Cobalt-Tertiary-Amine-Mediated Hydroxytrifluoromethylation of Alkenes with CF3Br and Atmospheric Oxygen

Article abstract of DOI:10.1021/acscatal.0c00498

The mild and efficient hydroxytrifluoromethylation of alkenes with bromotrifluoromethane (CF₃Br) and atmospheric oxygen mediated by cobalt-tertiary amine is described. This reaction proceeds with broad substrate scope and good functional group compatibility. Mechanistic studies indicate that the reaction proceeds through a radical pathway, which is enabled by combination of the previously unexplored highly efficient N-isopropyl-N,2-dimethylpropan-2-amine with Co(II) for the single electron reduction of CF₃Br to CF₃ radical.

Full text of DOI:10.1021/acscatal.0c00498

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Letter
Cobalt-Tertiary Amine Mediated Hydroxytrifluoromethylation
3
of Alkenes with CFBr and Atmospheric Oxygen
Qiankun Li, Wu Fan, Deqian Peng, Bingyin Meng, Shaohan Wang, Rui Huang, Shihao Liu, and Suhua Li
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c00498 • Publication Date (Web): 10 Mar 2020
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ACS Catalysis
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Cobalt-Tertiary Amine Mediated Hydroxytrifluoromethylation of
Alkenes with CF3Br and Atmospheric Oxygen
Qiankun Li,†,‡ Wu Fan,§ Deqian Peng,† Bingyin Meng,† Shaohan Wang,† Rui Huang,† Shihao Liu,† and
Suhua Li*,†,∥
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†School of Chemistry, Sun Yat-Sen University, Guangzhou 510275, China
‡Department of Applied Chemistry, Anhui Agricultural University, Hefei, Anhui 230036, China
§Key Laboratory of Tobacco Flavor Basic Research, Zhengzhou Tobacco Research Institute of CNTC, Zhengzhou 450001,
China
∥Key Lab of Functional Molecular Engineering of Guangdong Province, South China University of Technology, Guangzhou
510641, China.
KEYWORDS: alkene; hydroxytrifluoromethylation; bromotrifluoromethane; cobalt; tertiary amine.
ABSTRACT: The mild and efficient hydroxytrifluoromethylation of alkenes with bromotrifluoromethane (CF3Br) and atmospheric
oxygen mediated by cobalt-tertiary amine is described. This reaction proceeds with broad substrate scope and with a good
functional group compatibility. Mechanistic studies indicate the reaction proceeds through a radical pathway, which is enabled by
combination of the previously unexplored highly efficient N-isopropyl-N,2-dimethylpropan-2-amine with Co(II) for the single
electron reduction of CF3Br to CF3 radical.
Organofluorine compounds are important substrates in a
range of areas, including industrial chemicals, materials,
agrochemicals, and pharmaceuticals.1 In the context of drug
discovery, the replacement of a methyl with a trifluoromethyl
group (CF3) dramatically improves the chemical and metabolic
stability of the drug, while also increasing the lipophilicity —
all of which are key design elements when developing and
optimizing bioactive molecules.2 Over the past few decades,
great strides have been made in the development of methods
that enable the synthesis of CF3 containing molecules,3 with a
particular emphasis on the direct trifluoromethylation of
alkenes.4
Umemoto’s, and Langlois’ reagent is bromotrifluoromethane
(CF3Br),12 an inexpensive and abundant material that is used
as an effective fire extinguishant.13
Two common strategies have been developed in the
transformation of CF3Br:12a 1) converting CF3Br into a
nucleophilic CF3 with strong reducing reagents, including such
as Zn,14 Al15 or P(NEt2)3;12b, 16 2) converting CF3Br into a CF3
radical through electrochemical,17 sulfinatodehalogenation18 or
transition metal induced SET reduction such as Ir under
