Efficient synthesis of β-CF3/SCF3-substituted carbonyls via copper-catalyzed electrophilic ring-opening cross-coupling of cyclopropanols

Article abstract of DOI:10.1021/acs.orglett.5b00782

The first copper-catalyzed ring-opening electrophilic trifluoromethylation and trifluoromethylthiolation of cyclopropanols to form C_sp3-CF₃ and C_sp3-SCF₃ bonds have been realized. These transformations are effic

Full text of DOI:10.1021/acs.orglett.5b00782

Letter
pubs.acs.org/OrgLett
Efficient Synthesis of β‑CF3/SCF3‑Substituted Carbonyls via Copper-
Catalyzed Electrophilic Ring-Opening Cross-Coupling of
Cyclopropanols
Yong Li,§,† Zhishi Ye,§,† Tabitha M. Bellman,† Teng Chi,‡ and Mingji Dai*,†
†Department of Chemistry and Center for Cancer Research, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907,
United States
‡Department of Chemistry, Tsinghua University, Beijing 100084, China
S
* Supporting Information
ABSTRACT: The first copper-catalyzed ring-opening electrophilic
trifluoromethylation and trifluoromethylthiolation of cyclopropanols
to form Csp3−CF3 and Csp3−SCF3 bonds have been realized. These
transformations are efficient for the synthesis of β-CF3- and β-SCF3-
substituted carbonyl compounds that are otherwise challenging to
access. The reaction conditions are mild and tolerate a wide range of
functional groups. Application to a concise synthesis of LY2409021, a
glucagon receptor antagonist that is used in clinical trials for type 2 diabetes mellitus, is reported as well.
luorine-containing organic molecules have shown excep-
tional importance in numerous areas including pharmaceut-
F
ical industry, agriculture, and material sciences. Among various
fluorine-containing groups, trifluoromethyl (CF3) and trifluor-
omethylthiol (SCF3) groups often appear in life-saving drug
molecules as well as agrochemicals. Significant advances have
1
2
been made recently on the installation of CF3 and SCF3 groups
on sp2, sp, and activated sp3 (cf. allylic, benzylic, α-carbon of
carbonyls) carbons. However, synthetic options for the
introduction of these valuable groups on nonactivated aliphatic
carbons are still very limited.3
Figure 1. General hypothesis and this work.
Due to their intrinsic ring strain and straightforward synthesis,
cyclopropanols have been broadly used as starting materials in
various transition-metal-mediated or -catalyzed ring-opening
cross-coupling reactions.4 For example, palladium-catalyzed
cyclopropanol ring-opening followed by cross-coupling reactions
have been developed to form C−C bonds at the β-position.5 This
type of chemistry, however, suffers from competitive β-H
elimination to form α,β-unsaturated ketone byproducts or
requires special substrates or palladium-ligand combinations to
ensure the desired C−C bond formation. Despite the low cost of
copper catalyst,6 copper-catalyzed or -mediated cyclopropanol
ring opening cross-coupling reactions have been very rare.7 We
envisioned that cyclopropanols could be converted to various
valuable β-substituted carbonyl compounds including β-CF3/
SCF3-substituted products via copper-catalyzed ring-opening
cross-coupling reactions (Figure 1). In the catalytic cycle, the
Cu(I) catalyst would be oxidized by generic oxidant 2 to generate
Cu(II) or Cu(III) catalyst, which would then promote ring-
opening C−C bond cleavage of cyclopropanols and generate
Cu(II) or Cu(III) homoenolates 3 depending on the nature of
the Cu−Y bond. The latter would then undergo Csp3-Y bond
formation to provide product 4 and regenerate the Cu(I) catalyst.
This catalytic copper-homoenolate cross-coupling chemistry
would render cyclopropanols and the related systems as useful
alkyl cross-coupling partners to form important Csp3−Csp3 and
Csp3−heteroatom bonds.
