Mild and Diazo-Free Synthesis of Trifluoromethyl-Cyclopropanes Using Sulfonium Ylides

Article abstract of DOI:10.1021/acs.orglett.9b00557

The synthesis of several 1,1-disubstituted trifluoromethyl-cyclopropanes (TFCPs), known as tert-butyl bioisosteres, has been achieved from the reaction between trifluoromethylalkenes and unstabilized sulfonium ylides in yields of ≤97%. This method offers

Full text of DOI:10.1021/acs.orglett.9b00557

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Mild and Diazo-Free Synthesis of Trifluoromethyl-Cyclopropanes
Using Sulfonium Ylides
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†
,†,‡,§
Patrick Cyr,*,† Joel Flynn-Robitaille, Patrick Boissarie, and Anne Marinier*
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†
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Medicinal Chemistry, Institute of Research in Immunology and Cancer, Universite de Montreal, Montreal, QC H3C 3J7, Canada
‡
́
́
́
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Departement de chimie, Faculte des Arts et Sciences, Universite de Montreal, Montreal, QC H3C 3J7, Canada
§
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́
́
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Departement de pharmacologie, Faculte de Medecine, Universite de Montreal, Montreal, QC H3C 3J7, Canada
S
* Supporting Information
ABSTRACT: The synthesis of several 1,1-disubstituted trifluor-
omethyl-cyclopropanes (TFCPs), known as tert-butyl bioisosteres,
has been achieved from the reaction between trifluoromethylalkenes
and unstabilized sulfonium ylides in yields of ≤97%. This method
offers practical access to this cyclopropyl moiety of pharmacological
interest, employing a commercially available reagent at low
temperatures. The synthesis of cyclopropanes bearing other
electron-withdrawing groups as well as trisubstituted TFCPs was
also accomplished.
compounds, a need to develop a general and efficient method
for their synthesis arose.
The classical way to synthesize TFCPs consists of a [3+2]
cycloaddition between a trifluoromethylalkene and diazo-
methane, followed by nitrogen extrusion (Scheme 1a).2b,4
he cyclopropyl moiety is widely used in drug discovery
1
Tand found in numerous pharmaceutical products. Within
this family, the 1,1-disubstituted trifluoromethyl-cyclopropane
(TFCP) motif recently emerged as a useful bioisostere of tert-
butyl substitutents, as it generally provides increased metabolic
stability, leading to improved overall pharmacokinetic proper-
ties.2 Such a benefit inspired the incorporation of the TFCP
surrogate in many pharmaceutical lead compounds displaying
biological activities in various therapeutic areas, including
autoimmune diseases [I (Figure 1)],3a epilepsy (II),3b cancer
(III),3c and chronic neurodegenerative disorders (IV).3d As a
result of the increased use of TFCPs in biologically relevant
Scheme 1. Synthesis of TFCPs
Received: February 12, 2019
Figure 1. Bioactive pharmaceutical leads bearing the TFCP motif.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00557
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
While this stepwise approach successfully produced several
therapeutic leads,2b,3a the synthetic community has been
engaged in the development of a milder and more direct
method.5 Another key improvement would consist of the use
of a bench-stable reagent that would allow safer and easier
manipulation. More precisely, Baran used a sulfinate as a
radical precursor to directly generate TFCPs from heterocycles
(Scheme 1b).6 An alternative approach was developed by
Molander; he used photoredox catalysis to generate a radical
that could subsequently add on a trifluoromethylalkene
(Scheme 1c).7 These new strategies facilitated access to
trifluoromethyl-cyclopropyl groups; however, the former is
limited to specific heterocyclic structures, and the latter
requires the use of a photochemical reactor setup and a
reagent that is not commercially available.
