Copper-catalyzed intermolecular chloro- and bromotrifluoromethylation of alkenes

Article abstract of DOI:10.1021/acs.orglett.5b03080

A highly practical copper-catalyzed intermolecular halotrifluoromethylation of alkenes has been developed under mild reaction conditions. A variety of Cl/Br-containing trifluoromethyl derivatives were directly synthesized from a wide range of alkenes, including electron-deficient and unactivated alkenes.

Full text of DOI:10.1021/acs.orglett.5b03080

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Intermolecular Chloro- and
Bromotrifluoromethylation of Alkenes
Mingyang Fu, Long Chen, Yongpeng Jiang, Zhong-Xing Jiang,* and Zhigang Yang*
Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Wuhan University), Ministry of Education and Wuhan
University School of Pharmaceutical Sciences, Wuhan 430071, China
S
* Supporting Information
ABSTRACT: A highly practical copper-catalyzed intermolecu-
lar halotrifluoromethylation of alkenes has been developed
under mild reaction conditions. A variety of Cl/Br-containing
trifluoromethyl derivatives were directly synthesized from a
wide range of alkenes, including electron-deficient and
unactivated alkenes.
he incorporation of fluorinated residues into complex
Scheme 1. Previous and Present Works
T
molecular architectures has become almost irreplaceable in
pharmaceuticals and agricultural chemicals.1 In particular, the
CF3 group is considered as a useful structural motif in many
biologically active molecules because it can often influence
chemical and metabolic stability, lipophilicity, and binding
selectivity.2 Therefore, the development of new methods for
highly efficient and reliable introduction of a CF3 group into
organic molecules has attracted much attention.3 For instance, a
number of transition-metal-catalyzed methods for the trifluor-
omethylation of (hetero) aryl,3d,4 aryl halides,5 alkynes,6 and the
corresponding boronic acids7 have been successively reported.
In recent years, the trifluoromethylation of alkenes using
electrophilic trifluoromethylation reagents, such as Togni’s8 and
Umemoto’s9 reagents, has become a research hotspot and many
effective methods have been studied intensively.3d,10,11 For
example, the groups of Buchwald,11a Wang,11b and Liu11c have
independently explored the copper-catalyzed electrophilic allylic
trifluoromethylation of unactivated olefins. Furthermore, a
variety of alkene difunctionalizations involving trifluoromethy-
lation, such as oxy-, amino-, hydro-, azido-, cyano-, aryl-, and
halo-containing trifluoromethylation, have also been devel-
oped.12 Although similar vicinal halo trifluoromethylations of
alkenes have been reported (Scheme 1a),12a−e,m−r most of these
methods required more expensive photoredox catalysts than
CuBr2 such as RuCl2(PPh3)2, Ru(bpy)3(PF6)2, [Ir(dF(CF3)-
ppy)2(dtbbpy)]PF6, fac-[Ir(ppy)3], Ru(bpy)3]Cl2, Ru-
(phen)3Cl2, and [Cu(dap)2]Cl, base and light, and/or high
temperatures. These conditions lead to some limitations on the
large scale preparations of vicinal halo trifluoromethyl deriva-
tives. Thus, the development of low cost and more efficient as
well as facile large scale preparation approaches for halotrifluoro-
methylation of alkenes is still desirable and in high demand.
Furthermore, halogenated compounds are important building
blocks for a variety of useful derivatives, such as amine, hydroxyl,
hydrocarbon, and hydrogen. Herein, we report a convenient
protocol for the copper-catalyzed chloro- and bromotrifluoro-
methylation of electron-deficient alkenes and unactivated
unactivated alkenes with Togni’s reagent and dihalo sulfoxide
(SOX2) as the trifluoromethyl and halogen sources, respectively
(Scheme 1b).
Initially, the chlorotrifluoromethylation of 1-butyl-3-methyl-
ene-2-pyrrolidinon 1a with Togni’s reagent 2a was investigated
by using chlorotrimethylsilane (TMSCl) as the chlorine source
in the presence of 5 mol % CuBr2 in CHCl3 at room temperature
for 10 h. We were delighted to find that the desired product 3-
chloro-1-butyl-3-trifluoroethyl-2-pyrrolidinon 3a was indeed
observed with a 50% yield (Table 1, entry 1). Then, different
chlorine sources were examined. To our delight, oxalyl chloride
and thionyl chloride could afford the desired product in 96% and
95% yields, respectively (Table 1, entries 2 and 3). By employing
phosphorus trichloride, a 78% yield could be afforded (Table 1,
entry 4). A significant drop in the reactivity was found when
CuCl was used as a chlorine source (20%, Table 1, entry 5).
