Copper-Catalyzed Ring-Opening Radical Trifluoromethylation of Cycloalkanone Oximes

Article abstract of DOI:10.1021/acs.orglett.9b01803

The copper-catalyzed ring-opening C-trifluoromethylation of cycloalkanone oximes with Zn(CF₃)₂ complexes is described. The reaction proceeds in dichloromethane under mild conditions, providing an efficient and general entry to γ- or

Full text of DOI:10.1021/acs.orglett.9b01803

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Copper-Catalyzed Ring-Opening Radical Trifluoromethylation of
Cycloalkanone Oximes
Zhonglin Liu,† Haigen Shen,† Haiwen Xiao,† Zhentao Wang,*,‡ Lin Zhu,*,† and Chaozhong Li*,†,§
†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, P.R. China
‡College of Chemistry and Material Science, Shandong Agricultural University, Taian, Shandong 271018, P.R. China
§School of Materials and Chemical Engineering, Ningbo University of Technology, no. 201 Fenghua Road, Ningbo 315211, P.R.
China
S
* Supporting Information
ABSTRACT: The copper-catalyzed ring-opening C-trifluor-
omethylation of cycloalkanone oximes with Zn(CF3)2
complexes is described. The reaction proceeds in dichloro-
methane under mild conditions, providing an efficient and
general entry to γ- or δ-CF3-substituted nitriles via tandem
N−O and C(sp2)−C(sp3) bond cleavage and C(sp3)−CF3
bond formation. The protocol exhibits a broad substrate scope and wide functional group compatibility. A radical mechanism
involving the CF3 transfer from Cu(II)−CF3 complexes to alkyl radicals is proposed.
rifluoromethyl group is an important structural motif in
γ-Trifluoromethylated carboxylic acids or amides are
Tpharmaceuticals and agrochemicals. The incorporation of important structural motifs embedded in a number of
biologically active molecules. For example, γ-CF3-substituted
amide BDM41906 has been found to reduce the innate
resistance of Mycobacterium tuberculosis to ethionamide
(ETH).4 Another γ-CF3 amide 163-BP3 serves as a clickable
photoaffinity probe to effectively assess the target engagement
of inhibitors with γ-secretase in primary neuronal cells.5
However, no general method is available for the synthesis of γ-
trifluoromethylated carboxylic acid derivatives.
CF3 groups enhances the permeability of organic molecules,
making them more lipophilic and metabolically more stable. As
a consequence, C(sp3) trifluoromethylation has received
considerable attention in recent years.1 Various methods
have been developed for this purpose, including nucleophilic,
electrophilic, and radical trifluoromethylation.1 Two kinds of
radical-mediated trifluoromethylation can be found in the
literature, one based on the addition of CF3 radicals onto
unsaturated bonds and the other the trifluoromethylation of
alkyl radicals. While the former has been extensively
studied,1e,g,h,l,2 the latter3 is still in its infancy. We first
introduced the copper-mediated trifluoromethylation of alkyl
radicals in aqueous solution using (bpy)Cu(CF3)3 (bpy = 2,2′-
bipyridine) as the CF3 source.3a Copper-mediated decarbox-
ylative trifluoromethylation of aliphatic carboxylic acids and
benzylic C−H trifluoromethylation was later reported by the
groups of Liu3c and Cook3d and by our group.3b More recently,
the MacMillan group successfully accomplished decarboxyla-
tive trifluoromethylation and debromotrifluoromethylation via
the combination of photoredox and copper catalysis.3e,i We
also developed the light-free copper-catalyzed strategy for
benzylic C−H trifluoromethylation and remote C(sp3)−H
trifluoromethylation of carboxamides and sulfonamides.3f,g It is
thus desirable to develop more new methods based on alkyl
radical trifluoromethylation, especially in copper-catalyzed
manner. Herein we report the copper-catalyzed ring-opening
radical C-trifluoromethylation of cycloalkanone oximes with
Zn(CF3)3 complexes, providing not only an efficient and
general entry to γ- and δ-trifluoromethylated nitriles but also
further insight into the mechanism of trifluoromethylation of
alkyl radicals.
