Palladium-catalyzed decarboxylative methylthiolation of aromatic carboxylic acids by using DMSO as the sulfurizing reagent

Article abstract of DOI:10.1002/ejoc.201403147

By using simple and readily available DMSO as a convenient and environmentally friendly source of sulfur, a practical approach for the Pd-catalyzed decarboxylative methylthiolation of 2-nitrobenzoic acids was developed. A range of substituents on the aryl group of the ortho-nitrobenzoic acid were compatible with this process.

Full text of DOI:10.1002/ejoc.201403147

Job/Unit: O43147
/KAP1
Date: 30-10-14 18:17:30
Pages: 6
SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403147
Palladium-Catalyzed Decarboxylative Methylthiolation of Aromatic
Carboxylic Acids by Using DMSO as the Sulfurizing Reagent
Zhengjiang Fu,[a] Zhaojie Li,[a] Qiheng Xiong,[a] and Hu Cai*[a]
Keywords: Synthetic methods / Decarboxylation / Homogeneous catalysis / Palladium / Copper
By using simple and readily available DMSO as a convenient
of 2-nitrobenzoic acids was developed. A range of substitu-
and environmentally friendly source of sulfur, a practical ap- ents on the aryl group of the ortho-nitrobenzoic acid were
proach for the Pd-catalyzed decarboxylative methylthiolation
compatible with this process.
methyl thioethers from the reaction of aryl (pseudo)halides
or their equivalents and methanethiol (MeSH) has re-
mained almost untouched,[9] partly because of the fact that
the boiling point of MeSH is too low (6 °C) to conveniently
manipulate it at room temperature. Hence, the development
of a simple and facile method for the synthesis of aryl
methyl thioethers remains a highly appealing goal for or-
ganic chemists. In 2006, Yu and co-workers established a
Cu(OAc)2-mediated thioetherification of 2-phenylpyridine
with MeSSMe under an air atmosphere,[10a] and this proto-
col was also investigated in depth by Hocek recently for
the Cu-catalyzed C–H sulfenylation of 7-deazapurine with
MeSSMe.[10b] In addition, by using α-(methylthio)isobutyr-
ophenone as the methylthio donor, Yamaguchi realized the
Rh-catalyzed methylthiolation of benzothiazole in moder-
ate yield.[11] Although DMSO is a widely available and
cheap reagent, there are only four examples in which
DMSO was used as a methylthiolation surrogate to prepare
aryl methyl thioethers.[12] On this point, Qing reported the
Cu-mediated methylthiolation of the C–H bond of 2-phen-
ylpyridine with DMSO.[12a] Subsequently, Cheng developed
a Cu-mediated methylthiolation of Ar–X (X = I, Br) with
DMSO.[12b] Xu, Yu, and Gao described that heteroarene
C–H bonds directly reacted with DMSO to construct het-
eroaryl methyl thioethers by using AgF as a catalyst and
Cu(OAc)2 as a mediator/oxidant.[12c] Very recently, during
the preparation of this manuscript, Chen and Xiao reported
a three-component coupling reaction of arynes, α-bromo
carbonyl compounds, and DMSO to generate multisubsti-
tuted aryl methyl thioethers.[12d]
Introduction
As the simplest alkyl fragment, the methyl group is one
of the most prevalent building blocks in numerous small-
molecule drug candidates, for the reason that the methyl
group can modulate biological and physical properties of
a molecule.[1] Therefore, many transformations have been
developed to create compounds containing methyl groups.[2]
Among these methylated compounds, aryl methyl thio-
ethers are not only precursors of the corresponding sulfox-
ides and sulfones,[3] but they are a commonly occurring
component in biologically active and pharmaceutical mol-
ecules.[4]
Besides the common reduction of sulfoxides and sulfones
to sulfides,[5] classical methods for the synthesis of aryl
methyl thioethers include the directed or heteroatom-as-
sisted lithiation of aromatic C–H bonds and subsequent
electrophilic substitution with dimethyl disulfide.[6] In ad-
dition, a multistep transformation was developed that in-
volves the chlorosulfonylation of electron-rich aromatics
followed by reduction with zinc powder and 30% HCl and
then sulfur methylation with MeI.[4c] Ma and co-workers
developed a multistep methylthiolation procedure through
the Cu-catalyzed incorporation of in situ generated poly-
sulfide ions into aryl iodides followed by reduction with
NaBH4 and then subsequent S-methylation with MeI.[7]
However, these reported reactions generally suffer from
limitations with regard to fussy procedures and/or harsh
reaction conditions. Over the past decade, great progress
has been made in the one-step formation of a C–S bond
through transition-metal-catalyzed cross-coupling reactions
of aryl (pseudo)halides with thiols, disulfides, and other sul-
fur-containing reagents.[8] Nevertheless, the synthesis of aryl
Because carboxylic acids possess low toxicity and are
broadly available and inexpensive, transition-metal-cata-
lyzed decarboxylative coupling of aromatic carboxylic acids
is one focus of current catalysis studies.[13] In this context,
aromatic carboxylic acids are available for the in situ gener-
ation of organometallic intermediates by transition-metal-
promoted extrusion of CO2, for which the organometallic
intermediate serves as either the nucleophile or the electro-
[a] College of Chemistry, Nanchang University,
Nanchang 330031 China
E-mail: caihu@ncu.edu.cn
http://chem.ncu.edu.cn/Teacher_show.asp?id=13
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403147.
