Formal Insertion of Thioketenes into Donor-Acceptor Cyclopropanes by Lewis Acid Catalysis

Article abstract of DOI:10.1021/acs.orglett.7b03961

Donor-acceptor cyclopropanes were reacted under Lewis acid catalysis with 3-thioxocyclobutanones as surrogates for disubstituted thioketenes. A broad scope of 2-substituted tetrahydrothiophenes with a semicyclic double bond was obtained under mild conditions with high functional group tolerance and in excellent yield. A sequence of a formal [3 + 2]-cycloaddition followed by the subsequent release of disubstituted ketene is postulated as the mechanism.

Full text of DOI:10.1021/acs.orglett.7b03961

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Formal Insertion of Thioketenes into Donor−Acceptor
Cyclopropanes by Lewis Acid Catalysis
Andre U. Augustin,† Marius Busse,† Peter G. Jones,‡ and Daniel B. Werz*,†
́
‡
†Institute for Organic Chemistry and Institute for Inorganic and Analytical Chemistry, TU Braunschweig, Hagenring 30, 38106
Braunschweig, Germany
S
* Supporting Information
ABSTRACT: Donor−acceptor cyclopropanes were reacted under Lewis
acid catalysis with 3-thioxocyclobutanones as surrogates for disubstituted
thioketenes. A broad scope of 2-substituted tetrahydrothiophenes with a
semicyclic double bond was obtained under mild conditions with high
functional group tolerance and in excellent yield. A sequence of a formal
[3 + 2]-cycloaddition followed by the subsequent release of disubstituted ketene is postulated as the mechanism.
Scheme 1. [3 + 2]-Cycloaddition
n the recent past, donor−acceptor (D−A) cyclopropanes
Ihave become a center of attention in organic synthesis as
valuable three-membered building blocks. Even though the
pioneering work by Wenkert and Reissig took place in the
1970s and 1980s,1 only in the past decade have they been
extensively utilized by many groups to access complex carbo-
and heterocyclic scaffolds and have even been employed in
natural product synthesis.2 The vicinal arrangement of donor
and acceptor substituents in combination with a high ring strain
of ∼115 kJ/mol explains why they commonly react with 1,3-
zwitterionic character,3 and this special behavior paves the way
for numerous transformations. Whereas cycloaddition pro-
cesses4 have been the most popular, rearrangements5 and ring-
opening reactions6 by nucleophiles, electrophiles, or radicals
have also been investigated.
Within the broad variability of possible reactions, Stoltz and
co-workers reported a Lewis acid-mediated [3 + 2]-cyclo-
addition of D−A cyclopropanes with heterocumulenes under
mild conditions. Isocyanates, isothiocyanates, and carbo-
diimides undergo efficient insertion in a chemoselective manner
to form the respective five-membered heterocycles (Scheme
1a).7 Very recently, Yang extended this method to the insertion
into γ-butyrolactone-fused cyclopropanes to obtain single
stereoisomers of the corresponding thioimidates and amidines,8
whereas Wang showed an elegant intramolecular cross-
cycloaddition of allenes linked to cyclopropane 1,1-diesters to
afford [4.3.0]bicyclononane and [3.2.1]bicyclooctane scaffolds.9
On the basis of these results, we were keen to test whether a
formal thioketene insertion into D−A cyclopropanes is able to
deliver similar sulfur analogues (Scheme 1b). Because
thioketenes are rather unstable and only a few examples have
been reported,10 we turned our attention to 3-thioxocyclobu-
tanones as suitable surrogates for disubstituted thioketene
moieties. From our recent studies, we know that thioketones
could be inserted into polarized three-membered ring
systems.11 Thus, we proposed that tetrahydrothiophene
scaffolds with a semicyclic double bond should arise from an
analogous process with D−A cyclopropanes via a formal [3 +
2]-cycloaddition followed by a [2 + 2]-cycloreversion, releasing
disubstituted ketene.
