Transition-metal-free decarboxylative thiolation of stable aliphatic carboxylates

Article abstract of DOI:10.1039/d1ra00063b

A transition-metal-free decarboxylative thiolation protocol is reported in which primary, secondary, tertiary (hetero)aryl acetates and α-CN substituted acetates undergo the decarboxylative thiolation smoothly, to deliver a variety of functionalized aryl alkyl sulfides in moderate to excellent yields. Aryl diselenides are also amenable substrates for construction of C-Se bonds under the simple and mild reaction conditions. Moreover, the protocol is successfully applied to the late-stage modification of pharmaceutical carboxylates with satisfactory chemoselectivity and functional-group compatibility. This journal is

Full text of DOI:10.1039/d1ra00063b

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Transition-metal-free decarboxylative thiolation of
stable aliphatic carboxylates†
Cite this: RSC Adv., 2021, 11, 4593
*
Wei-Long Xing, De-Guang Liu and Ming-Chen Fu
A transition-metal-free decarboxylative thiolation protocol is reported in which primary, secondary, tertiary
(hetero)aryl acetates and a-CN substituted acetates undergo the decarboxylative thiolation smoothly, to
deliver a variety of functionalized aryl alkyl sulfides in moderate to excellent yields. Aryl diselenides are
also amenable substrates for construction of C–Se bonds under the simple and mild reaction conditions.
Moreover, the protocol is successfully applied to the late-stage modification of pharmaceutical
carboxylates with satisfactory chemoselectivity and functional-group compatibility.
Received 4th January 2021
Accepted 15th January 2021
DOI: 10.1039/d1ra00063b
rsc.li/rsc-advances
carboxylate unit, largely limits the scope of these methods in
large-scale application. In terms of practicality and scalability,
Introduction
the development of a general and efficient method for
transition-metal-free decarboxylative thiolation of stable
aliphatic carboxylates would be extremely attractive, albeit
challenging. Very recently, Audisio and coworkers developed
a carbon isotope exchange procedure on arylacetic acid salts in
dimethyl sulfoxide (DMSO) without adding transition metal
catalysts.11 Simultaneously, Lundgren's group also demon-
strated that isotopic exchange of carboxylic acids with 13CO2 can
proceed smoothly; therein, the authors elegantly developed
a new decarboxylative carbon–carbon bond-forming reaction.12
In a continuation of our studies on decarboxylative func-
tionalization,13 and inspired by these seminal works,11,12,14 we
wondered whether the alkyl carboxylates I could directly
decarboxylate in DMSO or DMF (N,N-dimethylformamide)
solution to form the corresponding anion II (Scheme 1A, path
a),15 or generate dienolate species IV in situ (path b).14b These
intermediates might undergo nucleophilic attack onto aryl
disuldes, and subsequently deliver the desired product III
(Scheme 1A).
