Redox-active benzimidazolium sulfonamides as cationic thiolating reagents for reductive cross-coupling of organic halides

Article abstract of DOI:10.1039/d0sc06446g

Redox-active benzimidazolium sulfonamides as thiolating reagents have been developed for reductive C-S bond coupling. The IMDN-SO₂R reagent provides a bench-stable cationic precursor to generate a portfolio of highly active N-S intermediates, which can be successfully applied in cross-electrophilic coupling with various organic halides. The employment of an electrophilic sulfur source solved the problem of catalyst deactivation and avoided odorous thiols, featuring practical conditions, broad substrate scope, and excellent tolerance.

Full text of DOI:10.1039/d0sc06446g

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Redox-active benzimidazolium sulfonamides as
cationic thiolating reagents for reductive cross-
coupling of organic halides†
Cite this: Chem. Sci., 2021, 12, 2509
All publication charges for this article
have been paid for by the Royal Society
of Chemistry
Weigang Zhang, Mengjun Huang, Zhenlei Zou, Zhengguang Wu,
Shengyang Ni,
*
Lingyu Kong, Youxuan Zheng,
Yi Wang
and Yi Pan
Redox-active benzimidazolium sulfonamides as thiolating reagents have been developed for reductive C–S
bond coupling. The IMDN-SO2R reagent provides a bench-stable cationic precursor to generate a portfolio
of highly active N–S intermediates, which can be successfully applied in cross-electrophilic coupling with
various organic halides. The employment of an electrophilic sulfur source solved the problem of catalyst
deactivation and avoided odorous thiols, featuring practical conditions, broad substrate scope, and
excellent tolerance.
Received 24th November 2020
Accepted 22nd December 2020
DOI: 10.1039/d0sc06446g
rsc.li/chemical-science
The high frequency of sulfur-containing moieties in natural of reductive thiolation16 have been described using thiol deriv-
products,1 bioactive molecules,2 pharmaceuticals,3 organic atives as S+ sources (Scheme 1b). We speculated that readily
materials,4 fragrances5 and asymmetric catalysis as chiral cata- accessible sulfonyl chloride as an electrophilic sulfur source
lysts/ligands6 has triggered the best endeavours for the selective could avoid the use of highly toxic thiols and signicantly the
construction of C–S bonds. The conventional cross-coupling of substrate scope.17 However, the direct reduction of sulfonyl
thiols with aryl halides generally relies on the conversion of
mercaptans to thiolates by means of transition-metal catalysis7
(such as Pd,8 Cu,9 and Ni10) and other metals,11 although these
efforts were plagued by several drawbacks. The strong coordi-
nation of thiolates to metals oen leads to catalyst deactivation
and displays low efficiencies. Therefore, high catalyst loading,
specic ligands, excessive heating and strong bases are oen
required to facilitate this transformation (Scheme 1a, le).
Recent development using photochemical12 and electro-
chemical13 induced thiol radicals as a sulfur source could avoid
the problem of catalyst poisoning, although restricted substrate
scope was displayed (Scheme 1a, middle). Despite the progress
made for C–S bond construction,14 the longstanding issues that
exist in the above-mentioned strategies should not be
overlooked.
Compared to classical cross-coupling processes, the nickel-
catalyzed reductive cross-coupling of two electrophilic partners
has emerged as a powerful tool for the replacement of air- and
moisture-sensitive organometallic reagents.15 The cross elec-
trophilic coupling for the construction of C–S bonds is more
challenging due to the lack of sulfur sources and homo-
coupling of organic halides (Scheme 1a, right). Several examples
State Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced
Organic Materials, Collaborative Innovation Center of Advanced Microstructures,
School of Chemistry and Chemical Engineering, Nanjing University, Nanjing
210023, China. E-mail: yiwang@nju.edu.cn
Scheme 1 Origin of the reaction design. (a) C–S formation from
organic halides. (b) The preparation of the electrophilic thiolating
reagent (R–S+). (c) This work: cationic active reagent for cross elec-
trophilic coupling.
† Electronic supplementary information (ESI) available. See DOI:
10.1039/d0sc06446g
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chloride inevitably resulted in dimerization to disulde.17b decreasing both Ni(OTf)2 and dtbbpy loading to 10 mol%, the
Putatively, activated by an electron-decient heterocycle such as yield reduced to 75%. In the absence of Ni(OTf)2 or Zn powder,
imidazole, sulfonyl chloride could be assembled into a bench- no desired product was observed (entries 9–10). Switching Zn
stable cationic reagent (Scheme 1b). Benzimidazolium sulfon- powder to an organic reductant tetrakis-(dimethylamino)
amides would be better electron acceptors18 and easily reduced ethylene (TDAE), still a low conversion of the reaction was
by PPh3 to generate a highly reactive N–S+ species in situ. The observed (entry 11). The results demonstrated that no organo-
positive charge of this intermediate is delocalized on both zinc reagents were generated. In the absence of the ligand,
nitrogens of imidazole. Followed by the cleavage of the weak N– MgCl2 or PPh3, the reaction resulted in low yields, indicating
S bond (BDE z 70 kcal molꢀ1),19 the electrophilic sulfur species that these ingredients were essential for this catalytic system
can be captured by metal catalysts for cross-coupling. Herein, (entries 12–14). Thus, the optimized conditions were selected
we have described a redox-active benzimidazolium sulfonamide for further investigation of the reaction scope.