To start our investigations, we used D−A cyclopropane 1a
and 3-thioxocyclobutanone 2a as model substrates. Initial
reactions were carried out in dichloromethane at 60 °C.
Whereas AlCl3, MgI2, and Zn(OTf)2 as Lewis acids showed no
conversion, product formation was observed with Sn(OTf)2
and Yb(OTf)3 in moderate yield (Table 1, entries 1−5).
Subsequently, other common Lewis acids have been subjected
to the reaction conditions, whereby Sc(OTf)3 seemed to be the
most promising catalyst with an initial product formation of
95% yield (Table 1, entry 6). Changing the solvent to toluene
resulted in a complex mixture, and THF showed no conversion
of cyclopropane 1a (Table 1, entries 7 and 8). Using
dichloroethane as solvent was invaluable and delivered the
desired product 3aa in quantitative yield (Table 1, entry 9). As
Received: December 20, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03961
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Scope with Regard to Donor−Acceptor
a
Cyclopropanes
entry
Lewis acid
solvent
temp (°C)
yield (%)
1
2
3
4
5
6
AlCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
THF
60
60
60
60
60
60
60
60
60
40
0
MgI2
0
Zn(OTf)2
Yb(OTf)3
Sn(OTf)2
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
0
47
31
95
b
7
complex mixture
b
8
b
0
quant
0
9
DCE
bc
,
10
DCE
a
Reaction conditions: 1a (100 μmol), 2a (200 μmol), Lewis acid (10
mol %), solvent (2.5 mL), under Ar, 16 h; yields represent isolated and
b
c
purified products. 12 hours; DCE = dichloroethane. Only formation
of intermediate 4aa was observed.
shown in entry 10, decreasing the reaction temperature to 40
°C was detrimental to product formation.
With the optimized conditions in hand, we explored the
generality of our protocol. Thus, we subjected various D−A
cyclopropanes 1 to the standard procedure. As shown in
Scheme 2, a broad variety of starting materials was tolerated.
Phenyl substituents bearing halogens undergo the reaction with
similar outcome (3ba−3ca), whereas methoxy or acetoxy
attached to the phenyl donor show slightly less product
formation (3da−3ea). Methyl substituents in the ortho, meta,
and para positions afforded 3fa−3ha in up to quantitative yield.
Even trifluoromethyl-substituted aryl moieties (3ia) and other
markedly electron-poor phenyl units (3ja−3ka) furnished the
desired products in excellent yields. The transformation also
proceeded smoothly with the highly electron-deficient per-
fluorophenyl donor in a respectable yield of 60% (3la).
Increasing the π-system to a naphthyl residue generated the
desired product 3ma quantitatively, whereas decreasing the π-
character to a vinyl donor leads to a less efficient transformation
(3na). Decoration of the three-membered ring with annulated
cyclohexyl (3oa) or thienyl (3pa) residues provided the desired
products in moderate yield, and nitrogen donors gave products
3qa−3ra in up to 90% yield. Besides dimethyl ester acceptors,
diethyl- and dibenzyl-substituted acceptors have been shown to
undergo the reaction in good yields (3sa−3ta).
We then investigated the outcome of the reaction using
different 3-thioxocyclobutanones. Those could be accessed
from the corresponding acyl chlorides by a two-step procedure
including ketene formation under basic conditions followed by
dimerization in good yields. As shown in Scheme 3, 5- and 6-
membered carbocycles were attached to the semicyclic double
bond system. A slight decrease in the yield was observed with
increasing ring size.
To obtain deeper insight into the reaction mechanism, we
carried out several control experiments (Scheme 4). First, we
were interested in whether a ketone or ketene moiety would
also be able to insert. Therefore, we employed diketone 2a′,
which was subjected to the general reaction conditions. In this
experiment, no conversion of cyclopropane 1a was observed.
