Nickel-Catalyzed Trifluoromethylselenolation of Aryl Halides Using the Readily Available [Me4N][SeCF3] Salt

Article abstract of DOI:10.1021/acs.orglett.7b01839

A convenient and efficient method for the construction of aryl trifluoromethyl selenoethers from the corresponding aryl halides in the presence of Ni(COD)₂ and an appropriate ligand is reported. Various aryl iodides, bromides, and chlorides were smoothly converted in this reaction by simply varying the ligand, which afforded aryl and heteroaryl trifluoromethyl selenoethers in good to almost quantitative yields. The reaction was also applicable to the synthesis of druglike molecules. This work is the first report for trifluoromethylselenolation of aryl chlorides. Advantages of the present Ni-catalyzed approach include mild reaction conditions, good functional group tolerance, inexpensive reagents, easy operation, and no use of additional additives. This protocol allows for a straightforward and reliable access to trifluoromethyl selenides that are latent screening candidates for new pharmaceuticals and agrochemicals.

Full text of DOI:10.1021/acs.orglett.7b01839

Letter
pubs.acs.org/OrgLett
Nickel-Catalyzed Trifluoromethylselenolation of Aryl Halides Using
the Readily Available [Me4N][SeCF3] Salt
Jia-Bin Han,† Tao Dong,† David A. Vicic,‡ and Cheng-Pan Zhang*,†
†School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 205 Luoshi Road, Wuhan, 430070,
China
‡Department of Chemistry, Lehigh University, 6 East Packer Avenue, Bethlehem, Pennsylvania 18015, United States
S
* Supporting Information
ABSTRACT: A convenient and efficient method for the
construction of aryl trifluoromethyl selenoethers from the
corresponding aryl halides in the presence of Ni(COD)2 and an
appropriate ligand is reported. Various aryl iodides, bromides,
and chlorides were smoothly converted in this reaction by
simply varying the ligand, which afforded aryl and heteroaryl
trifluoromethyl selenoethers in good to almost quantitative
yields. The reaction was also applicable to the synthesis of
druglike molecules. This work is the first report for trifluoromethylselenolation of aryl chlorides. Advantages of the present Ni-
catalyzed approach include mild reaction conditions, good functional group tolerance, inexpensive reagents, easy operation, and
no use of additional additives. This protocol allows for a straightforward and reliable access to trifluoromethyl selenides that are
latent screening candidates for new pharmaceuticals and agrochemicals.
luorinated groups are important functionalities in bioactive
anions, which were in situ generated from a mixture of
TMSCF3/fluoride,6a−c HCF3/base,6d,e CF3I/TDAE (tetrakis-
(dimethylamino)ethylene),6f,g and more.6h,i However, these
trifluoromethylation reactions suffered from harsh conditions,
low efficiencies, and/or a narrow range of substrates. To
overcome these disadvantages, direct trifluoromethylselenola-
tion was developed by using SeCF3 reagents like CuSeCF3,7a
Hg(SeCF3)2,7b [Me4N][SeCF3],7c ClSeCF3,7d,e and [(bpy)Cu-
(SeCF3)]2.8 Among these reagents, [Me4N][SeCF3] is the
most convenient and easily accessed SeCF3 source.9 Recently,
the Cu-catalyzed/mediated reactions of [Me4N][SeCF3] with
aryl diazonium salts, α-diazo esters, boronic acids and their
esters, and terminal alkynes allowed for several direct accesses
to trifluoromethyl selenoethers (Scheme 1).10 The Pd-catalyzed
conversion of aryl iodides as well as a few bromides into the
corresponding ArSeCF3 was also harnessed, which represents
the state-of-the-art method to incorporate the SeCF3 group into
aryl halides with [Me4N][SeCF3].11 Nevertheless, trifluorome-
thylselenolation of aryl chlorides with a practical SeCF3 source
still remains unknown. [Me4N][SeCF3] is more thermally
stable [decomposes at 207 °C (DTA/TG) or 215−217 °C
(visible decomposition in sealed glass ampules)]9 than
[Me4N][SCF3] and, therefore, would survive better under
sensitive reaction conditions. Despite the aforementioned
studies, this reagent is poorly exploited in chemical synthesis
relative to the [Me4N][SCF3] analogue.4
1
Fmolecules and advanced materials.
