Csp3-H Trifluoromethylation of Unactivated Aliphatic Systems

Article abstract of DOI:10.1021/acs.orglett.0c03891

A straightforward method for the undirected trifluoromethylation of unactivated methylene units was developed. The reaction proceeds in aqueous acetonitrile with Grushin's reagent, bpyCu(CF3)3, under broad-spectrum white-light irradiation. The trifluoromethylation tolerates a wide range of functional groups including ketones, esters, nitriles, amides, alcohols, and carboxylic acids. The C-H cleavage step is performed via intermolecular H atom abstraction, and the selectivities across a range of methylene units are reported. Mechanistic studies offer a general reaction coordinate for the overall transformation.

Full text of DOI:10.1021/acs.orglett.0c03891

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Letter
3
Csp −H Trifluoromethylation of Unactivated Aliphatic Systems
Jiachen He, Truong N. Nguyen, Shuo Guo, and Silas P. Cook*
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sı Supporting Information
ABSTRACT: A straightforward method for the undirected trifluoromethylation
of unactivated methylene units was developed. The reaction proceeds in aqueous
acetonitrile with Grushin’s reagent, bpyCu(CF ) , under broad-spectrum white-
3
3
light irradiation. The trifluoromethylation tolerates a wide range of functional
groups including ketones, esters, nitriles, amides, alcohols, and carboxylic acids.
The C−H cleavage step is performed via intermolecular H atom abstraction, and
the selectivities across a range of methylene units are reported. Mechanistic
studies offer a general reaction coordinate for the overall transformation.
3
he introduction of fluorine atoms into small molecules
selectively and safely has become of paramount
Scheme 1. Methods for Csp −H Trifluoromethylation
T
importance across a range of industries. Numerous approved
drugs and agrochemicals possess judiciously located fluorine
1
atoms. In general, the two most common fluorinated motifs in
biologically active small molecules include simple monofluori-
nated motifs with a single C−F bond or the presence of the
2
more electron-withdrawing trifluoromethyl groupCF . The
3
installation of such motifs is driven by a variety of reasons that
range from modulating the pK of nearby functionalities,
a
dramatically changing the overall dipole of the target molecule,
and even interrupting biological oxidation of the molecule to
2
tune pharmacokinetics. What is striking about a variety of
these examples is the large percentage of aromatic C−F and
C−CF groups. Far more methods exist to target their
3
3
installation relative to aliphatic fluorination. This leads to a
dearth of such compounds in typical screening libraries and
4
underrepresentation in chemical campaigns. By expending the
toolbox for selective installation of aliphatic C−F-containing
functionality, we can expand libraries and simplify potential
chemical routes to hypothetical molecules of interest.
These issues have driven academic and industrial groups
5
alike to focus on the problem of trifluoromethylation. One
3
strategy to generate aliphatic C(sp )−CF bonds proceeds
3
through carbon-based radicals generated from carboxylic
6
,7
8,9
directed C−H functionalization, pioneered by our group in
acids or halides; however, the direct functionalization of
carbon−hydrogen (C−H) bondsthe most abundant moiety
in organic moleculesrepresents a more direct approach to
1
2
2
016, has expanded beyond fluorination to include other
13
functionalities, including trifluoromethylation (Scheme 1b).
10
Recently, Macmillan and co-workers demonstrated the
trifluoromethylation of pyrrolidine using the electrophilic
trifluoromethylation. In this context, a small number of
recent publications have sought different approaches to
3
3
convert Csp −H bonds into Csp −CF systems. While
3
Received: November 24, 2020
Published: January 14, 2021
somewhat limited at this time, the most common trifluor-
omethylation employs benzylic C−H substrates (Scheme
5
a,11
1
a).
Remarkably, similar conditions were reported near
5a
11a
simultaneously by our group and the Liu group in 2018.
Catalytic copper in combination with bpyZn(CF ) was
accomplished by Li the following year.