Upon using dithioketone 2a″, a complex mixture resulted, but
we were able to isolate crude 3aa in 76% yield (Scheme 4,
a
Reaction conditions: 1 (100 μmol), 2a (200 μmol), Sc(OTf)3 (10
mol %), DCE (2.5 mL), under Ar, 60 °C, 12 h; yields represent
isolated and purified products; DCE = dichloroethane.
eq 1). Next, we observed that spiro compound 4aa was
obtained in 59% yield if one used TiF4 as Lewis acid (Scheme
4, eq 2). This observation strengthened our hypothesis that the
thiocarbonyl inserts first, followed by the release of
dimethylketene, and this assumption was proven by another
experiment. Compound 4aa was subjected to the general
reaction conditions; compound 3aa resulted in nearly
quantitative yield (Scheme 4, eq 3). Interestingly, no
B
DOI: 10.1021/acs.orglett.7b03961
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Letter
(R)‑4aa′.12 Coordination of Sc(OTf)3 to the oxygen of the
ketone paves the way for the terminating cleavage of
dimethylketene,13 whereby product (R)-3aa′ is released and
Sc(OTf)3 is able to undergo the next catalytic cycle.
Scheme 3. Scope with Regard to the 3-Thioxocyclobutanone
Motif
a
The utility of the formal thioketene insertion was
demonstrated by selected further transformations (Scheme
6). Undecorated thioenol ether derivative 3aa was subjected to
Scheme 6. Follow-up Chemistry
a
Reaction conditions: 1a (200 μmol), 2 (400 μmol), Sc(OTf)3 (10
mol %), DCE (5.0 mL), under Ar, 60 °C, 12 h; yields represent
isolated and purified products; DCE = dichloroethane.
Scheme 4. Control Experiments
ozonolysis to furnish thiolactone 6 in 36% yield. Oxidation with
equimolar amounts of m-CPBA delivered sulfoxide 7 (87%) as
a single diastereomer, whereas full oxidation with an excess of
m-CPBA resulted in nearly quantitative formation of sulfone 8.
Krapcho decarboxylation with KCN in wet DMSO afforded
monoester 9 in moderate yield and a diastereomeric ratio of 6:1
with the cis-isomer being favored. Treatment with DDQ
initiated an elimination reaction to furnish dihydrothiophene
10 in 87% yield.
In summary, we have developed a new process for the formal
insertion of thioketenes into D−A cyclopropanes under Lewis
acid catalysis. 3-Thioxocyclobutanone derivatives were success-
fully utilized as thioketene surrogates and led to a broad scope
of sulfur-containing heterocycles with a semicyclic thioether
moiety. Furthermore, additional experiments gave hints of a
mechanism that follows a formal [3 + 2]-cycloaddition and a
subsequent [2 + 2]-cycloreversion releasing dialkyl ketene.
conversion of 4aa was observed if the reaction was run without
Sc(OTf)3 as Lewis acid. For proving the formation of
dimethylketene, the reaction was performed in the presence
of phenol as trapping reagent. GC-MS analysis indeed showed
the desired trapping product (see Supporting Information).
As corroborated by our control experiments, we propose the
following reaction pathway (Scheme 5). Sc(OTf)3 activates
cyclopropane (S)-1a′ by interacting with the geminal diester
moiety to allow an SN2-type nucleophilic attack of the
thioketone 2a followed by a ring-closure to intermediate
ASSOCIATED CONTENT
* Supporting Information
■
S
Scheme 5. Proposed Mechanism
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03961.
Detailed experimental procedures and analytical data for
all new compounds (PDF)
Accession Codes
CCDC 1812319 contains the supplementary crystallographic
data for this paper (3aa). These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: d.werz@tu-braunschweig.de.
ORCID
Daniel B. Werz: 0000-0002-3973-2212
C
DOI: 10.1021/acs.orglett.7b03961
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Letter
Feng, X. Angew. Chem., Int. Ed. 2015, 54, 227. (d) Xia, Y.; Lin, L.;
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was supported by the European Research Council
(ERC Consolidator Grant “GAINBYSTRAIN” to D.B.W.).
■
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