The systematic
introduction of fluorine-containing moieties into a lead
compound has become a commonly invoked procedure in
modern day drug discovery units.1 Among all fluorine-rich
residues, the SeCF3 functionality has attracted a growing
interest in the past few years because of its unique electron-
withdrawing ability and high lipophilicity that can significantly
change the physicochemical and biological properties of a
molecule.2 Selenium is an essential element to humans and
other living organisms. Basic and clinical studies have revealed
that selenium supplements at an appropriate dosage have
protective roles and therapeutic effects against various types of
cancer3a−d and that inadequate levels of selenium increases the
risk of cancer.3 Since there has been no single SeCF3-containing
organic molecule found in nature, potential drugs or delivery
agents bearing this functionality have to be synthesized.1
Although the formation of C−SCF3 bonds has been
documented extensively, methods for direct trifluoromethylse-
lenolation are much less developed owing to the limited types
of SeCF3 transfer reagents4 and the relatively unexplored
applications of selenium compounds compared to the sulfur
derivatives.5 In view of their potential applications in the
pharmaceutical and agricultural industries, the development of a
convenient method for the synthesis of SeCF3-containing target
molecules is a subject of great importance. In particular, late-
stage trifluoromethylselenolation is highly sought-after to
explore the pharmacological properties of the SeCF3 group.
Traditionally, the incorporation of SeCF3 moieties into
organic scaffolds was mainly achieved by the nucleophilic
trifluoromethylation of diselenides and selenocyanates by CF3
Nickel has become an attractive alternative to palladium
because of its higher abundance, low cost, and most
Received: June 16, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01839
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Organic Letters
Letter
Scheme 1. Previously Described
Trifluoromethylselenolations with [NMe4][SeCF3]
Scheme 2. Ni-Catalyzed Trifluoromethylselenolation of Aryl
Iodides with [Me4N][SeCF3] in the Presence of 2,2′-
a
Bipyridine
importantly, power to activate a larger array of C−X bonds
(e.g., C−Cl) that are generally inert to palladium or
copper.12−15 In 2012, we reported the nickel-catalyzed
trifluoromethylthiolation of aryl iodides and bromides with
[Me4N][SCF3] that proceeded at room temperature in the
presence of bipyridine ligands.12 Later, Schoenebeck and co-
workers disclosed a nickel-catalyzed transformation of aryl
chlorides to the corresponding trifluoromethyl sulfides with
[Me4N][SCF3] and a sterically hindered electron-rich
phosphine ligand.13 Inspired by these early works on nickel
SCF3 chemistry, we wondered whether a related nickel-
catalyzed trifluoromethylselenolation of aryl halides (ArX, X
= I, Br, Cl) with [Me4N][SeCF3] would allow for a
straightforward and efficient installation of the SeCF3 group
in aromatic and heteroaromatic systems under mild conditions.
