The homologous conjugate addition of thiols to electron-deficient cyclopropanes catalyzed by a calcium(II) complex

Article abstract of DOI:10.1016/j.tetlet.2013.08.102

The synthesis of γ-sulfanyl malonates was achieved through the addition of thiols to electron deficient cyclopropanes. These reactions are catalyzed by calcium acetylacetonate, Ca(acac)₂. A variety of electron rich and electron deficient thiols were added without the need for prior activation or exogenous base. The thiol additions to donor-acceptor cyclopropanes bearing electron-rich and electron-deficient aromatic and heteroaromatic groups proceeded in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2013.08.102

Tetrahedron Letters 54 (2013) 5889–5891
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Tetrahedron Letters
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The homologous conjugate addition of thiols to electron-deficient
cyclopropanes catalyzed by a calcium(II) complex
⇑
Caroline M. Braun, Alyssa M. Shema, Callie C. Dulin, Kristine A. Nolin
University of Richmond, Richmond, VA 23173, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of c-sulfanyl malonates was achieved through the addition of thiols to electron deficient
Received 26 July 2013
Revised 21 August 2013
Accepted 23 August 2013
Available online 31 August 2013
cyclopropanes. These reactions are catalyzed by calcium acetylacetonate, Ca(acac)2. A variety of electron
rich and electron deficient thiols were added without the need for prior activation or exogenous base. The
thiol additions to donor–acceptor cyclopropanes bearing electron-rich and electron-deficient aromatic
and heteroaromatic groups proceeded in good to excellent yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Cyclopropanes
Homologous conjugate addition
Calcium catalysis
Thiol addition
Cyclopropanes have been shown to be powerful synthetic
building blocks.1a,b The C–C single bonds of the cyclopropyl ring
are uniquely reactive and their behavior resembles that of the C–
addition reactions.5b Herein, the addition of thiols to DA cyclopro-
panes to generate
-sulfanyl malonates is described.11
c
The addition of 4-chlorothiophenol to dimethyl 2-phenylcyclo-
C
p-bonds of olefins. Catalytic 1,4-additions of nucleophiles to
propane-1,1-dicarboxylate (1) was accomplished in the presence
a,b-unsaturated carbonyl compounds provide access to a myriad
of catalytic amounts of CaI2 yielding the corresponding c-sulfanyl
of b-functionalizations. The homologous reaction involving addi-
malonate 2 with 67% conversion after 24 h at 70 °C with complete
regioselectivity (Eq. 1). There was no activation of the thiol prior to
addition to the reaction solution and no exogenous base was
added. Reaction optimization began with the screening of several
commercially available calcium (II) complexes. While a number
of the complexes were shown to be catalytically active, calcium
acetylacetonate (Ca(acac)2) was the most robust (Table 1, entries
2–5). A solvent screen revealed cyclopentylmethyl ether (CPME)12
was just as effective as toluene as solvent with 100% conversion
after 17 h (entry 8). Dropping the catalyst loading from 5% to 2%
led to a decrease in reactivity with a conversion of only 21% (entry
9). However, increasing the concentration of the reaction to 1.0 M
increased the conversion to 38% without detectable decomposition
of the starting materials or product (entry 10). No conversion was
observed in the absence of Ca(acac)2 (entry 11).
tions to cyclopropyl carbonyl compounds provides access to
c
-
functionalized carbonyls. Cyclopropanes bearing geminal elec-
tron-withdrawing groups and an aromatic substituent are gener-
ally referred to as donor–acceptor (DA) cyclopropanes. This class
of cyclopropanes has proven to be particularly well suited to addi-
tion reactions.2a–c The vicinal donor–acceptor substituents work
synergistically to weaken the adjoining C–C bonds and, thus, dic-
tate the regioselectivity of the reaction. DA cyclopropanes have
been explored as electrophiles in homologous conjugate addition
(HCA) reactions3a–e and cycloaddition reactions.4a–f Recently, a
number of catalytic methods are currently available for the activa-
tion of these DA cyclopropanes.3d,5a–h
Unlike many metals commonly used in synthetic methodolo-
gies, calcium is relatively inexpensive and readily available.6
Despite its natural prevalence, the reactivity of calcium has re-
mained largely unexplored in the context of organic methodol-
ogy.7a–c The application of calcium(II) complexes as catalysts in
aldol,8 Michael,9a–c and Mannich-type10 reactions have been
reported. Based on this precedence, we envisioned the application
of calcium complexes as catalysts in homologous conjugate
Using the optimized reaction conditions (1.1 equiv of thiol,
1.0 M in CPME, and 5 mol % of Ca(acac)2), the scope of the reaction
with regard to the nature of the thiol was examined. For these
reactions, malonate cyclopropane 1 was used as the model sub-
⇑
Corresponding author. Tel.: +1 804 289 8247; fax: +1 804 287 1897.
E-mail address: knolin@richmond.edu (K.A. Nolin).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.102

