NH4I-catalyzed C–S bond formation via an oxidation relay strategy: Efficient access to dithioether decorated indolizines

Article abstract of DOI:10.1016/j.tetlet.2020.152368

An efficient NH₄I-catalyzed C–H/S–H cross-coupling reaction of indolizines with thiols is reported. Compared to previous methods, this environmentally friendly oxidation relay strategy uses O₂ as an oxidant to afford dithioether decorated indolizines in up to 98% yield. Promising results have been obtained, indicating the high applicability and atom economy of this method.

Full text of DOI:10.1016/j.tetlet.2020.152368

Tetrahedron Letters 61 (2020) 152368
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Tetrahedron Letters
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NH4I-catalyzed C–S bond formation via an oxidation relay strategy:
Efficient access to dithioether decorated indolizines
⇑
Yu Zhu, Liechao Yang, Liyun Fang, Xiaofan Du, Keda Chen, Chuanming Yu, Xinpeng Jiang
College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou 310014, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient NH4I-catalyzed C–H/S–H cross-coupling reaction of indolizines with thiols is reported.
Compared to previous methods, this environmentally friendly oxidation relay strategy uses O2 as an oxi-
dant to afford dithioether decorated indolizines in up to 98% yield. Promising results have been obtained,
indicating the high applicability and atom economy of this method.
Received 18 May 2020
Revised 4 August 2020
Accepted 12 August 2020
Available online 20 August 2020
Ó 2020 Elsevier Ltd. All rights reserved.
Keywords:
C–S bond formation
Sulfenylation
Indolizines
Thiols
Introduction
Zhao, and coworkers reported KI catalyzed ditholation of indoli-
zaines via cross-coupling of indolizaines and thiols with stoichio-
Indolizines can be widely found in natural products, fluorescent
materials [1], and a broad range of biologically active molecules
[2], including anticancer drugs [3], antimalarial drugs, apoptosis
inducers and antifungal drugs [4]. Therefore, significant effort has
been devoted to the construction and modification of this impor-
tant scaffold [5]. In the past few decades, C–S bond formation
attracted much attention due to sulfur-containing motifs existeing
in numerous pharmaceutically active compounds [6]. Transition-
metal-catalyzed cross-coupling represents one of the most power-
ful methodologies for thiolation [7]. However, these methods use
novel metal catalysts that are either expensive or damaging to
the environment. Therefore, developing a highly efficient approach
for the direct sulfenylation under metal-free conditions is still
remains a critical goal. A variety of reagents has been applied in
the past to construct C–S bonds, including thiols [8], disulfides
[9], sulfinic acids [10], sodium arenesulfinates [11], N-thioimides
[12], and sulfur powder [13]. However, despite the significant
advance made in this field, few examples have been reported in
the literature to date detailing dithiolation. Recently, Lenardão,
Schiesser, and coworkers developed a selenium dioxide promoted
synthesis of bis-sulfenlindoles (Scheme 1a) [14]. Meanwhile, Cao,
metric amount of peroxide TBHP as oxidant (Scheme 1b) [15].
However, these methodologies still suffer from relatively low
yields and the need of highly toxic catalysts or potentially explo-
sive peroxides. Therefore, the development of a safe and versatile
method to synthesize dithioether-decorated indolizines is still
highly desirable. Based on our recent work on heterocyclics [16],
herein, we report a metal-free synthesis of dithioether decorated
indolizines via an oxidation relay strategy.
Results and discussion
Initially, we carried out our studies with 2-phenylindolizine 1a
and 4-methylbenzenethiol 2a as model substrates in the presence
of 10 mol % of KI under oxygen atmosphere in DCE. In doing so, we
obtained the desired product 2-phenyl-1,3-bis (p-tolylthio)in-
dolizine 3a in 84% yield (entry 1, Table 1). Subsequent survey on
a series of solvents revealed that DCE provided the best results (en-
tries 2–4, Table 1). Attempts of using various iodine sources, such
as I2, NaI, NH4I, and TBAI showed that the use of NH4I afforded
the desired product 3a in 87% yield (entries 5–8, Table 1). Decreas-
ing the amount of NH4I to 5 mol % could improve the yield of 3a to
⇑
Corresponding author.
E-mail address: xjiang@zjut.edu.cn (X. Jiang).
https://doi.org/10.1016/j.tetlet.2020.152368
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