Therefore, we sought to develop mild and robust conditions
that could provide the desired TFCP substitution starting from
the corresponding, easily accessible,8 1,1-disubstituted trifluor-
omethylalkene. For that purpose, we envisioned using a
Corey−Chaykovsky cyclopropanation strategy (Scheme 1d).9
Such a reaction was first described by scientists at Merck Sharp
& Dohme Corp., although no yield was reported.9b On the
basis of previous studies,10 this transformation requires a
sufficiently nucleophilic sulfur ylide 2 to add to alkene 3
(Scheme 2). Intermediate 4 must then contain a leaving group
Table 1. Optimization of Reaction Conditions
b
entry cyclopropanating reagent 1
base
solvent
yield (%)
c
1
2
3
4
5
6
7
8
Me3SOI, 1a
Me3SI, 1b
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
LiHMDS
KHMDS
NaH
THF
THF
THF
DCM
toluene
DME
THF
THF
THF
THF
THF
0
c
<10
d
Ph2SMeBF4, 1c
Ph2SMeBF4, 1c
Ph2SMeBF4, 1c
Ph2SMeBF4, 1c
Ph2SMeBF4, 1c
Ph2SMeBF4, 1c
Ph2SMeBF4, 1c
Ph2SMeBF4, 1c
Ph2SMeBF4, 1c
57
48
54
42
d
d
d
52
19
32
51
9
10
11
t-BuONa
NaHMDS
e
65
a
b
Reactions were run on a 0.066 mmol scale. Yields determined from
analysis of the crude 1H NMR spectrum using triphenylmethane as an
c
internal standard. With 2.0 equiv of reagent, 4.0 equiv of base, and a
temperature gradient from −78 °C to rt. A temperature gradient
from −78 °C to rt. With 1.3 equiv of reagent and 1.6 equiv of base.
d
e
affording the desired TFCP products in yields ranging from
36% to 81% (Scheme 3, products 5a−5g). This demonstrates
the applicability of the method to relevant systems in medicinal
chemistry. When using the more electron-rich indole 3h, no
reaction occurred, most likely due to its reduced electro-
philicity. To test the necessity of having a heteroatom in the
ring attached to the trifluoromethylalkene, substituted phenyls
were also examined, displaying moderate to good yields
(Scheme 3, products 5i−5n, 50−97% yields). Gratifyingly,
electron-neutral rings 3k and 3l, as well as electron-rich ring
3n, afforded their corresponding TFCP products in good
yields (Scheme 3, 5k, 5I, and 5n, respectively), indicating that
an electron-withdrawing group is not required for the reaction
to proceed. A particularity of naphthyl product 5l is that it
could not be separated from the diphenyl sulfide byproduct
using flash chromatography. To facilitate its separation, we
decided to methylate back the diphenyl sulfide using methyl
trifluoromethanesulfonate (MeOTf) to create a salt. This
successful procedure opens the possibility of recycling the
cyclopropanating reagent, something that could be of interest
in large scale processes.
To broaden the scope of our methodology, we investigated
the applicability of the method to the synthesis of cyclo-
propanes presenting different substitution patterns. We began
by testing the cyclopropanation reaction on alkenes bearing
electron-withdrawing groups other than CF3. As could be
expected, pentafluoroethyl (7a)- and cyano (7b)-substituted
cyclopropanes (Table 2, entries 1 and 2, respectively) were
accessed with yields in the same range as those obtained for
TFCPs. On the other hand, when nitro-substituted alkene 6c
was exposed to the same reaction conditions (Table 2, entry
3), it resulted in a poor yield, probably due to the high
reactivity of the substrate.9a The cyclopropanation with
vinylsulfone 6d appeared to be less efficient than when
stabilized sulfonium ylides were employed10a but still provided
37% of 7d (Table 2, entry 4), whereas this substrate was
unreactive under Molander’s cyclopropanation conditions
(Scheme 1c).7 An interesting observation was also that 3-
nitrostyrene 6e proved to be completely unreactive to the
Scheme 2. Cyclopropanation of Trifluoromethylalkenes
with Sulfonium Ylide 2
favoring an intramolecular cyclization toward TFCP 5 instead
of undergoing fluoride elimination.9c Hence, our efforts
focused on the identification of such a reagent.
Different reagents known to be reactive in the standard
Corey−Chaykovsky cyclopropanation reaction were tested on
the medicinal chemistry-relevant scaffold 3a using NaHMDS
as the base and THF as the solvent (Table 1, entries 1−3).
