Highly enantioselective synthesis of trifluoromethyl cyclopropanes by using Ru(ii)-Pheox catalysts

Article abstract of DOI:10.1039/c8cc02286k

An asymmetric synthesis of various trifluoromethyl cyclopropanes from olefins, such as vinyl ferrocene, vinyl ethers, vinyl amines, vinyl carbamates and dienes, was achieved by using Ru(ii)-Pheox catalysts. This catalytic system can function at a low catalyst loading (3 mol%) compared with those reported previously, and the desired cyclopropane products are obtained in high yields with excellent diastereoselectivity (up to >99:1) and enantioselectivity (up to 97% ee).

Full text of DOI:10.1039/c8cc02286k

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Highly Enantioselective Synthesis of Trifluoromethyl
Cyclopropanes by Using Ru(II) Pheox Catalyst
–
Received 00th January 20xx,
Accepted 00th January 20xx
Manato Kotozaki, Soda Chanthamath,* Takuji Fujii, Kazutaka Shibatomi and Seiji Iwasa*
DOI: 10.1039/x0xx00000x
www.rsc.org/
An asymmetric synthesis of various trifluoromethyl cyclopropanes trifluoromethyl cyclopropane structure have been found such
from olefins such as vinyl ferrocene, vinyl ethers, vinyl amines, as analgesic , Insecticide and antibiotic
(Figure 1).5
vinyl carbamates and dienes was achieved by using Ru(II)–Pheox Among various methods to access cyclopropane-ring
1
2
3
catalyst. This catalytic system can perform under low catalyst substructure, the efficient way is transition-metal catalyzed
loading (3 mol%) compared with previous reports, and the desired cyclopropanation of olefins with diazo compounds.6 Recently,
cyclopropane products are obtained in high yields with excellent trifluorodiazoethane (CF3CHN2) is attracting attention as an
diastereoselectivity (up to >99:1) and enantioselectivity (up to carbene precursor for the construction of trifluoromethyl-
97% ee).
containing chiral cyclopropanes. In 1943, CF3CHN2 was first
synthesized from trifluoroethylamine and sodium nitrite.7
However, CF3CHN2 did not find wide application in synthesis
because of the potentially toxic and explosive gaseous
compound for a long time. In 2010, The Carreira group
developed convenient conditions to generate CF3CHN2 in situ
in a solution.8a Since then, trifluoromethylcarbene has proven
to be a versatile intermediate for the synthesis of
trifluoromethyl-containg compounds,8,9 which have found
widespread application in medical and agricultural chemistry
due to the unique properties of CF3-functionality. To date,
however, only a few studies have addressed the problem of
developing highly enantioselective cyclopropanation reaction
(Scheme 1). In 2011, the Carreira groups described the highly
enantioselective Co(III)–salen-catalyzed synthesis of
trifluoromethylated cyclopropanes under high catalyst loading
(10 mol%).8c In 2017, the Fasan groups also developed a
biocatalytic strategy for the asymmetric synthesis of
The derivatization of organic compounds with fluorinated units
often affects their physicochemical and biological properties.1,2
Consequently, approximately 20% of all pharmaceuticals and
agrochemicals contain at least one fluorine atom.3 In particular,
trifluoromethyl cyclopropanes constitute attractive synthons
in medicinal chemistry as they combine the conformational
rigidity of three-membered rings with the unique and often
highly beneficial feature of fluorinated substituent.4 Indeed,
several biological active compound substances with
F3C
CF3
O
H
N
O
Ar
NH HN
O
O
O
Analgesic 1
NH
N
HN
O
O
O
Carreira and co-workers8c
NHR
NaNO2/H2SO4/NaOAc
Co cat. (10 mol%)
O
O
O
R
NH3Cl
R
CF3
CF3
+
Ar
Ar
20% aq. NaCl, 15 °C
CF3
OH
4
5
6
6
Insecticide 2
Antibiotic 3
Fasan and co-workers10
Figure 1 Examples of biologically relevant trifluoromethyl cyclopropane
derivatives.
Mb (H64V, V68A)
Whole cells
R
N2
R
CF3
+
Ar
Ar
KPi (pH 7)
RT
CF3
NaNO2/H+
NH2
4
F3C
Scheme 1 Highly enantioselective synthesis of trifluoromethyl
cyclopropanes.
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trifluoromethyl cyclopropanes via myoglobin catalyzed the reaction with chiral Cu(I)–Box
Journal Name
8
and Pybox 912 complexes,
addition of trifluoromethylcarbene to olefins.10 However, the which have been reported to be efficient catalysts for
bulkiness of the CF3CHN2 moiety was found to be an important asymmetric cyclopropanation reactions; however, under these
factor in providing high enantiocontrol, and the conditions, the desired product was obtained in low yield with
