Diastereoselective Johnson-Corey-Chaykovsky trifluoroethylidenation

Article abstract of DOI:10.1039/c5cc04991a

(2,2,2-Trifluoroethyl)diphenylsulfonium triflate was found to be an efficient ylide reagent for the Johnson-Corey-Chaykovsky reaction to afford trifluoromethyl epoxides, cyclopropanes and aziridines. Interestingly, excellent but different diastereoselectivity was observed for these transformations. Both trifluoromethyl epoxides and cyclopropanes were obtained with trans-selectivity, whereas aziridines were obtained with cis-selectivity.

Full text of DOI:10.1039/c5cc04991a

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Diastereoselective Johnson-Corey-Chaykovsky
Trifluoroethylidenation
Cite this: DOI: 10.1039/x0xx00000x
Yaya Duan,†a Bin Zhou,†a JinꢀHong Lina and JiꢀChang Xiao*a
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
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the corresponding ylide I.7 It is well known that the βꢀfluorine
(2,2,2-Trifluoroethyl)diphenylsulfonium triflate was found
to be an efficient ylide reagent for the Johnson-Corey-
Chaykovsky reaction to afford trifluoromethyl-epoxides, -
cyclopropanes and -aziridines. Interestingly, excellent but
different diastereoselectivity was observed for these
elimination is very easy to happen simultaneously with the
deprotonation of the trifluoroethyl group, leading to the formation of
alkene II. But this tendency might be offset by the presence of
fluoride ion, driving the equilibrium from II to ylide I (Scheme 1).
Therefore, if the fluoride ion is employed as the base for the
deprotonation of 1, the formation of sulfonium ylide I may be
facilitated.
transformations. Both trifluoromethyl-epoxides and
-
cyclopropanes were obtained with trans-selectivity, but
aziridines were given in cis-selectivity.
The metabolism in vivo is an important issue in the development
of pharmaceutical chemistry. A prominent strategy to slow down the
in vivo metabolism of a drug is to introduce electronꢀwithdrawing
group(s) into the drug molecule.1 Trifluoromethyl group (CF3) has
proved to be a good choice due to its strong electronꢀwithdrawing
power and its potential in modifying the physicochemical and
biological properties of organic molecules. As a result, considerable
efforts have been directed towards the exploration of efficient
methods for the incorporation of trifluoromethyl group.2 Although
cyclizationꢀtype trifluoroethylidenation reaction can not only
incorporate trifluoromethyl group into molecules, but also construct
two new CꢀX (X = O, C, N, etc) bonds and a ring structure, this
chemistry remains a significant challenge, partially due to the fact
that the commonly used methods suffer from the use of potentially
explosive reagent.3
Scheme 1. The Decomposition Process of The Ylide Reagent 1.
In continuation of our research interest in the chemistry of
fluorinated ylides,8 we have now investigated the use of sulfonium
salt
1 as a sulfonium ylide reagent in the JohnsonꢀCoreyꢀ
Chaykovsky trifluoroethylidenation reactions with the use of
fluoride as the base to afford the trifluoromethylꢀepoxides, ꢀ
cyclopropanes and ꢀaziridines. It was found that all of these reactions
proceeded rapidly with excellent diastereoselectivity (Scheme 2).
JohnsonꢀCoreyꢀChaykovsky (JCC) reaction is a wellꢀknown
cyclization protocol for the construction of threeꢀmembered rings.4
The JCC reaction of C=X bonds (X = O, C, N) with (2,2,2ꢀ
trifluoroethylidene) sulfonium ylide may be able to introduce the
trifluoromethyl moiety into molecules to furnish the corresponding
trifluoromethylꢀepoxides,
ꢀcyclopropanes
and
ꢀaziridines Scheme 2. JohnsonꢀCoreyꢀChaykovsky Trifluoroethylidenation with reagent
1.
