Copper-promoted sulfenylation of sp2 C-H bonds

Article abstract of DOI:10.1021/ja3092278

An auxiliary-assisted, copper catalyzed or promoted sulfenylation of benzoic acid derivative β-C-H bonds and benzylamine derivative γ-C-H bonds has been developed. The method employs disulfide reagents, copper(II) acetate, and DMSO solvent at 90-130 °C. Application of this methodology to the direct trifluoromethylsulfenylation of C-H bonds was demonstrated.

Full text of DOI:10.1021/ja3092278

Communication
pubs.acs.org/JACS
Copper-Promoted Sulfenylation of sp2 C−H Bonds
Ly Dieu Tran, Ilya Popov, and Olafs Daugulis*
Department of Chemistry, University of Houston, Houston, Texas 77204-5003, United States
S
* Supporting Information
been published, and most of them involve functionalization of
2-phenylpyridine derivatives or deprotonative sulfenylation of
acidic heterocycles.13 No examples of transition-metal catalyzed
C−H bond trifluoromethylsulfenylation have been reported.
In 2005, we introduced picolinic acid and 8-aminoquinoline
auxiliaries as removable directing groups for palladium-
catalyzed C−H bond arylation.14a Subsequently, these directing
groups have been employed in palladium-catalyzed arylation,
alkylation, alkoxylation, and intramolecular amination of sp2
and sp3 C−H bonds.14 Reported methods for functionalization
of 2-arylpyridines show that copper catalysis is possible even for
nonacidic C−H bonds.9a,f−i,10 However, the substrate scope is
extremely limited due to presence of a nonremovable pyridine
moiety. We hypothesized that 8-aminoquinoline and picolinic
acid auxiliaries would facilitate ortho-trifluoromethylsulfenyla-
tion of benzoic acid and benzylamine derivatives. Thus, 8-
aminoquinoline was chosen as the auxiliary for the reaction
optimization. Commercially available and easy-to-handle bis-
(trifluoromethyl)disulfide was chosen as the electrophile since
most of trifluoromethylsulfide salts are either thermally unstable
or not readily available.15 Moreover, bis(trifluoromethyl)
disulfide can act as both thiolating reagent and oxidant.
Dimethyl sulfoxide (DMSO) was selected as a solvent due to
its ability to oxidize thiols to disulfides, allowing potential in
situ regeneration of CF3SH to (CF3S)2.16
ABSTRACT: An auxiliary-assisted, copper catalyzed or
promoted sulfenylation of benzoic acid derivative β-C−H
bonds and benzylamine derivative γ-C−H bonds has been
developed. The method employs disulfide reagents,
copper(II) acetate, and DMSO solvent at 90−130 °C.
Application of this methodology to the direct trifluor-
omethylsulfenylation of C−H bonds was demonstrated.
ryl trifluoromethyl sulfides are important pharmaceuticals
A
and agrochemicals.1 The introduction of trifluorome-
thylthio group into arenes leads to the increase of lipophilicity,
thus enhancing bioavailability.1,2 Moreover, aryl trifluoromethyl
sulfides are important intermediates for the synthesis of
trifluoromethyl sulfones and sulfoxides.3 Conventional methods
to introduce trifluoromethylthio moiety often require harsh
reaction conditions and stoichiometric amounts of transition
metals.1,4 Recently, efficient methods utilizing milder protocols
have been developed. Buchwald demonstrated trifluorome-
thylthiolation of aryl bromides by employing a palladium
catalyst and AgSCF3 reagent.5 Aryl bromides and iodides can
also be converted to ArSCF3 by a nickel-catalyzed method
developed by Vicic.6 More recently, Qing group reported the
preparation of aryl trifluoromethyl sulfides from aryl boronic
acids by a copper-catalyzed method.7 All these methods require
prefunctionalized starting materials. Consequently, a method
for direct trifluoromethylthiolation of aromatic C−H bonds
would be highly advantageous due to potential shortening of
synthetic pathways.8 We report here a method for an auxiliary-
assisted sulfenylation of benzamide β-C−H bonds and
benzylamine derivative γ-C−H bonds that is promoted by
copper(II) acetate (Scheme 1).
The reaction of 8-aminoquinoline 4-t-butylbenzoic acid
amide with (CF3S)2 was investigated with respect to the
amount of Cu(OAc)2 (Table 1). Stoichiometric copper acetate
afforded good conversion to the desired product (entry 1).
Table 1. Optimization of C−H Bond
a
Trifluoromethylsulfenylation
Scheme 1. Trifluoromethylsulfenylation
entry
x
% yield
1
2
3
4
1
61
70
74
44
In recent years, abundant first-row transition metals such as
copper have been explored as alternative catalysts for C−H
bond functionalization.9−13 Yu showed that 2-phenylpyridine
can be sulfenylated, aminated, halogenated, cyanated, and
hydroxylated under copper catalysis.10 Deprotonative arylation
and perfluoroalkylation of arenes and heterocycles using copper
catalysis has also been developed.11 Several copper-catalyzed
intramolecular heterocycle syntheses have been published.12
However, only a few methods for C−H bond sulfenylation have
0.8
0.5
0.2
a
Yields were determined by NMR. See Supporting Information for
details.
Received: September 17, 2012
Published: October 29, 2012
© 2012 American Chemical Society
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Decreasing the amount of Cu(OAc)2 to 0.8 and 0.5 equiv