reagent (IMDN-SO2R) for Ni-catalyzed reductive coupling of
The generality of the reductive thiolation was evaluated
organic halides for a portfolio of C(sp)–S, C(sp2)–S and C(sp3)–S under the optimized conditions (Scheme 2). A wide range of aryl
bond formations (Scheme 1c). This strategy avoids the forma- iodides containing either electron-withdrawing or electron-
tion of disulde by-products and the use of organometallic donating functionality were tolerated, delivering products with
reagents, which facilitates purication and enhances the func- methoxy (3a, 3c), triuoromethoxy (3b), methyl (3d), acetyl (3e),
tionality tolerance.
ester (3f), boronate (3g), and phenyl (3h) groups in good to
To determine the suitable conditions for the reductive excellent yields (63–94%). 5-Iodobenzo[d][1,3]dioxole and 2-
coupling of the cationic reagent with organic halides, we rst iodouorene also furnished the corresponding adducts (3i, 3j)
studied the reductive thiolation of p-iodo-methoxybenzene (2a) in 91% and 82% yields, respectively. Notably, aryl iodides
and 1a (2 equiv.) with a survey of Ni catalysts in the presence of bearing sensitive groups such as amine (3k) and hydroxyl (3l)
dtbbpy (20 mol%), PPh3 (2.5 equiv.), Zn powder (3.0 equiv.) and were engaged in the cross-coupling to forge the C–S bond in
MgCl2 (2.0 equiv.) in DMA at 60 ꢁC (Table 1). Ni(OTf)2 as good yields. Aryl bromides (3a, 3m) were also found compatible.
a catalyst was able to promote the reductive process to afford the The scope of the heteroaryl halide coupling partner was also
desired aryl thioether product 3a in 92% isolated yield (entry 1). explored. Various ve- and six-membered heterocycles,
When using Ni(cod)2, Ni(acac)2, Ni(OAc)2$4H2O and Ni(PCy3)2- including thiophene (3n), pyrazole (3o), quinoline (3p), carba-
Cl2, lower yields were obtained (entries 2–5). Decreasing the 1a zole (3q), indole (3r), isothiazole (3s), benzofuran (3t), benzo-
loading to 1.5 equiv., the yield of 3a reduced to 75% (entry 6). thiophene (3u), benzothiazole (3v), pyrimidine (3w), pyrazine
Switching 1a to a 2-phenyl substituted imidazolium sulfon- (3x), and pyridine (3y, 3z) derived heteroaryl bromides and
amide reagent 1b, similar yields were achieved (entry 7). When iodides were treated with 1a to produce the corresponding
suldes in good yields. In the cases of relatively unreactive
organic chlorides, the corresponding coupling products (3aa–
3cc) could be obtained in low yields under the standard
conditions. Subsequently, we assessed the scope of aryl
sulfonamides. Reagents 1c–1k containing electron-withdrawing
and electron-donating substitutions on the benzene ring affor-
ded the desired products in good to excellent yields (3dd–3ll).
Sterically hindered imidazolium sulfonamides 2,4,6-trimethy-
lated 1j and 2,4,6-triisopropylated 1k showed good compati-
bility in this reaction to give the corresponding products 3kk
and 3ll in high yields.
Table 1 Optimization of the reaction conditions. Reaction condition:
2a (0.20 mmol), 1a (0.40 mmol, 2.0 equiv.), MgCl2 (2.0 equiv.), PPh3
(2.5 equiv.), Zn (3.0 equiv.), Ni(OTf)2 (20 mol%) and dtbbpy (20 mol%) in
1
DMA (2 mL) at 60 ꢁC under Ar. aCrude yields determined by H NMR
spectroscopy using dibromomethane as an internal standard. bIsolated
yield. dtbbpy ¼ 4,40-di-tert-butyl-2,20-bipyridine. TDAE ¼ tetrakis(di-
methylamino)ethylene
The more challenging aliphatic halides have also been
examined with the redox-active reagent 1a (Scheme 3). Primary
and secondary alkyl halides yielded alkyl suldes (5a–5k and 5l)
in good to excellent yields. No dimerization side-product was
observed. Functionalities including esters (5b, 5i, and 5j),
sulde (5c), alkene (5f), acetal (5h) and ether (5k) are tolerated.
Some sensitive functional groups including silyl ether (5e) and
organoboronate (5g) were well tolerated, provided in 75% and
57% yields, respectively. Alkenyl halides were also tolerated to
afford 7a and 7b in good yields. In addition, alkynyl bromides
were employed for reductive thiolation with benzimidazolium
sulfonamides 1a and 1c–1i to afford the corresponding C(sp)–S
bond coupling products (9a–9h) in moderate to good yields.