Eur. J. Org. Chem. 0000, 0–0
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Z. Fu, Z. Li, Q. Xiong, H. Cai
SHORT COMMUNICATION
phile depending on the nature of the employed metal salt; that unsatisfactory yields were obtained if we used Cu2O or
this demonstrates the potential of aromatic carboxylic acids CuBr instead of CuI (Table 1, entries 5 and 6). Sub-
as versatile coupling partners. Thus, decarboxylative cou- sequently, upon evaluating the effect of the counterion of
pling provides an attractive alternative to traditional metal- the Pd catalyst on the reaction, we were pleased to find that
catalyzed coupling reactions. A pioneering contribution by replacing Pd(OAc)2 with PdCl2 readily gave a significantly
the group of Myers exhibited a Pd-catalyzed decarb- improved yield (91%). Thus, this PdCl2 catalyst was a much
oxylative Heck coupling of arene carboxylic acids with ole- better choice than either Pd2(dba)3 (dba = dibenzylidene-
fins,[14] and the work was improved by Su[15] and others[16] acetone) or Pd(OAc)2 (Table 1, entries 7 and 8). Intensive
by using cheap and green Pd/O2 as the catalyst and elec- studies demonstrated a beneficial effect of adding the phos-
tron-rich olefins as the coupling components. Gooßen,[17] phine ligand to the palladium catalyst;[17a–c,27] thus, dif-
Forgione,[18] and others[19] established the decarboxylative ferent phosphine ligands were screened in the model reac-
cross-coupling of aryl (pseudo)halides with (hetero)aro- tion (Table 1, entries 9–13). Among the phosphine ligands
matic carboxylic acids alkenyl carboxylic acids, alkynyl screened, to our delight, P(otol)3 proved to have the ideal
carboxylic acids, and α-oxocarboxylic acids respectively. In steric and electronic properties, and 2a was delivered in syn-
addition to aryl (pseudo)halides, the scope of the coupling thetically useful levels (94%; Table 1, entry 9). Considering
partners in decarboxylative transformations could be ex- that P(otol)3 is far more expensive than PPh3, PPh3 was
tended to alkynes,[20] other alkenes,[21] organoboron rea- chosen in combination with PdCl2 for the reaction. Screen-
gents,[22] Togni’s electrophilic trifluoromethylating agent,[23] ing the loadings of PPh3, PdCl2, and CuI revealed that
sulfoximines,[24] thiols and disulfides.[25] This above concept 10 mol-% PPh3 in conjunction with 10 mol-% PdCl2 and
was further expanded to decarboxylative C–H bond func- 2 equiv. of CuI provided an excellent yield (Table 1, en-
tionalization by Crabtree,[26a] Glorius[26b] and others,[26c–26i]
who made a big stride in the development of reactions in-
volving C–H activation/decarboxylation sequences. To date,
Table 1. Optimization of the reaction conditions.[a]
no method for the decarboxylative methylthiolation has
been explored between aromatic carboxylic acid and
DMSO. Although Liu employed thiols and disulfides in de-
carboxylative C–S couplings, MeSH as a coupling partner
was absent from the protocol to synthesize methyl aryl thio-
ethers.[25a] Compared to the toxicity, cost, and low boiling
point of MeSH, DMSO is an ideal methylthiolation surro-
gate. Herein, we reveal the first synthesis of aryl methyl
thioethers through the Pd-catalyzed decarboxylation of
benzoic acids with DMSO.