cyclopropanation of CF3CHN2 with olefins such as vinyl moderate enantioselectivity (Table 1, entries 8-9).
ferrocene, vinyl ethers, vinyl amines, vinyl carbamates and
With the optimized conditions in hand, we next explored
dienes has not been reported yet. Herein, we report a highly the scope and generality of the catalytic system (Table 2). First,
stereoselective asymmetric cyclopropanation of various olefins a variety of vinyl arenes were reacted with CF3CHN2. Styrene
with CF3CHN2 catalyzed by Ru(II)–Pheox complexes.11
derivatives bearing electron-donating groups, such as 4-MeO,
To implement approach, we initially tested the possibly to and 2-MeO groups, were transformed into the corresponding
carry out the Ru(II)–Pheox catalyzed cyclopropanation of p- trifluoromethyl cyclopropanes in high yields with excellent
MeO-styrene. We first examined the reaction of CF3CHN2 with diastereo- and enantioselectivities (Table 2, entries 1-2).
MeO-styrene 4a in the presence of 3 mol% of Ru(II)–Pheox 7a However, 4-Me2N-styrene showed reduced yield because of
at room temperature (Table 1, entry 1). To our delight, the side reactions. The reaction of styrene derivatives bearing
desired trifluoromethyl cyclopropane product 6a was obtained electron-withdrawing groups at the 4-position also proceeded
in 94% yield with high trans-selectivity (95:5 dr) and high with high stereoselectivity and moderate yields (Table 2,
enantioselectivity (96% trans ee). Chiral Ru(II)–Pheox catalysts entries 5-6). Moreover, vinyl ferrocene could also be
bearing
electron-donating
or
electron-withdrawing cyclopropanated to afford the corresponding product 6g in
substituents (R = OMe, NO2, CF3) provided no improvement in high yield and with high diastereo- and enantioselectivity
yield or enantioselectivity (Table 1, entries 4-6). Moreover, (Table 2, entries 7). Since ferrocene derivatives have found
performing the reaction at lower temperatures afforded widespread applications in catalytic and pharmaceutical
higher enantioselectivities (Table 1, entry 3). Next, we tested chemistry, and the incorporation of CF3-cyclopropyl motif into
this scaffold may find new applications13.
Encouraged by these results, we turned our attention to
the cyclopropanation of electron-rich olefins such as vinyl
2 | J. Name., 2012, 00, 1-3
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ethers, vinyl amines, and vinyl carbamates (Table 3). Under the diastereoselectivity slightly decreased in the cyclopropanation
optimized conditions, all reactions was proceeded in high yield of vinyl carbamate (Table 3, entry 5). This is probably due to
with high enantioselectivity. However, 4-Br phenyl vinyl ether hydrogen bonding between the N-hydrogen of the vinyl
6j showed reduced reactivity because of the electron carbamate and the fluorine of the carbenoid intermediate,
w i t h d r a w i n g p r o p e r t i e s . U n f o r t u n a t e l y , t h e which leads to a cis-selective approach of the reactants as
described
in
our
previous
report.11d
Benzyl
benzyl(vinyl)carbamate 6n also decreased diastereoselectivity
because of steric hindrance. Moreover, the cyclopropanation
of benzyl benzoyl(vinyl)carbamate 6o was also investigated
(Table 3, entry 8). Interestingly, the diastereoselectivity could
be increased to 92:8 dr, while the reactivity decreased.
Finally, to demonstrate the utility of our direct
enantioselective cyclopropanation, we prepared vinyl
cyclopropane 6p with high enantiopurity. This compound can
easily transform to trifluoromethylcyclopropane carboxylic
acid 10 by oxidative cleavage which was known to be a key
intermediate in the formation of insecticide 25a and antibiotic
35c
.
In summary, we have developed a highly stereoselective
Ru(II)–Pheox-catalyzed asymmetric cyclopropanation of
various olefins with CF3CHN2. Variously functionalized
trifluoromethyl cyclopropanes were synthesized in high yields
(up to 99%) with excellent enantioselectivity (up to 97% ee).
CF3CHN2 proved to be efficient carbene precursors for
asymmetric olefin cyclopropanation reactions catalyzed by
Ru(II)–Pheox complexes. Further investigations on the
application
of
functionalized
chiral
trifluoromethyl
cyclopropanes in organic synthesis are currently underway in
our laboratory.
This work was supported by a Grant-in-Aid for Scientific
Research (B) (No. 26288087) from the Japan Society for the
Promotion of Science.
Notes and references
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