Copper-catalyzed intermolecular trifluoromethylarylation of alkenes: Mutual activation of arylboronic acid and CF3+ reagent

Article abstract of DOI:10.1021/ja504458j

A novel copper-catalyzed intermolecular trifluoromethylarylation of alkenes is developed using less active ether-type Togni's reagent under mild reaction conditions. Various alkenes and diverse arylboronic acids are compatible with these conditions. Preliminary mechanistic studies reveal that a mutual activation process between arylboronic acid and CF₃⁺ reagent is essential. In addition, the reaction might involve a rate-determining transmetalation, and the final aryl C-C bond is derived from reductive elimination of the aryl(alkyl)Cu(III) intermediate.

Full text of DOI:10.1021/ja504458j

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Communication
Copper-Catalyzed Intermolecular Trifluoromethylarylation of
Alkenes: Mutual Activation of Arylboronic Acid and CF3+ Reagent
Fei Wang, Dinghai Wang, Xin Mu, Pinhong Chen, and Guosheng Liu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja504458j • Publication Date (Web): 01 Jul 2014
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Copper-Catalyzed Intermolecular Trifluoromethylarylation of
Alkenes: Mutual Activation of Arylboronic Acid and CF3 Reagent
+
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Fei Wang, Dinghai Wang, Xin Mu, Pinhong Chen and Guosheng Liu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai, China, 200032
Supporting Information
Scheme 1. Intermolecualr Difunctionalization of Alkenes.
ABSTRACT:
A
novel copper-catalyzed intermolecular
trifluoromethylarylation of alkenes has been developed using less
active ether type Togni’s reagent under mild reaction condition.
Various alkenes and diverse arylboronic acids are compatible with
this reaction condition. Preliminary mechanistic studies revealed
that a mutual activation process between arylboronic acid and
+
CF3 reagent are essential. In addition, the reaction possibly
involves a rate-determining transmetallation, and the final aryl C-
C bond is derived from reductive elimination of aryl(alkyl)Cu(III)
intermediate.
The rich variety of CF3-containing molecules that occur as
pharmaceuticals and agriculture chemicals has inspired
considerable interests in the development of new methods for
their synthesis.1 Among them, direct introduction of CF3 group
into organic compounds is particularly attractive.2 For instance,
copper-catalyzed trifluoromethylation have received much
attention for the synthesis of CF3-containing aromatic and
aliphatic compounds.3 , 4 In 2012, our group reported the first
intramolecular trifluoromethylarylation of activated alkenes using
palladium catalyst to generate a series of CF3-containing oxindole
(top, Scheme 1). In addition, Szabó demonstrated that B2pin2
could accelerate the Cu-catalyzed trifluoromethylation of alkenes
using Togni’s reagent as CF3 source.4q, 9c We envisioned that,
similar to TMSNu, arylboronic reagent could also activate the
CF3+ reagent 2a to release a CF3 radical in the presence of copper
catalyst. Notably, the reaction could simultaneously generate an
activated arylboronic reagent, which possibly reacts with above
mentioned alkyl radical or carbon cation intermediate, or reacts
with Cu catalyst to reach final Calkyl-Caryl bond forming (bottom,
Scheme 1). If so, the three components intermolecular reaction
might be expected. In order to test this hypothesis, initial studies
were focused on the reaction of styrene 1a with Togni’s reagent
2a and PhB(OH)2 3a in the presence of copper catalyst. We are
delighted to find that the desired trifluoromethylarylation product
4a was indeed observed. After extensive screening of different
reaction parameters, the optimized reaction condition was
obtained to provide the desired product 4a in 76% yield (entry 1,
table 1). Some essential observations were listed as: (1) when
5
6
derivatives. Later on, Sodeoka demonstrated the similar
transformation could be achieved using Cu(I)/Togni’s reagent.
Nevado7 discovered a copper-catalyzed intramolecular trifluoro-
methylarylation of alkenes involving a 1,4-aryl migration and
desulfonylation process. The related intramolecular 1,2-aryl
migrations were also described by Wu8a, Tu8b and Sodeoka.8c All
those aryl transfer was proposed to undergo a radical process. We
speculated that, if this arylation can be expanded to
intermolecular fashion, a large number of vicinal CF3- and aryl-
containing aliphatic compounds could be easily obtained from
various simple alkenes. However, related intermolecular reaction
involving three or more components coupling is much more
challenging and remains an underdeveloped process. Herein, we
reported a novel copper-catalyzed intermolecular trifluoromethyl-
arylation of alkenes using arylboronic acid as arylation reagent, in
Table 1. Optimization of the Reaction Condition.a,b
+
which a mutual activation of arylboronic acid and CF3 reagent
was identified as essential step for this reaction. More importantly,
preliminary studies revealed that
a
rate-determining
transmetallation was involved, and the final aryl C-C bond was
derived from reductive elimination of aryl(alkyl)-Cu(III)
intermediate, rather than previously suggested radical pathway.