If electrophilic trifluoromethylation or trifluoromethylthiola-
tion reagents could be used as oxidants, we expected to install CF3
or SCF3 groups at the β-position of saturated carbonyl
compounds via copper-catalyzed Csp3−CF3 or Csp3−SCF3 bond
formation, respectively (Figure 1, Y = CF3 or SCF3). This method
could provide a complementary and umpolung strategy for
synthesizing β-CF3/SCF3 substituted ketones,8 which are
otherwise challenging to access via other synthetic methods
including the conjugate additions of the corresponding CF3/
SCF3 nucleophile to α,β-unsaturated carbonyl systems.9 Due to
the rich and diverse chemistry of the carbonyl group, the β-CF3/
SCF3-substituted products could be readily converted to many
useful fluoroalkyl products as well. While mechanistically
interesting and synthetically appealing, the proposed catalytic
process from 1 to 4 is very challenging because in order to
Received: March 18, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00782
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Letter
selectively form the desired Csp3−CF3/SCF3 bond, the following
competing side reactions must be suppressed: (i) homodimeriza-
tion of 3 to form 1,6-diketones,7a (ii) elimination or oxidation to
form α,β-unsaturated enones, and (iii) protonation of 3 to form
ethyl ketones. Herein, we report the first copper-catalyzed
electrophilic trifluoromethylation and trifluoromethylthiolation
of cyclopropanols to synthesize various β-CF3/SCF-substituted
carbonyl compounds with an application to LY2409021 (17), a
glucagon receptor antagonist that is used in clinical trials for type
2 diabetes mellitus.10
We then wondered whether this new catalytic cycle could be
transferred to make β-SCF3-substituted ketones. While simply
replacing Togni reagent B with other electrophilic SCF3 reagents
did not give a satisfactory outcome, we were able to quickly
optimize the reaction (see the Supporting Information, Table 2)
and found that β-SCF3-substituted ketones could be prepared in
good to excellent yield with CuSCF3 (0.1 equiv), bipyridine (0.2
equiv), and 2.0 equiv of reagent C12 in DMSO at room
temperature. CuSCF3 is superior to other copper catalysts
because it avoided the introduction of noninnocent anionic
counterions to complicate the cross-coupling process. Again, the
substrate scope of this reaction is broad, and many functional
groups are compatible with the mild reaction conditions (Figure
3). Notably, terminal olefins that are incompatible in the β-
We started with cyclopropanol 5a (Figure 2 and the
Supporting Information, Table 1). When it was treated with
Figure 3. Substrate scope for trifluoromethylthiolation.
Figure 2. Substrate scope for trifluoromethylation. aIsolated yield
otherwise noted. b0.64 g of 6a produced. cYield based on 19F NMR.
trifluoromethylation conditions (Figure 5, 5v → 22) are well
tolerated in the trifluoromethylthiolation conditions (cf. 7v).
The β-CF3/SCF3-substituted ketone products could be readily
converted to other valuable CF3/SCF3-containing compounds
(Figure 4A and the Supporting Information, Figures 1 and 2). For
example, 6a could be transformed to indole 8 via Fisher indole
synthesis, alkyne 9 via a one-carbon homologation, or amine 10
via reductive amination reaction. It could be reduced to 11 as well,
the first-generation Togni reagent A derived from 2-iodobenzoic
acid11 in MeOH with a catalytic amount of Cu(MeCN)4BF4,
desired β-CF3 ketone 6a was produced in 40% yield but
accompanied by a significant amount of β-iodoketone and α,β-
unsaturated ketone byproducts. Further reaction optimization
did show that Togni reagent B is effective to suppress the
formation of these byproducts. Cationic copper catalyst is
necessary for high yield in comparison to CuCl, CuBr and CuTc.
Increasing the amount of reagent B to 1.5 equiv is beneficial, but
further increase results in more unidentified byproducts. Overall,
we were able to obtain desired β-CF3 ketone product 6a in 90%
yield with optimized reaction conditions. The reaction does not
take place in the absence of copper catalyst.
We then showed that this reaction is very general and tolerates
a wide range of functional groups (Figure 2). Both aryl- and alkyl-
substituted cyclopropanols worked smoothly to provide the
desired β-CF3 ketones in good to excellent yield. Bromide (6b),
aryl and alkyl ether (6a, 6d, 6g), ester (6h), primary and
secondary TBS-ether (6i and 6s), tosyl (6j), epoxide (6k), α,β-
unsaturated ester/aldehyde (6l, 6m), alcohol (6o), and amide
(6n) functional groups are also compatible with the reaction
conditions. Notably, β-CF3 aldehyde could be synthesized in
good yield as well (6r). When cyclopropanol 5t was used, a 2.4/1
mixture of products 6ta and 6tb was produced that slightly
favored product 6ta. The reaction is amenable for scale up; 6a
could be produced in a 0.64 g in 93% yield.
Figure 4. Representative transformation of β-CF3-substituted ketones
and an efficient synthesis of LY2409021.
