Copper-Mediated Trifluoromethylation of Benzylic Csp3?H Bonds

Article abstract of DOI:10.1002/chem.201802766

Trifluoromethyl-containing compounds play a significant role in medicinal chemistry, materials and fine chemistry. Although direct C?H trifluoromethylation has been achieved on Csp²?H bonds, direct conversion of Csp³?H bonds to Csp³?CF₃ remains challenging. We report herein an efficient protocol for the selective trifluoromethylation of benzylic C?H bonds. This process is mediated by a combination Cu^III?CF₃ species and persulfate salts. A wide range of methylarenes can be selectively trifluoromethylated at the benzylic positions. A combination of experimental and theoretical mechanistic studies suggests that the reaction involves a radical intermediate and a Cu^III?CF₃ species as the CF₃ transfer reagent.

Full text of DOI:10.1002/chem.201802766

A Journal of
Accepted Article
Title: Copper Mediated Trifluoromethylation of Benzylic Csp3-H Bonds
Authors: Matthew Paeth, William Carson, Jheng-Hua Luo, David L
Tierney, Mu-Jeng Cheng, Zhi Cao, and Wei Liu
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To be cited as: Chem. Eur. J. 10.1002/chem.201802766
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Copper Mediated Trifluoromethylation of Benzylic Csp3-H Bonds
Matthew Paeth[a],‡, William Carson[a],‡, Jheng-Hua Luo[b], David Tierney[a], Zhi Cao[c], Mu-Jeng Cheng[b],,
and Wei Liu[a]*
Abstract: Trifluoromethyl-containing compounds play a significant
role in medicinal chemistry, materials and fine chemistry. Although
direct C-H trifluoromethylation has been achieved on Csp2-H bonds,
direct conversion of Csp3-H bonds to Csp3-CF3 remains challenging.
We report herein an efficient protocol for the selective
trifluoromethylation of benzylic C-H bonds. This process is mediated
by a combination CuIII-CF3 species and persulfate salts. A wide
range of methylarenes can be selectively trifluoromethylated at the
benzylic positions. A combination of experimental and theoretical
mechanistic studies suggests that the reaction involves a radical
intermediate and a CuIII-CF3 species as the CF3 transfer reagent.
is the direct conversion of Csp3-H bonds to Csp3-CF3 bonds
(Scheme 1b). Few methods have been developed for the direct
trifluoromethylation of Csp3-H bonds. Allylic C-H bond
trifluoromethylation has been achieved by Liu[8] and Wang[9]
using copper complexes as the catalysts. Direct benzylic C-H
trifluoromethylation has been achieved by Hamashima,[10] but
the methods are limited to the ortho position of ketone groups or
the para position of phenol groups. On the contrary, the analog
Csp3-H fluorination reactions have been well developed since
Groves and Lectka pioneered the radical C-H fluorination
systems.[11] In these systems, an alkyl radical is generated via C-
H abstraction, which then reacts with an electrophilic fluorination
source, forming the fluorinated product. We postulated that
direct Csp3-H trifluoromethylation reactions could be feasible if a
suitable CF3 source is identified that can transfer CF3 groups to
alkyl radicals. Recently, elegant work of Li has shown that a
Organic molecules bearing fluorine atoms have emerged
as
important
pharmaceuticals,
agrochemicals,
and
radiopharmaceuticals.[1] As many as 35% of agrochemicals and
20% of pharmaceuticals on the market contain at least one
fluorine atom.[1b, 2] Among the many fluorine-containing groups,
trifluoromethyl (CF3) groups have received considerable
attention,[1d] as the introduction of CF3 into pharmaceuticals can
substantially alter their properties, making them more bioactive,
lipophilic and metabolically stable, increasing their interaction
with target proteins and promoting their ability to cross the
blood-brain barrier.[3] As a result, the number of CF3-containing
drug molecules continues to rise every year, and therefore, it is
critical that researchers explore novel methods that allow for
efficient trifluoromethylation reactions.[3-4]
CuIII-CF3 complex can efficiently transfer a CF3 group to an alkyl
12]
radical.[7d,
Inspired by these results, we report herein a
general method for the direct trifluoromethylation of benzylic
Csp3-H bonds (Scheme 1).
CF3 groups are mostly incorporated at aromatic rings in
pharmaceuticals and agrochemicals, partially due to the well-
developed methods for the construction of arene-CF3 moieties
compared to less explored Csp3 trifluoromethylation.[5] For
example, palladium[5b-f] and copper[5g-r] complexes have been
widely utilized to mediate/catalyze the cross-coupling reactions
of
aryl-halides
with
various
CF3 reagents.