On the basis of our group’s recent success in developing
intermolecular difunctionalizaiton of alkenes, 9 we found that
TMSNu (Nu = N3, CN) act as Lewis acid to activate the ether type
Togni’s reagent (2a), and the final C-N and C-C bond formation
was derived from an alkyl radical or carbon cation intermediate
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+
other CF3 reagents 2b and 2c were employed, no reaction
occurred (entry 2); (2) PhBPin and PhBF3K were inactive (etnry
3); (3) other type of arylmetallic reagents, such as PhSnBu3 and
PhSiMe3, were failed to yield product 4a, and the starting material
was recovered quantitatively (entry 4); (4) both [Cu(CH3CN)4]PF6
and [Cu(CH3CN)4]BF4 were effective, but CuI and Cu(OTf)2
exhibited lower reactivity, and no reaction occurred in the absence
of copper catalyst (See SI); (5) slightly lower yield of 4a was
obtained under air, and a significant amount of side product 4a’
was observed; less 4a and more 4a’ were given under dioxygen
atmosphere (entries 5-6).
also compatible with this transformation to give regioisomers 5q
and 5q’ in 55% yield with good regioselectivity (1:8 ratio).
1
2
3
4
5
6
7
8
Table 3. Substrate Scope of other Arylboronic Acids.a,b
Ar
Cu(CH3CN)4PF6
CF3
(10 mol%)
DMA, 40 oC, N2
R
[CF3]
2a
+
ArB(OH)2
3
+
R
1
4 or 5
CF3
(1.5 equiv) (2.0 equiv)
CF3
CF3
OMe
5a R =
9
OMe 68%
4k Me 83%
4e CO2Me 63%
R
CF3
5b m-, 76%
5c p-, 74%
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4q 87%
With the optimized reaction conditions in hand, the substrate
scope of the styrenes was firstly examined and the results were
summarized in Table 2. A variety of styrenes bearing mono-
substitutents on aryl ring were initially surveyed. Both electron-
donating and electron-withdrawing groups were compatible for
this transformation, and various functional groups, such as
halogen, ester, nitro, nitrile, aldehyde, ketone and hydroxyl group,
were tolerated to give desired products 4a-4q in moderate to
excellent yields. For the styrenes with disubstitutents on the aryl
ring, including 2,6-dichlorostyrene, the reactions were proceeded
smoothly to generate 4r-4s in moderate yields. The reaction of 2-
vinylnaphthalene delivered 4t in 58% yield. The styrenes
containing heterocycles were also suitable to produce products
4u-4w in satisfactory yields. Compared with monosubstituted
styrenes, 1,1-disubstituted styrenes exhibited slightly lower
reactivity to give product 4x in 45% yield. However, the cyclic
styrenes exhibited good reactivities to give products 4y and 4z as
a single isomer in moderate yields.
CF3
CF3
CF3
Cl
Br
t-Bu
Cl
Ph
5d 73%
5e 88%
CF3
5f 71%
CF3
CF3
Cl
Cl
F
Br
5g 76%
5h 82%
5i 64%
CF3
CF3
CF3
Cl
Br
O
MeO
N
MeO2C
HO
5k 52%
5l 45%
F3C
5j 58%
CF3
CF3
OMe
O
Br
S
N
NCH2C
5m 74%
5n 32%
5o
25%
CF3
Table 2. Substrate Scope of Styrene.a,b
O
O
CF3
CF3
H
H
5q
5q'
O
H
5p 69% (1:1)c
55% (1:8)d
aAll the reactions were conducted in 0.2 mmol scale. bIsolated yield. cDiastereoselectivity.
dRegioselectivity.