3
2
1
1b
Fluoroamide-
©
2021 American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c03891
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Letter
1
4
a
trifluoromethyl source of Togni’s reagent II. While these
studies offer unique solutions to these specific substrates, we
sought a more general trifluoromethylation reaction of
unactivated, aliphatic C−H bonds (Scheme 1c).
Scheme 2. Substrate Scope for Trifluoromethylation
To begin, we surveyed the reaction conditions for the
trifluoromethylation of cyclohexane with Grushin’s reagent,
bpyCu(CF ) (Table 1). The trifluoromethylation proceeded
3
3
a
Table 1. Optimization of Pertinent Reaction Parameters
b
entry
catalyst
yield (%)
1
2
3
4
5
6
7
8
9
standard conditions
without K S O
under air
no white LEDs
365 nm
110
47
66
nd
85
trace
62
trace
82
2
2
8
50 °C instead of white LEDs
0.05 M MeCN/H O (11:1)
2
MeCN/H O (1:5)
2
MeCN/H O (1:1)
2
10
11
12
13
MeCN/H O (5:1)
acetone instead of MeCN
98
trace
23
2
(CH ) COH instead of MeCH
3
3
adding (TMS) SiH
trace
3
a
Unless otherwise noted, all the reactions were run with 1a (0.2
b
mmol) and 2a (0.04 mmol) in 0.4 mL of solvent for 12 h. Yields
were determined by F NMR spectroscopy with fluorobenzene as the
1
9
internal standard.
well with or without persulfate present (Table 1, entries 1−3),
but not without light irradiation (Table 1, entries 4−6). As
Grushin’s reagent can be excited by both longwave UV and
5
a,b
blue light, the reaction proceeded well under 365 nm LED
irradiation or with broad-spectrum white-light irradiation
(
Table 1, entries 1 and 5). While the trifluoromethylation
a
All reactions were run on a 0.2 mmol scale with 1 (1 mmol) and 2a
proceeded in low yield in water, the addition of acetonitrile
cosolvent dramatically increased the yieldpresumably by
solubilizing bpyCu(CF ) (Table 1, entries 7−11). Supersilane
inhibited the reaction, suggesting a critical role for the initial
trifluoromethyl radical produced upon irradiation (Table 1,
entry 13). With the optimal conditions, more than one
trifluoromethyl from Grushin’s reagent can produce the new
carbon−carbon bond (Table 1, entry 1).
With suitable conditions for the trifluoromethylation of
cyclohexane obtained, a variety of unactivated, aliphatic
substrates were evaluated (Scheme 2). The reaction worked
reasonably well across a range of methylene substrates to
produce products 3a−3q. Moreover, the exceptionally mild
reaction conditions tolerated a number of commonly reactive
functional groups such as ketones (3c−3e), ethers (3q),
nitriles (3f), esters (3g and 3p), a range of amide derivatives
(
0.2 mmol) in 2 mL of solvent for 12 h unless otherwise noted.
b
19
Yields and regioselectivities determined by F NMR analysis of the
crude reaction mixtures with fluorobenzene as the internal standard.
3
3
5a
c
d
9
0% in 1.0 mmol scale. 24 h.
trifluoromethylation (3d, 3e, 3m, and 3p). Moreover, the yield
of certain substrates could be improved by changing the ratio
of MeCN/H O. For example, 3i was produced in only 42%
yield in 11:1 MeCN/H O, but trifluoromethylation improved
2
2
to 56% in 1:1 MeCN/H O. Consequently, these conditions
2
represent an operationally simple and convenient method for
the trifluoromethylation of a wide range of substrate classes..
