C–S and C–N bond formation via Mn-promoted oxidative cascade reaction: Synthesis of C3-sulfenated indoles

Article abstract of DOI:10.1016/j.tet.2017.09.003

Thioethers are of synthetic value in pharmaceutical molecules and nature products, herein, we report an oxidative cascade reaction that delivers multiple substituted indole thioethers with great efficiency. This transformation utilized ortho-azido aromati

Full text of DOI:10.1016/j.tet.2017.09.003

Accepted Manuscript
C-S and C-N bond formation via Mn-promoted oxidative cascade reaction: Synthesis
of C3-sulfenated indoles
Lin He, Xianwei Li
PII:
S0040-4020(17)30916-X
10.1016/j.tet.2017.09.003
TET 28954
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 June 2017
Revised Date: 3 August 2017
Accepted Date: 4 September 2017
Please cite this article as: He L, Li X, C-S and C-N bond formation via Mn-promoted oxidative cascade
reaction: Synthesis of C3-sulfenated indoles, Tetrahedron (2017), doi: 10.1016/j.tet.2017.09.003.
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ACCEPTED MANUSCRIPT
Graphical Abstract
C-S and C-N Bond Formation via Mn-Promoted
Oxidative Cascade Reaction: Synthesis of
C3-Sulfenated Indoles
Leave this area blank for abstract info.
Lin He,a Xianwei Li*b
aDepartment of Pharmacy, Changzhi Medicinal Collage, Changzhi 046000, China
b School of Chemical Engineering and Light Industry, Guangdong University of Technology, No. 100 Waihuan
Xi Road Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
1

ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
C-S and C-N bond formation via Mn-promoted oxidative cascade reaction: synthesis
of C3-sulfenated indoles
Lin Hea, Xianwei Lib,*
aDepartment of Pharmacy, Changzhi Medicinal Collage, Changzhi 0460000, China
b School of Chemical Engineering and Light Industry, Guangdong University of Technology, No. 100 Waihuan Xi Road Guangzhou Higher Education Mega
Center, Guangzhou, 510006, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Thioethers are of synthetic value in pharmaceutical molecules and nature products, herein, we
report an oxidative cascade reaction that delivers multiple substituted indole thioethers with
great efficiency. This transformation utilized ortho-azido aromatic alkynes as the substrates, and
sulfonyl hydrazides as the sulfenation reagent promoted by Mn(III) catalyst. Notably, great
functional group tolerance, in combination with nitrogen and water as the byproducts,
highlighted the sustainable chemistry of this protocol.
Available online
Keywords:
Oxidative cascade reaction
thioether
2011 Elsevier Ltd. All rights reserved.
indoles
azido
molecular oxygen
1. Introduction
sulfenated indoles hold great synthetic utility in various areas
across pharmaceutical, material area and serve as versatile
To control the synthesis of architecturally complex molecules
through catalysis is a key aspect in modern drug discovery.1
Cascade reaction provides an efficient platform for the rapidly
increase the molecular complexity of simple substrates via quick
construction of multiple chemical bonds that delivers valuable
molecules.2,3 In this context, radical addition to unsaturated C-C
bonds initiated cascade reactions4 have received much attention
due to their synthetic application in complex molecules. These
transformations hold the advantages as follows: 1) multiple
chemical bonds were formed in one-pot manner; 2) regio- and
stereoselectivity were observed to highlight the synthetic
potential for the rapid access to complex molecules, thus these
concepts are accordance with requirments of green chemistry in
modern organic chemistry.
building block in organic synthesis. Towards this goal, much
efforts have been exploited in this research field toward
expedient access to their derivatives. General methods8 to afford
these molecules include: 1) nucleophlic substitution of halogen
derived indoles with aryl thiphenol derivatives; 2)
transition-metal catalyzed cross-couplings as well as C-H bond
fucntionalization of indoles with various sulfenation reagents.
The construction of C-S bond with great efficiency has been a
long-standing endeavor of chemical community,5 since thioether
and their derived functionalities are of enormous utility in
material science and drug discovery.6 For instance, several drug
candidates listed in Scheme 1 contained thioether key moiety.
For example, pergolide,7 which has been showed activity against
at the postsynaptic dopamine receptor and served as medicine to
treat of Parkinson's disease, contained indole-derived thiother key
structural moiety.
Scheme 1. Thioether-containing bioactive molecules.
Despite the synthetic power of C-S bond in organic
synthesis, due to the strong coordination ability of sulfur to metal
center, the choice of metal catalysts in combination of sulfenation
reagents is crucial to realize catalytic C-S bond formation.8 C3-
Considering the overall efficiency and sustainable chemistry
of the transformations, great advancements have been achieved
by using various types of sulfenation reagents,9 such as aryl thiol,
disulfide, 1-(thio)-1H-pyrrole-2,5-dione derivatives, sulfinic acid
and its sodium salt, sulfonyl hydrazides, et. al. In combination of
different types of radical acceptor, chemists have realized various
structurally diverse sulfur-containing complex molecules.
* Corresponding author.
Email address: xwli@gdut.edu.cm; jtwd228@126.com
2

