Nickel-catalyzed synthesis of aryl trifluoromethyl sulfides at room temperature

Article abstract of DOI:10.1021/ja210364r

Inexpensive nickel-bipyridine complexes were found to be active for the trifluoromethylthiolation of aryl iodides and aryl bromides at room temperature using the convenient [NMe₄][SCF₃] reagent.

Full text of DOI:10.1021/ja210364r

Communication
pubs.acs.org/JACS
Nickel-Catalyzed Synthesis of Aryl Trifluoromethyl Sulfides
at Room Temperature
Cheng-Pan Zhang and David A. Vicic*
Department of Chemistry, University of Hawaii, 2545 McCarthy Mall, Honolulu, Hawaii 96822, United States
*
S Supporting Information
a
Table 1. Conditions for Reaction Optimization
ABSTRACT: Inexpensive nickel−bipyridine complexes
were found to be active for the trifluoromethylthiolation
of aryl iodides and aryl bromides at room temperature
using the convenient [NMe ][SCF ] reagent.
4
3
entry
mol % Ni(COD)2
ligand (mol %)
solvent
% yield
he broad-spectrum anticoccidial and antiprotozoal
1
2
5
10
10
10
15
15
15
15
15
15
15
15
15
15
15
0
dmbpy (10)
dmbpy (10)
dmbpy (10)
dmbpy (20)
dmbpy (30)
dmbpy (30)
dmbpy (30)
dmbpy (30)
dmbpy (30)
bpy (30)
THF
THF
THF
THF
THF
THF
toluene
dioxane
DME
THF
THF
THF
THF
THF
THF
THF
19
50
47
62
84
96
12
25
70
72
82
95
2
T
activities of toltrazuril and its sulfoxide and sulfone
1
b
3
metabolites and the broad-spectrum insecticide activity of
4
5
c
6
7
8
9
10
11
12
13
14
15
16
dtbpy (30)
dtbpy (30)
phen (30)
terpyridine (30)
none
c
0
32
0
none
a
All of the reactions were run on a 0.1 mmol scale in 2 mL of solvent
for 22 h. The PhI:[NMe ][SCF ] molar ratio was 1:1. The yields of
4
3
1
9
PhSCF were determined by F NMR analysis using trifluorome-
thylbenzene as an internal standard. The reaction was conducted at
6
3
b
c
0 °C. 1.2 equiv of [NMe ][SCF ] was employed in this reaction.
4
3
4
−7
historically been generally limited to electron-poor arenes.
Although much progress has been made in recent years in
8
metal-catalyzed thioetherification reactions, many of these
methods for forming new C −S bonds using aryl halide
aryl
substrates fail when the nucleophile is trifluoromethyl thiolate.
The state-of-the-art method of incorporating a SCF group
3
into unactivated or electron-rich aryl halides is outlined in eq 1.
Buchwald recently found that a wide range of aryl bromides
could be converted into aryl trifluoromethyl sulfides through a
palladium-catalyzed process employing the hindered BrettPhos
Fipronil have played major roles in rendering the SCF group a
3
privileged functionality that is prominent in the agrochemical and
pharmaceutical patent literature. A large number of medicinally
active compounds bearing SR groups (R = perfluoroalkyl) have
f
f
9
ligand. While this method leads to high yields of aryl
now been developed, such as the hypertensive agents based on
2
trifluoromethyl sulfides from aryl iodides and bromides, the
combined use of an expensive ligand, an expensive palladium
salt, a quaternary amine additive, and a stoichiometric amount
Losartan analogues. This trend of incorporating the SCF3
pharmacophore in lead compounds is expected to grow as the
3
extremely large Hansch lipophilicity parameter (π = 1.44) for its
of an expensive silver SCF derivative makes such a reaction
3
size makes the SCF group appealing for the design of new
3
2
unattractive for larg-scale commercial use.
molecules capable of crossing lipid membranes.
Novel methods for preparing aryl−SCF molecules from a
3
2
variety of precursors exist, but unfortunately, the simple and
Received: November 4, 2011
Published: December 7, 2011
direct attachment of a SCF group to aryl halide substrates has
3
©
2011 American Chemical Society
183
dx.doi.org/10.1021/ja210364r | J. Am. Chem.Soc. 2012, 134, 183−185

