Copper-catalyzed trifluoromethylthiolation of aryl halides with diverse directing groups

Article abstract of DOI:10.1021/ol501742a

The expansion of cross-coupling components in Cu-catalyzed C-X bond forming reactions have received much attention recently. A novel Cu-catalyzed trifluoromethylthiolation of aryl bromides and iodides with the assistance of versatile directing groups such as pyridyl, methyl ester, amide, imine and oxime was reported. CuBr was used as the catalyst, and 1,10-phenanthroline as the ligand. By changing the solvent from acetonitrile to DMF, the coupling process could even take place at room temperature.

Full text of DOI:10.1021/ol501742a

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Trifluoromethylthiolation of Aryl Halides with
Diverse Directing Groups
Jiabin Xu,†,§ Xin Mu,‡,§ Pinhong Chen,‡ Jinxing Ye,*,† and Guosheng Liu*,‡
†Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of Education, School of Pharmacy, East China
University of Science and Technology, 130 Meilong Road, Shanghai, China, 200237
‡State Key Laboratory of Organometallics Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai, China, 200032
S
* Supporting Information
ABSTRACT: The expansion of cross-coupling components in
Cu-catalyzed C−X bond forming reactions have received much
attention recently. A novel Cu-catalyzed trifluoromethylthiola-
tion of aryl bromides and iodides with the assistance of versatile
directing groups such as pyridyl, methyl ester, amide, imine and
oxime was reported. CuBr was used as the catalyst, and 1,10-
phenanthroline as the ligand. By changing the solvent from
acetonitrile to DMF, the coupling process could even take place at room temperature.
ince the prominent breakthroughs on the catalytic
As part of our ongoing programs, we are interested in
developing Cu-catalyzed fluorination methods to achieve the
direct synthesis of arylfluorides and related organofluorines
from arylhalides.10 Recently, we reported a copper-catalyzed
fluorination of aryl bromides in the presence of an ortho-pyridyl
group; preliminary mechanistic studies indicated the precoordi-
nation of a pyridine group to a copper catalyst was essential for
the success of catalytic transformation.10a Thus, we envisioned
that ortho-directing groups, especially with more synthetic
utility, could be introduced into arylhalide substrates to
facilitate the copper-catalyzed trifluoromethylthiolation.
In order to test this possibility, an aryl bromide bearing an
ortho-pyridyl group was first investigated in the presence of a
copper catalyst. As shown in Table 1, substrate 1a was treated
with modified fluorination reaction conditions replacing AgF
with AgSCF3 at 120 °C. We were delighted to obtain the
desired trifluoromethylthiolation product 2a in 96% yield
(entry 1). However, when the reaction temperature was
lowered down to 80 °C, the yield was decreased to 38%, and
no reaction occurred at room temperature (entries 2−3). Then,
various Cu(I) catalysts were screened at room temperature, and
CuBr was proven to be the most efficient catalyst (entries 4−
6). Furthermore, the addition of bidentate nitrogen ligands was
beneficial for this coupling reaction. For instance, the reaction
with neocuproine provided 2a in 88% yield, and 1,10-
phenanthroline gave 2a in 95% yield (entries 7−8). It is
worth noting that no reaction occurred in the absence of a
copper catalyst from room temperature to 120 °C (entry 9). In
addition, phenyl bromide without a directing group was inert
toward this trifluoromethylthiolation indicating that ortho-
1
SUllmann-type cross-coupling reactions, much effort has
been fulfilled to enrich the pool of coupling partners. The
nucleophilic components have encompassed a variety of
carbon, nitrogen, and oxygen sources with various chemical
environments. These Cu-catalyzed reactions are robust to
synthesize a variety of complex molecular architectures with a
plethora of functional groups, making them highly attractive.2
Quite recently, direct introduction of fluorine-containing
moieties into arene rings using copper catalysts have received
much attention due to far-reaching applications of organo-
fluorines in pharmaceuticals and materials science.3 For
instance, some CuCF3 complexes have been explored for the
preparation of aryl-CF3, and a number of copper-catalyzed
trifluoromethylation reactions have been developed.4
Similar to the trifluoromethylation, related trifluoromethyl-
thiolation of aryl halides for Ar−SCF3 synthesis is also
attractive, but far from successful.4f So far, only two catalytic
systems were reported. Buchwald and co-workers reported a
palladium-catalyzed trifluoromethylthiolation of aryl bromides
using a sterically bulky phosphine ligand.5 Vicic and co-workers
later achieved a nickel-catalyzed trifluoromethylthiolation of
aryl iodides and bromides.6 For cheap metal catalysts, the
CuSCF3 complex, generated in situ, has been used to react with
aryl halide (Br or I), but is less effective toward electron-rich
substrates.7 Until recently, Weng and Huang reported an
(bpy)CuSCF3 complex, which is effective for both electron-rich
and -deficient substrates.8 However, a stoichiometric amount
copper−SCF3 complex was required in those transformations,
and catalytic trifluoromethylthiolation of aryl halides remained
an underdeveloped issue.9 Herein, we reported a novel copper-
catalyzed trifluoromethylthiolation of aryl iodides and bromides
in the presence of diverse ortho-directing groups including both
strong and weak coordinating groups.