Next investigation was focused on the reaction of unactivated
alkenes. When aliphatic alkene 6a and 2a were treated under
above optimized reaction condition, however, the desired product
7a was obtained in low yield (around 20% yield) and poor
reproducibility. With further screening of reaction condition, we
are delight to find that addition of water or alcohol could
significantly promote trifluoromethylarylation reaction and give a
reproducible yield. In addition, copper catalyst could be lowered
down to 5 mol %. MeOH was proven to be the best additive to
provide product 7a in moderate yield (51%). With the modified
reaction condition, a series of unactivated alkenes 6 with various
ArB(OH)2 3 could be transformed to the desired products 7a-7l in
satisfactory yields (Table 4). It should be noted that the side
reaction of allylic C-H trifluoromethylation was hard to inhibit,
and the related products were observed in 10-20% yields.10
In order to rationalize reaction pathway, preliminary
mechanistic studies were surveyed. Firstly, addition of TEMPO
could significantly inhibit the trifluoromethylarylation reaction,
and oxytrifluoromethylated product 8a and TEMPO-CF3 adduct
8b were observed (eq 1). In addition, both reactions of Z-9 and E-
9 afforded product 10 with the same diastereoselectivity (5:1) in
albeit low yields (eq 2). These results indicated that a CF3 radical
was involved in the reaction, and a benzyl radical species was
generated through the addition of CF3 radical to alkenes.11
Inspired by above results, we turned our attention to
investigate the reactivity of diverse arylboronic acids (Table 3).
To our delight, a range of arylboronic acids were suitable to react
with various styrenes, and a series of function group, such as ether,
ester, halides and CF3, could survive to give the desired products
5a-5m, 4k,4e and 4q in good to excellent yields. Notably, the
reaction of 2-OHC6H4B(OH)2 proceeded smoothly to produce 5k
in moderate yield. In addition, the reaction of (hetero)-ArB(OH)2
also provided products 5n-5o in albeit low yields. Finally, estrone
derivative was also employed to the reaction condition to deliver
product 5p in 69% yield. And a conjugated diene substrate was
Secondly, compared to the standard reaction condition,
Togni’s reagent 2a was inert in the absence ArB(OH)2.12 Thus, it
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Table 4. Substrate Scope of Unactivated Alkenes.a,b
1
2
3
Cu(CH3CN)4PF6
(5 mol%)
MeOH (2 equiv.)
DMA, 40 oC, N2
Ar
[CF3
]
2a
R
CF3
+
R
ArB(OH)2
3
6
7
4
5
6
7
O
O
CF3
CF3
N
7a
7b
7c
7d
H 51% (20%)c
OMe 54%
CO2Me 57%
tBu 63%
N
R =
O
O
3
3
O
O
R
7e 51%
CF3
8
CF3
CF3
9
OCF3
O
O
Ph
Ph
Ph
10
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12
13
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Fig 2. Electron effect of arylboronic acids and styrenes: (A) time
course of diverse ArB(OH)2; (B) Hammett plots of styrenes.
R
7f R = H 63%
7g
7h
7i
CO2Me 61%
59%
58%
observations implied that addition of CF3 radical to styrenes
should be a fast step to generate a alkyl radical int.III, and this
species should be involved after the rate-determining step. While
ArB(OH)2 should be involved in the rate-determining step or
before.
CF3
CF3
CF3
O
O
Cl
HO
O
BnO
Et2
N
2
8
3
Cl
O
7j
7k
7l
44%
54%
41%
aAll the reactions were conducted in 0.2 mmol scale. bIsolated yield. cwithout MeOH.
As our originally proposed, if the final C-C bond formation
was derived from the intermediate of benzyl radical (int.III) or
benzyl carbon cation (int.VI) with ArB(OH)2 (see path c and d in
Scheme 2), the reaction should involve a rate-determining CF3
radical forming step. If so, the reaction of EP-AA should be faster
since its adduct int.I is more reactive (see Fig 1), which is
opposite with the result in Fig 2A. Thus, these observations
concluded that path c and d (Scheme 2) is less likely.
Cu(CH3CN)4PF6
[CF3+] 2a
(10 mol%)
N
(1.5 equiv.)
4a
35%
TEMPO (1 equiv.)
DMA (1 mL)
N2, 40oC
Ph
1a
O
(1)
(2)
+
+
PhB(OH)2 3a
CF3
CF
TEMPO-
8b 41%
3
Ph
8a 17%
(2 equiv.)
O
O
O
standard
condition
Ph
Z-9
or
[CF3+] 2a
O
+
+
B(OH)2
(1.5 equiv.)
Ph
(2 equiv.)
Z-9: 10 27% (d.r. 5:1)
Ph
E-9
Scheme 2. Proposed Mechanism.