Journal of the American Chemical Society
Communication
a b
Table 2. Exploration of Substrate Scope ,
to transition metals and often readily decomposed before any
appreciable couplings were observed.
The apparent constraint that any transition-metal-catalyzed
method for preparing aryl trifluoromethyl sulfides using the less
expensive SCF salts must be realized under extremely mild
3
conditions led us to focus our attention on nickel. The
bipyridine nickel system, in particular, became an attractive
starting point because the low-valent [(bpy)Ni] fragment is
known to activate aryl chlorides, aryl bromides, and aryl iodides
11
at room temperature, producing intermediates that are known
12
to be active in cross-coupling catalysis.
Table 1 highlights selected examples of our initial screens and
follow-up optimizations. The highly soluble bipyridine derivatives
4
(
,4′-dimethoxybipyridine (dmbpy) and 4,4′-di-tert-butylbipyridine
dtbpy) afforded product in nearly quantitative yields (Table 1,
entries 6 and 12). The catalyst loadings were relatively high at
5%, but these loadings are mitigated by the inexpensive
1
combination of all the reagents employed in the reaction mixture.
The more soluble bipyridine ligands outperformed unsubstituted
bipyridine (Table 1, entry 10), affording over 12% higher yields.
Other polypyridine architectures such as 1,10-phenanthroline (phen;
Table 1, entry 13) and 2,2′:6′,2″-terpyridine (Table 1, entry 14) were
ineffective and gave yields lower than Ni(COD) alone (Table 1,
2
entry 15).
Table 2 shows that the nickel catalyst can be used to
incorporate the SCF functionality effectively in a variety of aryl
3
halides. Interestingly, the present system works better for electron-
rich aryl halides than it does for electron-poor ones (Table 2,
entries 1−7). This reactivity complements the chemistry exhibited
4,5
6
by copper and silver, which are known to be more active
toward the trifluoromethylthiolation of electron-poor arenes.
Remarkably, successful perfluorothioetherification reactions were
observed even for aryl bromides at room temperature, albeit in
slightly lower yields than for the aryl iodides (Table 2, entries
1
0−12). Aryl chlorides were unreactive toward the nickel-catalyzed
process. Aryl chlorides were also shown to be unreactive in the
Buchwald system. The result in Table 1, entry 15 demonstrates
9
that other ligands besides diimines may promote reactivity, and we
are currently investigating which ligands show promise for aryl
chloride trifluoromethylthiolations.
ASSOCIATED CONTENT
■
a
All of the reactions were run on a 0.1 mmol scale in 2 mL of solvent,
except entries 9 and 10. The ArX:[NMe ][SCF ] molar ratio was
:1.2. The yields of ArSCF were determined by F NMR analysis
3
b
*
S
Supporting Information
4
3
Experimental details and spectroscopic and analytical data for
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
19
1
using trifluoromethylbenzene as an internal standard. Isolated yields
for reactions run on a 0.2 mmol scale in 4 mL of THF are shown in
parentheses. The reaction was conducted at r.t. and at 60 °C. Neither
run afforded product. Addition of NaI or KI in these reactions
resulted in no formation of ArSCF . The reaction was conducted
under solvent-free conditions, and 60 equiv of PhCl was employed.
TMEDA was also investigated as a ligand, but same result was found.
c
d
AUTHOR INFORMATION
■
e
3
Corresponding Author
vicic@hawaii.edu
ACKNOWLEDGMENTS
The employment of AgSCF in the protocol outlined in eq 1
■
3
was necessitated by the fact that many convenient SCF salts are
D.A.V. thanks the Office of Basic Energy Sciences of the U.S.
Department of Energy (DE-FG02-07ER15885).
3
thermally unstable. Important work by Clark suggested that the
cheaper and more soluble [NMe ][SCF ] reagent decomposes at
4
3
7
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dx.doi.org/10.1021/ja210364r | J. Am. Chem.Soc. 2012, 134, 183−185