Divergent Reactivity of Thioalkynes in Lewis Acid Catalyzed Annulations with Donor–Acceptor Cyclopropanes

Article abstract of DOI:10.1002/chem.201602755

Efficient methods for the convergent synthesis of (poly)cyclic scaffolds are urgently needed in synthetic and medicinal chemistry. Herein, we describe new annulation reactions of thioalkynes with phthalimide-substituted donor–acceptor cyclopropanes, which gave access to highly substituted cyclopentenes and polycyclic ring systems. With silyl-thioalkynes, the Lewis acid catalyzed [3+2] annulation reaction with donor–acceptor cyclopropanes took place to afford 1-thio-cyclopenten-3-amines. On the other hand, an unprecedented polycyclic compound was formed with alkyl-thioalkynes through a reaction pathway directly involving the phthalimide group. The two transformations proceeded in good yields and tolerated a large variety of functional groups.

Full text of DOI:10.1002/chem.201602755

DOI: 10.1002/chem.201602755
Communication
&
Organic Synthesis
Divergent Reactivity of Thioalkynes in Lewis Acid Catalyzed
Annulations with Donor–Acceptor Cyclopropanes
Sophie Racine, Bence Hegedꢀs, Rosario Scopelliti, and Jꢁrꢂme Waser*[a]
tivity and selectivity in annulation reactions and give access to
Abstract: Efficient methods for the convergent synthesis
heteroatom-substituted ring systems. The first report of
of (poly)cyclic scaffolds are urgently needed in synthetic
a [3+2] annulation between DA cyclopropanes and ynol ethers
and medicinal chemistry. Herein, we describe new annula-
to form cyclopentenones was described by Ready and co-
tion reactions of thioalkynes with phthalimide-substituted
workers in 2008 (Scheme 1A).[7a] In 2014, Johnson and co-work-
donor–acceptor cyclopropanes, which gave access to
highly substituted cyclopentenes and polycyclic ring sys-
tems. With silyl-thioalkynes, the Lewis acid catalyzed [3+2]
annulation reaction with donor–acceptor cyclopropanes
took place to afford 1-thio-cyclopenten-3-amines. On the
other hand, an unprecedented polycyclic compound was
formed with alkyl-thioalkynes through a reaction pathway
directly involving the phthalimide group. The two trans-
formations proceeded in good yields and tolerated a large
variety of functional groups.
Synthetic methods giving access to a broad chemical diversity
in only a few steps are of great interest. There is a strong need
in the pharmaceutical and agrochemical industry for new mo-
lecular scaffolds with a rigid structure and multiple heteroatom
substitutions that allow a more specific binding to biological
targets.[1] In this context, annulation reactions of donor–accept-
or cyclopropanes (DA cyclopropanes) have been highly suc-
cessful for the synthesis of saturated carbo- and heterocycles.[2]
In particular, [3+2] and [4+2] annulations of nitrogen-based
DA cyclopropanes with aldehydes, ketones, and enol-ethers
have been extensively explored in our group and gave highly
substituted tetrahydrofuryl- and cyclopentylamines.[3] Later, an
enantioselective version of the [3+2] annulation was devel-
oped,[4] as well as the synthesis of nucleoside analogs using
nucleobase-substituted DA cyclopropanes.[5]
Scheme 1. Annulations of donor–acceptor (DA) cyclopropanes with elec-
tron-rich alkynes.
Carbonyl compounds, imines, and enol ethers are privileged
partners in Lewis acid catalyzed [3+2] annulations with DA cy-
clopropanes.[2] In contrast, alkynes remain poorly investigated
in [3+2] annulations,[6] although cyclopentenes are of great in-
terest as building blocks in organic chemistry. In particular, al-
kynes bearing adjacent heteroatoms exhibit an improved reac-
ers reported the first use of ynamides to give highly substitut-
ed cyclic enamides (Scheme 1B).[7b] Finally, Severin and co-
workers reported in collaboration with our group the only ex-
ample of a [3+2] annulation of nitrogen-based DA cyclopro-
panes and triazene-substituted alkynes (Scheme 1B).[7c]
So far, the use of thioalkynes in [3+2] annulations has not
been reported, although they have been successfully applied
in [4+2],[8a–f] [3+2][8g] and [2+2][8h–i] cycloadditions as well as in
the Pauson–Khand reaction.[8j] Only two examples of [3+2] an-
nulations of thioalkynes were reported, but none of them was
based on the use of DA cyclopropanes.[9] The development of
a [3+2] annulation between DA cyclopropanes and thioalkynes
would provide a novel easy access to 1-thio-cyclopenten-3-
[a] S. Racine, B. Hegedꢀs, Dr. R. Scopelliti, Prof. Dr. J. Waser
Laboratory of Catalysis and Organic Synthesis
Ecole Polytechnique Fꢁdꢁrale de Lausanne
EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne (Switzerland)
Fax: (+41)21-693-9700
E-mail: jerome.waser@epfl.ch
Homepage: http://lcso.epfl.ch/
Supporting information and ORCID(s) for the author(s) of this article can be
found under http://dx.doi.org/10.1002/chem.201602755.