Table 1. Optimization of reaction conditions. a
ACCEPTED MANUSCRIPT
Yieldb
(%)
Entry
Catalyst
CuI
Additive
Ligand
-
20
11
1
-
-
-
-
-
2
2
Cu(OAc)2
FeCl3
-
26
-
15
3
FeCl2
4
Rh2(OAc)4
Pd(OAc)2
AgNO3
-
-
n.d.
n.d.
n.d.
44
Scheme 2. Synthesis of C3-thioether with sulfonyl hydrazide via transition
5
-
-
metal catalysis.
6
-
-
7
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
-
-
Recently, we have achieved copper-catalyzed direct
oxidative functionalization of indoles with aryl sulfonyl
hydrazines as the sulfenation reagent.8e In this reaction, cheap
metal catalyst in combination with molecular oxygen as the green
oxidant made this protocol applicable in direct synthesis as well
as late-stage modification of sulfur-containing pharmaceuticals.
8
K2CO3
LiBr
K3PO4
TBAF
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
LiBr
-
49
9
-
57
10
11
12
13
14
15
16
17c
18d
-
52
-
31
-
64
DABCO
1,10-phen
Bpy
72
Nevertheless, the scope of thioether substrates was usually
limited and the reaction conditions were relatively harsh.
Therefore, the development of versatile and efficient methods for
constructing different useful skeletons bearing thioether group
under mild conditions is highly desirable. On our continuous
research interest in the development of aerobic oxidative
transformations10 that enable quick access to valuable molecules,
herein, we report a radical addition to C-C multiple bond initiated
cascade reaction, delivering C3-sulfenated indole derivatives.
Compared to our previous results, this oxidative
difunctionalizations of alkynes11 deliver highly substituted
indole-substituted thioethers, and afford structurally divergent
87 (85)
68
DBU
67
1,10-phen
1,10-phen
trace
35
a
Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), catalyst (10 mol%) ,
o
additive (10 mol%), ligand (10 mol%) were stirred at 80 C under oxygen
b
atmosphere for 12 hours. GC yield with biphenyl as the internal standard.
Yield in the parenthesis was determined after flash column chromatography. c
HOAc as the solvent. d DMF as the solvent.
Fig. 1 Optimization of reaction conditions. a
products from easily accessible starting materials.
More
Quick solvent screening revealed that only solvents DMF or
DMSO led to a noticeable conversion. As shown in Table 1,
various metal catalysts were tested, Mn(OAc)3 was identified to
be the most efficient catalyst for the C3-sulfenation reaction,
furnishing the desired C3-thioether indole 3a in 44% yield. Other
metal catalysts such as Ag(I), Fe(III), or Cu(II) complexes, which
could work as one-electron oxidants,15 were not viable for this
transformation, the deleterious side reaction is indole product
without sulfenation reaction. Further investigations of the
reaction parameters indicated that both additive and solvent play
critical roles in this transformation. Addition of base additive,
such as K2CO3 was beneficial for this transformation, while LiBr
additive led to practical yield, and the desired C3-thioether 3a
was obtained in 64% GC yield. Dinitrogens ligand were found to
accelerate this reaction, and 1,10-phen was critical to maintaining
high yields, as well as suppressing the decomposition of alkyne
substrate 1a.
significantly, this methodology builds fundament for the further
research on intermolecular aminosulfenation of alkynes, of which,
the obtained products are of great value as synthetic
intermediates.
2. Results and Discussion
Reactions design. Considering the synthetic utilities of highly
substituted sulfonated indoles, as well as the limited methods
toward these molecules, efficient methodologies are highly
desirable. Since Ortho-azido aromatic alkynes and alkenes serve
as important synthetic intermediates for constructing important
bioactive small molecules.4b,12 We speculated that employing
Ortho-azido aromatic alkynes to a catalytic system than enable
the radical addition initiated the cascade reaction, the desired
sulfenated indole products could be obtained under relative mild
conditions.
With the optimal condition in hand, we further explored the
generality of this oxidative cascade reaction. Various substituted
sulfonyl hydrazides were tested, as summarized in Scheme 3.
To
commence
our
research,
we
selected
1-azido-2-(phenyl-ethynyl)benzene (1a, 0.2 mmol) as the
substrate, and 4-methylbenzenesulfonohydrazide 2a as the
sulfenation reagent under oxidation conditions. Previous work
has demonstrated that azides might both act as precursors of
metal carbenoids and nitrogen centered radical,13 thus, the choice
of metal catalyst might be crucial for these transformations.
Moreover, due to the rich chemistry of C-C triple bond, et. al.
while difunctionalization of alkynes with nucleophiles and
electrophiles have been developed as state-of-art,14 radical
addition of C-C triple bonds initiated cascade reaction remained a
hot topic arena for the rapid construction of multiple
functionalized molecules.
3