respectively, which are valuable ring structures and have received
much attention in pharmaceuticals, agrochemicals and synthetic
chemistry.5 However, this method has never been realized despite
the fact that sulfonium salt 1 (Ph2S+CH2CF3 OTfꢀ) has already been
known for over twenty years,6 probably owing to the instability of
Serious drawbacks such as multiꢀstep synthetic procedure existed
in the reported synthesis of salt 1,6 which prompted us to explore a
convenient and scalable method for its preparation. After screening
various conditions for the reaction of different sulfides with 2,2,2ꢀ
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DOI: 10.1039/C5CC04991A
trifluoroethyl trifluoromethane ꢀsulfonate (See ESI, Table S2.1), we
finally found that diphenyl sulfide can be quarternized smoothly to
give 1 at high temperature (150 C) under neat conditions (Scheme
from Ep1’ to Ep2’ would undergo an eclipsed interaction between
the aryl group and the Ph2S or CF3 group, thus leading to the
collapse of Ep1’ and the regeneration of ylide intermediate I (mode
1’). Therefore, the reaction would be very likely to proceed via
mode 1, giving transꢀtrifluoromethylꢀepoxides predominantly.
o
3).
Scheme 3. The Synthesis of Salt 1
Using the fluoride as the base, the reaction of sulfonium salt 1
with 4ꢀnitrobenzaldehyde was initially investigated. TBAT (tetraꢀnꢀ
butylammonium difluorotriphenylsilicate) was shown to be the
suitable base for the formation of the ylide I (See ESI, Table S3.1).
After being refluxed in CH2Cl2 for 20 min in the presence of 4 Å
MS, 61% yield of the trifluoromethylꢀepoxide (3a) could be obtained
with excellent trans diastereoselectivity (trans/cis > 99/1). Its
structure was further confirmed by single crystal Xꢀray analysis9 and
the relative configuration of other products was surmised by
analogy. The reaction with other aldehydes also proceeded smoothly,
Scheme 5. The Mechanism of Epoxidation Reaction.
giving the corresponding trifluoromethylꢀepoxides with
a
To our delight, the ylide
I was also applicable to the
diastereoselectivity of above 99:1. In the case of 3k, only trace
amount of product could be detected, suggesting that the electronꢀ
donating groups on the aryl ring reduced the electrophilicity of the
aldehyde carbon toward the ylidic carbon. The substitution position
made no difference to the yield, indicating that the steric hindrance
didn’t significantly influence the epoxidation (Scheme 4). Compared
with the previously reported 2,2,2ꢀtrifluoroethyl phosphonium and
sulfone reagents which react with aldehydes to produce
trifluoromethylꢀolefins, sulfonium salt 1 shows completely different
reactivity.7bꢀe
trifluoromethylꢀcyclopropanation of vinyl ketones (Scheme 6). Since
both TBAT and TBAF were effective for this cyclopropanation,
cheaper TBAF was chosen as the suitable base (See ESI, Table
S3.2). After being stirred at room temperature for 2 h, the
corresponding cyclopropanes could be achieved in almost
quantitative yield. The relatively lower isolated yield of 5e might
result from its high volatility. The substituent on the aryl ring had no
effect on the reaction. Similar to the above epoxidation, excellent
trans diastereoselectivity (trans/cis > 99/1) could be also obtained
for this cyclopropanation. Alphatic α,βꢀunsaturated ketone such as
cyclohexyl vinyl ketone shows low reactivity (5n). EꢀPhenyl
propenyl ketone is inert under these conditions, meaning that the
reaction might be sensitive to steric effects. The transꢀconfiguration
was determined by 1Hꢀ1H NOESY analysis of product 5a (See ESI).
Scheme 4. Substrate scope of epoxidation reaction. Isolated yields. Yields in
parentheses were determined by 19F NMR.
It is believed that the ylide epoxidation proceeds via two steps,
CꢀC bond formation and ring closure via SN2ꢀlike intramolecular
nucleophilic substitution (Scheme 5). In the CꢀC bond formation
step, the intermediate Ep1 and Ep1’ might both be generated, owing
to the Coulombic interaction between the negative oxygen and
positive sulphur.10 To realize the subsequent intramolecular
nucleophilic substitution, the bond rotation from Ep1 to Ep2 or from
Ep1’ to Ep2’ must be achieved first. However, the bond rotation
Scheme 6. Substrate scope of cyclopropanation reaction. Isolated yields.
Yields in parentheses were determined by 19F NMR.