Results and Discussion
We commenced our investigation by taking the reaction
of 2-nitrobenzoic acid (1a) with DMSO as the model reac-
tion for the optimization studies. Table 1 presents some se-
lected results from these optimization studies, which re-
vealed the effects of the catalyst, ligand, Cu additive, and
other reaction parameters on the reaction outcome. At first,
in the presence of stoichiometric amounts of CuI as a medi-
ator, and a large excess amount of DMSO as both the cou-
pling partner and the solvent, the reaction was performed at
160 °C under a nitrogen atmosphere and furnished desired
product methyl 2-nitrophenyl sulfide (2a) in 34% yield
(Table 1, entry 1). A slightly increased yield (42%) was ob-
tained with the addition of Pd(OAc)2 (10 mol-%) and PPh3
(30 mol-%) into the reaction system (Table 1, entry 2).
However, in the absence of either the phosphine ligand or
the Cu additive, the reaction provided an inferior yield
[a] Conditions: 1a (0.2 mmol), DMSO (2 mL), 160 °C, 20 h.
[b] Yield of isolated product; average of two runs. [c] PMes3
tris(2,4,6-trimethylphenyl)phosphine, TTMPP = tris(2,4,6-trimeth-
oxyphenyl)phosphine, TFP = tri(2-furyl)phosphine. [d] 1,10-Phen-
anthroline (10 mol-%) as another ligand. [e] 2,6-Lutidine (20 mol-
(15%) or no product, respectively (Table 1, entries 3 and 4);
the results indicated that the phosphine ligand played an
important role and that the Cu additive was essential to
the catalytic reaction.[17a,17b] A brief survey of different CuI
=
compounds under otherwise identical conditions revealed %) as another ligand. [f] Reaction conducted at 140 °C.
2
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Palladium-Catalyzed Decarboxylative Methylthiolation
tries 14–17). Nitrogen ligands had a detrimental effect on Table 2. Scope of the aromatic acid substrate.[a]
the reaction conversion and the yields were remarkably
lower (Table 1, entries 18 and 19). The influence of reaction
temperature on the catalytic process was also investigated,
lowering of the reaction temperature to 140 °C offered
much lower efficiency (17%; Table 1, entry 20).
Having identified the optimal conditions, the scope of
this reaction with respect to benzoic acids was explored un-
der the standard conditions of entry 14 in Table 1. As
shown in Table 2, the Pd-catalyzed decarboxylative sulfe-
nylation of carboxylic acids was shown to be effective for
ortho-nitrobenzoic acids with DMSO as the methylthiol-
ation surrogate. It was observed that a range of 2-nitro-
benzoic acids with different substituents, including electron-
donating (methoxy and methyl) and electron-withdrawing
groups (chloro, fluoro, and trifluoromethyl), on the aro-
matic ring were amenable to this protocol, and the corre-
sponding products were delivered in moderate to good
yields. PdCl2 (10 mol-%) and CuI (2 equiv.) with PPh3
(10 mol-%) furnished acceptable yields for 5-methoxy-2-ni-
trobenzoic acid (1b) and 4,5-dimethoxy-2-nitrobenzoic acid
(1c) in DMSO at 160 °C; however, 4-methoxy-2-nitroben-
zoic acid (1d) was a less effective substrate and offered the
product in only moderate yield (41%) at a slightly elevated
temperature. In the reaction of 2-nitrobenzoic acid bearing
a methyl group, the yields of the desired products were
clearly increased in the case of 4-methyl-2-nitrobenzoic acid
(1f) with P(otol)3 and 5-methyl-2-nitrobenzoic acid (1g)
with PPh3 relative to that obtained for their isomer 3-
methyl-2-nitrobenzoic acid (1e). It was reported that
DMSO can slightly decompose into methyl mercaptan and
dimethylthiomethane at elevated temperatures, especially
under acidic conditions.[12a,28] As a result, p-toluic acid
(1 equiv.) as an additive was required to promote smooth
decarboxylative methylthiolation of the 2-nitrobenzoic ac-
ids bearing electron-withdrawing substituents (see com-
pounds 1h–l). Only in the case of 1m was a moderate yield
(45%) obtained upon introducing an electron-deficient
fluoro group at the C4 position of the 2-nitrobenzoic acid
motif, regardless of the presence or absence of the p-meth-
ylbenzoic acid additive. Nevertheless, an attempt to improve
the transformation failed in the reaction of a 2-nitrobenzoic
acid motif bearing an electron-donating group (see com-
pounds 1b–g) with the help of the p-toluic acid additive.