R3
ACCEPTED MANWUeSCnexRt IePxTplored functional groups compatility towards
Ph
S
ortho azido alkynes in this transformation, and the results were
Mn[III] catalysis
R3 SO2NHNH2
Ph
depicted in Scheme 4. Both aryl and aliphatic substituted phenyl
N
- N2, - H2O
N3
H
alkynes exhibited good efficiency in this cascade reaction.
Methyl, methoxyl and chloro-substituted diaryl alkynes (3i, 3j,
2
1
3
3k) were suitable platforms in this regioselective
difucntionalization reaction. Moreover, heterocycles, such as
thiophene-derived alkynes showed great practicality (3l).
MeO
F
F
S
S
S
S
Great chemoselectivity towards alkynes was also exhibited in
Ph
Ph
Ph
Ph
N
N
H
N
this transformation, when both alkene and alkyne functionality
existed in the substrate 1m, and this reaction took place only at
C-C triple bond with C-C double bond inert. Both linear and
cyclic aliphatic alkyl-aryl alkynes gave the desired C3-thioether
indoles in high yields (3n, 3o, 3p). Significantly, cyan-derived
substrate 1q could also give the desired thioether product with
CN available for further modification.
N
H
H
H
3a
3b
3c
3d
, 75%
, 85% (80% )
, 86%
, 72%
Cl
F
Cl
N
Cl
S
S
S
S
Ph
Ph
Ph
Ph
N
N
H
N
H
To further demonstrate the synthetic generality of this
reaction, we investigate the substrate generality as to substituents
on aryl ring of alkynes. As summarized in Scheme 5, this
reaction was not sensitive to steric hindance as well as electron
effect. C5, C6-substituted as well as disubstituted methyl group
was well tolerated (3s, 3t, 3u). Functional groups, such as
methoxyl (3v), fluoro (3w), chloro (3x), bromo (3y) and
trifluoromethyl (3z) showed good efficiency in delivering
C3-thioether indoles. The compatibility of halogen functionality
holds synthetic potential for further decoration for rapid access to
complex molecules constructions. Ester group as a versatile
functionality was also compatible (3za), leaving room for further
modification to give more functionalized indole derivatives.
However, no desired product was detected with nitro group on
aryl ring (3zc).
H
N
H
3e
3f
3g
3h
, n.d.
, 78%
, 81%
, 70%
a
Reaction conditions: 1 (0.5 mmol), 2a (0.6 mmol), Mn(OAc)3 (10 mol%),
LiBr (10 mol%), 1,10-phen (10 mol%) in DMSO under 1 atm oxygen
atmosphere at 80 C for 12 h. Yields referred to isolated yields. Yield in the
o
parenthesis refers to 3 mmol scale transformation.
Scheme 3. Mn(III)-promoted thioamination of alkynes to C3-thioether
indolesa
Electron-donating substituted 2 showed better performance
than that of electron-withdrawing phenyl substrates. Fluoro and
trifluoro methyl groups, which were widely used in medicinal
and material functionality showed good reactivity in this
transformation, delivering the desired C3-sulfenated indoles in
good yields (3c, 3d, 3e). Steric demand aryl sulfonyl hydrazide
led to the decreased yield (3c). Moreover, halogen functional
groups were well tolerated (3f, 3g), holding the synthetic
potential for the further decoration via cross-coupling reactions.
To our disappointment, nitrogen heterocycle, such as
pyridine-derived sulfonyl hydrazide was not tolerated in this
reaction.
Notably, compared to our previous studies on
Cu(I)-catalyzed oxidative functionalization of indoles, this
cascade reaction has tremendously expanded the synthetic utility
in delivering multiple functionalized thioether indole derivatives.
a
Reaction conditions: 1 (0.5 mmol), 2a (0.6 mmol), Mn(OAc)3 (10 mol%),
LiBr (10 mol%), 1,10-phen (10 mol%) in DMSO under 1 atm oxygen
atmosphere at 80 oC for 12 h. Reaction was monitored by TLC for the
completion of the reaction. Yields referred to isolated yields.
Scheme 5. Mn(III)-promoted thioamination of alkynes to give C3-thioether
indolesa
a
Reaction conditions: 1 (0.5 mmol), 2a (0.6 mmol), Mn(OAc)3 (10 mol%),
LiBr (10 mol%), 1,10-phen (10 mol%) in DMSO under 1 atm oxygen
atmosphere at 80 oC for 12 h. Yields referred to isolated yields.
Scheme 4. Mn(III)-promoted thioamination of alkynes to C3-thioether
indolesa
Plausible Reaction Mechanism. To gain more insight
into the mechanism of this reaction, several control experiments
were performed (Scheme 6). Exposure of 1a alone to the standard
4