As a unique class of strained molecules, cyclobutanone
oximes are easily accessible and useful substrates in organic
synthesis. In particular, the reductive cleavage of the N−O
bond generates iminyl radicals6 that undergo ring-opening C−
C bond homocleavage, providing a safe entry to nitriles free
from the use of toxic cyanide ions. Such a process can be
catalyzed by transition metals (Fe, Ir, Pd, or Cu) or promoted
by photoinduced single electron transfer.7 We envisioned that
a copper-catalyzed trifluoromethylation of alkyl radicals might
be possible: The Cu(I)-initiated N−O/C−C bond cleavage of
oximes might be followed by the Cu(II)-assisted CF3 transfer
to alkyl radicals, providing γ-trifluoromethylated nitriles as the
Received: May 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01803
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
final products and regenerating the Cu(I) catalyst. However,
this design is challenging because the interaction of Cu(II)
salts with CF3 reagents such as Rupert−Prakash reagent
(Me3SiCF3)8 typically gives CF3 radicals. Furthermore, the
direct N-trifluoromethylation9 of iminyl radicals might be
competitive (vide infra).
We commenced our investigations by using 2-benzylcyclo-
butanone O-(tert-butoxycarbonyl)oxime (1aa) as the model
substrate (Table 1). Treatment of 1aa with (bpy)Cu(CF3)3 at
Information for details). Finally, the analogs of 1aa with
different O-substituents were also tested. The reaction of O-
acyl or O-benzoyl oxime 1ab or 1ac also led to the formation
of 2a, whereas O-methyl and O-H oximes failed to give the
desired product (entries 12−15, Table 1).
With the optimized conditions (entry 9, Table 1) in hand,
we set out to explore the scope of the method. As shown in
Scheme 1, a variety of 2-unsubstituted cyclobutanone oxime
esters were converted smoothly to the corresponding nitriles
2b−2p. 2-Monosubstituted cyclobutanone oxime esters under-
went chemoselective ring-opening trifluoromethylation at
Table 1. Optimization of Conditions
Scheme 1. Ring-Opening Trifluoromethylation of
Cycloalkanone Oxime Esters
a
b
entry
R
[Cu]/ligand
−/−
CuOTf/bpy
CuOTf/bpy
[CF3]
yield (%)
1
2
3
4
5
6
7
8
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Ac
(bpy)Cu(CF3)3
Togni’s reagent
Umemoto reagent
Me3SiCF3/CsF
Me3SiCF3/CsF
0
0
0
2
9
c
CuOTf/bpy
c
Cu(OTf)2/bpy
Cu(OTf)2/−
Cu(OTf)2/bpy
Cu(OTf)2/−
Cu(OTf)2/bpy
CuOTf/bpy
(bpy)Zn(CF3)2
(bpy)Zn(CF3)2
7
5
(DMPU)2Zn(CF3)2
(DMPU)2Zn(CF3)2
(DMPU)2Zn(CF3)2
(DMPU)2Zn(CF3)2
(DMPU)2Zn(CF3)2
(DMPU)2Zn(CF3)2
(DMPU)2Zn(CF3)2
(DMPU)2Zn(CF3)2
37
77
53
0
57
58
0
9
10
11
12
13
14
15
−/bpy
Cu(OTf)2/bpy
Cu(OTf)2/bpy
Cu(OTf)2/bpy
Cu(OTf)2/bpy
Bz
Me
H
0
a
Conditions: 1a (0.20 mmol), [Cu] (0.04 mmol), ligand (0.044
b
mmol), [CF3] (0.24 mmol), DCM (4.0 mL), rt, 12 h. Isolated yield
based on 1a. 3 equiv of TMSCF3 and 3 equiv of CsF were used.