Received: June 16, 2014
Published: July 18, 2014
© 2014 American Chemical Society
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Letter
a
similar to the para-methylpyridyl group, pyridyl and para-
chloropyridyl could promote this reaction to give desired
products 2j−2k in excellent yields. In addition, even as inert
substrates toward Cu-catalyzed fluorination due to the steric
effect,10a aryl bromides 1l and 1m were good substrates to give
corresponding products 2l and 2m in excellent yields, in which
the reaction of 1l was conducted at elevated temperatures. This
might be reasoned as the “softer” property with the “stronger”
nucleophilicity of the SCF3 anion compared to the fluoride
anion which was less sensitive toward steric hindrance. Finally,
other types of aryl bromides, such as benzo[h]quinoline
bromide 1n and benzofuran bromide 1o, were also tested, and
these reactions proceeded smoothly to give trifluoromethylth-
iolation products 2n and 2o in good and moderate yields.
Unfortunately, ortho-pyridyl phenyl chloride was an inert
substrate under the standard conditions.
Table 1. Screening of Reaction Conditions
b
entry
Cu(I)
ligand
temp (°C) yield (%)
1
2
3
4
5
6
7
8
9
Cu(MeCN)4PF6
−
−
−
−
−
−
120
96
38
0
Cu(MeCN)4PF6
80
Cu(MeCN)4PF6
CuOAc
CuI
rt
rt
24
5
rt
CuBr
rt
80
88
95
0
CuBr
neocuproine
phenanthroline
−
rt
CuBr
rt
−
CuBr
rt or 120
rt or 120
c
10
phenanthroline
0
Next, we sought to explore more synthetically useful
coordinating groups which could be further converted to
SCF3-containing synthons. Aryl halides bearing an imine
moiety were initially investigated (Scheme 2). We are delighted
a
Reaction conditions: 1a (0.1 mmol), AgSCF3 (0.15 mmol), Cu(I)
b
catalyst (0.01 mmol) in dry CH3CN (1 mL) for 6 h. 19F-NMR yield
c
with CF3−DMA as internal standard. Phenyl bromide as substrate.
Scheme 2. Substrate Scope of Arylhalides with Imine,
Oxime, and Other Stronger Chelating Groups
a
,b
directing groups played an important role in this transformation
(entry 10).
Having established the standard reaction conditions, we
explored the scope of aryl bromides 1 with pyridyl groups
(Scheme 1). A broad range of functional groups, such as alkyl,
ether, halides, ester, etc., were tolerated under the standard
reaction condition to provide the expected products 2a−2i in
good to excellent yields. Both electron-rich and -poor aryl
bromides were proven to be good substrates. Furthermore,
Scheme 1. Substrate Scope of Arylbromides with Pyridyl
a
,b
Groups
a
b
All reactions were conducted in 0.2 mmol scale under N2. Isolated
c
yield. Isolated yield of aldehyde product hydrolysized from imine
product. d 30 mol % of CuBr/Phen in CH3CN at 140 °C. e In CH3CN
at 80 °C.
to find that, when solvent was switched from CH3CN to DMF,
the reaction of aryl iodides could be achieved under very mild
reaction conditions (room temperature). For less active aryl
bromides, reactions also proceeded very well with a slightly
higher temperature (80 °C). For the N-aryl and alkyl imines,
the reactions of aryl bromides and iodides could take place to
give corresponding products 4a−4c in high yields. It is worth
noting that a series of heteroaromatic bromides, such as
bromopyridine and bromothiophene, could also be converted
to the SCF3-substituted heteroaryl products 4d−4e in good
yields. For product 4e, a higher catalyst and ligand loading with
elevated temperature were required in acetonitrile. Further-
a
All reactions were run in 0.2 mmol scale under N2 at room
b
c
temperature. Isolated yield. At 120 °C.
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more, the oxime directing group is also eligible for this
transformation to give related products 4f−4h in excellent
yields. For the other slightly stronger chelating groups,
oxazoline and triazole groups were demonstrated as good
directing groups to promote the coupling process (4i−4j).
Finally, a range of acetyl protected 2-iodoanilines were also
evaluated, and acetonitrile proved to be the best solvent. Both
electron-rich and -poor substrates were operative under
standard reaction conditions, and all of the reactions afforded
the desired products 4k−4o in excellent yields.