To demonstrate the synthetic potential of this cross-elec-
trophile coupling, a gram scale reaction was performed with 1a
and p-iodo-methoxybenzene 2a under the standard conditions
Entry Variation
Yielda/% Entry Variation
Yielda/%
1
2
3
4
5
6
7
None
Ni(acac)2
Ni(cod)2
96 (92)b
42
63
8
9
10 mol% [Ni] 83
No Ni(OTf)2
No Zn
nd
nd
21
46
39
20
10
11
12
13
14
Ni(OAc)2$4H2O 21
TDAE for Zn
No dtbbpy
No MgCl2
No PPh3
Ni(PCy3)2Cl2
1.5 equiv. 1a
2.0 equiv. 1b
57
75
88
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a
Scheme 2 Substrate scope of (hetero)aryl and benzimidazolium sulfonamides. Reaction was performed at 80 ꢁC.
Scheme 3 Substrate scope of alkyl, alkenyl and alkynyl bromide. aNi(PCy3)2Cl2 instead of Ni(OTf)2 and without dtbbpy. b4-(Trifluoromethyl)
pyridine (0.2 mmol) and THF (2 mL) were used instead of dtbbpy and DMA.
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(Scheme 4a). The reductive thiolation was also applied in the
late-stage modication of biologically active molecules and
synthesis of pharmaceutically active molecules. D-Glucose (10a),
(+)-a-tocopherol (10b), rosin amine (10c), and 17a-methyl-
drostanolone-derived (10d) alkyl halides were compatible to
afford thiolated products in good yields (Scheme 4b). Treating
benzimidazolium sulfonamide 1n with piperazine-derived
iodobenzene 11 generated the thiolated intermediate 12 and
deprotection with TFA afforded anti-depressive vortioxetine 13
(ref. 20) in 50% overall yields (Scheme 4c).
To investigate the mechanism for this reductive thiolation,
a series of control experiments have been carried out. First, the
treatment of benzimidazolium sulfonamide 1a with PPh3 fur-
nished the key N–S+ intermediate Int-I and Ph3P ¼ O, which
were conrmed by 1H NMR, HRMS data and 31P NMR (Scheme
5a, see the ESI†). A mixture of Int-I and 2a was able to afford 3a
in 80% yield under the standard conditions, indicating that
the reaction did go through this route (Scheme 5b). Further-
more, the key nickel-complex 14 was prepared and reacted
with Int-I to furnish thioether 3d in 15% yield (Scheme 5c).
Finally, sulfone 15 was used in the absence of benzimidazo-
lium sulfonamide 1a and 2a under standard conditions. No
Scheme 5 Mechanistic studies and proposed mechanism.
reduced product 3a was detected, which indicates that the
PPh3 reduction occurs before the cross-coupling (Scheme 5d).
On the basis of the experimental results and previous
reports,16c,g a plausible mechanism for the reductive thiolation
of organic halides is proposed (Scheme 5e). Initially, the
reduction of the Ni(II) salt by zinc affords the active Ni(0)
catalyst A, which undergoes oxidative addition into the C–X
bond of organic halides to give the intermediate R–Ni(II)X B.
The following reduction of B forms R–Ni(I) intermediate
C.15b,16g Then C and Int-I undergo stepwise single-electron
transfer with the possibility of radical trapping within a solvent
cage to afford intermediate D before the generation of R–Ni(III)-
SAr E and benzoimidazole residue 16. Finally, the reductive
elimination of E furnishes the desired thioether product and
Scheme 4 Further transformations. (a) Gram-scale experiment. (b)
Late-stage modification of natural products. (c) The synthesis of vor-
tioxetine using our protocol.
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Conclusions
In summary, we have developed a universal reductive thiolation
protocol of organic halides with benzimidazolium sulfon-
amides. This bench-stable crystalline reagent is readily achiev-
able in large quantities from abundant sulfonyl chloride. The
key design of this redox-active reagent is the cationic nature.
The reduction potential of sulfonyl group can be improved due
to the cationic nature and in favor of in situ generating elec-
trophilic N–S+ reagent by the reduction of triphenylphosphine.
This approach features practical conditions, broad substrate
scope, and excellent functional group tolerance for the incor-
poration of sulfur-containing moieties into organic molecules.
Further study of the cationic reagent IMDN-SO2R is underway in
our laboratory.
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There are no conicts to declare.
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´
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Professor Shaolin Zhu is gratefully acknowledged for helpful
discussion. This work was supported by the National Natural
Science Foundation of China (No. 21772085 and 21971107) and
the Fundamental Research Funds for the Central Universities
(No. 020514380220, 020514380131, 020514913412, and
020514913214). We also thank the Collaborative Innovation
Center of Advanced Microstructures and Jiangsu Provincial Key
Laboratory of Photonic and Electronic Materials at Nanjing
University for support.
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