visible-light,19 Ni,20 Pd,21 or Pt.22
Although with similar structure, CF3Br is less reactive than
CF3I because of their reduction potential difference: CF3Br
−2.07 V, CF3I −1.52 V (on a glass-carbon cathode).23 Until
now, we find only three reports on the trifluoromethylation of
alkenes directly with CF3Br: i) Zhang group developed a
The most commonly used intermediate for this process is
the trifluoromethyl radical,5 which itself most commonly
generated by one of three major routes:6 1) single electron
transfer (SET) reduction of electrophilic trifluoromethylating
reagents such as CF3I,7 N-hydroxybenzimidoylchloride
trifluoroacetate,8 Umemoto’s reagent or Togni’s reagents9 with
photoredox or copper catalysts; 2) SET oxidation of Langlois’
reagent (CF3SO2Na) in the presence of the oxidants like
peroxides or appropriate photoredox catalysts;10 3) oxidation
of trifluoromethyl metal such as AgCF3 and CuCF3.11 Despite
much progresses, most of the existing trifluoromethylation
reagents suffer from drawbacks, such as: multiple step(s) for
the preparation, instable, expensive, or some are highly
oxidative that would cause compatibility problems. It is
therefore highly desirable to explore new methods that could
make use of inexpensive and mild trifluoromethylation
reagents.
method
of
Ir
catalyzed
visible
light
induced
hydrotrifluoromethylation of mono-substituted alkyl alkenes
(Scheme 1. a);19 ii) Kitazume group reported an example of
ultrasound-promoted
Zn
and
Cp2TiCl2
mediate
hydrotrifluoromethylation of isoprene (Scheme 1. b),24 and iii)
Wang group realized a transformation of 1,3-enynes into
fluoroalkylated
allenes
by
nickel-catalyzed
1,4-
carbofluoroalkylation via a radical relay coupling (Scheme 1.
c).20
Building upon the foundation of these studies, we
envisioned a simultaneous installation of two functional
groups onto
difunctionalization of alkenes would be a pathway to
increasing molecular complexity and would have wide
application. Herein, we report a cobalt/tertiary amine mediated
a carbon–carbon double bond — such
The primary starting material for the preparation of several
trifluoromethylation reagents, including TMSCF3, Togni’s,
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Table 1. Optimization of the tertiary aminesa
Page 2 of 7
Scheme 1. The reaction of CF3Br with alkenes.
1
2
CoCl26H2O (1 equiv)
OH
a) Hydrotrifluoromethylation of Alkenes
Amine (4 equiv)
CF3
H
+
CF3Br
fac-Ir(ppy)3
3
4
balloon CH3CN (1 mL), rt
20 ~ 24 h
+
CF3Br
Alkyl
CF3
1 mmol
Alkyl
1-1
2-1
blue LED
5
6
7
8
Et
nPr
nPr
Et
Et
b) Hydrotrifluoromethylation of isoprene
N
N
N
N
nPr
Et
Et
Zn/Cp2TiCl2
+
CF3Br
A1 NR
A3 NR
A4 NR
A2 57% (20%)
67% (4%)b,c
CF3
ultrasound
9
Et
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c) Carbotrifluoromethylation of 1,3-Enynes
N
Et
N
N
N
Et
R2
N
R3
R1
R2
OMe
Et
A5 NR
cat. [Ni]
R3-M
+
CF3Br
A6 NR
A7 NR
A8 NR
CF3
R1
Et
Cy
Cy
N
N
Me
N
N
d) Hydroxytrifluoromethylation of Alkenes (This work)
Et
A9 26% (50%)
A10 NR
A11 NR
A12 66% (9%)
93%b (1%)
R3
R1 R2
[Co]/tertiary amine
94%d (2%)
R1
R4
CF3Br
CF3
+
HO
Air (O2)
N
Et
R2
N
R4 R3
N
N
N
A13 NR
A14 NR
A16 NR
A16 NR
hydroxytrifluoromethylation of alkenes with CF3Br under mild
conditions (Scheme 1. d).
aReaction conditions: 1-1 (1.0 mmol, 1.0 equiv), CF3Br (1
atm, balloon), CoCl2•6H2O (1.0 equiv), amine (4.0 equiv),
CH3CN (1.0 mL) in 25 mL Schlenk tube, rt. Yields in the
brackets are the recovery of starting alkenes based on crude 1H
NMR. bReaction conditions: 1-1 (1.0 mmol, 1.0 equiv), CF3Br
(1 atm), CoCl2•6H2O (1.0 equiv), amine (4.0 equiv), CH3CN
(4.0 mL) in 50 mL Schlenk flask equipped with an air balloon,
Tertiary aliphatic amines have long been used as SET
reductants.25 Aiming to develop practical and simple catalytic