improved the yield of the product (entries 2 and 3). However,
if 0.2 equiv Cu(OAc)2 was employed, only 44% of 2 was
formed (entry 4). Consequently, 0.5 equiv of Cu(OAc)2 was
chosen for further studies.
The scope of the reaction with respect to carboxylic acid
derivatives is shown in Table 2. Various amides containing
We were pleased to discover that other aryl and alkyl
disulfides are also active sulfenylating reagents. Reactions of o-
toluic acid amide with various disulfides are presented in Table
3. A short optimization revealed that the reaction using
a
Table 3. Disulfide Scope in C−H Bond Sulfenylation
Table 2. Copper-Catalyzed Trifluoromethylsulfenylation of
a
Carboxylic Acid Derivatives
a
Yields are isolated yields. Amide (1 equiv), RSSR (2−2.5 equiv),
b
Cu(OAc)2 (0.5 equiv), DMSO, 100−110 °C. K2CO3 additive (1
equiv). Please see Supporting Information for details.
diphenyl disulfide reagent requires K2CO3 base in order to
achieve high conversion (12). Various dialkyl (13−16) and
diaryl disulfides (12, 17) are reactive and products were
obtained in excellent yields. Slightly lower yield was obtained
by using di-t-butyl disulfide (14), presumably due to increased
steric bulk. Nitro group is tolerated under the reaction
conditions (17), further demonstrating the excellent functional
group tolerance of the method.
Benzylamine derivatives can also be sulfenylated by employ-
ing Cu(OAc)2, disulfide reagents, and a picolinic acid directing
group. In contrast with 8-aminoquinoline benzamides, benzyl-
amine picolinamides require stoichiometric amount of copper-
(II) acetate promoter and higher reaction temperatures. Using
the optimized conditions, various benzylamine derivatives were
sulfenylated at γ-sp2 C−H bonds in moderate to good yields
(Table 4). p-Fluoro-α,α-dimethylbenzylamine and 2,4-dimeth-
yl-α-methylbenzylamine amides were mono-n-butylsulfenylated
in good yields (18 and 19). p-Methoxyphenylsulfenylation of
α,α-dimethylbenzylamine picolinamide affords monosubstitu-
tion product in 62% yield accompanied by disubstitution
product in 16% yield (20A and 20B).
α-Ethylbenzylamine and α-methyl-3-methoxybenzylamine
amides gave a mixture of approximately equal amounts of
mono- and disubstitution products (21A, 21B, 22A, and 22B).
Trifluoromethylsulfenylation of N-(1-methyl-1(4-
fluorophenyl)ethyl)picolin-amide gave 5% yield of monosub-
stitution product.
While the mechanism of the reaction is unclear at this
moment, two relevant observations may be discussed. First, it is
known that sulfide ligands stabilize high-valent Cu(III).18 In
some cases, disulfides can oxidize Cu(I) to Cu(III).18b Second,
Stahl has shown that nucleophiles can react with arylcopper-
(III) species affording C-heteroatom coupling products.19
The 8-aminoquinoline group can be efficiently removed in a
two-step procedure by amide N-methylation followed by base
hydrolysis. The trifluoromethylthiolated acid was obtained in
high yield (Scheme 2).
a
Yields are isolated yields. Amide (1 equiv), CF3SSCF3 (2−2.5 equiv),
Cu(OAc)2 (0.5 equiv), DMSO, 90−110 °C.
different electron donating and withdrawing groups are suitable
substrates providing products in moderate to good yields. The
reaction does not show any profound electronic preference, and
both electron-rich (2, 3, 7) and electron-poor benzamides (4, 5,
6, 8) afford products in good yields. The reaction afforded
difunctionalization products even with meta-substituted amides
(9) in contrast with our previous palladium catalyzed arylation
methodology where only monoarylated products were obtained
in such cases.14a,b Moreover, the reaction demonstrated
excellent functional group tolerance. Bromide (5), ester (6),
and chloride functionalities (8) are tolerated. Both five- and six-
membered heterocyclic substrates are also reactive. Nicotina-
mide (10) and 3-thiophenecarboxylic acid amide (11) were
converted to disubstituted products in synthetically useful
yields. Selective monotrifluoromethylsulfenylationation of N-
(4-t-butylbenzoyl)-8-aminoquinoline could not be achieved
under a variety of conditions. Either low conversion or about 1/
1 mixture of mono and disubstituted products were obtained.17
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for an increased usefulness of the reaction. The reaction shows
high generality, excellent selectivity toward ortho C−H bonds,
as well as good functional group tolerance. This method
provides a novel and straightforward way for the preparation of
aryl trifluoromethyl thioethers. Mechanistic studies of the
transformation as well as attempts to isolate reaction
intermediates are in progress.
Table 4. Copper-Mediated Sulfenylation of Amine
Derivatives
a
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and characterization data for
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
olafs@uh.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Welch Foundation (Grant No. E-1571), National
Institute of General Medical Science (Grant No.
R01GM077635), Camille and Henry Dreyfus Foundation,
and Norman Hackerman Advanced Research Program for
supporting this research.
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