B
DOI: 10.1021/acs.orglett.5b00782
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which renders the carbonyl group derived from cyclopropanol a
traceless group. Similar synthetic transformations could be
conducted on the corresponding β-SCF3-substituted carbonyl
products as well (see the Supporting Information, Figure 2). We
then applied the trifluoromethylation reaction to synthesize a
therapeutic candidate LY2409021 (Figure 4B). LY2409021 is a
glucagon receptor antagonist that is currently used in clinical
trials for type 2 diabetes mellitus. Its CF3-containing alkyl chain
has been shown to be critical for its activity. Our synthesis started
with β-CF3 ketone 6b. After CBS reduction and Mitsunobu
reaction with 13, 6b was converted to 14 in excellent yield and
enantioselectivity. The bromide group of 14 then served as a
convenient handle to synthesize 16 via a palladium-catalyzed
carbonylative amination reaction.13 The latter was then
converted to LY2409021 (17) upon hydrolysis.
Figure 6. Proposed catalytic cycle.
To gain information about the reaction mechanism, we
investigated the effect of TEMPO on both the trifluoromethy-
lation and trifluoromethylthiolation reactions (Figure 5). Very
would produce product 6/7 and regenerate Cu(I) catalyst. At this
stage, the possibility of involving Cu(III) intermediates (cf. B/C
→ D′ → E′ → F′ → 6/7) cannot be ruled out. Since distinct
patterns of reactivity have been observed, the trifluoromethyla-
tion and trifluoromethylthiolation reactions may proceed in
different pathways as well, and further studies are necessary to
understand these processes
In summary, the first Cu-catalyzed trifluoromethylation and
trifluoromethylthiolation of cyclopropanols have been developed
to synthesize β-CF3/SCF3-substituted carbonyl compounds. The
reaction conditions are mild and compatible with a wide range of
functional groups. The products can be readily transformed to
many other useful CF3/SCF3-containing compounds which are
otherwise difficult to access. Their potential application has been
demonstrated by preparing LY2409021, a clinical drug for type 2
diabetes mellitus. While the detailed reaction mechanisms have
not yet been understood, these two novel catalytic reaction
modes of copper-homoenolate chemistry render cyclopropanol
and related systems valuable alkyl cross-coupling partners and
open new gates for discovering new reactivity and reaction modes
for Csp3−Csp3 or Csp3−heteroatom bond formation.
Figure 5. Preliminary probe of reaction mechanisms. aYield based NMR
analysis with internal standard.
different results were obtained when a 1/1 ratio of TEMPO to B/
C was added. For the trifluoromethylation reaction, TEMPO−
CF3 (20) was obtained in 95% yield with 98% yield of 19, 37%
yield of 18, as well as 63% recovery of recycled 5a. The formation
of 20 indicates the involvement of CF3 radical, which was
supported by the conversion of cyclopropanol 5v with a terminal
olefin to double trifluoromethylated product 22.14 In the case of
trifluoromethylthiolation, no TEMPO−SCF3 (21) was obtained.
When substrate 5w was used in the trifluoromethylthiolation
reaction, 7w was produced in 54% yield, and the terminal olefin is
tolerated under the reaction conditions. In this case, no cyclized
product 23 was observed, indicating that a copper-promoted
radical cyclopropanol ring-opening process to produce an β-alkyl
radical was unlikely15 and copper-promoted β-carbon elimi-
nation might be involved to generate a copper homoenolate.
When enone 18 was subjected to the trifluoromethylation or
trifluoromethylthiolation reaction, no 6a or 7a, respectively, was
obtained, which suggest that α,β-unsaturated ketone intermedi-
ate is not involved in the production of the desired product.
With these preliminary observations, a mechanistic model
involving several plausible pathways was proposed (Figure 6).
One possibility is that the reactions may proceed with oxidation
of Cu(I) catalyst by reagent B/C to form a Cu(II) intermediate D
as well as the CF3/SCF3 radical.14 Intermediate D would then
undergo ligand exchange with cyclopropanol 5 to form E, which
would proceed with cyclopropane ring C−C bond cleavage to
provide homoenolate F.7a,b Csp3−Y bond formation from F
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and characterization for new com-
pounds are provided. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mjdai@purdue.edu.
Author Contributions
§Y.L. and Z.Y. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Xia group at Purdue University for assistance with
mass spectrometry, Dr. Philip Hipskind at Eli Lilly and Company
for discussions, the NIH for supporting shared NMR resources to
the Purdue Center for Cancer Research (P30CA023168), and
the support from the ACS Petroleum Research Foundation (PRF
No. 54896-DNI1). T.C. thanks the Tsinghua Xuetang Program
for financial support.
C
DOI: 10.1021/acs.orglett.5b00782
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DOI: 10.1021/acs.orglett.5b00782
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