Organosulfur chemistry has attracted increasing attention due
to the importance of sulfur-containing compounds in bioactive
natural products, functional materials, and pharmaceuticals,
such as butoconazole, nelnavir and axitinib (Fig. 1).1 There-
fore, the development of convenient and efficient protocols for
constructing C–S bonds is of great signicance in organic
synthesis.2 The conventional approach to the direct construc-
tion of C(sp2)–S bonds usually involves the use of transition-
metal catalysts to realize thiolation of aryl halides with thiols
or disuldes.3 Signicant achievements have been made by the
groups of Hartwig,4 Fu and Peters et al.5 For construction of
C(sp3)–S bonds, nucleophilic substitution reaction of alkyl
halide with mercaptan is the most straightforward, but this is
limited to primary alkyl halides. Research on the use of diaryl
disuldes as sulfur sources to construct secondary and tertiary
C(sp3)–S bonds remains scarce. Alkyl carboxylic acids, which are
environmentally benign and widely available building blocks,
have been widely used as organic synthons in cross-coupling
reactions;6 Thus, they can offer an appealing alternative to the
traditional methods.7 In 2014, Feng and Xu's group used one
equivalent of AgNO3 to successfully realize the decarboxylative
C(sp3)–S cross-coupling reaction of alkyl carboxylic acid with
diary disuldes.8 Fu's group reported a visible-light-induced
decarboxylative arylthiation using alkyl carboxylic redox-active
esters with aryl thiols.9 Recently, Liu and Wang et al. also real-
ized the construction of C(sp3)–S bonds by using alkyl carboxylic
redox-active esters mediated by equivalent manganese
powder.10 However, the required equivalent of precious metals
and oxidant, or stoichiometric chemical premodication of the
Herein, we report an efficient and operationally simple
protocol for the synthesis of aryl alkyl suldes through
transition-metal-free decarboxylative cross-coupling of aryl
disuldes. This method has broad substrate scope, (hetero)aryl
acetates, and a-CN substituted acetates are amenable, has
satisfactory functional group tolerance, and proceeds with good
Department of Chemistry, University of Science and Technology of China, Hefei
230026, China. E-mail: fumingchen@ustc.edu.cn
† Electronic supplementary information (ESI) available: Experimental protocols
and spectral data. See DOI: 10.1039/d1ra00063b
Fig. 1 Thioether-containing pharmaceutical agents.
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Table
1
Key reaction-controlling parameters of decarboxylative
thiolationa
Different cation instead of K+
Li+
72
Na+
81
Rb+
84
Cs+
87
Ca2+
28b
H+
0
Yield of 3 (%)
Different solvent instead of DMSO
DMF DMA MeCN Dioxane Glyme Diglyme DCE
Scheme 1 The initially hypothesized mechanism and the focus of this
work.
Yield of 3 (%) 81
Control experiments
1
81
7
0
0
0
0
to excellent yields (Scheme 1B). In addition, this protocol was
successfully applied to synthesize aryl alkyl selenides, and, to
our knowledge, is the rst general method for the synthesis of
aryl alkyl selenides using stable aliphatic carboxylates without
the use of transition-metal catalysts.
Reaction
(0.2 mmol), 2 (0.3
mmol)
temperature:
0.2 mmol
H2O
60 ꢀC
Yield of 3 (%) 69
52
65
a
Reaction conditions: 1 (0.3 mmol, 1.5 eq.), 2 (0.2 mmol, 1.0 eq.), DMSO
(2.0 mL), 80 ꢀC, 24 h. The yield was determined by GC analysis using
b
diphenylmethane as internal standard.
CNC6H5CH2CO2)2Ca instead of 1.
0.15 mmol (p-
Results and discussion
To verify our hypothesis presented in Scheme 1A, we rst
selected potassium 2-(4-cyanophenyl)acetate (1) and diphenyl
disulde as model substrates. To our delight, aer careful
optimization of all reaction parameters, optimal conditions
were identied in which the desired product 3 was obtained in
97% yield in DMSO solution at 80 ꢀC for 24 h. The salt effect of
the counter-cation of the carboxylate on the reaction was
investigated (Table 1, row 1). The reaction proceeded smoothly,
albeit in lower yield, when the Li+ salt of 1 was used. Na+, Rb+,
and Cs+ salts of 1 gave good yields of 3 of 81, 84, and 87%,
respectively. The conversion dramatically decreased with diva-
lent metal salts of 1 (Ca2+), and 2-(4-cyanophenyl)acetic acid
failed to give the desired product. The nature of the solvent was
crucial for the success of the carboxylate decarboxylation.16 The
decarboxylative thiolation occurred smoothly in polar aprotic
solvents, such as DMF or DMA (Table 1, row 2), only 7% yield of
3 was detected in MeCN solution, and the reaction was
completely suppressed in dioxane, glyme, diglyme, or DCE
solution. Control experiments showed that changing the ratio
of the substrates (1, 0.2 mmol; 2, 0.3 mmol) reduced the yield of
product 3 to as low as 69%. The conversion decreased dramat-
ically when the reaction temperature was reduced to 60 ꢀC,
delivering the desired product in 52% yield. It should be noted
that this protocol was not very sensitive to humidity; 65% yield
of the desired product could be obtained in the presence of one
equivalent of water.