systems, we proposed that a combination of an appropriate
transition metal with a tertiary aliphatic amine would reduce
the CF3Br to CF3 radical through a SET process. In our initial
studies, we investigated the trifluoromethylation of styrene (1-
1) with CF3Br in the presence of 1 equiv of CoCl2•6H2O and 4
equiv of NEt3 (A1, Table 1) in CH3CN, but no product was
observed. After screening of several commercially available
tertiary amines, we found that when the reaction was
performed in the presence of Hünig's base (DIPEA, A2), the
hydroxytrifluoromethylation product 2-1 was formed in 57%
(NMR yield), with 20% of recovered styrene. We next
explored different metal salts with DIPEA as the tertiary
amine, and confirmed that cobalt was the optimal among those
screened [See Table S1 in supporting information (SI)]. These
preliminary results led to an empirical reactivity trend of this
reaction affected by tertiary amines: The reactivity is very
sensitive to the steric hindrance of the tertiary amines. Less
hindered (A1, A3, A4) and bidentate (A5), aromatic (A6) or
too bulky amines (A7) usually gave no product; proper
hindrance in the amine enable the reaction (A2, A9); bidentate
methoxyl-DIPEA (A8) would inhibit the reaction totally. With
the preliminary data and recognition of the empirical rules at
hand, we sought to improve the activity of the system by fine-
tuning of the steric hindrance around the amine. When the
ethyl group of DIPEA was replaced by a methyl, no product
was produced (A10). The same result was obtained when two
cyclohexyls replaced the two isopropyls (A11). Finally, when
N-isopropyl-N-methyl-tert-butylamine (A12) was used, the
yield improved to 66%. More to our surprise, neither
removing a methyl of isopropyl (A13), nor changing a methyl
to ethyl (A14) in A12 produced any product. No reaction was
observed when either pyridine (A15) or bipyridine (A16) were
used.
c
rt. 5% NMR yield of 3,3,3-trifluoro-1-phenylpropan-1-one
was obtained. dReaction conditions: 1-1 (1.0 mmol, 1.0 equiv),
CF3Br (3.1 equiv), Co(BF4)2•6H2O (0.3 equiv), amine (4.0
equiv), CH3CN (4.0 mL), H2O (76 μL) in 50 mL schlenk flask
equipped with an air balloon, rt.
To minimize the usage of CF3Br in the reaction, a 50 mL-
flask (for 1 mmol scale) was charged with 1 atm CF3Br (~ 3.1
mmol) and other reaction mixture first, then with an extra air
balloon. To our surprise, a 93% yield of the product 2-1 was
obtained in 4 mL of CH3CN solution, but no reaction with O2
balloon. Under the same conditions, DIPEA is much less
efficient under this optimized condition (67% yield vs. 93%
yield). Further optimization of the reaction conditions revealed
that Co(BF4)2•6H2O generally performs better than
CoCl2•6H2O after compare their reactivity performance in
different substrates (See Table S3). Finally, 0.3 equiv of
Co(BF4)2•6H2O gave similar result (94% NMR yield) at room
temperature. Control experiments revealed that removing of
either the cobalt source or the tertiary amine, gave no product
of 2-1. In addition, there is no noticeable effect of light on this
reaction (See Table S4).
With the optimized reaction conditions developed, we
explored the scope of the method with a range of alkenes (1-1
~ 1-40, Table 2). The reaction exhibited broad alkene substrate
scope: mono-, di, tri-, and even tetra-substituted alkenes
worked well, to afford the β-CF3-alchols in moderate to
excellent yields. The reaction also exhibits good functional
group tolerance, proceeding smoothly with fluoride (1-7),
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Table 2. Hydroxytrifluoromethylation of Alkenes with CF3Br: Alkene scopea
