Iodine-catalyzed sulfuration of isoquinolin-1(2H)-ones applying ethyl sulfinates

Article abstract of DOI:10.1039/d1nj00390a

An efficient sulfuration of isoquinolin-1(2H)-ones at the C-4 position is reported by employing ethyl sulfinates, and the corresponding products are obtained in moderate to excellent yields in the presence of iodine. This synthetic strategy provides a range of thioether-isoquinolin-1(2H)-ones while tolerating a number of functional groups on the isoquinoline nitrogen atom and benzene ring. In addition, pyridin-2(1H)-one is also reacted smoothly and afforded the corresponding thioether product in moderate yield. A plausible mechanism is suggested based on the preliminary mechanistic studies.

Full text of DOI:10.1039/d1nj00390a

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Iodine-catalyzed sulfuration of
isoquinolin-1(2H)-ones applying ethyl sulfinates†
Cite this: New J. Chem., 2021,
45, 4934
Yangxiu Mu,a Minghua Yang,*b Fengxia Li,a Zafar Iqbal,a Rui Jiang,a Jing Hou,a
ab
Xin Guo,c Zhixiang Yangb and Dong Tang
*
Received 25th January 2021,
Accepted 4th March 2021
DOI: 10.1039/d1nj00390a
rsc.li/njc
An efficient sulfuration of isoquinolin-1(2H)-ones at the C-4 position is controlling the properties of target molecules, and selective
reported by employing ethyl sulfinates, and the corresponding products C–H functionalization of isoquinolines developed has provided
are obtained in moderate to excellent yields in the presence of iodine. powerful synthetic access to abundant isoquinolin-1(2H)-one
This synthetic strategy provides a range of thioether-isoquinolin-1(2H)- derivatives. Recently, the C3, C4 and C8-selective functionaliza-
ones while tolerating a number of functional groups on the isoquinoline tion of isoquinolines was well documented in the literature.
nitrogen atom and benzene ring. In addition, pyridin-2(1H)-one is also For instance, Samanta and co-workers11 described the catalyst
reacted smoothly and afforded the corresponding thioether product in controlled C3 and C8-selective amidation of isoquinolone
moderate yield. A plausible mechanism is suggested based on the derivatives. Despite great progress having been achieved, the
preliminary mechanistic studies.
development of efficient methodologies to generate functional
isoquinoline derivatives is still highly desirable and a formid-
The construction of carbon–sulfur bonds has gained considerable able challenge. Recently, Zhu’s group12 successfully developed
attention in organic chemistry owing to the prevalence of nitrogen- a AgSbF6-mediated selective thiolation of isoquinolin-1(2H)-
containing motifs in natural products, pharmaceuticals, agrochem- ones at the C-4 position (Scheme 1a). Following continuous
icals, and functional materials.1 Consequently, many useful and study of our group on the formation of carbon–sulfur bonds,13
efficient synthetic methods have been developed for the formation we herein report the iodine-catalyzed reaction for the formation
of carbon–sulfur bonds. In this regard, many sulfur sources, such as of C-4 thio isoquinolin-1(2H)-ones by employing arylsulfinates.
thiol,2 sulfenyl chloride,3 disulfide,4 sulfonylhydrazide,5 sulfinic
We commenced our study with 2-methylisoquinolin-1(2H)-
acid,6 sodium sulfinates,7 S-phenyl sulfonothioate8 and sulfur,9 have one 1a and ethyl 4-methyl benzenesulfinate 2a as the model
been used to achieve this goal. Although the classical approaches substrates to optimize the reaction conditions (Table 1). We
furnished efficient methods, diverse strategies and sulfur sources were pleased to obtain 3aa in 22% yield (Table 1, entry 1) when
are still under development, culminating in more useful, economic trifluoromethanesulfonic anhydride (Tf2O) was used as a
and environmentally benign synthetic design.
catalyst in 1,2-dichloroethane (DCE) after 12 h at 25 1C. Then,
Isoquinolines as a very important class of heterocycles are the reaction was tested under the conditions reported in the
ubiquitously implicated in a large number of bioactive com- previous literature reports,14 and only disappointing results
pounds and natural products.10 Generally, the introduction of
functional groups to the core skeleton is a useful approach for
a Agricultural Resource and Environment Institute of Ningxia Academy of
Agriculture and Forestry Science, Yinchuan 750002, P. R. China.