Finally, ketone as a directing group was also surveyed. As
shown in Scheme 3, a related transformation did proceed very
well in the acetonitrile at 80 °C. The ortho-SCF3 arylketones
10a−10c could be efficiently obtained in good yields. However,
with these weak chelating groups, aryl bromides exhibited low
reactivity. For instance, the trifluoromethylthiolation reaction of
aryl bromide with the amide group was achieved at high
temperature (120 °C) to give a good yield, but the reaction of
ortho-ester and ketone aryl bromides exhibited poor reactivity
even with higher temperatures.
To gain further insights into the reaction mechanisms of the
Cu-catalyzed cross-coupling reactions, several radical scav-
engers, such as Tempo, BQ, and BHT, have been added to
investigate the viability of the radical process (see Supporting
Information (SI)). No suppressing effect was observed
indicating that the involvement of the free radical process is
unlikely.
Additional chelating groups were also investigated for this
transformation (Scheme 3). We were delighted to find that
Scheme 3. Cu-Catalyzed Thiotrifluoromethylation of Aryl
a
Iodides Containing Amide and Ester Directing Groups
In order to address the importance of directing groups in this
reaction, competition experiments were conducted. For pyridyl
directing groups, an electron-rich substituent will react faster
than its electron-deficient counterpart (eq 1). Similar trends
were discovered in benzamide substrates (eq 2). The more
electron density that is within the directing group, the better
the coordination ability with the copper catalyst to promote the
oxidative addition toward the C−X bond.11 Evaluation of the
electronic properties on the aryl halide moiety suggested the
electron-deficient aryl halide reacts faster than the electron-rich
aryl halide substrates (see SI for details). This phenomenon is
consistent with a previous report on the fluorination,10a which
suggested a Cu(I/III) mechanism was involved in the catalytic
cycle for the aryl-SCF3 bond formation.
a
Reaction conditions: 0.2 M arylhalides in 0.2 mmol scale, isolated
b
yield. Aryl bromide in CH3CN at 120 °C
Based on the above results, a mechanism is proposed as
shown in Scheme 4. The initial precoordination of arylhalides
with CuISCF3 promotes an intramolecular oxidative addition to
give the Cu(III) intermediate II. Subsequent ligand exchange
with AgSCF3 and reductive elimination of IV provided the
desired trifluoromethylthiolation product. Alternatively, the
oxidative addition of arylhalides to CuSCF3 might also involve a
complicated cooperative effect of silver as in the case of
intermediate III, which could also release Cu(III) complex IV
and AgX. Weng’s study indicated that the stoichiometric
trifluoromethylthiolation reaction can be achieved without a
directing group, but with a higher temperature and slow
reaction rate. The possible reason is that the oxidative addition
carboxamide was a good directing group to promote the
desired trifluoromethylthiolation at room temperature in DMF,
and a variety of functional groups, such as halide, ether, could
be tolerated in the reaction conditions to provide products 6a−
6g in excellent yields. Further studies revealed that carboxylic
ester groups were proven to be efficient in promoting the
catalytic cross-coupling process, but with slightly lower
reactivity. Aryl iodides bearing ortho-carboxylic ester groups
could be efficiently coupled with AgSCF3 to give products 8a−
8g in high yields at 80 °C. For substrate 7g, the absence of any
cyclization byproduct indicated the radical process was unlikely.
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Letter
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Thus, introducing a directing group could promote the
oxidative addition, which resulted in the achievement of the
catalytic reaction. In addition, silver also plays an important role
for this transformation, because other SCF3 sources, such as
Me4NSCF3, exhibited much lower reactivity than that of
AgSCF3 (see SI).
In conclusion, we have developed the first Cu-catalyzed
trifluoromethylthiolation of aryl bromides and iodides. Diverse
coordinating groups have been identified that are very essential
to promoting the catalytic reactions. For the strong
coordinating pyridyl group, the cross-coupling reaction could
take place even at room temperature. A detailed reaction
mechanism is still under investigation.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization, mechanistic study
data, and additional data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(10) (a) Mu, X.; Zhang, H.; Chen, P.; Liu, G. Chem. Sci. 2014, 5, 275.
(b) Zhang, Z.; Wang, F.; Mu, X.; Chen, P.; Liu, G. Angew. Chem., Int.
Ed. 2013, 52, 7549.
(11) For the electron effect on the oxidative addition of arylhalide
with a copper catalyst, see ref 10a and: Huang, Z.; Hartwig, J. F. Angew.
Chem., Int. Ed. 2012, 51, 1028.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: gliu@mail.sioc.ac.cn.
*E-mail: yejx@ecust.edu.cn.
Author Contributions
(12) Cheng, S.-W.; Tseng, M.-C.; Lii, K.-H.; Lee, C.-R.; Shyu, S.-G.
Chem. Commun. 2011, 47, 5599.
§J.X. and X.M. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the 973 program
(No. 2011CB808700), NSFC (Nos. 21225210, 21202185, and
21121062), STCSM (11JC1415000), and CAS/SAFEA Inter-
national Partnership Program for Creative Research Teams.
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