Radical C(sp2)-H Trifluoromethylation of Aldehydes in Aqueous Solution

Article abstract of DOI:10.1021/acs.orglett.8b03012

The copper-mediated C(sp²)-H trifluoromethylation of aldehydes is described. The reaction of aldehydes with (bpy)Cu(CF₃)₃, Et₃SiH, and K₂S₂O₈ in aqueous acetone at room temperatu

Full text of DOI:10.1021/acs.orglett.8b03012

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Radical C(sp2)−H Trifluoromethylation of Aldehydes in Aqueous
Solution
Pei Zhang,† Haigen Shen,‡ Lin Zhu,*,‡ Weiguo Cao,*,† and Chaozhong Li*,‡,§
†Department of Chemistry, Shanghai University, 99 Shangda Road, Shanghai 200444, China
‡Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
§School of Materials and Chemical Engineering, Ningbo University of Technology, No. 201 Fenghua Road, Ningbo 315211, China
S
* Supporting Information
ABSTRACT: The copper-mediated C(sp2)−H trifluoromethylation of
aldehydes is described. The reaction of aldehydes with (bpy)Cu(CF3)3,
Et3SiH, and K2S2O8 in aqueous acetone at room temperature provides the
corresponding trifluoromethyl ketones in satisfactory yields. The protocol is
applicable to both aliphatic and aromatic aldehydes and exhibits a broad
substrate scope and wide functional group compatibility. A mechanism involving Cu(II)-mediated trifluoromethylation of acyl
radicals is proposed.
he introduction of trifluoromethyl groups into organic
molecules is of paramount importance in pharmaceuticals
harsh reaction conditions due to their electron deficiency. It is
certainly highly desirable to develop a convenient and general
method for the synthesis of trifluoromethyl ketones.
T
and agrochemicals owing to their profound effect on properties
such as lipophilicity, permeability, and metabolic stability.1 In
this aspect, trifluoromethyl ketones are a unique class of
fluorinated compounds with important biological properties
such as covalent enzyme inhibitors.2 In the meantime, they are
versatile synthetic intermediates for trifluoromethylated
heterocycles and drugs.3 Conventional methods for the
preparation of trifluoromethyl ketones include the nucleophilic
addition of organometallic reagents to trifluoroacetates4 and
the addition of a trifluoromethyl anion to esters, acid chlorides,
or Weinreb amides5 (Figure 1a). A more general approach is
We have recently introduced the trifluoromethylation of
alkyl halides with (bpy)Cu(CF3)3 (bpy = 2,2′-bipyridine)7 via
the proposed mechanism of CF3 group transfer from Cu(II)−
CF3 intermediates to alkyl radicals.8 This method was then
extended to the decarboxylative trifluoromethylation of
aliphatic carboxylic acids9 and benzylic C(sp3)−H trifluor-
omethylation.10 These reactions dealt with alkyl radicals. We
wondered whether acyl radicals could exhibit a reactivity
similar to alkyl radicals in trifluoromethylation given that both
acyl radicals and alkyl radicals are nucleophilic.11 Herein, we
report the unprecedented C(sp2)−H trifluoromethylation of
aldehydes via acyl radical intermediacy, providing the one-step
synthesis of trifluoromethyl ketones from aldehydes (Figure
1c).
We commenced our investigations by using 6-(1,3-dioxo-
isoindolin-2-yl)hexanal (1a) as the model substrate (Table 1).
Aldehyde 1a was initially subjected to treatment with excess (3
equiv) K2S2O8 and stoichiometric amounts of (bpy)Cu(CF3)3
and triethylsilane in aqueous acetone at room temperature, a
typical combination for the trifluoromethylation of alkyl
bromides8 (entry 1, Table 1). The expected trifluoromethyl
ketone 2a was obtained in 56% yield. Adjusting the amount of
Et3SiH or K2S2O8 did not show much effect (entries 2−4,
Table 1). Increasing the amount of water resulted in a
decreased yield of 2a (entry 5, Table 1). However, when the
ratio of acetone to water was raised from 5:1 to 10:1, we were
pleased to find that 2a could be obtained in 86% 19F NMR
yield or 82% isolated yield (entry 6, Table 1). Switching the
cosolvent acetone to acetonitrile led to the decreased yield of
−
the two-step method starting from aldehydes, i.e., the CF3
addition to give trifluoromethylated carbinols followed by
oxidation (Figure 1b).6 These methods use strongly basic
nucleophiles under anhydrous conditions and, thus, suffer from
a limited substrate scope and poor functional group tolerance.