2
Y. Zhu et al. / Tetrahedron Letters 61 (2020) 152368
alent provided product 3a in 37% yield. Thus, optimized reaction
conditions for this model reaction (1a reacted with 2.1 equivalent
of 2a and 5 mol % of NH4I in DCE under O2 atmosphere at 60 °C)
were established.
With optimized conditions in hands, we investigated the cou-
pling of various thiols 2 with 2-phenylindolizine 1a (Table 2).
The reactions proceeded smoothly to afford dithiolated products
3 with excellent functional group compatibility. Thiols bearing
either electron-donating (Me and OMe) or electron-withdrawing
(F, Cl, Br, and CF3) groups on the para-position of the phenyl ring
of thiols displayed good reactivity, providing the corresponding
products 3a–3f in 82–94% yields. Similarly, ortho- and meta- sub-
stituted thiols with methoxy, methyl, and choloro groups could
Table 2
NH4I-catalyzed sulfenylation of 2-phenylindolizine 1a with thiols 2.
Scheme 1. Synthetic protocols of dithioether decorated indolizines.
94% (entries 9 and 10, Table 1). Further screening of the reaction
temperature revealed that reaction at 60 °C resulted in the best
yield (entries 11 and 12, Table 1). Increasing the amount of p-
toluenethiol to 3 equivalents did not increase the yield of 3a (entry
13, Table 1). Furthermore, carrying out the reaction in air afforded
3a in only 83% yield. Decreasing the amount of thiol 2a to 1 equiv-
Table 1
Optimization of the reaction of 1a and 2a.
Entry
Solvent
Catalyst
(10 mol %)
Time
(h)
Yield
(%)b
1
DCE
KI
KI
KI
KI
I2
NaI
TBAI
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
NH4I
6
84
26
79
43
72
83
–
87
94
86
82
91
94
83
37
2c
DMSO
MeNO2
MeCN
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
72
24
72
6
7
6
7
7
6
6
3
4c
5
6
7
8
9d
10e
11d,f
12d,g
13d,h
14d,i
15d,j
48
7
28
7
DCE
DCE
DCE
aReaction conditions: 1a (0.26 mmol), 2a (0.55 mmol, 2.1 eq), and catalyst (10 mol
%) was reacted in solvent (1 mL) under oxygen atmosphere at 60 ℃. bIsolated yield.
cThe yields were determined by 1H NMR analysis of the crude reaction mixture
using 1,3,5-trimethoxybenzene as an internal standard. d5 mol % of catalyst was
f
used. e20 mol % of catalyst was used. 80 ℃. g40 ℃. h3 equivalents of p-toluenethiol
aReaction conditions: 1a (0.26 mmol), 2a (0.55 mmol, 2.1 eq), NH4I (5 mol %) in DCE
(1 mL) under O2 (1 atm) at 60 ℃. b10 mol % of NH4I were used.
i
j
was used. In air. 1a (0.26 mmol), 2a (0.26 mmol, 1 eq).