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aReaction conditions: 1 (1.0 mmol), CF3Br (3.1 equiv), Co(BF4)2•6H2O (0.3 mmol, 30 mol %), A12 (4.0 mmol), H2O (76 μL),
CH3CN (4.0 mL), rt, 24 h; Some starting alkenes were recovered based on the crude 1H NMR in some examples, see SI for details.
b65 oC. c45 oC. dReaction conditions: 1 (1.0 mmol), CF3Br (3.1 equiv), Co(BF4)2•6H2O (0.01 mmol, 1 mol %), A12 (4.0 equiv), H2O
(106 μL), DMF (4.0 mL), 80 oC, 24 h; efollowed by reduction with NaBH4 (1.0 equiv) in methanol. f50 ºC.
chloride (1-8), bromide (1-9), CF3 (1-10), ester (1-4, 1-11, 1-
31, 1-38, 1-39), amide (1-6, 1-32) and ketone (1-20, 1-35, 1-
38) functionality. Alkenes bearing heteroaryl, such as
thianaphthene (1-16), indole (1-17), quinoline (1-18), and
pyridine (1-19, 1-26), were also applicable to the reaction and
produced the corresponding products in good to high yields.
The alkene 1-24, comprising a cyclopropyl group, rendered
the product in good yield without opening of the three-
membered ring. Similarly, the cyclobutyl (1-25) also tolerates
the reaction conditions. Electron deficient acrylate (1-31) and
acrylamide (1-32) gave moderate yields of -hydroxy-β-CF3-
ester (2-31) or amide (2-32) with slight increase of
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temperature. It is noteworthy that good regio-selectivity could
be reached in this reaction from a conjugated diene (1-22).
Complex molecules with biology activities are also compatible
with this transformation: the modified estrone (1-20, 1-34),
dehydroepiandrosterone acetate (1-38), cholesteryl acetate (1-
39), and exemestane (1-35) each afforded the corresponding
products in moderate to good yields.
Page 4 of 7
radical addition with styrene producing a trifluoropropyl
radical intermediate Int 5. Meanwhile, Int 1 is reformed via
ligand exchange of Int 2 with a tertiary amine. The
intermediate Int 5 was then captured by the atmospheric O2
from air to form peroxide radical Int 6, which abstract a
hydrogen atom to form the hydroperoxide Int 7, followed by
the cobalt-tertiary amine complex Int 1 mediated reduction to
β-CF3-alchols. While the precise SET process between Int 1
and CF3Br is not fully understood at this stage, we posit that
the distance between cobalt center to the nitrogen in tertiary
amine, which is predominantly determined by the steric
hindrance of that amine, is crucial to the SET process in this
reaction based on the results in Table 1 and this mechanism.26
1
2
3
4
5
6
7
8
In order to glean mechanistic insights of the reaction,
several control experiments were performed. The cyclic
compound 4-1a (43% yield) and an aldehyde 4-1b (12%
yield), the ring-opening product 4-2a (4%) and unexpected 4-
2b (10%) were formed through radical clock substrate 3-1 and
3-2 under the standard conditions demonstrating that a radical
pathway is involved in the reaction. We reason that the
cyclopropyl of 1-24 survived in the reaction due to the double
stabilization of benzyl and tertiary radical. Isotope labelling
studies with H218O and 18O2 confirmed that the installed
oxygen atom was derived totally from the oxygen gas, which
is also supports a radical mechanism [Scheme 2, (3) and (4)].
In order to clarify whether cobalt and tertiary amine participate
the final reduction, hydroperoxide 5 was selected as a
simplified model, which was efficiently transferred into
alcohol in standard conditions without CF3Br [Scheme 2, (5)].
Control experiments show that when either cobalt or A12 is
removed, the reduction is dramatically suppressed, revealing
that both cobalt and A12 play a synergist role in the reduction.
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OH
CF3Br
[Co]-Amine
Int 1
CF3
+
R
Amine
Int 3