Direct
trifluoromethylation of arenes and heteroarenes has been made
feasible via the in-situ generation of CF3 radicals (Scheme 1a).[6]
Facile introduction of a CF3 group on organic molecules at Csp3
positions are also as formidable challenges in synthetic
chemistry. Currently, Csp3-CF3 bonds are usually formed via the
transformation of existing functional groups.[7]
Scheme 1. Previous art and current work on trifluoromethylation
We started our study by using 4-tertbutyltoluene as the
model substrate. An extensive study of oxidants and CF3
An under-explored opportunity in Csp3 trifluoromethylation
species revealed that
(compound 1), Zn(CH3)2 and (NH4)2S2O8 promoted the
conversion of 4-tertbutyltoluene to its benzylic
a
combination of CuIIIbpy(CF3)3
[a]
M. Paeth, W. Carson, Prof. Dr. D. Tierney，Prof. Dr. W. Liu
Department of Chemistry and Biochemistry
Miami University
trifluoromethylated product in a mixture of CH3CN/H2O at 45C
(Table 1, entry 1). 1 was first pretreated with Zn(CH3)2 for 30
min. Trace amounts of ring trifluoromethylated product were
observed under this condition. The choice of the persulfate salt
is vital to the reaction, as other persulfate salts including sodium
persulfate and potassium persulfate afforded lower yield (entry
2 and 3). Other oxidants, including NHPI and its tetrachloro-
analogue Cl4NHPI, failed to afford any products despite their
known ability to break strong Csp3-H bonds (entry 4 and 5).[13]
Decreased yields were observed at lower or elevated
651. E. High Street, Oxford, Ohio, 45056
E-mail: wei.liu@miamioh.edu
‡These author contributed equally to this work.
J-H Luo, Prof. Dr. M-J Cheng
Department of Chemistry
[b]
[c]
National Cheng Kung University
1 University Road, Tainan City, Taiwan
E-mail: mjcheng@mail.ncku.edu.tw
Synfuels China, Beijing, 100195 and Institute of Coal Chemistry,
Chinese Academy of Sciences,
Taiyuan, Shanxi, 030001, China
temperatures (entry
acetonitrile/water is crucial for the success of this reaction. No
products were formed in the absence of water, and other
6
and 7).
A
combination of
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10.1002/chem.201802766
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most likely due to the presence of electron-withdrawing groups
on the other benzylic position as well as the steric hindrance.
Although free amines are not tolerated under the oxidative
trifluoromethylation conditions, amines protected with common
protecting groups can be successfully trifluoromethylated at the
benzylic positions (19-20).
combinations of CH3CN/water afforded diminished yields (entry
8). Replacement of acetonitrile with other organic solvents led to
poor yields (entry 9). We have also synthesized a series of new
CuIII-CF3 compounds to test the effect of the bipyridine ligands
on this reaction (entry 11-13). Although the introduction of
methoxy and methyl groups at the 4,4’ positions of bipyridine did
not improve the yield of the reaction, bipyridine bearing two tert-
butyl groups afforded similar results as compound 1 (entry 12).
Finally, control experiments have shown that in the absence of
dimethylzinc or (NH4)2S2O8, no trifluoromethylated products were
formed.
Table 1. Reaction optimization
entry
variation from the standard conditions
yieldb (%)
benzylic/ring
1
2
Nonea
Na2S2O8 instead of
K2S2O8 instead of (NH4)2S2O8
NHPIc instead of (NH4)2S2O8
Cl4NHPIe instead of (NH4)2S2O8
Reaction run at 40°C
Reaction run at 55°C
Pure MeCN as solvent
DCM instead of MeCN
2 instead of 1
67%
53%
46%
0%
12:1
9:1
3
6:1
4
N.D.d
N.D.
5.6:1
2.5:1
N.D.
N.D.
7:1
5
0%
6
36%
32%
6%
7
8
9
2%
Figure 1. Substrate scope of the copper mediated benzylic C-H
a
trifluoromethylation reaction. Isolated yields of pure compounds. 19F NMR
10
11
12
13
14
15
51%
32%
65%
19%
0%
yields due to volatility of the products. b2.5 equiv. of 4 was used instead of 1. c
reaction was run at 50°C with 3 equiv. of 1 and 3 equiv. of (NH4)2S2O8
3 instead of 1
6.7:1
11.1:1
1.3:1
N.D.