Y. Zhu et al. / Tetrahedron Letters 61 (2020) 152368
3
Table 3
for 2-naphthalenethiol, furnishing 3x in 78% yield. Last but not
least, substitution of the ring of indolizines was also well tolerated
under standard conditions and afforded products 3y-3aa in good to
excellent yields.
NH4I-catalyzed sulfenylation reactions of 2-phenylindolizines 1 and 4-methylben-
zenethiol 2a.
Furthermore, several control experiments were carried out to
generate a plausible reaction mechanism (Scheme 2). Firstly, the
radical scavenger 1-oxyl-2,2,6,6-tetramethylpiperidine (TEMPO)
was added to the reaction mixture. The slightly lower yield (89%)
of 3a ruled out the possibility of a radical mechanism. Secondly,
no desired product 3a was produced in the absence of NH4I or oxy-
gen, indicating that the NH4I/O2 catalytic system played a signifi-
cant role in this transformation. When 5 mol % of iodine was
used as a catalyst instead of NH4I, 73% of 3a could still be obtained
under standard conditions, verifying the key role of iodine in this
catalytic cycle (Scheme 2a). Thirdly, diphenyl disulfide 5a failed
to provide dithiolation product 3a, instead, 20% of the monothiola-
tion product 4a was formed under standard conditions with 2-
phenylindolizin, suggesting that the S–H bond plays an important
role for the reaction outcome (Scheme 2b) [17]. Finally, the reac-
tion of monothiolation product 4a and 2a produced 3a in 82% yield
under standard conditions, revealing that the in situ generated
monothiolation product may represent the key intermediate in this
reaction (Scheme 2c).
On the basis of the present results and former reported results
[8c,18],
a plausible reaction mechanism was generated as
outlined in Scheme 3. Iodine ions (IÀ) were oxidized by oxygen
to form iodine, which then reacted with thiol 2 to produce
sulfenyl iodide. This in situ generated intermediate reacted with
2-phenylindolizin
Meanwhile, diphenyl disulfide
1
to form monothiolation product 4.
may also be formed by
5
oxidation of thiol 2 and then reacted with 2-phenylindolizin 1 to
convert to the monothiolation product 4. Due to the increase of
electron density on the indolizine ring, 4 is prone to undergo a
second sulfenylation to generate the final dithiolation product 3.
Conclusion
In summary, we have developed an efficient and environmen-
tally benign method for the dithiolation of 2-phenylindolizines.
In this protocol, NH4I was used as the catalyst and oxygen served
as the sole oxidant. A variety of functionalized 2-phenylindolizines
were well tolerated and provided the dithioether decorated indoli-
zines in up to 98% yield. Further studies on the applicability of
these disulfenylated products in medicinal chemistry are currently
underway in our laboratory.
a
Conditions: 1a (0.26 mmol), 2a (0.55 mmol, 2.1 eq), and NH4I (5 mol %) in DCE
(1 mL) under O2 (1 atm) at 60 ℃.
Declaration of Competing Interest
also afford the desired products 3g-3j in 81–98% yields. Interest-
ingly, thiophene-2-thiol and naphthyl thiol were also found to be
well tolerated in this transformation to provide 3k and 3l in 82%
and 77% yields, respectively. Moreover, increasing the catalyst
loading to 10 mol %, the use of butanethiol and 1-dodecanethiol
could also afford the desired products 3m and 3n in good yields.
After studying various thiol species, we investigated the scope
and limitation of 2-phenylindolizines 1 (Table 3). Substrates bear-
ing either electron-donating (Me and MeO) or electron-withdraw-
ing groups (F and Br) in para-, ortho-, and meta-position on the
phenyl ring of 2-phenylindolizines afforded the corresponding
products 3o-3u in 77–90% yields. Moreover, dichloro- and
dimethoxyl substituted 2-phenylindolizines exhibited good reac-
tivity characteristics to produce 3v and 3w in 87% yield. Addition-
ally, this reaction displayed good functional group compatibility
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgements
We acknowledge the National Natural Science Foundation of
China (grant number 21506191 and 21676252) for their financial
support.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2020.152368.

4
Y. Zhu et al. / Tetrahedron Letters 61 (2020) 152368
Scheme 2. Control experiments. aYields determined by 1H NMR analysis of the crude product using 1,3,5-trimethoxybenzene as an internal standard.
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