami, S. Chem. Pharm. Bull. 1986, 34, 1434–1446.
5. This reaction is precedented. For example, see: (a) Jungheim, L. N.; Barnett, C. J.;
Gray, J. E.; Horcher, L. H.; Shepherd, T. A.; Sigmund, S. K. Tetrahedron 1998, 44,
3119–3126; (b) See also Ref.4a
6. Acceleration of m-CPBA oxidations of sulfur atoms by Lewis acids is known: Li,
Y.; Matsuda, M.; Thiemann, T.; Sawada, T.; Mataka, S.; Tashiro, M. Synlett 1996,
461–464.