Trimethylsulfoxonium iodide (Me3SOI, 1a) gave no reaction
(Table 1, entry 1), whereas the trimethylsulfonium iodide
(Me3SI, 1b) induced decomposition of the starting material
while providing small quantities of TFCP 5a (Table 1, entry
2). Only methyl(diphenyl)sulfonium tetrafluoroborate
(Ph2SMeBF4, 1c)9b,d furnished the desired TFCP-containing
product in significant quantities (Table 1, entry 3). Cherishing
the idea of developing a method using a commercially available
reagent, we selected sulfonium 1c for further optimization of
the reaction conditions. Other solvents for this reaction failed
to provide an increase in yield compared to that found with
THF (Table 1, entries 4−6). Similarly, the screening of other
bases for the cyclopropanation reaction confirmed NaHMDS
as being optimal (Table 1, entries 7−10). Decreasing the
amount of reagent 1c and base used to 1.3 and 1.6 equiv,
respectively, afforded TFCP 5a in 65% yield (Table 1, entry
11).
Once the optimized reaction conditions were established,
the substrate scope of the cyclopropanation reaction was
studied (Scheme 3). To our delight, the methodology
appeared to be quite general to a variety of heterocycles,
B
DOI: 10.1021/acs.orglett.9b00557
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Substrate Scope of Trifluoromethylalkenes
Table 2. Application to Other Substitutions on
Cyclopropanes
a
a
b
Reactions were run on a 0.44 mmol scale. Following the standard
a
b
Reactions were run on a 0.44 mmol scale. The reaction was run on
reaction conditions, the solvent was removed and the resulting
mixture was treated with 10 equiv of MeOTf in THF at rt for 16 h.
c
a 1.00 mmol scale. With 2.0 equiv of Ph2SMeBF4 and 2.3 equiv of
NaHMDS. Following the standard reaction conditions, the solvent
d
was removed and the resulting mixture was treated with 10 equiv of
MeOTf in THF at rt for 2 days.
temperatures. Moreover, substituted cyclopropanes with a
broad substitution pattern, including a variety of heterocyclic
molecules, could be synthesized using the optimized reaction
conditions. We anticipate that this new method of forming
TFCPs will facilitate the incorporation of this key tert-butyl
bioisostere in drug discovery campaigns.
reaction conditions (Table 2, entry 5). This result suggests the
possibility of chemoselectively performing the reaction on a
trifluoromethylalkene when using a substrate bearing several
alkenes.
To investigate the synthesis of trisubstituted TFCPs, various
sulfonium salts were tested. Ethyl(diphenyl)sulfonium tetra-
fluoroborate 1d (Table 2, entry 6) enabled the formation of 7f
in good yield as a mixture of stereoisomers, with a slight
selectivity toward the syn isomer. However, when benzyl-
(diphenyl)sulfonium tetrafluoroborate 1e was employed
(Table 2, entry 7), cyclopropane 7g was obtained in low
yield but with complete selectivity in favor of the syn isomer,
and most of the unreacted starting material could be cleanly
recovered (98% brsm). Both of these results display the
impacts of steric hindrance on the sulfonium reagent, which
are to decrease the reaction rate and to affect the orientation of
the sulfonium ylide during the addition.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00557.
■
S
Optimization table, experimental procedures, character-
ization data, and copies of NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: p.cyr@umontreal.ca.
*E-mail: anne.marinier@umontreal.ca.
ORCID
In summary, we have developed a straightforward method-
ology for the formation of TFCPs from readily accessible
trifluoromethylalkenes. The disclosed process allows the use of
a commercially available reagent without the need for high
Patrick Cyr: 0000-0001-5320-3483
C
DOI: 10.1021/acs.orglett.9b00557
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by the Fondation Marcel et Rolande
Gosselin and a Project Grant (PJT-153131) from the
Canadian Institutes of Health Research.
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DOI: 10.1021/acs.orglett.9b00557
Org. Lett. XXXX, XXX, XXX−XXX