c
room temperature resulted in no reaction at all (entry 1, Table
1). The reaction of 1aa with Togni’s reagent10 or Umemoto
reagent11 in the presence of CuOTf/bpy failed to give the
expected product 2a (entries 2 and 3, Table 1). However, 2a
was obtained in a low yield when Me3SiCF3/CsF was
employed as the CF3 source (entries 4 and 5, Table 1). In
these reactions (entries 2−5, Table 1), a significant amount of
CF3H was observed by 19F NMR, implying the generation of
CF3 radicals. The results urged us to try more stable CF3 anion
sources. We then chose zinc complexes (bpy)Zn(CF3)2 and
(DMPU)2Zn(CF3)2 (DMPU = 1,3-dimethyl-3,4,5,6-tetrahy-
dro-2(1H)-pyrimidinone) as CF3 sources, which could be
easily prepared from ZnEt2 and CF3I under mild conditions.12
The Cu(OTf)2-catalyzed reaction of 1aa and (bpy)Zn(CF3)2
with or without extra bpy afforded a low yield of 2a (entries 6
and 7, Table 1). However, we were delighted to find that the
treatment of 1aa with Cu(OTf)2 and (DMPU)2Zn(CF3)2 in
dichloromethane (DCM) at room temperature provided
product 2a in 37% yield (entry 8, Table 1). Further addition
of ligand bpy led to a sharp increase of product yield (entry 9,
Table 1). The reaction could also be catalyzed by CuOTf,
albeit in a lower efficiency (entry 10, Table 1). The necessity of
copper catalyst was evidenced by a control experiment (entry
11, Table 1). Further screening on the solvent and ligand
showed no improvement (see Table S1 in the Supporting
a
Conditions: 1 (0.20 mmol), Cu(OTf)2 (0.04 mmol), bpy (0.044
mmol), (DMPU)2Zn(CF3)2 (0.24 mmol), DCM (4.0 mL), rt, 12 h.
b
c
d
Isolated yield based on 1. 19F NMR yield. trans:cis = 77:23
e
determined by 2D NMR experiments. trans:cis = 94:6 determined by
f
2D NMR experiments. The reaction was performed in DCE at 50 °C.
g
dr = 50:50.
B
DOI: 10.1021/acs.orglett.9b01803
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
room temperature, providing 2q−2z and 2za in satisfactory
yields. Oxetan-3-one oximes also proved to be suitable
substrates, as evidenced by the preparation of ether 2zb. A
wide functional group compatibility was observed. For
example, esters, ketones, ethers, amides, imides, carbamates,
and thiophenes were well tolerated. Furthermore, this protocol
was also applicable to cyclopentanone oximes despite their
decreased reactivity in ring opening. By increasing the reaction
temperature to 50 °C, the ring-opening trifluoromethylation of
2-arylcyclopentanone oximes in 1,2-dichloroethane (DCE)
proceeded nicely, providing the corresponding δ-trifluorome-
thylated nitriles 3a−3d in high yields. Similarly, the reaction of
bicyclic [2.2.1] ketoxime 4a furnished 1,3-cis-substituted
cyclopentane 5a (eq 1). However, the analogous substrate
aldehyde 8c or amine 8d was readily achieved from 2l via
reductive hydrogenation (Scheme 2). Thus, the above ring-
opening of cyclobutanone oxime esters provides a general and
efficient entry to γ-trifluoromethylated carboxylic acid
derivatives.