Moreover, the oxidation of trifluoromethyl carbinols requires
Received: September 20, 2018
Figure 1. Synthesis of trifluoromethyl ketones.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03012
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Optimization of Reaction Conditions
Scheme 1. C(sp2)−H Trifluoromethylation of Aldehydes
peroxide
(equiv)
yield
b
a
entry
silane (equiv)
solvent (v/v)
(%)
1
2
3
4
5
6
Et3SiH (1)
Et3SiH (1)
Et3SiH (2)
Et3SiH (2)
Et3SiH (2)
Et3SiH (2)
K2S2O8 (3)
K2S2O8 (4)
K2S2O8 (4)
K2S2O8 (5)
K2S2O8 (4)
K2S2O8 (4)
Me2CO/H2O (5:1)
Me2CO/H2O (5:1)
Me2CO/H2O (5:1)
Me2CO/H2O (5:1)
Me2CO/H2O (1:1)
56
56
61
56
28
86 (82)
Me2CO/H2O
(10:1)
7
8
Et3SiH (2)
Et3SiH (2)
K2S2O8 (4)
K2S2O8 (4)
MeCN/H2O (10:1)
CH2Cl2/H2O
(10:1)
60
0
9
Et3SiH (2)
Et3SiH (2)
Et3SiH (2)
Ph3SiH (2)
(EtO)3SiH (2)
none
BPO (4)
DTBP (4)
TBHP (4)
K2S2O8 (4)
K2S2O8 (4)
K2S2O8 (4)
none
Me2CO/H2O
(10:1)
Me2CO/H2O
(10:1)
Me2CO/H2O
(10:1)
Me2CO/H2O
(10:1)
Me2CO/H2O
(10:1)
Me2CO/H2O
(10:1)
Me2CO/H2O
(10:1)
Me2CO/H2O
(10:1)
trace
trace
trace
73
10
11
12
13
14
15
16
66
2
Et3SiH (2)
none
0
none
0
a
Conditions: 1a (0.20 mmol), (bpy)Cu(CF3)3 (0.20 mmol), solvent
b
(4.4 mL), silane, peroxide, rt, 12 h. 19F NMR yield (with PhCF3 as
the internal standard) based on 1a, and isolated yield is in
parentheses.
2a, whereas no 2a could be detected using CH2Cl2 as the
cosolvent (entries 7 and 8, Table 1). When benzoyl peroxide
(BPO), di(tert-butyl) peroxide (DTBP), or tert-butyl hydro-
peroxide (TBHP) was used in place of K2S2O8, only a trace of
amount of 2a could be observed (entries 9−11, Table 1).
Further screening on the silane indicated that Et3SiH exhibited
better performance than triphenylsilane or triethoxysilane
(entries 12 and 13, Table 1). Finally, control experiments
indicated that both Et3SiH and K2S2O8 were required for the
trifluoromethylation (entries 14−16, Table 1).
With the optimized conditions in hand (entry 6, Table 1),
we set out to examine the scope of the method, and the results
are summarized in Scheme 1. A variety of primary alkyl
aldehydes underwent efficient C(sp2)−H trifluoromethylation
providing the corresponding trifluoromethyl ketones 2a−2o in
satisfactory yields. The presence of a wide range of functional
groups was nicely tolerated by the process. For example,
ketones, esters, amides, imides, carbamates, sulfonates,
sulfonamides, nitriles, alkyl carboxylic acids, and alkyl or aryl
chlorides all proved to be compatible with the reaction.
Notably, the protocol was also applicable to aldehydes having
weak benzylic C(sp3)−H bonds, as exemplified by the
synthesis of 2i in 73% yield. No benzylic C(sp3)−H
trifluoromethylation was observed.
a
Conditions: 1 (0.30 mmol), (bpy)Cu(CF3)3 (0.30 mmol), Et3SiH
(0.60 mmol), K2S2O8 (1.2 mmol), acetone (6 mL), H2O (0.6 mL), rt,
12 h. Isolated yield based on 1. The reaction was performed under
UV irradiation (365 nm).
b
c
ing products 2p or 2q smoothly. However, the reaction of
open-chain secondary alkyl aldehydes gave the expected
products in poor (∼30%) yields along with decarbonylation
byproducts in comparable amounts. This might be attributed
to the easy decarbonylation of secondary alkyl-substituted acyl
radicals. To improve the efficiency of trifluoromethylation,
faster trapping of acyl radicals is required, which might be
possible by increasing the concentration of active Cu(II)−CF3
species responsible for trifluoromethylation. Given that the UV
photolysis of (bpy)Cu(CF3)3 produced the CF3 radical and
Cu(II)−CF3 intermediate,8 we then carried out the reaction
under UV photolysis (365 nm). Gratifyingly, the correspond-
ing trifluoromethylation products 2r−2v were achieved in
good to high yields.
