One-pot three-step thioconjugate addition-oxidation-Diels-Alder reactions of ethyl propiolate

Article abstract of DOI:10.1016/j.tetlet.2012.08.054

Ethyl propiolate undergoes one-pot three-step thioconjugate addition-oxidation-Diels-Alder cycloaddition when treated with a variety of thiols in the presence of catalytic base, meta-chloroperbenzoic acid, lithium perchlorate, and cyclopentadiene. The reaction of S-aryl thiols is catalyzed by trialkylamines, and the reaction of aliphatic thiols requires catalytic alkoxide base. Yields of the major diastereomer of the conveniently functionalized bicyclic products range from 47% to 81% depending upon the thiol reactant, which compares favorably to yields observed when the entire synthesis is performed step-by-step.

Full text of DOI:10.1016/j.tetlet.2012.08.054

Tetrahedron Letters 53 (2012) 5766–5768
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot three-step thioconjugate addition-oxidation-Diels–Alder reactions
of ethyl propiolate
⇑
C. Wade Downey , Smaranda Craciun, Christina A. Vivelo, Ana M. Neferu, Carly J. Mueller, Stephanie Corsi
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:
Ethyl propiolate undergoes one-pot three-step thioconjugate addition-oxidation-Diels–Alder cycloaddi-
tion when treated with a variety of thiols in the presence of catalytic base, meta-chloroperbenzoic acid,
lithium perchlorate, and cyclopentadiene. The reaction of S-aryl thiols is catalyzed by trialkylamines, and
the reaction of aliphatic thiols requires catalytic alkoxide base. Yields of the major diastereomer of the
conveniently functionalized bicyclic products range from 47% to 81% depending upon the thiol reactant,
which compares favorably to yields observed when the entire synthesis is performed step-by-step.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 7 August 2012
Accepted 10 August 2012
Available online 26 August 2012
Keywords:
Diels–Alder
Lithium
One-pot
Sulfone
Ynoate
Enoate
Thiol
One-pot reaction methodology has generated significant inter-
est in the synthetic community over the past decade.1 Ynoate es-
ters such as ethyl propiolate are intriguing substrates for one-pot
reactions because they are known to act as one-pot bisacceptors
in the presence of an excess of a single nucleophile.2 Our group’s
long-standing interest in one-pot reactions3 has led us to the inves-
tigation of ynoate esters as platforms for sequential conjugate
addition reactions by two disparate nucleophiles.4 We now report
the ability of ethyl propiolate, a representative ynoate ester, to un-
dergo sequential thioconjugate addition and Diels–Alder reaction
in one pot.
The cycloaddition step was first optimized using the indepen-
dently synthesized and purified Z sulfone product derived from
p-toluenethiol and ethyl propiolate. When the sulfone was stirred
with 2 equiv cyclopentadiene in CH2Cl2 at reflux for 1 h, 67%
conversion to a 3.3:1 (endo:exo) mixture of diastereomers was
observed. As illustrated in Table 1, a number of Lewis acids were
tested in the reaction as well. In the presence of catalyst
(5 mol %), the reaction proceeded at a reasonable rate at room
Table 1
Optimization of Diels–Alder cycloaddition
As we have reported in the previous communication,5 we have
developed a one-pot synthesis of (Z)-b-sulfonyl enoates from ethyl
propiolate (Eq. 1). Because this class of enoates is known to act as
dienophiles in Diels–Alder cycloadditions,6 we set out to incorpo-
rate the Diels–Alder reaction into our one-pot process. The overall
process would provide a usefully functionalized building block for
further synthetic manipulation.7
Entry
Lewis acid
Endo:exo
% Conva
1
2
3
4
5
6
7
None
LICIO4
3.3:1
5.1:1
4.2:1
5.7:1
3.0:1
3.7:1
3.1:1
67b
63
70
38
27
29
24
ð1Þ
MgBr2ꢀOEt2
ZnBr2
In(OTf)3
Sn(OTf)3
Yb(OTf)3
a
Determined by 1H NMR spectroscopy.
Reaction stirred at 40 °C.
⇑
Corresponding author. Tel.: +1 804 484 1557; fax: +1 804 287 1897.