E-mail: tangdongabcd@126.com
b Department of Chemistry, Lishui University, Lishui, 323000, P. R. China.
E-mail: mhyang@lsu.edu.cn
c Department of Pharmaceutical Engineering, School of Chemistry and Chemical
Engineering, North Minzu University, Yinchuan 750002, P. R. China
† Electronic supplementary information (ESI) available: 1. General procedure for
the preparation of various N-substituted isoquinolones. 2. General procedure for
the preparation of various ethyl C-substituted benzenesulfinates. 3. 1H and 13C
NMR spectral data of the products. 4. Copies of 1H and 13C NMR spectra. See DOI:
Scheme 1 Sulfuration of isoquinolin-1(2H)-ones at the C4 position.
10.1039/d1nj00390a
4934 | New J. Chem., 2021, 45, 4934À4937
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Table 1 Optimization of the reaction conditionsa
Table 2 Synthesis of 2-methyl-4-(phenylthio)isoquinolin-1(2H)-one by
using different ethyl sulfinatesa,b
Entry
Catalyst
Solvent
Temp. (1C)
Yieldb (%)
1
2
3
Tf2O
NH4I
I2
DCE
DCE
DCE
EtOH
Dioxane
CH3CN
DMSO
Dioxane
DMF
Toluene
CH3CN
CH3CN
CH3CN
CH3CN
25
25
25
90
100
120
120
120
120
120
140
140
140
140
22
NR
Trace
NR
NR
4
5c
6
NH4I/1,10-Phen
I2
I2
I2
I2
I2
I2
I2
I2
I2
25
7
8
9
10
11
12d
13d,e
14d,f
Trace
Trace
Trace
17
38
55
75
93
a
1a (0.20 mmol), 2a (0.20 mmol), catalyst (20 mol%), solvent (2 mL).
Isolated yield based on 1a. For 6 h. 2a (0.40 mmol). For 16 h.
For 24 h.
b
f
c
d
e
were observed (Table 1, entries 2–4). To our delight, the reac-
tion performed in CH3CN afforded the target product 3aa in
25% yield at 120 1C in the presence of I2 (Table 1, entry 6).
Evaluation of solvents revealed that CH3CN was superior to
dimethylsulfoxide (DMSO), 1,4-dioxane, dimethyl formamide
(DMF), and toluene (Table 1, entries 7–10). Furthermore, the
yield of 3aa further improved to 38% by increasing the tem-
perature to 140 1C (Table 1, entry 11), which shows that the
temperature has a remarkable influence on the reaction.
Increasing the stoichiometric ratio of 2a to 2 equivalents
increased the reaction yield to 55%. However, the substrate
1a was still observed when the model reaction was performed
for 12 hours, and prolonging the reaction time to 16 and
24 hours resulted in yields of 75% and 93%, respectively
(Table 1, entries 13 and 14), indicating the influence of reaction
time on the progress of the reaction.
With the optimized reaction conditions in hand (Table 1, entry
14), the scope of 2 was then explored by employing various ethyl
arylsulfinates to react with isoquinolin-1(2H)-one (1a) (Table 2).
Generally, the aryls with electron-withdrawing and electron-
donating groups, such as halogen, trifluoromethyl, methoxy,
methyl and naphthyl, reacted smoothly affording the corres-
ponding products in good to excellent yield (Table 2, 3ab–g and
3aj–o), and the position of the substituent had no remarkable
influence on the reaction (Table 2, 3ab, 3ac and 3ad). A substrate
with a p-cyano group provided a remarkably low yield of 17%, and
a
Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), I2 (20 mol%) and
b
MeCN (2 mL) at 140 1C for 24 hours. Isolated yield based on 1a.