Br
Amine
+
[Co]-Amine
OH

[Co]-Amine
O
Int 1

F3C
Int 2
CF3
Int 4
R
Int 7

O
R
[H]
O
N
[Co]

CF3
CF3
R
R
Int 6
Int 5
[Co]-Amine
O2 (Air)
Scheme 2. Mechanism studies
Figure
1.
Proposed
Mechanism
for
the
hydroxytrifluoromethylation of alkene
In conclusion, we have described an efficient
cobalt/tertiaryamine mediated the hydroxytrifluoromethylation
of alkenes with a broad substrate scope and functional group
tolerance. The straightforward reaction employs CF3Br as the
trifluoromethyl source and atmospheric dioxygen as the source
of the hydroxyl oxygen. The reaction conditions are very mild,
and each reagent is readily available and inexpensive.
Mechanistic studies demonstrate that a radical reaction
mechanism is involved, and that the oxygen atom in hydroxy
group is derived from the atmospheric dioxygen. The
compatibility of this reaction with complex drug molecules
pave the way to its application in the late-stage drug
modification, which would greatly accelerate the drug
discovery process. In addition, we examined the reactivity of
various tertiary amines, and proposed that the efficiency of
cobalt-amine mediated SET process is largely determined by
the distance between cobalt center to the nitrogen in tertiary
amine. This understanding led to the discovery of a previously
unexplored highly efficient SET reductant N-isopropyl-N,2-
dimethylpropan-2-amine (A12).
ASSOCIATED CONTENT
AUTHOR INFORMATION
19
Based upon both previous reports10c,
and the above
Corresponding Author
described results, a plausible mechanism for the new
hydroxytrifluoromethylation reaction is proposed (Figure 1).
First, the CF3Br accepts one electron from cobalt-tertiary
amine complex Int 1 via SET, forming a cobalt-amine radical
cation Int 2, a CF3 radical and a bromide, followed by a
* Suhua Li, Email: lisuhua5@mail.sysu.edu.cn.
Notes
The authors declare the following competing financial interest(s):
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characterization data, NMR spectra (PDF)
ACKNOWLEDGMENT
The authors gratefully acknowledge financial support from Sun
Yat-Sen University, the National Natural Science Foundation of
China [21971260, 21702229 (W. F.)], Guangdong Natural
Science
Funds
for
Distinguished
Young
Scholar
(2018B030306018), the Program for Guangdong Introducing
Innovative and Entrepreneurial Teams (2017ZT07C069); the
Open Fund of the Key Laboratory of Functional Molecular
Engineering of Guangdong Province, South China University of
Technology (2018kf04). The authors are grateful to Prof. John E.
Moses of La Trobe University and Prof. Bing Gao of Hunan
University for advice and for proofreading on the manuscript. The
authors thank Mr. Bo Li in this group for reproducing the
synthesis of 2-9, 2-26 and 2-36 in Table 2.
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Catalyzed C(sp3)–C(sp3) Bond Formation Using a Hypervalent
Iodine Reagent: An Efficient Allylic Trifluoromethylation. J. Am.
Chem. Soc. 2011, 133, 16410-16413; (d) Zhu, R.; Buchwald, S. L.
Copper-Catalyzed Oxytrifluoromethylation of Unactivated Alkenes.
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