E-mail address: wdowney@richmond.edu (C.W. Downey).
b
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.054

C. W. Downey et al. / Tetrahedron Letters 53 (2012) 5766–5768
5767
Table 2
Table 3
Diels–Alder cycloaddition with cyclohexadiene
One-pot three-step reaction with aryl thiols
Entry
R
Endo:exo
% Conva
1
2
3
Ph
>20:1
>20:1
>20:1
30
50
80
Entry
1
RSH
Product
dra
Yieldb (%)
p-Me-C6H4
Bn
Determined by 1H NMR spectroscopy of the unpurified reaction mixture. Iso-
1
70:30
75
a
lated yields never exceeded 25%.
2
3
4
5
2
3
4
5
76:24
87:13
76:24
71:29
81c,d
temperature. The two most effective catalysts were LiClO4 and
MgBr2ꢀOEt2, which displayed high selectivity and conversion after
only 1 h. Ultimately, LiClO4 was chosen for further study because
it displayed slightly higher selectivity and successfully mediated
complete conversion to products overnight. Moreover, the LiClO4
catalyst was already known to be compatible with our one-pot
b-sulfonyl enoate synthesis (Eq. 1),5 so its additional use as cyclo-
addition catalyst was especially convenient.
81
56
57e
When cyclopentadiene was replaced with the less reactive
cyclohexadiene, we were surprised to observe that LiClO4 was
the only catalyst tested that displayed any reactivity at all, provid-
ing the endo product in 50% conversion after reflux overnight. Dia-
stereoselectivity was extremely high, greater than 20:1 in favor of
the endo isomer in every trial. More surprisingly, CH2Cl2 was the
only solvent in which reactivity occurred. Similar results were ob-
served for substrates derived from other thiols (Table 2). Unfortu-
nately, in no case was an isolated yield greater than 25% observed,
despite seemingly clean reaction as determined by thin layer chro-
matography and 1H NMR spectroscopy. Other dienes tested (iso-
6
7
6
7
80:20
76:24
60
67c
dr = Diastereomer ratio = (major isomer:R
minor isomers), determined by 1H
NMR spectroscopy of the unpurified reaction mixture.
Isolated yield of major endo diastereomer for reaction performed on 2 mmol
scale.
a
b
c
No LiClO4 added during third step.
0.5 equiv LiClO4 used.
Modified reaction conditions: 1,2-dichloroethane used as solvent; step 2 at
d
e
prene,
furan,
N-methylpyrrole,
N-BOC-pyrrole,
2-
83 °C.
methylthiophene) showed no reactivity under our conditions.
With these results in hand, we chose to concentrate our efforts
toward development of the reaction with cyclopentadiene. Final
optimization of the one-pot three-step heteroconjugate addition-
oxidation-Diels–Alder cycloaddition reaction proceeded apace.
Reaction solvent and catalyst were completely compatible with
our previously developed (Z)-b-sulfonyl enoate synthesis.5 None-
theless, residual amine or alkoxide base and m-CPBA derivatives
present in the reaction mixture during the one-pot three-step reac-
tion required an increase in catalyst loading for the cycloaddition
step (1 equiv vs 5 mol %). Given the inexpensive nature of the cat-
alyst, we found this increase acceptable.
captan reacted analogously to the S-aryl thiols, providing the major iso-
mer in 67% yield. Diastereoselectivity varied somewhat from substrate
to substrate, ranging from 3:1 (major endo isomer:Rminor isomers) for
p-bromothiophenol to 15:1 for p-methoxythiophenol. Both the exo
isomer derived from the Z enoate and diastereomers resulting from
the cycloaddition of the E enoate were frequently observed as minor
products, but in all cases the major endo isomer was easily purified
by column chromatography.