With access to this unique trifluoromethylation reaction, we
sought to understand some of the fundamental steps involved
in the reaction (Scheme 3). Based on previous work
(
3h−3j, 3l), and even a free carboxylic acid (3n). The reaction
demonstrating the homolysis of Grushin’s reagent under
1
5
5a,b
could also provide Ruppert−Prakash derivative 3o. While the
reaction performed reasonably well over a range of substrates,
we were intrigued by the various selectivities observed in the
reaction. While in some cases, trifluoromethylation α to an
acidifying functional group was detected in small quantities
both long-wave UV and visible-spectrum light,
we
postulated the formation of trifluoromethyl-based radicals as
key, long-lived species in the reaction. Interestingly, we found
the combination of TEMPO and Grushin’s reagent, lacking
substrate 1, produced TEMPO−CF under the reaction
3
(3c, 3f, 3j and 3n), other systems provided no detectable a
conditions (Scheme 3a). Moreover, we found a positive
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Scheme 3. Key Mechanistic Experiments
Figure 1. Proposed mechanism.
homolyzed persulfate represents an alternative C−H abstract-
ing entity for the reaction (path a). That said, previous work by
our group has also demonstrated that the role of persulfate
may be more important for providing an ancillary ligand on
copper intermediates to lower the activation barrier to radial
5b
recombination and reductive elimination.
In summary, we have developed an efficient copper-based
system for the trifluoromethylation of unactivated methylenes
in a wide range of chemical environments with interesting
selectivities. Using simple, air- and moisture-tolerant reagents,
the efficient construction of C−CF and Si−CF bonds can be
3
3
accomplished under aqueous conditions. The reaction proved
tolerant of a range of common functional groups that should
provide a valuable transformation for practicing organic
chemists. Mechanistic studies and experiments on the relative
rates of Grushin’s reagent homolysis in different solvents
remain ongoing.
ASSOCIATED CONTENT
sı Supporting Information
■
*
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03891.
Experimental details, compound characterization, and
NMR data (PDF)
correlation between the amount of organic solvent in the
reaction with the amount of TEMPO−CF produced (entry 1
3
vs entry 2, Scheme 3a). We attribute this responsive
photophysical behavior to the lack of aqueous solubility of
bpyCu(CF ) , but studies remain ongoing. Control reactions
AUTHOR INFORMATION
Corresponding Author
■
3
3
with deuterated substrate (entries 1 and 4, Scheme 3b) and
deuterated reagents (entries 2 and 3, Scheme 3b) suggest that
the C−H bond-cleaving step is performed by the trifluor-
omethyl-based radicals produced in the reaction. To examine
whether C−H cleavage might be the slow step of the overall
transformation, we conducted a parallel KIE study (Scheme
Silas P. Cook − Department of Chemistry, Indiana University,
Bloomington, Indiana 47405-7102, United States;
orcid.org/0000-0002-3363-4259; Email: sicook@
indiana.edu
Authors
3
c). Not surprisingly, a large, positive KIE of 5.4 was observed
Jiachen He − Department of Chemistry, Indiana University,
Bloomington, Indiana 47405-7102, United States
Truong N. Nguyen − Department of Chemistry, Indiana
University, Bloomington, Indiana 47405-7102, United States
Shuo Guo − Department of Chemistry, Indiana University,
Bloomington, Indiana 47405-7102, United States
in this experiment. Taken together, these data enabled the
formulation of a mechanistic hypothesis for the overall
transformation (Figure 1).
The proposed roles for the reagents needed for the
trifluoromethylation of unactivated methylene groups is
delineated in Figure 1. The reaction likely proceeds through
the homolysis of Grushin’s reagent to generate an active,
relatively long-lived trifluoromethyl-based radical. The newly
formed trifluoromethyl-based radical can proceed through path
b to abstract a C−H bond of the substrate, thereby generating
a new carbon-based, secondary radical. This radical can
recombine with the newly formed Cu(II) species to form a
secondary alkyl copper species that undergoes rapid reductive
elimination to give the desired products 3 and inactive
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03891
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We acknowledge funds from Indiana University in partial
support of this work. We also gratefully acknowledge the NIH
■
Cu(I)CF . We cannot rule out a second path wherein
3
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(
R01GM121668). Eli Lilly & Co. and Amgen supported this
work through the Lilly Grantee Award and the Amgen Young
Investigator Award. We thank IU mass spectrometry for
HRMS spectra (NSF Grant No. CHE1726633).
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