To our delight, we found that reaction of 1-iodo-4-
methoxybenzene (1a) with [Me4N][SeCF3] (1.5 equiv) in
the presence of 5 mol % of Ni(COD)2 and 10 mol % of 2,2′-
bipyridine (bpy) at room temperature for 6 h furnished (4-
methoxyphenyl)(trifluoromethyl)selane (3a) in 96% yield
(Table S1). Tables S1−S3 summarize important examples of
our screenings and follow-up optimizations. The results of
these screens indicated that diimine ligands outperformed
diamine, phosphine, and diphosphine ligands and also indicated
that THF, DME, and 1,4-dioxane were suitable solvents for the
trifluoromethylselenolation of 1a. Based on the exhaustive
screening data, we chose a combination of 1, [Me4N][SeCF3]
(1.2 equiv), Ni(COD)2 (5 mol %), relatively cheap 2,2′-
bipyridine (10 mol %), THF, room temperature, and 2 h as the
standard reaction conditions for the trifluoromethylselenolation
of aryl iodides (Scheme 2). Various aryl iodides bearing either
electron-donating or -withdrawing groups on the phenyl rings
under the standard reaction conditions were all smoothly
converted to the corresponding trifluoromethyl selenoethers in
good to quantitative yields (Scheme 2). The steric hindrance of
the substrates had a considerable influence on the trans-
formation. 1-Iodo-3-methoxybenzene (1e) and 1-iodo-2-
methoxybenzene (1f) reacted with [Me4N][SeCF3] yielded
86% of 3e and 79% of 3f, while the reaction of 1a provided 3a
in 92% isolated yield. By increasing the amounts of Ni(COD)2
and 2,2′-bipyridine to 10 and 12 mol %, respectively, the
reaction of 2-iodo-1,3,5-trimethylbenzene (1d) with [Me4N]-
[SeCF3] supplied 88% of 3d. The chloro, sterically hindered
bromo, free amino, and keto groups, amides, and ester were all
tolerated in the reaction (3k−r). Heteroaryl iodides such as 5-
iodo-1H-indole (1s), 1-(4-iodophenyl)-1H-pyrrole (1t), 6-
iodoquinoline (1u), 4-iododibenzo[b,d]furan (1v), and 1-
a
Reaction conditions: 1 (0.2 mmol), [NMe4][SeCF3] (0.24 mmol),
Ni(COD)2 (5 mol %), bpy (10 mol %), THF (2 mL), room
temperature, 2 h. Isolated yields. Ni(COD)2 (10 mol %), bpy (12
mol %). The reaction was run on a 1.0 mmol scale (see the SI).
b
c
benzyl-4-iodo-1H-pyrazole (1w) reacted with [Me4N][SeCF3]
in the presence of Ni(COD)2 (5 or 10 mol %) and 2,2′-
bipyridine (10 or 12 mol %) at room temperature for 2 h to
form 3s−w in almost quantitative yields. It is remarkable that
treatment of (E)-1-(2-iodovinyl)-4-methoxybenzene (1x) with
[Me4N][SeCF3] under the standard reaction conditions gave
3x in 99% yield (E-isomer only). Similarly, the reaction of 4-
iodo-N-(2-morpholinoethyl)benzamide (1y, see the SI) with
[Me4N][SeCF3] afforded 3y, a fluorinated analogue of the
depression and anxiety drug moclobemide, in 92% yield.
Next, the nickel-catalyzed trifluoromethylselenolation of aryl
bromides with [Me4N][SeCF3] was studied. The reaction of 4-
bromo-1,1′-biphenyl (4a) and [Me4N][SeCF3] (1.2 equiv) in
THF in the presence of 5 mol % of Ni(COD)2 and 10 mol % of
2,2′-bipyridine at room temperature for 12 h produced 3b only
in 41% yield (Table S7). Increasing the catalyst loading of
Ni(COD)2 from 5 to 10 mol % could clearly promote the yield
of 3b (97%, Table S7). Diimine ligands such as 4,4′-di-Me-bpy,
4,4′-di-MeO-bpy, and 4,4′-di-t-Bu-bpy were also suitable
ligands for the trifluoromethylselenolation of 4a. It should be
noted that the reaction of 4a and [Me4N][SeCF3] with 12, 15,
or 20 mol % of diimine ligand and 10 mol % of Ni(COD)2 gave
lower yields of 3b than that using 10 mol % of Ni(COD)2 and
10 mol % of 2,2′-bipyridine (Tables S5 and S7). These results
suggested that the excess bipyridine relative to Ni(COD)2
inhibited the formation of 3b (Tables S5 and S7). This
consequence was different from the outcomes of 1a, for which
almost no obvious changes in the yields of the product were
observed when amounts of bipyridine ligand equal or two times
to Ni catalyst were used (Table S2).