Considering thionyl chloride is a cheap and commonly used
reagent, SOCl2 was chosen as the best chlorine source for the
following investigation. Among the solvents tested (Table 1,
entries 6−11), dioxane slightly decreased the yield to 88%. Other
solvents, such as DCM, DCE (1, 2-dichloroethane), MeOH,
DMSO, and DMF, were found to be less effective for this
Received: October 23, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03080
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a b
,
Table 1. Optimization of Reaction Conditions
Scheme 2. Scope of Chlorotrifluoromethylation
b
+
entry
CF3
chlorine source
solvent
yield (%)
1
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2a
2a
TMSCl
(COCl)2
SOCl2
PCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
dioxane
DCM
50
96
95
78
20
88
73
60
66
71
49
37
NR
NR
NR
95
2
3
4
5
CuCl
6
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
7
8
DCE
9
MeOH
DMSO
DMF
10
11
12
13
14
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
c
15
d
16
a
+
Reaction conditions: 1a (0.2 mmol), CF3 (0.3 mmol, 1.5 equiv),
CuBr2 (5 mol %) and [Cl] (0.2 mmol, 1.0 equiv in solvent (1.0 mL) at
b
rt for 10 h. Yields was determined by 19F NMR spectroscopy using
c
d
PhCF3 as an internal standard. Without CuBr2. Reaction on a 1.0
mmol scale with a catalyst loading of 1 mol %.
reaction. For comparison, other electrophilic CF3+ reagents were
also studied. Using Togni’s reagent 2b led to much lower yield,
probably due to its lower reactivity (37% yield, Table 1, entry
12). When Umemoto’s reagents 2c and 2d were employed, no
reaction occurred (Table 1, entries 13−14). Moreover, the
controlled experiment indicated the copper catalyst was essential
in catalyzing the reaction (Table 1, entry 15). The reaction was
carried out on a 1.0 mmol scale, and reducing the catalyst loading
to 1 mol % led to no loss of reactivity (Table 1, entry 16).
Under the optimal reaction conditions (Table 1, entry 16), we
investigated the scope of the copper-catalyzed three-component
chlorotrifluoromethylation of alkenes. First, different alkyl and
aryl substituted groups on the nitrogen atom of 2-pyrrolidinon
(1a−e) were compatible with the reaction conditions affording
the corresponding products with excellent yields (3a−e, Scheme
2). Meanwhile, a single crystal of the N-phenyl substituted
chlorotrifluoromethyl 2-pyrrolidinon 3c was obtained, and the
product structure was also confirmed. Six-membered α,β-
unsaturated cyclic amides were then examined, which led to
the corresponding adducts 3f−g in good yields. Furthermore,
internal α,β-unsaturated 2-pyrrolidinon was also a suitable
substrate for the reaction and afforded the desired product 3h
in good yield and diastereoselectivity (anti/syn = 10:1). Second,
linear unsaturated amides were tested under the same reaction
conditions. Only a 45% yield was obtained when N,N-
diethylmethacrylamide was used as a substrate. When oxalyl
chloride was employed as the chlorine source and dioxane was
used instead of CHCl3, a high yield was observed (Scheme 2, 3i,
a
Reaction conditions: 1 (2.0 mmol), 2a (3.0 mmol, 1.5 equiv), CuBr2
(1 mol %) and SOCl2 (2.0 mmol, 1.0 equiv in CHCl3 (10.5 mL) at rt
for 10 h. Yield of isolated product. Oxalyl chloride (2.0 equiv) was
used as the chlorine source, and dioxane was used as solvent. The
results from trans- and cis-alkenes were obtained in brackets and
b
c
d
parentheses, respectively.
85% vs 45%). Then, substrates bearing Et, nBu, Bn, or H on the
α-position of the amide were also suitable substrates for the
reaction and afforded the corresponding products 3j−m with
good yields (70−88%). When phenyl substitution on the α-
position was tested under the reaction conditions, an eliminated
product 3n was obtained, probably because the bulky phenyl
group hinders binding of Cl to the amide. Next, under the similar
reaction conditions with (COCl)2 as the chlorine source,
unactivated alkenes such as 1-dodecylene, 3-(benzyloxy)-
propene, and phenylbutene underwent the chlorotrifluoro-
methylation smoothly, delivering the corresponding products
3o−q in 75−85% yields. To examine the effect of substrate
conformation, two pairs of geometric isomers of alkenes were
synthesized and subjected to the chlorotrifluoromethylation
reaction under the optimal reaction conditions. It was found that,
regardless of the alkene geometry of the substrate (trans or cis),
B
DOI: 10.1021/acs.orglett.5b03080
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the corresponding adducts 3r and 3s were obtained in similar
yields and the same product diastereomeric ratio (3r, anti/syn =
5:1; 3s was only diastereomer obtained). A 45% yield was
obtained when tetrasubstituted alkene 1-methyl-3-iso-
propylideneindolin-2-one 1t was used as a substrate.
In order to gain more insight into the reaction mechanism,
several control experiments were conducted under the standard
conditions (Scheme 5). When 1.5 equiv of radical scavenger
Scheme 5. Control Experiments
Inspired by the chlorotrifluoromethylation of alkenes, we
turned our attention to bromotrifluoromethylation of alkenes.