Table 4
One-pot three-step reaction with alkyl thiols
As displayed in Table 3, we found the reaction to be general and
reliable for S-aryl thiols with only minor changes in the reaction con-
ditions from case to case. In a typical reaction procedure, the S-aryl
thiol andaminebasewere mixed inCH2Cl2 at roomtemperature, then
cooled to ꢁ78 °C and treated with ethyl propiolate. After 1 h, m-CPBA
and LiClO4 wereadded and thereaction mixture was warmed to room
temperature. Afterstirring atreflux for2 h, cyclopentadiene andaddi-
tional LiClO4 were added, and the reaction was stirred at room tem-
perature overnight. Aqueous workup and column chromatography
provided the pure major endo diastereomer in good yields. Electron-
rich aryl thiols were the most successful substrates (entries 1–3). In
some cases, the addition of a second equivalent of LiClO4 during the
cycloaddition step was unnecessary to achieve high yield and selec-
tivity.8 In the case of p-bromothiophenol, the reaction was performed
in 1,2-dichloroethane in order to achieve a higher reflux temperature
during the oxidation step, ensuring full oxidation to the sulfone. In
general, halogenated thiophenol derivatives appear to react some-
what less selectively than their counterparts, which corresponds to
lower isolated yields of the major cycloaddition adduct. Benzyl mer-
Entry
1
RSH
Product
dra
Yieldb (%)
47
8
74:26
2
3
9
81:19
84:16
51
57
10
dr = Diastereomer ratio = (major isomer:R
minor isomers), determined by 1H
NMR spectroscopy of the unpurified reaction mixture.
a
b
Isolated yield of major diastereomer for reaction performed on 2 mmol scale.

5768
C. W. Downey et al. / Tetrahedron Letters 53 (2012) 5766–5768
Figure 1. Comparison of one-pot reaction with step-by-step synthesis.
For purely aliphatic thiols, similar reaction conditions were em-
summer fellowship. S. Craciun acknowledges the Grainger Science
Initiative and the University of Richmond School of Arts and Sci-
ences for summer fellowships. S. Corsi acknowledges the Univer-
sity of Richmond Department of Chemistry for a Puryear-Topham
fellowship. We are indebted to NSF (CHE-0541848) and the Uni-
versity of California-Riverside for mass spectral data.
ployed, differing only in the substitution of catalytic i-Pr2NEt with
catalytic KOt-Bu and phase transfer catalyst tetrabutylammonium
bromide (TBABr). As illustrated in Table 4, these challenging sub-
strates performed reliably, providing consistent yields of the major
endo diastereomer.
A one-pot process provides inherentadvantages over step-by-step
synthesis, most obviously in the limitation of time and material costs
associated with multiple purification steps. To be truly useful, how-
ever, the yield, selectivity, and purity of the final product must be
comparable to what would be achieved by step-by-step synthesis. A
mathematical comparison of two routes to product 2 shows that
our one-pot process is favorable compared to the step-by-step syn-
thesis, as measured by the yield of the major isomer. To wit, the yield
of the purified, isolated major endo diastereomer of product 2 as gen-
erated throughour one-potthree-step reaction was71%, whichcorre-
sponds to an average of 89% yield for each of the three steps. Figure 1
shows a comparison of this approach to a traditional step-by-step
synthesis also performed in our laboratory. In the step-by-step syn-
thesis, the yield for the thioconjugate addition step was 93%, the yield
of the Z isomerafter oxidation to the sulfone was 87%, and theyieldfor
the Diels–Alder step was 82%. The overall yield for the entire step-by-
step synthesis was 66%, which demonstrates that the one-pot process
is superior in overall yield as well as in convenience. Although any
complex one-pot reaction sequence is prone to loss of yield through
side reactions occurring under the complex reaction conditions, in
the present case those complexities have been more than compen-
sated by the prevention of product loss during multiple purification
steps. One advantage of the step-by-step process is that less LiClO4
catalyst is necessary to achieve the final product, because no catalyst
is necessary to scavenge residual amine during the oxidation step.5
Nonetheless, that advantage is more than offset by the convenience,
speed, and economic advantages of our one-pot reaction.
Supplementary data
Supplementary data (experimental procedures and spectral
data) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2012.08.054. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
References and notes
1. For recent reviews, see: (a) Vaxelaire, C.; Winter, P.; Christmann, M. Angew.
Chem., Int. Ed. 2011, 50, 3605–3607; (b) Arns, S.; Barriault, L. Chem. Commun.