N.D.
4 instead of 1
5 instead of 1
No Zn(Me)2
We then further explored the utilities of this method for
constructing benzylic trifluoromethyl molecules. First, we
expanded the reactions to a gram scale. Despite the fact that
stoichiometric amounts of 1 are used in this reaction, its
synthesis can be easily scaled up. Although previous methods
for the synthesis of 1 required either large excess of TMSCF3 or
tedious column chromatography purification,[14] we found that it
can be synthesized from a one-step procedure and purified by
crystallization in CH2Cl2. This allowed us to synthesize 1 in a
large scale without column chromatography (Figure 2a). In
addition, when the trifluoromethylation of 4-methylphenylacetone
was run on a gram scale, the desired product was obtained in
49% yield (Figure 2b). Moreover, given that late-stage
trifluoromethylation of bioactive molecules is highly useful in the
area of medicinal chemistry and agrochemicals, we have applied
our protocol to a derivative of a non-natural amino acid, 4-
methylphenylalanine, and a systemic fungicide, Iprovalicarb.
Delightfully, both of these two bioactive molecules can be
selectively trifluoromethylated at the arene methyl group without
affecting other functional groups (Figure 2c-d). It is noteworthy
that these trifluoromethylated analogues of bioactive molecules
could be difficult to achieve and require multiple-step synthesis
by other known methods.
No (NH4)2S2O8
0%
[a] Reactions were carried out on a 0.07 mmol scale in 1.2 mL MeCN and
0.6 mL H2O. [b] Determined by 19FNMR using 1-fluoro-3-nitrobenzene as the
internal standard. [c] NHPI
= N-hydroxyphthalimide. [d] N.D. = not
determined. [e] Cl4NHPId = tetrachloro N-hydroxyphthalimide;
With the optimized conditions in hand, we then investigated
the scope of this trifluoromethylation protocol. As shown in
Figure 1, good reactivity was observed with a wide range of
methylarenes. This method tolerates various functional groups,
including alkyl, halide, ester, acetyl, nitrile, amide and acetoxy
groups. Different petroleum derived hydrocarbons including
toluene and xylenes can be selectively trifluoromethylated at the
benzylic positions (Figure 1, 7-10). In addition, the fact that
different halogens (11-15) were well tolerated is interesting as
this could allow further modification of the trifluoromethylated
products. Substrates bearing two benzylic positions can be
selectively trifluoromethylated at the methyl position (16 -20),
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known to form [MeCu(CF3)3]- 21 which displays two 19F NMR
peaks at -30.1 and -32.0 ppm.[12] In the presence of substrate
and (NH4)2S2O8, the peaks of 21 decreased gradually with
simultaneous formation of CH3CF3 and the product (Figure S1).
This result suggests that once compound 1 undergoes reductive
elimination to form CH3CF3, a reactive species is formed to
abstract the hydrogen from the substrate and form the product.
In addition, EPR experiments have shown that bipyridine bound
CuII species were also formed in the reaction mixture (Figure
S2).
A possible mechanism is proposed to account for the
above experimental observations (Figure 4). The reductive
elimination of 21 affords [CuI(CF3)2]−, 22. In the presence of
bipyridine and persulfate, 22, is oxidized to form CuIIbpyCF3, 23,
with the concurrent formation of one equivalent of a sulfate
2-
Figure 2. Synthetic application of the copper mediated benzylic C-H
trifluoromethylation reaction. a) gram-scale synthesis of compound 1. b) gram-
scale trifluoromethylation of 4-methylphenylacetone. c) selective benzylic
radical anion (SO4¯). Reactions between S2O8 and transition
metals to form SO4 are well documented in literature[15] The
highly reactive SO4 can abstract a hydrogen atom from the
¯
¯
trifluoromethylation of
a non-natural amino acid derivative. d) selective
substrate to form a benzyl radical. Compound 23 can react with
the benzyl radical undergoing a single electron transfer, to form
a benzyl-bound CuIII species 24. Compound 24 then undergoes
reductive elimination, affording the product and a CuICF3
compound 25.
benzylic trifluoromethylation of Iprovalicarb; the unreacted starting material
was subjected to the same trifluoromethylation protocol and the yield was
determined by combining the purified products in both reactions (rsm 1×).