10
CF3
E-9 10
:
39% (d.r. 5:1)
CF3
+
OH
B OH
I
[CF3
]
2a
path b
K1
CF3
I
is possible that 2a was activated by ArB(OH)2 3,13 then reacted
with Cu(I) to generate CF3 radical species. Observation of only
one CF3 signal in the mixture of 2a and 3a (at -10oC) suggested a
fast equilibrium was existed between 2a with 3a and int.I
(2a• 3a). In addition, the CF3 signal gradually shifted to down
field and broadened with increase the amount of PhB(OH)2 (Fig 1,
middle). Furthermore, the interaction of electron-poor arylboronic
acid (EP-AA 3r, Fig 1, left) with 2a was stronger than that of
electron-rich arylboronic acid (ER-AA 3c, Fig 1, right), which
means Togni’s reagent 2a with EP-AA should be more reactive
with Cu(I) than ER-AA.
O
+
OH
OH
k2
'
Ar
Int. I
3
B
ArB(OH)2
O
+ Cu(I)
Int. I
Int. V
ArCu(I)
k2
+
+ Cu(II)
Ar
I
k3
'
same with
Cu(I)
.
O
CF3
B
path a
OH
HO
.
4,5
CF3
ArCu(II)
+
Int. II
R
fast
k4 step
path c and d
Ar
path a
ArB(OH)2
path c
CF3
CF3
R
k3
R
4,5
Int. III
CF3
4 and 5
R
Int. III
CuIIIAr
CF3
Cu(II)
ArB(OH)2
CF3
ArCu(II)
R
R
path d
Int. IV
Thirdly, we moved our attention to the mechanism of final C-
C bond formation. The electronic effect of arylboronic acids and
styrenes were evaluated under the standard condition at 25 ℃. As
shown in Fig 2A, ER-AA (R = OMe, Me) presented faster
reaction rate than that of EP-AA (R = Cl, CO2Me). However, no
significant electronic effect of styrenes was observed with much
Int. VI
Based on above analysis, an alternative pathway involving
ArCu(II) species was proposed to address the final C-C bond
formation (path a and b in Scheme 2): Treatment of activated
+
CF3 speceis int.I by Cu(I) catalyst to release CF3 radical, the
reaction simultaneously generated a new activated arylbronoic
small Hammett ρ-value (-0.087, Fig 2B). In addition, the reaction
acid int.II and
a Cu(II) species, which could undergo
rate exhibited the saturation dependence on the concentration of
PhB(OH)2 and the zero-order dependence on styrene.10 Those
transmetallation to give a ArCu(II) species (path a). Then, the
ArCu(II) could be oxidized by alkyl radical int.III to yield a
Cu(III) species int.IV,14 which delivers the final product through
reductive elimination.15 Due to the saturation dependence on the
concentration of PhB(OH)2 and the independence on styrene,
transmetallation (path a) should be involved as a rate-determining
step.16,17 In addition, another possible pathway involves an initial
transmetallation to give ArCu(I) and int.V, then ArCu(I) was
oxidized by int.V to yield ArCu(II) and release CF3 radical (path
b), which can be also used to well address above observations.
For the case of path a, the reaction of int.I of EP-AA with
Cu(I) (k2) is faster, but following transmetallation step (k3) is
favored for the ER-AA;16b In contrast, both two steps (k2’ and k3’)
are favored for the ER-AA in path b. In order to differentiate these
two possibility, the competing experiments were conducted, and
Fig 1. The reactions of 3 and 2a monitored by 19F-NMR.
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no significantly different reaction rate of EP-AA and ER-AA was
1
2
3
4
5
6
7
8
observed (eq 3), which is obviously different from individual
reactions (Figure 2A). The possible reason is that the
concentration of int.II of EP-AA is higher than that of ER-AA,
but the transmetallation of ER-AA (k3) is faster than EP-AA. Thus,
the k3[int.II] value of EP-AA is reasonably close with the ER-AA,
resulting the similar yields of 4a and 5 in one pot reaction. This
observation is more consistent with the path a, and against the
path b.18
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In summary, we have developed a novel copper-catalyzed
intermolecular trifluoromethylarylation of alkenes under mild
reaction condition. Diverse alkenes and arylboronic acids were
compatible to the reaction condition for the efficient synthesis of
CF3-containing diarylmethane derivatives efficiently. Preliminary
mechanistic studies revealed the mutual activation process
between arylboronic acid and the CF3+ reagent is vital to generate
initial CF3 radical. And transmetallation of ArB(OH)2 to Cu(II)
was involved as a key step, and the final C-C bond formation is
derived from a Cu(III) species. Further application and more
mechanistic investigation of this process are in progress.