2007, 2211–2221; (c) Padwa, A. Pure Appl. Chem. 2004, 76, 1933–1952; (d)
Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun. 2003, 551–564; (e)
Broadwater, S. J.; Roth, S. L.; Price, K. E.; Kobaslija, M.; McQuade, D. T. Org.
Biomol. Chem. 2005, 3, 2899–2906.
2. For the addition of a bisthiol to ethyl propiolate, see: (a) Gaunt, M. J.; Sneddon,
H. F.; Hewitt, P. R.; Orsini, P.; Hook, D. F.; Ley, S. V. Org. Biomol. Chem. 2003, 1,
15–16; For the addition of a bisthiol to ynones, see: (b) Xu, C.; Bartley, J. K.;
Enache, D. I.; Knight, D. W.; Lunn, M.; Lok, M.; Hutchings, G. J. Tetrahedron Lett.
2008, 49, 2454–2456; For the bisaddition of cyclopentadiene to methyl
propiolate, see: (c) Lasne, M. C.; Ripoll, J. L. Bull. Soc. Chim. Fr. 1986, 766–770.
3. (a) Downey, C. W.; Johnson, M. W. Tetrahedron Lett. 2007, 48, 3559–3562; (b)
Downey, C. W.; Johnson, M. W.; Tracy, K. J. J. Org. Chem. 2008, 73, 3299–3302; (c)
Downey, C. W.; Johnson, M. W.; Lawrence, D. H.; Fleisher, A. S.; Tracy, K. J. J. Org.
Chem. 2010, 75, 5351–5354; (d) Downey, C. W.; Fleisher, A. S.; Rague, J. R.;
Safran, C. L.; Venable, M. E.; Pike, R. D. Tetrahedron Lett. 2011, 52, 4756–4759.
4. For the addition of two distinct nucleophiles to an ynoate through a similar
strategy, see: Ramazani, A.; Sadri, F. Phosphorus Sulfur Silicon Relat. Elem. 2009,
184, 3126–3133.
5. See preceding article in this journal.
6. Sulfone- and sulfoxide-substituted enoates are known to undergo Diels–Alder
reactions. For examples, see: (a) Buss, A. D.; Hirst, G. C.; Parsons, P. J. J. Chem.
Soc., Chem. Commun. 1987, 1836–1837; (b) De Lucchi, O.; Lucchini, V.;
Marchioro, C.; Valle, G.; Modena, G. J. Org. Chem. 1986, 51, 1457–1466.
7. For the use of a similar Diels–Alder strategy toward the synthesis of biologically
active molecules, see: (a) Arai, Y.; Yamamoto, M.; Koizumi, T. Bull. Chem. Soc. Jpn.
1988, 61, 467–473; (b) Arai, Y.; Hayashi, Y.; Yamamoto, M.; Takayema, H.;
Koizumi, T. J. Chem. Soc., Perkin Trans. I 1988, 3133–3140; (c) Ruffoni, A.; Casoni,
A.; Pellegrino, S.; Gelmi, M. L.; Soave, R.; Clerici, F. Tetrahedron 2012, 68, 1951–
1962.
8. Table 3, entry 2: Reaction was performed with 0.5 equiv LiClO4 in the second
step and no added LiClO4 in the third step. Virtually identical results were
obtained when the reaction was performed with 1.0 equiv LiClO4 added during
both the second and third steps. Table 3, entry 7: Reaction was performed with
no added LiClO4 in the third step. Virtually identical results were obtained when
the reaction was performed with 1.0 equiv LiClO4 added during the third step.
In conclusion, this one-pot three-step thioconjugate addition-
oxidation-Diels–Alder reaction shows great efficiency for a wide
range of thiols when reacted with ethyl propiolate and cyclopenta-
diene. Expansion of the reaction scope to include less reactive
dienes and other ynoate derivatives, including chiral variants, is
underway and will be reported in due course.
Acknowledgments
Acknowledgment is made to the Donors of the American Chem-
ical Society Petroleum Research Fund and to the Thomas F. Jeffress
and Kate Miller Jeffress Memorial Trust for support of this research.
C.A.V. acknowledges the Howard Hughes Medical Institute for a