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amines. Thio-substituted five-membered rings exhibit a bioac-
tivity against diabetes, HIV, as wells as psychological, neurolog-
ical, and proliferative disorders.[10] Furthermore, the sulfur atom
allows numerous unique chemical transformations, in addition
to the hydrolysis to ketones, which is also possible with enam-
ides and enolethers[11a] For example, vinyl sulfides are easily
turned into electron-deficient vinyl sulfones by oxidation,[11b–c]
which gives access to reductive desulfonylations,[12a–b] and Mi-
chael additions.[12c–d] Recently, we developed a new chemose-
lective alkynylation of thiols with cyclic hypervalent iodine re-
agents,[13] making thioalkynes easily accessible starting materi-
als, and therefore even more attractive partners for [3+2] an-
nulations.
Herein, we present new Lewis acid catalyzed annulations be-
tween DA cyclopropanes and thiolalkynes, giving access either
to cyclopentenes or complex polycyclic ring systems in de-
pendence on the alkyne substituent (Scheme 1C). The [3+2]
annulation of silyl-substituted thioalkynes with phthalimide
and aryl-substituted DA cyclopropanes provided a fast access
to cyclopentenes in high yield and regioselectivity. In contrast,
alkyl-substituted thioalkynes underwent an unprecedented an-
nulation process with phthalimide-substituted DA cyclopro-
panes to give access to new polycyclic ring systems, which
highlights the unique reactivity of thioalkynes.
We first investigated the [3+2] annulation of the triisopro-
pylsilyl (TIPS) thioalkyne 1a and the phthalimide DA cyclopro-
pane 2a, which has been successfully used in annulations with
enol ethers and aldehydes (Scheme 2).[3] The thioalkyne 1a
was synthesized from the corresponding thiol using commer-
cially available 1-[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-
Scheme 2. A) First attempts with the triisopropylsilyl (TIPS) thioalkyne 1a in
the [3+2] annulation with the DA cyclopropane 2a. B)?Regioselectivity in
dependence on the silyl group in 1. C) Reactions of the triethylsilyl (TES)
alkyne 1b in [3+2] annulations. Reactions in A and B with 0.07 mmol alkyne
1, in C with 0.23 mmol 1. Isolated yields after column chromatography are
reported.
3(1H)-one (TIPS-EBX) as previously reported by our group.[13a]
A
preliminary screening of Lewis acids showed that the desired
product could be obtained as a mixture of two regioisomers
(1:3 ratio) in low yield with scandium triflate as the catalyst
(Scheme 2A). Low yield and regioselectivity were also ob-
served with indium triflate, and hafnium triflate led to com-
plete degradation of the cyclopropane 2a. Zinc triflate, copper
triflate, indium chloride, and iron chloride did not give a con-
version to the desired cyclopentenamine. A comparison be-
tween TIPS, TES (triethylsilyl), and TMS (trimethylsilyl) thioal-
kynes 1a–c was then performed (Scheme 2B). The outcome of
the [3+2] reaction was strongly dependent on the hindrance
of the silane functional group. The yield increased from 29%
with TIPS to 51% with TES and then decreased to 40% with
TMS. The main regioisomer switched from the 1-thio-cyclo-
penten-5-amine 3a’ with the TIPS-thioalkyne 1a, to 1-thio-cy-
clopenten-3-amines 3b and 3c with TES and TMS-thioalkynes
1b and 1c, respectively. Complete regioselectivity was ob-
served with the TMS-thioalkyne 1c. Although the yield of 3c
could be improved to 79% when using 5 mol% of indium tri-
flate, the yields were low to moderate when other thioalkynes
were tested.[14] This was due to the substantial removal of the
TMS group under the reaction conditions. We therefore turned
our attention to more stable TES thioalkynes, which still pro-
vided good regioselectivity in the [3+2] annulation reaction.
With scandium triflate as catalyst, the yield could be increased
to 63% by using a slight excess of the cyclopropane 2a
(Scheme 2C). With indium and hafnium triflate, product 3b
was obtained with a 13:1 regioselectivity in 45% and 73%
yield, respectively.
With hafnium triflate, the catalyst loading could be lowered
to 10 mol% to provide compound 3b in 75% yield in 15 min
at room temperature (Scheme 3A). Products 3d and 3e, bear-
ing an electron-donating group on the aromatic ring, were ob-
tained in better yields than in the case of electron-withdrawing
substituents (products 3 f and 3g). A shorter reaction time
(few minutes instead of 15 min) was also observed in the case
of more electron-rich benzene rings. Primary, secondary, and
tertiary alkyl thioalkynes gave also good results. Compounds
3h–j were isolated in 79%, 81%, and 85% yield, respectively.