Supporting Information
Synthetic procedures, characterization, mechanistic study data and
additional data. This material is available free of charge via the
Internet at http://pubs.acs.org.
Corresponding Author
gliu@mail.sioc.ac.cn
ACKNOWLEDGMENT
We are grateful for financial support from 973 program (No.
2011CB808700), NSFC (Nos. 21225210, 21202185, and
21121062), STCSM (11JC1415000), and the CAS/SAFEA
International Partnership Program for Creative Research Teams.
(10) For details, see the Supporting Information (SI).
(11) For the side product 4a’ generation (entries 5-6, table 1) from
benzyl radical species and dioxygen, see: Deb, A.; Manna, S.; Modak, A.;
Patra, T.; Maity, S.; Maiti, D. Angew. Chem. Int. Ed. 2013, 52, 9747.
(12) In the absence of arylboronic acid, no trifluoromethylation of
alkenes was occurred, and CF3+ reagent 2a was quantitatively recovered.
(13) No significant interaction between ester type Togni’s reagent 2b
with 3a was observed. For details, see SI.
(14) The oxidation of Cu(II) by alkyl radical to give Cu(III) was also
proposed, see: (a) Ye, Y.; Sanford, M. S. J. Am. Chem. Soc. 2012, 134,
9034. (b) Tran, B. L.; Li, B.; Driess, M.; Hartwig, J. F. J. Am. Chem. Soc.
2014, 136, 2555.
(15) The reductive elimination of Cu(III) to form C-C bond, see: (a)
Wang, Z.-L.; Zhao, L.; Wang, M.-X. Chem. Commun. 2012, 48, 9418. (b)
Wang, Z.-L.; Zhao, L.; Wang, M.-X. Org. Lett. 2012, 48, 9418.
( 16 ) The slow transmetallation of ArB(OH)2 to Cu(II) was also
reported by Stahl, see: (a) King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am.
Chem. Soc. 2009, 131, 5044. And the transmetallation of ER-AA with
Cu(II) exhibits faster rate than that of EP-AA, see: (b) King, A. E.; Ryland,
B. L.; Brunold, T. C.; Stahl, S. S. Organometallics 2012, 31, 7948.
(17) The reaction rate was increased by addition of MeOH. It is
possible that addition of MeOH could accelerate transmetallation step, see
SI.
REFERENCES
( 1 ) (a) Smart, B. E. Chem. Rev. 1996, 96, 1555. (b) Filler, R.;
Kobayashi, Y. Biomedicinal Aspects of Fluorine Chemistry; Elsevier:
Amsterdam, 1982. (c) Welch, J. T.; Eswarakrishman, S. Eds. Fluorine in
Bioorganic Chemistry; Wiley: New York, 1991. (d) Banks, R. E.; Smart,B.
E.; Tatlow, J. C. Eds. Organofluorine Chemistry: Principles and
Commercial Applications; Plenum Press: New York, 1994. (e) Purser, S.;
Moore, P. R.; Swallow, S., Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320.
(2) For reviews for trifluoromethylation, see: (a) Schlosser, M. Angew.
Chem. Int. Ed. 2006, 45, 5432. (b) Ma, J.-A.; Cahard, D. J. Fluorine Chem.
2007, 128, 975. (c) Ma, J.-A.; Cahard, D. Chem. Rev. 2008, 108, PR1. (d)
Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475. (e)
Studer, A. Angew. Chem. Int. Ed. 2012, 51, 8950.
(3) (a) Chen, P.; Liu G. Synthesis 2013, 45, 2919. (b) Ye, Y.; Sanford,
M. S. Synlett 2012, 23, 2005. (c) Liu, T.; Shen, Q. Eur. J. Org. Chem.
2012, 34, 6679. (d) Wu, X.-F.; Neumann, H.; Beller, M. Chem.–Asian.
J. 2012, 7, 1744.
(4) For recent copper catalyzed trifluoromethylation of alkenes, see: (a)
Parsons, A. T.; Buchwald, S. L. Angew. Chem. Int. Ed. 2011, 50, 9120. (b)
(18) Reviewer raised an possible alternative pathway, which involves a
initial oxidation of Cu(I) by int.I to give a CuIIICF3, and subsequently
undergoes
a rate-determining transmetallation with ArB(OH)2. The
formed ArCuIIICF3 complex could further release ArCuII and CF3 radical,
which latter could react with alkenes to generate alkyl radical, and
recombine with ArCu(II) to generate int.IV. For more details of this
mechanism, see ref. 9c and the SI.
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