indole formation process. Notably, the features that nitrogen and
reaction condition, the cyclization product indole 4 could be
obtained in low efficiency (eq. 1); Disulfide 5 was generated in
quantitative yield with 2a in this catalytic oxidative condition (eq.
2). These controlled experiments revealed that sulfenyl radical
might be generated in this transformation. More significantly,
sulfenyl radical addition to the C-C triple facilitated the
subsequent cyclization reaction.
ACCEPTED MANUSCRIPT
water as the byproducts, mild conditions and great functional
compatibility, which might find utility for further elaboration of
medicinal molecules as well as natural products. Future work for
the further development of radical initiated cascade reactions
would be the central of our research topic.
4. Experimental Section
When the radical scavenger TEMPO (2 equiv) or BHT (2
equiv) was added under the standard conditions, the yield of
product 3a declined obviously, indicating the transformation
should proceed via a free-radical pathway (eq. 3).
4.1. General Methods. Melting points were measured with a
BÜCHI B-545 melting point instrument and were uncorrected.
1H and 13C NMR spectra were recorded using a Bruker Avance
400 MHz NMR spectrometer. The chemical shifts are referenced
to signals at 7.26 and 77.0 ppm, respectively, and chloroform is
solvent with TMS as the internal standard. Mass spectra were
recorded on a Shimadzu GCMS-QP5050A spectrometer at an
ionization voltage of 70 eV equipped with a DB-WAX capillary
column (internal diameter: 0.25 mm, length: 30 m). Elemental
analyses were performed with a Vario EL elemental analyzer. IR
spectra were obtained as potassium bromide pellets or as liquid
films between two potassium bromide pellets with a Bruker
Vector 22 spectrometer. High-resolution mass spectra were
obtained with Shimadazu LCMS-IT-TOF mass spectrometer.
TLC was performed by using commercially prepared 100–400
mesh silica gel plates (GF254) and visualization was effected at
254 nm. Other reagents were purchased as reagent grade and
used without further purification.
4.2. General Procedure for the Synthesis of C3-thioether
indoles 3. A mixture of alkynes 1 (0.5 mmol), 2 (0.6 mmol),
Mn(OAc)3 (23 mg, 20 mol%), LiBr (10 mol%), 1,10-phen (10
mol%) in DMSO under 1 atm oxygen atmosphere in a test tube
(15 mL) equipped with a magnetic stirring bar. The mixture was
stirred at 80 oC for given time. After the reaction was completed,
10 mL ethyl acetate (3×10 mL) was added into the tube. The
combined organic layers were washed with brine to neutral, dried
over MgSO4, and concentrated in vacuum. Purification of the
residue on a preparative TLC afforded the desired products.
Scheme 6. Control experiments
On the basis of these results, a possible mechanism is proposed
in Scheme 7.16,17 In this scenario, one-electron oxidation of
sulfonyl hydrazide 2 by higher-oxidation-state MnIII catalyst with
the assistance of base and molecular oxygen would provide the
corresponding sulfide radical species A,18 which may undergo
addition to C-C triple bond, delivering the sulfide substituted
alkenyl radical intermediate B. Subsequent release of N2 of B
with an azido moiety affords the N-centered radical species C,
which further undergoes hydrogen-atom abstraction to deliver the
desired product 3. Notably, disulfide A’, which might be
generated from the oxidative coupling of the sulfide radical A,
was also detected as side product in this catalytic system.
4.2.1. 2-Phenyl-3-(p-tolylthio)-1H-indole (3a): Yield: 88% (55.4
mg), yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.73 (d,
J = 7.6 Hz, 2H), 7.63 (d, J = 7.6 Hz, 1H), 7.46-7.32 (m, 4H), 7.24 (t,
J = 7.6 Hz, 1H), 7.14 (t, J = 7.2 Hz, 1H), 6.97 (dd, J = 19.6, 8.0 Hz,
4H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 141.9, 135.8,
135.6, 134.4, 131.5, 131.3, 129.7, 128.8, 128.7, 128.2, 125.8, 123.3,
121.2, 120.1, 111.2, 99.9, 20.9 ppm; νmax(KBr)/cm-1 3328, 2926,
1621, 1438, 1408, 686; MS (EI) m/z 121, 165, 223, 267, 283, 315;
HRMS-ESI (m/z): calcd for C21H17NNaS, [M+Na]+: 338.0974,
found 338.0979.
3-((4-Methoxyphenyl)thio)-2-phenyl-1H-indole (3b): Yield: 80%
1
(53.0 mg), yellow oil; H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H),
7.75 (d, J = 7.6 Hz, 2H), 7.64 (d, J = 7.6 Hz, 1H), 7.49 - 7.33 (m,
4H), 7.23 (d, J = 6.4 Hz, 1H), 7.15 (t, J = 7.2 Hz, 1H), 7.05 (d, J =
8.4 Hz, 2H), 6.71 (d, J = 8.4 Hz, 2H), 3.69 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 157.6, 141.6, 135.8, 131.6, 131.2, 129.8, 128.7,
128.6, 128.2, 127.8, 123.3, 121.1, 120.0, 114.6, 111.2, 100.9, 55.3
ppm; νmax(KBr)/cm-1 3335, 2906, 1628, 1429, 1405, 686; MS (EI)
m/z 139, 155, 207, 281, 310, 331; HRMS-ESI (m/z): calcd for
C21H17NNaOS, [M+Na]+: 354.0923, found 354.0929.
Scheme 7 A plausible reaction mechanism
3. Conclusion
3-((2-Fluorophenyl)thio)-2-phenyl-1H-indole (3c): Yield: 79% (50.4
mg), yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.70 (d,
J = 7.2 Hz, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.37 (dt, J = 14.2, 7.2 Hz,
4H), 7.25 (t, J = 7.6 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.05 - 6.93 (m,
2H), 6.79 (dd, J = 9.6, 6.0 Hz, 1H), 6.71 (t, J = 7.6 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 159.1 (d, JC-F = 242.0 Hz), 142.6, 135.9,
131.2, 131.1, 128.9, 128.2, 127.4 (d, JC-F = 2.5 Hz), 126.5, 126.4,
126.0 (d, JC-F = 7.2 Hz), 124.5 (d, JC-F = 3.2 Hz), 123.5, 121.3,
In summary, we have developed an efficient method of
Mn(III)-catalyzed cascade reaction that affords multiple
functionalized thioether indole derivatives. This transformation
involved sulfide radical generation induced by Mn(III) catalyst
and oxygen oxidant, addition to unsaturated C-C bond, nitrogen
radical generation from the corresponding azido moiety and
5