With respect to the scope of isoquinolin-1(2H)-ones, we also
the substrate containing a p-nitro substituent on the benzene ring evaluated the reaction under standard conditions and the
did not participate in this protocol. It’s worth noting that the results are summarized in Table 3. First, isoquinolin-1(2H)-
bulky substituents, such as naphthyl and tertiary butyl, were well- ones with substituents such as benzyl and ethyl on the N atom
tolerated affording the corresponding products in 95% and 91%, were found to be compatible with the reaction conditions,
respectively. The results indicated that the steric hindrance had furnishing the desired products in 99% and 68% yields, respec-
no obvious effect on this transformation.
tively (Table 3, 3ba and 3ca). The substrate with an allyl group
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Table 3 Synthesis of 2-methyl-4-(phenylthio)isoquinolin-1(2H)-one by
using different substituents of isoquinolin-1(2H)-onea,b
Scheme 2 Primary mechanism studies.
Scheme 3 Plausible mechanism.
Furthermore, 2-methylisoquinolin-1(2H)-one (1a) was treated
with 1,2-diphenyldisulfane 4b giving the product 3ap in 76%
yield. These results suggest that the disulfide is the key inter-
mediate in this catalytic process.
On the basis of our experimental results and previous studies,
a plausible mechanism is proposed and illustrated in Scheme 3.
Initially, ethyl sulfinate is activated by iodine to give complex
A which is then transformed into dimer intermediate B through
free radical polymerization. The dimer B then undergoes reduc-
tive elimination to afford disulfide C by releasing acetaldehyde
and hydrogen peroxide.16 In the next step, the intermediate C
splits into the active iodide species D in the presence of I2,17
leading to the formation of intermediate E through regioselective
electrophilic attack by 2. Finally, the desired product 3 is afforded
by elimination of HI from the intermediate E.
a
Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), I2 (20 mol%) and
b
MeCN (2 mL) at 140 1C for 24 h. Isolated yield based on 1.
at the N atom afforded the corresponding product 3da in 24%
yield. Moreover, the substances devoid of substituents on the N
atom were also tolerated under standard conditions, and
isoquinolin-1(2H)-one gave the product 3ia in 58% yield. Sub-
strates carrying methyl, chloro, bromo, or methoxy substitution
on the benzene ring were also compatible, giving moderate to
good yields (Table 3, 3fa, 3ga, 3ha and 3ia). However, the nitro-
substituted isoquinolin-1(2H)-one transformed into the corres-
Conclusions
ponding products 3ja in lower yield. Gratifyingly, a pyridin- In summary, we developed a direct and efficient I2-mediated
2(1H)-one such as 1-benzylpyridin-2(1H)-one was successfully sulfuration of isoquinolin-1(2H)-ones at the C4-position by
converted to the product 3ga in satisfactory yield of 49%.
using ethyl sulfinates. This reaction has a broad scope of
In order to understand the reaction mechanism, some substrates and affords the target products in good to excellent
control experiments were performed (Scheme 2). When 2a yields. Furthermore, a plausible mechanism was proposed
was performed under optimized reaction conditions, the inter- based on our experimental results as well as previous reports.
mediate product 4a was observed by liquid chromatography– The protocol provides a method to access sulfuration of
mass spectrometry (LC–MS). The formation of 4a in a similar isoquinolin-1(2H)-ones, and ethyl sulfinates proved to be an
kind of reaction had been reported in the previous literature.15 alternate sulfuration reagent in synthetic organic chemistry.
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A mixture of isoquinolin-1(2H)-ones (0.2 mmol), ethyl sulfinate
(0.4 mmol) and I2 (20 mol%) in MeCN (2 mL) was taken in a
sealed tube, and the reaction mixture was stirred for 24 h at
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solvent was evaporated and the crude product was purified by
column chromatography with PE/EA = 3/1 as the eluent on
silica gel to afford product 3.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We greatly acknowledge financial support from Ningxia Key
Research and Development Program (2018BEB04034 and
2019BEB04028) and the Natural Science Foundation of Zhejiang
Province (LY18B020004).
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