carboxylates, were readily converted into the corresponding aryl
alkyl suldes in moderate to excellent yields. A broad range of
functional groups, such as cyano (3), aryl halides (5, 6, 7), tri-
uoromethyl (8), triuoromethoxy (9), sulfonate (10), ether (16),
and even nitro (11, 12) groups proved compatible. The aryl
halides provided versatile synthetic handles for further func-
tionalization. The steric hindrance of aryl acetates has no clear
inuence on the reaction (11, 12). Increasing the reaction
temperature and addition of 18-crown-6 could promote the
efficiency of the reaction (5, 16). Potassium naphthalene acetate
was also an amenable substrate (13). Moreover, both mono-
phenyl and diphenyl substituted phenylacetates successfully
underwent decarboxylative thioetherication in high yields of
93% (14) and 97% (15), respectively. Notably, various potentially
reactive heterocycles, such as pyridines (17 and 18), thiophene
(19), pyrimidine (20), isoxazole (21), and benzo[d]thiazole (22)
were well tolerated in this protocol.
Cyano structures are versatile synthetic intermediates and
possess biological activity.17 Substituted cyanoacetates have
been reported as cyano synthons through decarboxylative
coupling under high-temperature conditions using palladium
catalyst by Liu and coworkers.18 To our delight, a series of
substituted cyanoacetates were also successfully applied to
decarboxylative thiolation with diphenyl disulde without
transition-metal catalysts (23–30). Cyanoacetate salts bearing
one or two a-substituents were compatible with the reaction
conditions, as was a four-membered ring structure with an a-
With the optimized conditions in hand, we further investi-
gated the scope of the decarboxylative thiolation. As shown in
Table 2, a myriad of (hetero)aryl acetates and a-CN substituted
acetates, including primary, secondary, and even tertiary
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Table 2 Scope of aliphatic carboxylates for C–S couplinga
Table 3 Scope of disulfides for C–S couplinga
a
Reaction conditions: carboxylates (0.3 mmol), disuldes (0.2 mmol),
DMSO (2 mL), 80 ꢀC, 24 h, under Ar atmosphere. Isolated yield. b 120 ꢀC.
thiolation was obtained (30), which might be due to the effect of
ring tension.
Remarkably, some pharmaceutical carboxylates (31–36) were
smoothly transformed into suldes with satisfactory chemo-
selectivity and functional-group compatibility, demonstrating
the potential of this method for post-synthetic-drug modica-
tion. Notably, diclofenac (32) and carprofen (35) were also
competent substrates in this transformation, with the unpro-
tected N–H structure retained.
We next investigated a diverse set of disuldes to further
highlight the versatility of this method (Table 3). A range of aryl
disuldes served as effective cross-coupling partners with
carboxylates to form compounds bearing C–S bonds in good to
Table 4 Scope of aliphatic carboxylates for C–Se couplinga
a
Reaction conditions: carboxylates (0.3 mmol), diphenyl disulde (0.2
mmol), DMSO (2 mL), 80 ꢀC, 24 h, under Ar atmosphere. Isolated
yield. b DMF (2 mL), 150 ꢀC. c 18-crown-6 (0.3 mmol) was added.
substituent, which provides an efficient and simple practical
method for the synthesis of a-CN suldes. It should be noted
that using potassium 1-cyanocyclopropane-1-carboxylate as the
substrate, only the ring-opening product of decarboxylative
a
Reaction conditions: carboxylates (0.3 mmol), diphenyl diselenide (0.2
mmol), DMSO (2 mL), 80 ꢀC, 24 h, under Ar atmosphere. Isolated yield.