5890
C. M. Braun et al. / Tetrahedron Letters 54 (2013) 5889–5891
Table 1
Reaction optimization
Entry
Solvent
Concn (M)
Time (h)
Catalyst
Cat. loading (%)
Conv.b (%)
1
2
3
4
5
6
7
8
9
Toluene
Toluene
Toluene
Toluene
Toluene
EtOAc
2-MeTHF
CPME
CPME
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
1.0
0.2
24
24
24
24
24
23
22
17
23
24
24
CaI2
5
5
5
5
5
5
5
5
67
12
77
100
0
50
78
100
21
38
0
Ca(tartrate)
Ca(OAc)2
Ca(acac)2
Ca(OH)2
Ca(acac)2
Ca(acac)2
Ca(acac)2
Ca(acac)2
Ca(acac)2
None
2
2
n/a
10
11
CPME
CPME
aOptimization reactions were carried out with 1 (0.3 mmol) and 4-chlorothiophenol (0.33 mmol) in dry solvents.
b
Conversions were determined 1H NMR.
strate. The results are summarized in Table 2. Various aromatic thi-
ols reacted efficiently to provide the corresponding -sulfanyl mal-
onates in good to excellent yields with complete regioselectivity.
Electron-rich thiophenol derivatives (entries 1 and 2) were added
in good to excellent yields (83–94%) while electron deficient thiols
5f, 5g, and 5h in 86, 89, and 94% respectively. Alkyl substituted DA
cyclopropanes were also subjected to the reaction conditions. As
expected, they proved to be less reactive with a conversion of less
than 10% when R = iPr.
The following cycle is proposed for the catalytic addition of
thiols to DA cyclopropanes activated by the Lewis acidic Ca(acac)2
complex (Scheme 1). The complex is a pre-catalyst that undergoes
ligand exchange to generate an active catalytic species, 6. The thiol
subsequently adds to the activated cyclopropane to generate cal-
c
were slightly less reactive providing the corresponding c-sulfanyl
malonate in good yields (entries 3–5, 75–93%). The addition of 2-
naphthalenethiol led to the formation of 3e in 75% yield. Alkyl thi-
ols could also be successfully added in good yield; however, a high-
er catalyst loading, 10 mol %, was required. This is demonstrated
with the addition of dodecanethiol to yield 3f in 75% yield. Next,
the reactivity of differentially substituted donor–acceptor cyclo-
propanes toward the addition of 4-chlorothiophenol was exam-
ined. Varying of the substitution at the para position of the
aromatic ring had minimal effects on the yield of the reaction.
DA cyclopropane with electron-rich aromatic substitution, 4a and
4b, underwent nucleophilic ring opening to supply 5a and 5b in
85% and 88% yields respectively (Table 3, entries 1 and 2). Cyclo-
propanes bearing electron deficient aromatic rings, 4c and 4d, were
cium enolate 7. A proton transfer generates the coordinated c-sul-
fanyl malonate product. Finally, ligand exchange completes the
catalytic cycle and regenerates 6. The thiols will, most likely, not
require deprotonation prior to addition; however, a catalytic
amount of thiolate will form as an acid/base equilibrium is estab-
lished with the mildly Brønsted basic acetylacetonate ligand.
In closing, Ca(acac)2 has been shown to be a versatile catalyst
for the homologous conjugate addition of thiols to DA cyclopro-
panes. A wide range of aryl substituted DA cyclopropanes and thi-
ols were found to be reactive under the standard reaction
conditions. Elaboration of this reaction is currently underway in
our laboratories and will be reported in due time.
also transformed to the corresponding
c-sulfanyl malonates in
good yield, 73–89% (entries 3 and 4). Addition of 4-chlorothiophe-
nol to 1-napthylsubstituted cyclopropane 4e yielded thioether 5e
in 88% yield. Cyclopropanes with thiophene, furan, and indole sub-
stitutions were very reactive and readily transformed to thioethers
Table 3
Addition of 4-chlorothiophenol to differentially substituted cyclopropanes
Table 2
Addition of thiols to cyclopropane 1
Entry
Thiol
Yield (%)ab
Entry
R
Yield (%)ab
1
2
3
4
5
6
7
4-Methyoxythiophenol
4-Methylthiophenol
4-Bromothiophenol
4-Chlorothiophenol
4-Flourothiophenol
2-Naphthalenethiol
Dodecanethiolc
83
94
93
80
75
75
75
3a
3b
3c
2
3d
3e
3f
1
2
3
4
5
6
7
8
4-OCH3Ph
4-CH3Ph
4-ClPh
4-FPh
1-Naphthyl
2-Thiophenyl
5-Methyl-2-furanyl
3-(N-Ts)-indolyl
4a
4b
4c
4d
4e
4f
85
88
89
73
88
86
89
94
5a
5b
5c
5d
5e
5f
4g
4h
5g
5h
a
Reactions were carried out with cyclopropane
(1.1 mmol) in 1.0 mL of dry CPME in the presence of 5% Ca(acac)2.
1 (1.0 mmol) and thiol
a
Reactions were carried out with cyclopropane 1 (1.0 mmol) and 4-chlorothi-
ophenol (1.1 mmol) in 1.0 mL of dry CPME in the presence of 5% Ca(acac)2.
b
Yield of the isolated product after chromatography on silica gel.
10 mol % of Ca(acac)2 used.
c
b
Yield of the isolated product after chromatography on silica gel.

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5891
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Acknowledgments
Acknowledgment is made to the Donors of the American Chem-
ical Society Petroleum Research Fund for support of this research.
The authors would also like to thank the Arnold and Mabel Beck-
man Foundation, the Thomas F. and Kate Miller Jeffress Trust,
and the University of Richmond for additional support and
research fellowships.
Supplementary data
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08.102.