B
DOI: 10.1021/acs.orglett.7b01839
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Organic Letters
Letter
Scheme 3 summarizes the trifluoromethylselenolation of aryl
bromides with [Me4N][SeCF3] at room temperature in the
reactions of aryl iodides (Table S2). A variety of screens
(Tables S9−S14) were carried out to determine the optimal
conditions for the trifluoromethylselenolation of aryl chlorides
with nickel. The combination of 5, [Me4N][SeCF3] (1.5
equiv), Ni(COD)2 (10 mol %), dppf (20 mol %), 50 °C, and
12 h was ultimately used to probe the scope of the reaction
(Scheme 4) with different aryl chlorides. For some challenging
Scheme 3. Ni-Catalyzed Trifluoromethylselenolation of Aryl
Bromides with [Me4N][SeCF3] in the Presence of 2,2′-
a
Bipyridine
Scheme 4. Ni-Catalyzed Trifluoromethylselenolation of Aryl
a
Chlorides with [Me4N][SeCF3] in the Presence of dppf
a
Reaction conditions: 4 (0.2 mmol), [NMe4][SeCF3] (0.24 mmol),
Ni(COD)2 (10 mol %), bpy (10 mol %), THF (2 mL), room
b
temperature, 12 h. Isolated yields. Ni(COD)2 (12 mol %), bpy (12
c
d
mol %). Ni(COD)2 (15 mol %), bpy (15 mol %). Ni(COD)2 (20
e
mol %), bpy (20 mol %). [NMe4][SeCF3] (0.6 mmol), Ni(COD)2
(30 mol %), bpy (30 mol %).
a
Reaction conditions: 5 (0.2 mmol), [NMe4][SeCF3] (0.3 mmol),
Ni(COD)2 (10 mol %), dppf (20 mol %), toluene (2 mL), 50 °C, 12
b
h. Isolated yields. Ni(COD)2 (15 mol %), dppf (30 mol %).
presence of 10 mol % of Ni(COD)2 and 10 mol % of 2,2′-
bipyridine. For some elusive cases, satisfactory yields of the
desired products were also obtained under the standard
conditions, but increasing the catalyst loadings from 10 to 12,
15, or 20 mol % helped the complete conversion of the starting
bromides, making the purification of the products easier (see
the SI). Despite the catalyst loadings being relatively high at 15
or 20 mol %, these loadings are mitigated by the inexpensive
combination of all the reagents employed in the reaction
mixture. As a result, aryl bromides bearing either electron-
donating or -withdrawing groups on the phenyl rings readily
formed the corresponding trifluoromethyl selenoethers in good
to high yields under the standard reaction conditions or
modified ones (Scheme 3). This reaction was also applicable to
heterocycles such as 4-(4-bromophenyl)morpholine (4e), 2-(4-
bromophenyl)-1,3-dioxolane (4g), 6-bromochroman-4-one
(4i), methyl 6-bromopicolinate (4n), 5-bromo-1-tosyl-1H-
indole (4o), and 5-bromoquinoline (4p). In addition, bis(4-
bromophenyl)methanone (4q) reacted with [Me4N][SeCF3]
(3 equiv) in the presence of 30 mol % of Ni(COD)2 and 30
mol % of 2,2′-bipyridine at room temperature for 12 h to give
3aq (89%) as a doubly trifluoromethylselenolated product.
When the Ni(COD)2/bipyridine catalytic system was used
for the transformation of aryl chloride at 40 °C, only a trace of
the trifluoromethylselenolation product was formed (Table S9).