The mechanism of the reaction was then studied. When
the trifluoromethylation of 4-tertbutyltoluene was conducted in
the presence of 2 equiv. of CBrCl3, brominated product was
formed at the expense of 6. In addition, no trifluoromethylated
products were observed when the reaction is conducted in the
presence of TEMPO. Furthermore, when the reaction is
conducted under an air atmosphere, the formation of 6 is also
suppressed while benzylic alcohol and aldehyde were generated
in 15% and 37% yields, respectively. A competition deuterium
kinetic isotope effect (KIE) study, employing a 1:1 mixture of
toluene and toluene-d8 revealed a KIE value of 3.1 ± 0.4. This
value suggests that C-H cleavage is partially rate-determining in
the overall reaction.
CH3
III
reductive
bipyridine
elimination
+
Cu
CF3
21
CuI
SO4
N
N
CF3
CF3
2-
F3C
F3C
S2O8
CuII
CH3CF3
F3C
CF3
22
23
CH2
CH3
SO4
H abstraction
Zn(CH3)2
1
substrate
N
CH2CF3
N
reductive
elimination
CuIII
N
N
+
I
CF3
F3C
Cu
CF3
product
25
24
Figure 4. Proposed mechanism for the copper mediated benzylic C-H
trifluoromethylation.
We have also used density functional theory (DFT, B3LYP
favor) combined with the Poisson−Boltzmann continuum
solvation model to calculate the Gibbs free energy surface (see
SI). We found that 21 can be converted to 22 + CH3CF3(g)
through reductive elimination with G‡ = 25.2 kcal/mol and ∆G = -
64.1 kcal/mol. This is followed by oxidation of 22 to [CuII(CF3)2]
−
2
(calculated E = 1.78 V vs SHE, see SI for details) by S2O8 or
−

SO4
(E = 2.43 V vs SHE[16]). The subsequent ligation of
Figure 3. Probing the C-H abstraction step. a. trifluoromethylation reaction is
inhibited by TEMPO. b. Brominated product is formed in the presence of
CBrCl3. c. KIE experiments using 1:1 toluene and toluene-d8.
bipyridine to [CuII(CF3)2] is downhill by 22.2 kcal/mol. An
alternative pathway, in which a bipyrine bound CuI species
[bpyCuI(CF3)2]− is oxidized to 23, was less likely, as we found
bipyridine was unable to bind to 22 (see SI).
The transfer of CF3 from Cu to the benzyl radical is
particularly interesting and our DFT calculation results (Figure
5) have shown that the benzyl radical binds to [CuIIbpy(CF3)2] 23
to form [CuIIIbpy(CF3)2(CH2Ph)] 24 with a low kinetic barrier (G‡
= 4.2 kcal/mol and ∆G = -8.5 kcal/mol). PhCH2CF3 is formed
We further planned to understand how the CF3 group is
transferred from Cu to the benzyl radical. We monitored the
trifluoromethylation of 4-tertbutyltoluene by both 19F NMR and
EPR. Treatment of 1 with Zn(CH3)2 at room temperature is
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through the reductive elimination of 24 with G‡ = 21.8 kcal/mol
and ∆G = -40.9 kcal/mol. All of the calculated G‡’s are less than
30.0 kcal/mol, indicating that they are thermally surmountable.
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△
G
(kcal/mol)
N
N
CuIII
F3C
CF3
H2C
N
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CuIII
F3C
H2C
CF3
13.3
4.2
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0.0
CH2
-8.5
N
I
N
N
N
+
Cu
CuII
CF3
F3C
CF3
N
N
25
CuIII
F3C
H2C
23
CF3
CH2CF3
24
-49.4
Figure 5. Calculated free energy profile for the transfer of CF3 from Cu to the
benzyl radical.
In summary, we have developed a general method for the
conversion of benzylic C-H bonds to C-CF3 bonds. This reaction
is conducted in mild conditions and tolerated by a wide range of
common functional groups. A combination of experimental and
theoretical experiments has provided insights into the
mechanism of the reaction. We expect that this new Csp3-H
trifluoromethylation reaction will allow medicinal chemists to
efficiently generate the trifluoromethylated analogs of the drug
leads and offer rapid evaluation of structure activity
relationship.[17] Our future efforts will be focusing on expanding
this stoichiometric method to its catalytic variant. These studies
are currently ongoing in our lab.
[6]
Acknowledgements
W.L. thanks Miami University for start-up funding. Z.H.L. and
M.J.C. acknowledge financial support from the Ministry of
Science and Technology of the Republic of China under grant
no. MOST 105-2113-M-006-017-MY2.
[7]
Keywords: C-H activation • fluorination • copper •
trifluoromethylation • late-stage diversification
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