© 2021 The Author(s). Published by the Royal Society of Chemistry
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Fig. 2 The Gibbs free energies of the feasible mechanism.
excellent yields (57–97%); these compounds contained electron- through electrostatic interaction. Aer abstracting the proton of
rich (37, 38), electron-decient (39), and hindered (40–42) the carboxyl group, the generated thiophenol IN6 leaves briey,
functional groups. In addition, heterocyclic-aryl disuldes 43– and the decarboxylation of the remaining species IN5 becomes
45, which have potential physiological activity and are useful in achievable (TS5, 18.4 kcal molÀ1); this is easier than the direct
medicinal chemistry, were also amenable substrates and gave decarboxylation of benzyl carboxylate ion (TS7, 21.1 kcal molÀ1
,
the desired products in good yields.
see ESI for details†). When the new benzyl carbanion interme-
Based on the success of the decarboxylative C–S bond diate IN7 forms aer decarboxylation, the thiophenol IN6
formation in this protocol and the similar reactivity in “returns” the previously captured proton to IN7. Thereby, the
construction of C–Se bonds,19 we further investigated the reac- formation of the product P0 is exergonic by 24.5 kcal molÀ1, and
tions of diphenyl diselenide with stable aliphatic carboxylates to the energy barrier of this step is 7.1 kcal molÀ1. In addition, we
generate related aryl selenide scaffolds (Table 4), which are also considered the classical carbanion decarboxylation
widely applied in antioxidants, uorescent probes, and func- pathway and a cooperative attack-decarboxylation pathway; the
tional organic materials.20 To our delight, both (hetero)aryl results clearly indicate that this proposal of proton transfer is
acetates and a-CN substituted acetates underwent decarbox- dominant (see ESI for related calculation details†). Different
ylative cross-coupling of diphenyl diselenide under the stan- from previous reports, this transformation might proceed
dard reaction conditions described above, providing a simple through a novel pathway involving proton migration, electro-
general approach to synthesize a diverse range of organo- philic attack, decarboxylation, and proton exchange, providing
selenium compounds.
great potential and a different perspective for decarboxylative
To gain more mechanistic insights into this reaction, a series cross-coupling.
of mechanism experiments and density functional theory (DFT)
calculations were carried out (see ESI for detailed data†). Based
on these results and on the previous works,11,12,14,15 a plausible
Conclusions
mechanism involving dienol formation and proton transfer was
proposed (Fig. 2). First, the benzyl carboxylate ion substrate IN1
We have developed a mild and efficient protocol for the C–S
undergoes benzyl C–H proton migration with the assistance of
additional IN1, to deliver an electrostatic-dominated dimer
intermediate IN1-dimer. Due to the inhomogeneity of the
charge distribution, the migrated proton is easily transferred to
the original carboxyl anion with a free-energy decrease of
11.7 kcal molÀ1, and the corresponding dienol anion IN3 is
obtained. This strategy is more advantageous than the intra-
molecular proton migration (TS1, 23.2 kcal molÀ1 vs. TS2,
44.1 kcal molÀ1). Subsequently, the disulde substrate IN2
electrophilically attacks the dienol anion IN3 to deliver the
corresponding sulfurized product IN4. At the same time, the
released thiophenol anion binds to the carboxyl O–H bond
cross-coupling of aryl disuldes with stable aliphatic carboxyl-
ates without the use of transition-metal catalysts. A wide range
of primary, secondary, and tertiary (hetero)aryl acetates and a-
CN substituted acetates underwent the decarboxylative thio-
lation smoothly in moderate to excellent yields. Moreover, this
protocol was also successfully applied to construct C–Se bonds
with aryl diselenide. DFT calculations revealed that the pathway
involved dienol formation, and proton transfer is dominant in
this protocol. The simple and mild conditions of this protocol
will allow a wide range of applications for the synthesis of
biologically and pharmaceutically active molecules containing
aryl sulfur/selenium moieties.
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Conflicts of interest
There are no conicts to declare.
Acknowledgements
This work was supported by the Natural Science Foundation of
Anhui (2008085MB40) and the USTC Research Funds of the
Double First-Class Initiative (YD2060002003). The authors
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