Finally, compound 3k was obtained in 96% yield from the
TES-benzyl thioalkyne 1k. The electronic properties of the
phthalimide cyclopropane played also an important role in the
reaction (Scheme 3B). When the [3+2] reaction was conducted
with the electron-rich methoxy-substituted phthalimide 2b the
yield dropped to 36% (product 3l). In contrast, the yield in-
creased to 96% with the nitro-substituted phthalimide 2c
(product 3m). With a maleimide substituent, a similar yield
and regioselectivity were obtained (product 3n).[15] The reac-
tion was also successful with the methoxy-phenyl-substituted
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Scheme 4. A) Discovery and B) scope of the new annulation process.
polycyclic products were isolated in good yields with thiophe-
nol derivatives (products 5a–d). When sulfur was substituted
with a pentyl or a benzyl group, the corresponding products
5e and 5 f were obtained in 61% and 65% yield, respectively.
The cascade reaction also tolerated other alkyl groups on the
alkyne, leading to compounds 5g and 5h in 78% yield. Un-
fortunately, when the reaction was conducted with phenyl-thi-
oalkynes, complete degradation was observed.
Several transformations of the compounds 3b and 5a were
then performed (Scheme 5). Our attempts to remove the TES
group with TBAF (tetrabutylammoniumfluoride) failed. Fortu-
nately, the TES group was easily removed in TFA (trifluoroacetic
acid) at 08C. The phthalimide protecting group was cleaved
using ethylene diamine under reflux in 69% yield.[3a] The vinyl
sulfide 3b was easily oxidized to the corresponding sulfone 8
in 64% yield.[11b–c] Interestingly, when compound 5a was treat-
ed with catalytic hafnium triflate, the [3+2] product 3p was
isolated in 61% yield.[17] Finally, product 5a was cleanly con-
verted to the corresponding thioester 9 in the presence of
para-toluene sulfonic acid.
Scheme 3. Scope of the [3+2] reaction between TES thioalkynes and donor–
acceptor cyclopropanes. A) Variation of the thioalkynes with 0.23 mmol
alkyne 1. B) Variation of the DA-cyclopropanes with 0.10 mmol 2. Isolated
yields after column chromatography are reported.
DA cyclopropane 2e under the same reaction conditions, af-
fording the [3+2] annulation product 3o in 70% yield and
high regioselectivity.
Next, alkyl-thioalkynes were examined. Surprisingly, when
the [3+2] reaction catalyzed by scandium triflate was conduct-
ed with the methyl-thioalkyne 4a, a new compound 5a was
isolated in 60% yield and only traces of the [3+2] product
were detected (Scheme 4A). The polycyclic structure of com-
pound 5a could be established by X-ray analysis.[16] Such par-
ticipation of the phthalimide group is unprecedented with DA
aminocyclopropanes, which highlights the unique reactivity of
thioalkynes. The scope of the cascade reaction was investigat-
ed with various alkyl-thioalkynes (Scheme 4B). The desired
We propose a speculative mechanism to explain the out-
come of the developed annulation reactions (Scheme 6).
Attack of the more nucleophilic C2 position of alkyne 1 pro-
ceeds to give the sulfonium intermediate I. In the case of the
very bulky TIPS group, steric effects dominate and favor the C1
attack. From intermediate I, two different cyclizations can
occur: attack of the malonate anion onto the thioketene to
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unique reactivity of both DA aminocyclopropanes and thioal-
kynes, and set the basis for further applications in annulation
reactions and other transformations in the future.
Acknowledgements
The EPFL and the NCCR chemical biology (funded by the Swiss
National Science Foundation) are acknowledged for financial
support.
Keywords: alkynes
·
annulation
·
donor–acceptor
cyclopropanes · Lewis acids · polycycles
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phthalimide carbonyl oxygen to give the oxonium II (path
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Received: June 10, 2016
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COMMUNICATION
Divergent reactivity: New annulation
reactions of thioalkynes with donor–ac-
ceptor aminocyclopropanes are de-
scribed. With silyl-thioalkynes, the Lewis
acid catalyzed [3+2] annulation reaction
took place to afford 1-thio-cyclopenten-
3-amines. In contrast, an unprecedented
polycyclic compound was formed with
alkyl-thioalkynes.
&
Organic Synthesis
S. Racine, B. Hegedꢀs, R. Scopelliti,
J. Waser*
&& – &&
Divergent Reactivity of Thioalkynes in
Lewis Acid Catalyzed Annulations with
Donor–Acceptor Cyclopropanes
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