Notably, 4-chloro-2-nitrobenzoic acid (1i) and 5-chloro-2-
nitrobenzoic acid (1j) formed hoped-for products 2i and 2j
in which the chloro moiety survived. This chloro moiety
can be used for late-stage modification through transforma-
tion of the C–Cl bond to provide further potential applica-
tion of this methodology. Using ortho weakly coordinating
substituent on the aromatic ring of the aromatic carboxylic
acid core to control the reactivity and/or regioselectivity of
a transformation is well established,[14–16] and it seems that
a nitro group at the ortho position of the benzoic acid sub-
strate is crucial for the decarboxylative methylthiolation re-
[a] Reaction conditions: 1 (0.2 mmol), PdCl2 (10 mol-%), PPh3
action to stabilize the transition structure of the decarbox-
ylation procedure and to enhance the formation rate of the
aryl–metal intermediate in this process.
(10 mol-%), CuI (2 equiv.), DMSO (2 mL), 160 °C, 20 h.
[b] Average of two runs. [c] 180 °C. [d] P(oTol)3 instead of PPh3.
[e] Reaction performed with p-toluic acid (1 equiv.).
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Z. Fu, Z. Li, Q. Xiong, H. Cai
SHORT COMMUNICATION
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Conclusions
In summary, we established a practical Pd-catalyzed
method for the decarboxylative methylthiolation of 2-nitro-
benzoic acids with inexpensive and widely available DMSO
as the sulfurizing reagent. The process demonstrated a prac-
tical approach to build up methyl 2-nitrophenyl thioethers
in moderate to good yields with high selectivity and exhib-
ited a good functional tolerance with respect to both elec-
tron-donating and -withdrawing groups. Thus, the pro-
cedure is a viable and low-costing alternative to existing
methods for the preparation of aryl methyl thioethers. Fur-
ther investigations into the scope of the substrate as well as
the mechanism are now in progress.
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Experimental Section
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General Methods: Reagents used for the experiments were commer-
cially available and were used as received unless otherwise noted.
DMSO was distilled from CaH2 under reduced pressure and was
stored under a nitrogen atmosphere. All reactions were performed
under a nitrogen atmosphere with strict exclusion of dioxygen and
moisture by using Schlenk techniques. Column chromatography
was performed on silica gel 300–400 mesh. The yields reported are
the yields of the isolated products and are the averages of two runs.
1H NMR, 13C NMR, and 19F NMR spectra were recorded at 400,
100, and 377 MHz, respectively, in CDCl3 as the solvent. HRMS
were performed by Shanghai Mass Spectrometry Centre, Shanghai
Institute of Organic Chemistry, Chinese Academic of Sciences.
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General Procedure: An oven-dried Schlenk tube equipped with a
stir bar was charged with PdCl2 (3.5 mg, 0.02 mmol, 10 mol-%),
phosphine ligand (0.02 mmol, 10 mol-%), CuI (76.2 mg, 0.4 mmol),
and aromatic carboxylic acid (0.2 mmol). The tube was fitted with
a rubber septum, and it was then evacuated and refilled with nitro-
gen (3ϫ). Under an atmosphere of nitrogen, DMSO (2 mL) was
added by syringe. The rubber septum was replaced with a Teflon
screw cap under nitrogen flow. With stirring, the reaction mixtures
were heated at 160 °C for 20 h (unless otherwise specified), and
then cooled down to room temperature. The resultant mixture was
filtered through a short plug of silica gel and then concentrated
in vacuo. The residue was then purified by flash chromatography
on silica gel to provide the corresponding product.
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Acknowledgments
The authors gratefully acknowledge financial support by the
National Natural Science Foundation of China (NSFC) (grant
numbers 21301088 and 21162015), the National Key Basic Re-
search Program of MOST of China (grant number
2012CBA01204), and Natural Science Foundation of Jiangxi Prov-
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Received: August 29, 2014
Published Online: ᭿
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5

Job/Unit: O43147
/KAP1
Date: 30-10-14 18:17:30
Pages: 6
Z. Fu, Z. Li, Q. Xiong, H. Cai
SHORT COMMUNICATION
Decarboxylative Methylthiolation
Z. Fu, Z. Li, Q. Xiong, H. Cai* ....... 1–6
Palladium-Catalyzed
Decarboxylative
Methylthiolation of Aromatic Carboxylic
Acids by Using DMSO as the Sulfurizing
Reagent
Aryl methyl thioethers are synthesized by
the Pd-catalyzed decarboxylation of aro-
matic carboxylic acids with DMSO. Simple
and readily available starting materials, ex-
cellent functional group tolerance, high sel-
ectivities, and moderate to good yields pro-
vide this efficient and practical protocol
with a broad utility in organic synthesis.
Keywords: Synthetic methods / Decarb-
oxylation / Homogeneous catalysis / Pal-
ladium / Copper
6
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Eur. J. Org. Chem. 0000, 0–0