It was known that modulation of the steric and electronic
properties of the ligands can tremendously affect Ni-catalyzed
reactions.13−15 We envisioned that the bulky electron-rich
phosphine ligands would have a good partnership with nickel
for trifluoromethylselenolation of aryl chlorides,13 even though
such ligand gave poor catalytic efficiency in the nickel-catalyzed
c
Ni(COD)2 (20 mol %), dppf (40 mol %).
substrates, varying the catalyst/ligand loadings of Ni(COD)2/
dppf from 10 mol %/20 mol % to 15 mol %/30 mol % or 20
mol %/40 mol % could accelerate the conversion of the
chlorides and consequently facilitate the formation of
trifluoromethyl selenoethers (e.g., 3ba, 3bb, 3bg, 3bk, and
3bm). Products with keto, formyl, or cyano substituent, ester,
or sulfamine groups (3ba−bd and 3bf−bg) were all
successfully constructed. Heteroaryl chlorides like 6-chloroqui-
noline (5h), 8-chloroquinoline (5i), 7-chloro-2-methylquino-
line (5j), 2-chloro-9H-thioxanthen-9-one (5k), 5-chlorobenzo-
[b]thiophene (5l), 5-chloro-2-methylbenzo[d]thiazole (5m),
and 5-chloro-2-methylbenzo[d]oxazole (5n) reacted with
[Me4N][SeCF3] under the standard conditions or modified
conditions to provide 3bh−bn in 49−95% yields. Notably, the
reaction of the cholesterol reducing drug Fenofibrate with
[NMe4][SeCF3] (1.5 equiv) in toluene in the presence of 20
mol % of Ni(COD)2 and 40 mol % of dppf at 50 °C for 12 h
gave the trifluoromethylselenolated analogue 3bo in 78%
isolated yields.
In conclusion, we have developed a comprehensive set of
mild and efficient methods for the preparation of aryl
trifluoromethyl selenoethers from the full aryl halide series (X
= I, Br, Cl) in the presence of Ni(COD)2 and ligand. In these
strategies, various aryl and heteroaryl trifluoromethyl sele-
noethers were synthesized in good to almost quantitative yields
with commonly used and relatively inexpensive reagents. The
best conditions for a particular aryl halide were obtained simply
by changing the ligand on nickel. Diimine ligands favored the
C
DOI: 10.1021/acs.orglett.7b01839
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Organic Letters
Letter
Kumar, R.; Mukhtar, H.; Ahmad, N. Mol. Med. 2011, 17, 134−143.
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iodides appeared to require a low dosage of the catalyst, and
excess bipyridine ligand relative to Ni(COD)2 did not
significantly affect the yields. Aryl bromides required a higher
percentage of Ni(COD)2 and bipyridine, and an excess of
bipyridine relative to Ni(COD)2 considerably inhibited the
trifluoromethylselenolation reactions. These results suggest that
the activation of aryl iodides occurs more readily than the
bromides and that unproductive ligand coordination is
competitive with the activation of the aryl bromide substrates.
Importantly, the challenging aryl chloride substrates could be
trifluoromethylselenolated by employing dppf as the optimal
ligand on nickel. This work represents the first report for the
direct trifluoromethylselenolation of aryl chlorides. Finally, the
reactions developed herein are amenable to the synthesis of
potentially bioactive molecules and drug analogues and could
serve as a promising resource for the construction of
trifluoromethyl selenides for life science applications. A more
detailed investigation of the reaction mechanisms is currently
underway in our laboratories.
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
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Experimental information, reaction condition optimiza-
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: cpzhang@whut.edu.cn, zhangchengpan1982@hotmail.
com.
ORCID
Cheng-Pan Zhang: 0000-0002-2803-4611
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
C.P.Z. thanks the Wuhan University of Technology, the
Fundamental Research Funds for the Central Universities, the
National Natural Science Foundation of China (21602165), the
“Chutian Scholar” Program from Department of Education of
Hubei Province (China), the “Hundred Talent” Program of
Hubei Province, and the Wuhan Youth Chen-Guang Project
(2016070204010113) for financial support. D.A.V. thanks the
Office of Basic Energy Sciences of the U.S. Department of
Energy (DE-SC0009363) for support of this work.
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