Scheme 2. Conversion of Trifluoromethylated Product 2l
To gain further insight into the reaction mechanism, the
following mechanistic experiments were designed. The treat-
ment of (bpy)Cu(CF3)3 with ZnEt2 in DMF at 0 °C produced
cleanly the [Cu(Et)(CF3)3]− anion (9) in almost quantitative
19F NMR yield (eq 5). Complex 9 was quite stable at 0 °C. At
room temperature, the reductive elimination of 9 took place
very slowly, and EtCF3 (10) was observed in only about 3%
yield after 3 h while most of 9 remained unchanged. In sharp
contrast, the reaction of Cu(OTf)2 with excess (3 equiv)
(DMPU)2Zn(CF3)2 and BEt3/O2 (as ethyl radical source) in
DMF at 0 °C for 3 h gave EtCF3 in 18% yield, while no
complex 9 could be observed (eq 6). Furthermore, when the
reaction of cyclobutanone oxime 1b was performed at 0 °C for
12 h, the expected product 2b was formed in 45% yield along
with 35% of 1b remaining. However, no alkyl-Cu(CF3)3
complex analogous to 9 could be detected by 19F NMR
throughout the reaction. These experiments do not support the
assumption that the interaction of alkyl radicals with Cu(II)−
CF3 intermediates produces the corresponding alkylcopper-
(III) complexes.
4b without α-phenyl-substitution failed to give the expected
ring-opening product under the above optimized conditions.
Instead, the direct N-trifluoromethylated bicyclic imine was
obtained in 78% yield (see SI for details). Nevertheless, after
reoptimization of reaction conditions (Table S2), we were
pleased to find that, by lowering the amount of Cu(OTf)2 and
using (bpy)Zn(CF3)2 in place of (DMPU)2Cu(CF3)2, the
expected ring-opening product 5b was achieved in 48% yield
(eq 2). Under similar conditions, the reaction of tricyclic
ketoxime 4c afforded trifluoromethylated bicyclic product 5c
in a highly stereoselective manner (eq 3). In another case, the
ring-opening of unsaturated ketoxime 6 was followed by 5-exo
cyclization prior to C-trifluoromethylation, producing CF3-
containing cyclopentane 7 in 61% yield as a mixture of two
stereoisomers in 80:20 ratio determined by 19F NMR (eq 4).
This result not only served as a solid evidence for the radical
mechanism of the reaction but also offered a new way for the
carbotrifluoromethylation of unactivated alkenes free from the
addition of CF3 radicals. Further extension of the above
method to the ring-opening of cyclohexanone oxime esters was
unsuccessful.
ZnEt2 (1.5equiv)
(bpy)Cu(CF )3 ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→⎯ [Cu(Et)(CF )3]−
3
3
DMF,0°C,3h
(5)
9, 96%
Cu(OTf)2,bpy
(DMPU)2Zn(CF3)2
BEt3/O2 ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→ [Cu(Et)(CF )3]− + Et−CF
3
3
DMF,0°C,3h
(6)
9,not observed
10,18%
A plausible mechanism for the ring-opening trifluoromethy-
lation is shown in Figure 1. The transmetalation13 of CF3
groups to Cu(I) from trifluoromethylzinc complexes such as
(DMPU)2Zn(CF3)2 generates Cu(I)−CF3 intermediates.
The chemistry detailed above has clearly demonstrated the
generality of ring-opening trifluoromethylation. The trifluor-
omethylated nitriles thus obtained serve as versatile synthetic
intermediates. For example, γ-trifluoromethylated carboxylic
acid 8a or amide 8b could be easily obtained from ring-
opening product 2l via hydrolysis, while γ-trifluoromethylated
Figure 1. Proposed mechanism.
C
DOI: 10.1021/acs.orglett.9b01803
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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AbuSalim, D. I.; Cook, S. P. Aqueous benzylic C−H trifluoromethy-
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C. Decarboxylative trifluoromethylation of aliphatic carboxylic acids. J.
Am. Chem. Soc. 2018, 140, 6522. (f) Liu, Z.; Xiao, H.; Zhang, B.;
Shen, H.; Zhu, L.; Li, C. Copper-catalyzed remote C(sp3)−H
trifluoromethylation of carboxamides and sulfonamides. Angew.
Chem., Int. Ed. 2019, 58, 2510. (g) Xiao, H.; Liu, Z.; Shen, H.;
Zhang, B.; Zhu, L.; Li, C. Copper-catalyzed late-stage benzylic
C(sp3)−H trifluoromethylation. Chem. 2019, 5, 940. (h) Zhang, Z.;
Zhu, L.; Li, C. Copper-catalyzed carbotrifluoromethylation of
unactivated alkenes driven by trifluoromethylation of alkyl radicals.