In the initial CꢀC bond formation step of the cyclopropanation, the
Coulombic interaction between the enolate anion and sulfonium
would favor the generation of the intermediate Cy1 and Cy1’
(Scheme 7). To realize the intramolecular nucleophilic substitution,
the strong eclipsed interaction similar to the above epoxidation
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might not exist during the course of the bond rotation from Cy1 to
Four different intermediates Az1, Az1’, Az2 and Az2’ might be
Cy2 or from Cy1’ to Cy2’. Nevertheless, the Coulombic interaction generated during the nucleophilic attack of the ylide I on the imine
in Cy1’ was weaker than that in Cy1, leading to the conversion from carbon (Scheme 9).13 However, the negative charge developed on
Cy1’ to Cy1 via CꢀC bond rotation in the enolate (H2CꢀCHCOAr). the nitrogen will be dispersed by the strong electronꢀwithdrawing
In addition, the steric interaction between CF3 and ArCO groups in group SO2R2, thus leading to weak Coulombic interaction between
Cy2’ might also bring about the same CꢀC bond rotation in the the positive sulfonium and the negative nitrogen in Az1 and Az1’.
enolate, resulting in the conversion from Cy2’ to Cy2. Therefore, the Besides, strong steric interaction exists in both Az1 and Az1’, and
intramolecular nucleophilic substitution of Cy2 would become the neither of these intermediates can readily undergo bond rotation to
predominant pathway of this ylide cyclopropanation.11
form Az2 and Az2’ respectively due to strong eclipsed interaction,
meaning that intramolecular nucleophilic substitution of Az1 or Az1’
to form products wouldn’t occur easily. Therefore, only Az2 and
Az2’ are considered for this aziridination reaction. Apparently,
strong steric interaction also exists in both Az2 and Az2’. Excellent
cis diastereoselectivity was observed, which should be because the
activation barrier for ring closure of Az2’ to afford cisꢀproduct is
lower, and the ring closure of Az2’ is more rapid than that of Az2, a
hypothesis which is supported by the crossover experiments
performed by the group of Aggarwal13a and DFT calculation carried
out by the group of Sunoj.13c
Scheme 7. The Mechanism of Cyclopropanation Reaction.
The successful ylide epoxidation and cyclopropanation prompted
us to further investigate the possibility of the aziridination (Scheme
8). Using TBAF as the base, the reaction of salt 1 with various Nꢀ
tosyl benzaldimines proceeded very well, giving the trifluoromethylꢀ
aziridine in high yields (7aꢀ7k, Scheme 8). Aliphatic imine can also
be converted well into the desired product (7k). NꢀMesyl imines
were also suitable substrates for this transformation (7l-7m), but Nꢀ
Boc and NꢀCbz imines show almost no reactivity toward the
aziridination under these conditions. Contrary to the above
epoxidation and cyclopropanation, the aziridination demonstrated
high cis diastereoselectivity (cis/trans
> 97/3). The relative
configuration was further confirmed by the Xꢀray analysis of 7i.12
Scheme 9. The Mechanism for Aziridination Reaction.
Conclusions
In summary, trifluoroethylsulfonium triflate 1 has been developed
into a versatile and convenient sulfur ylide reagent for Johnsonꢀ
CoreyꢀChaykovsky trifluoroethylidenation reactions. The reactions
proceeded smoothly to afford the final products with excellent
diastereoselectivity. Interestingly, trifluoromethylꢀepoxides,
ꢀ
cyclopropanes were obtained as transꢀdiastereomers, while
trifluoromethylꢀaziridines were found to be cisꢀdiastereomers.
Different diastereoselectivity observed in this ylide reaction might
result from the Coulombic interaction and steric hindrance generated
in the transition state.
Notes and references
We thank the National Natural Science Foundation (21172240, 21421002,
21472222), the 973 Program of China (2015CB931900, 2012CBA01200),
and the Chinese Academy of Sciences.
a
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China
Prof. JiꢀChang Xiao
Tel: +86ꢀ21ꢀ54925340
Fax: +86ꢀ21ꢀ64166128
Email: jchxiao@sioc.ac.cn
† These authors contributed equally to this work.
Scheme 8. Substrate scope of aziridination reaction. Isolated yields. Yields in
parentheses were determined by 19F NMR.
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