Subsequently, the substrate scope of the bromotrifluoro-
methylation of alkenes was examined in the presence of 1 mol
% CuBr2 and thionyl bromide (Scheme 3). A series of α,β-
ab
,
Scheme 3. Scope of Bromotrifluoromethylation
TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) was added into
the reaction system, the desired transformation was almost shut
down and a small amount of the TEMPO−CF3 adduct was
detected. To our surprise, no trifluoromethyl-substituted
compound was observed except for Togni’s reagent 2a when
1a was treated in the absence of chlorine source SOCl2. It
indicated that the chlorine source plays a critical role in the three-
component reaction.
According to the experimental results and related publica-
tions,11,12 we proposed a probable mechanism (Scheme 6). First,
Scheme 6. Plausible Reaction Mechanism
a
Reaction conditions: 1 (2.0 mmol), 2a (3.0 mmol, 1.5 equiv), CuBr2
(1 mol %), and SOBr2 (2.0 mmol, 1.0 equiv in 10.5 mL CHCl3) at rt
b
c
for 10 h. Yield of isolated product. PBr3 (2.0 equiv) as the bromine
source and dioxane as the solvent.
unsaturated cyclic amide substrates, as well as linear unsaturated
amides with different alkyl substituted groups on the α-position
of the amide, and and unactivated alkyene substrate could be
smoothly converted to Br-containing trifluoromethyl products
4a−k with good yields (52−91%, Scheme 3). It is worth noting
that thionyl bromide could not work well on linear unsaturated
amides and unactivated alkene. Instead, good results were
obtained by using phosphorus tribromide as the bromine source
and dioxane as the solvent under the current catalytic system.
To probe the potential scalability of this method, we
performed Cu(II)-catalyzed bromotrifluoromethylation of
N,N-diethylacrylamide on a gram scale with a 1 mol % catalyst
loading. Pleasantly, as shown in Scheme 4, the reaction
proceeded smoothly and the desired product 4j yield was
increased from 52% to 71%.
Togni’s reagent 2a is activated by CuBr2, generating radical ·CF3
by a single-electron-transfer (SET) process, with the release of
Cu3+ species. The stabilized radical ·CF3 was added to an
electron-deficient alkene, and the radical intermediate A was
formed. Following the second SET process, carbocation
intermediate B is afforded, with regeneration of the active Cu2+
catalyst to restart the catalytic cycle. Finally, chlorotrifluoro-
methylation product 3a is obtained after the cationic
intermediate B is nucleophilically attacked by Cl− from thionyl
chloride.
In summary, we have developed a copper-catalyzed inter-
molecular chloro- and bromotrifluoromethylation of alkenes
under mild reaction conditions. The reactions were catalyzed by
a copper(II) catalyst to give the Cl-/Br-containing trifluor-
omethyl derivatives in high yields (up to 97%). In particular, the
procedure is capable of tolerating a relatively wide range of
substrates for the bromotrifluoromethylation, and good results
(52−91% yield) can also be obtained. Furthermore, an excellent
yield can also be obtained on a gram scale, which showed the
potential value of the catalyst system. Further studies on catalytic
Scheme 4. Scale-Up of Cu(ll)-Catalyed
Bromotrifluoromethylation
C
DOI: 10.1021/acs.orglett.5b03080
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Letter
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ASSOCIATED CONTENT
* Supporting Information
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03080.
Crystallographic data for 3c (CIF)
Experimental procedures, compounds characterizations,
copies of 1H/19F/13C NMR, MS/HRMS spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
́
Chem., Int. Ed. 2012, 51, 4577. (e) Mizuta, S.; Galicia-Lopez, O.; Engle,
K. M.; Verhoog, S.; Wheelhouse, K.; Rassias, G.; Gouverneur, V. Chem. -
Eur. J. 2012, 18, 8583. (f) Janson, P. G.; Ghoneim, I.; Ilchenko, N. O.;
*E-mail: zxjiang@whu.edu.cn.
*E-mail: zgyang@whu.edu.cn.
Notes
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Szabo, K. J. Org. Lett. 2012, 14, 2882. (g) Li, Y.; Studer, A. Angew. Chem.,
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (Nos. 21402144,
21372181, and 21572168), the Fundamental Research Funds
for the Central Universities (No. 2042014kf0030) and the
Innovation Seed Fund of Wuhan University School of Medicine.
́
(o) Ilchenko, N. O.; Janson, P. G.; Szabo, K. J. Chem. Commun. 2013, 49,
6614. (p) Kong, W.; Casimiro, M.; Merino, E.; Nevado, C. J. Am. Chem.
Soc. 2013, 135, 14480. (q) Wang, X.; Ye, Y.; Ji, G.; Xu, Y.; Zhang, S.;
Feng, J.; Zhang, Y.; Wang, J. Org. Lett. 2013, 15, 3730. (r) He, Y.-T.; Li,
L.-H.; Yang, Y.-F.; Zhou, Z.-Z.; Hua, H.-L.; Liu, X.-Y.; Liang, Y.-M. Org.
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