Chin. J. Chem. 2019, 37, 452. (i) Kornfilt, D. J. P.; MacMillan, D. W.
C. Copper-catalyzed trifluoromethylation of alkyl bromides. J. Am.
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Mathys, V.; Soetaert, K.; Kiass, M.; Delorme, V.; Djaout, K.; Trebosc,
V.; Kemmer, C.; Wintjens, R.; Wohlkonig, A.; Antoine, R.; Huot, L.;
Hot, D.; Coscolla, M.; Feldmann, J.; Gagneux, S.; Locht, C.; Brodin,
P.; Gitzinger, M.; Deprez, B.; Willand, N.; Baulard, A. R. Reversion of
antibiotic resistance in Mycobacterium tuberculosis by spiroisoxazo-
line SMARt-420. Science 2017, 355, 1206. (b) Flipo, M.; Desroses,
M.; Lecat-Guillet, N.; Villemagne, B.; Blondiaux, N.; Leroux, F.;
Piveteau, C.; Mathys, V.; Flament, M.-P.; Siepmann, J.; Villeret, V.;
Wohlkonig, A.; Wintjens, R.; Soror, S. H.; Christophe, T.; Jeon, H. K.;
Locht, C.; Brodin, P.; Deprez, B.; Baulard, A. R.; Willand, N.
Ethionamide boosters. 2. Combining bioisosteric replacement and
structure-based drug design to solve pharmacokinetic issues in a series
of potent 1,2,4-oxadiazole ethR inhibitors. J. Med. Chem. 2012, 55, 68.
(5) Crump, C. J.; Murrey, H. E.; Ballard, T. E.; am Ende, C. W.; Wu,
X.; Gertsik, N.; Johnson, D. S.; Li, Y.-M. Development of sulfonamide
Ketoximes 1 is then reduced by Cu(I)−CF3, resulting in the
N−O bond cleavage of 1 and the formation of Cu(II)−CF3
intermediates. Subsequent β-scission6,7,14 of the iminyl radicals
A thus formed gives the corresponding alkyl radicals B. Further
CF3 group transfer3a,b,a,b,f,h from Cu(II)−CF3 to B affords the
trifluoromethylated products 2 along with the regeneration of
the Cu(I) catalyst.
In conclusion, we have developed a practical protocol for the
ring-opening trifluoromethylation of cycloalkanone oximes,
providing an efficient and general entry to trifluoromethylated
nitriles. As the procedure is catalytic in copper, broad in scope,
and operationally simple, the method should find important
application in the preparation of trifluoromethylated com-
pounds. The Cu(I)-mediated reductive cleavage of oxime N−
O bonds is nicely coupled with Cu(II)-assisted CF3 group
transfer, rendering the overall process catalytic in copper. More
importantly, the use of easily available (DMPU)2Zn(CF3)2 or
−
(bpy)Zn(CF3)2 as CF3 sources enables the successful
implementation of ring-opening trifluoromethylation, while
other common trifluoromethylating reagents give poor results.
This finding should inspire future development of new catalytic
radical trifluoromethylation methods of practical value.
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.9b01803.
Full experimental details, characterizations of new
1
compounds, copies of H, 13C, and 19F NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: clig@mail.sioc.ac.cn.
*E-mail: wzht423@mail.ustc.edu.cn.
*E-mail: zhulin@mail.ustc.edu.cn.
ORCID
Chaozhong Li: 0000-0002-5135-9115
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project was supported by the National Natural Science
Foundation of China (grants 21421002, 21532008, 21602239,
21801190, and 21871285), by the Strategic Priority Research
Program of the Chinese Academy of Sciences (grant
XDB20020000), and by the Shanghai Scientific and Techno-
logical Innovation Project (18JC1410600).
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DOI: 10.1021/acs.orglett.9b01803
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