Other than primary and secondary alkyl aldehydes, tertiary
alkyl aldehydes such as adamantine-1-carbaldehyde also
underwent C−H trifluoromethylation to give tert-alkyl
trifluoromethyl ketone 2x, albeit in a low yield. However,
only decarbonylative byproducts could be obtained in the
reaction of open-chain tertiary alkyl aldehydes (see SI for
details). Notably, no decarbonylative trifluoromethylation
products could be observed. Furthermore, aromatic aldehydes
We next extended the method to secondary alkyl aldehydes.
Under the optimized conditions indicated above, cycloalkyl
aldehydes such as piperidine-4-carboxaldehyde 1p or cyclo-
hexanecarboxaldehyde 1q were converted to the correspond-
B
DOI: 10.1021/acs.orglett.8b03012
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
could also be utilized to participate in the C(sp2)−H
trifluoromethylation. Under slightly altered conditions, aryl
trifluoromethyl ketones 4a and 4b were synthesized in around
60% yield from the corresponding aromatic aldehydes 3a and
3b, as shown in eq 1.
Figure 2. Proposed mechanism.
In conclusion, we have successfully developed the copper-
mediated C(sp2)−H trifluoromethylation of aldehydes in
aqueous solution, providing an efficient and general method
for the synthesis of trifluoromethyl ketones. As the procedure
is operationally simple, broad in scope, and tolerant of sensitive
functional groups, this method should find important
applications in the synthesis of trifluoromethylated molecules.
Furthermore, the proposed mechanism of CF3 group transfer
from Cu(II)−CF3 intermediates to acyl radicals should inspire
further research in this new field.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03012.
Full experimental details, characterizations of products,
1
and copies of H, 13C, and 19F NMR spectra (PDF)
The above results clearly demonstrate the broad substrate
scope and wide functional group compatibility of C(sp2)−H
trifluoromethylation of aldehydes, thus allowing the late-stage
modification of more complex molecules. For example,
cholanal 5 was converted to the corresponding trifluoromethyl
ketone 6 in 50% yield (eq 2).
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: clig@mail.sioc.ac.cn (C.L.).
*E-mail: zhulin@mail.ustc.edu.cn (L.Z.).
*E-mail: wgcao@staff.shu.edu.cn (W.C.).
The involvement of acyl radicals in the C(sp2)−H
trifluoromethylation can be inferred from the above results.
To gain further insight into the mechanism, unsaturated
aldehyde 7 was prepared as the radical probe. The reaction of 7
under the optimized conditions afforded the cyclized product 8
(eq 3). This provides unambiguous evidence for the acyl
radical intermediacy. Moreover, to rule out the possibility of
trifluoromethyl carbinol intermediacy, we prepared trifluor-
omethyl carbinol 9 according to a literature method5a and
subjected it to the treatment with Et3SiH and K2S2O8 in
aqueous solution, with or without the presence of (bpy)Cu-
(CF3)3 (eq 4). No oxidation product 10 could be observed
while 9 remained unchanged. In another experiment, upon
addition of Et3SiH into (bpy)Cu(CF3)3 solution at room
temperature, the yellowish color turned to dark brown,
indicating the reduction of the Cu(III) complex.
ORCID
Weiguo Cao: 0000-0002-6482-2877
Chaozhong Li: 0000-0002-5135-9115
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project was supported by the National Basic Research
Program of China (973 Program) (Grant 2015CB931900), by
the National Natural Science Foundation of China (Grants
21421002, 21472220, 21532008, 21602239, and 21871285),
by the Strategic Priority Research Program of the Chinese
Academy of Sciences (Grant XDB20020000), and by the
Shanghai Scientific and Technological Innovation Project
(18JC1410600).
A plausible mechanism for the C(sp2)−H trifluoromethyla-
tion is thus proposed based on the above results and our
previous findings.8,9a As shown in Figure 2, single electron
reduction of persulfate generates the SO4 radical anion that
abstracts a hydrogen atom from an aldehyde to give the
corresponding acyl radical.12 In the meantime, the reduction
(presumably by Et3SiH) or UV photolysis9a of (bpy)Cu(CF3)3
produces Cu(II)−CF3 intermediates. Further trifluoromethyl
group transfer from Cu(II)−CF3 to the acyl radical furnishes
the corresponding alkyl trifluoromethyl ketone and Cu(I) ion.
The Cu(I) ion undergoes further single electron transfer with
persulfate to generate another SO4 radical cation.
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DOI: 10.1021/acs.orglett.8b03012
Org. Lett. XXXX, XXX, XXX−XXX