119.9, 115.1 (d, JC-F = 20.8 Hz), 111.3, 97.1 ppm; νmax(KBr)/cm-1
331; HRMS-ESI (m/z): calcd for C21H17NNaOS, [M+Na]+:
354.0923, found 354.0926.
3341, 2920, 1635, 1437, 1324, 689; MS (EI) m/z A121C, C16E5, P19T6,E28D7, MANUSCRIPT
319; HRMS-ESI (m/z): calcd for C20H14FNNaS, [M+Na]+:
342.0723, found 342.0729.
2-(4-Chlorophenyl)-3-(phenylthio)-1H-indole (3k): Yield: 80% (53.6
1
mg), yellow oil; H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.64
3-((3-Fluorophenyl)thio)-2-phenyl-1H-indole (3d): Yield: 80% (51.0
mg), yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 7.70 (d,
J = 7.2 Hz, 2H), 7.61 (d, J = 8.0 Hz, 1H), 7.48 - 7.32 (m, 4H), 7.26
(t, J = 7.6 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.09 (dd, J = 14.2, 7.6
Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.72 (dd, J = 15.6, 8.8 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 163.3 (d, JC-F = 245.8 Hz), 142.3,
142.0 (d, JC-F = 7.3 Hz), 135.9, 131.2, 130.9, 130.1 (d, JC-F = 8.5
Hz), 128.9, 128.8, 128.1, 123.6, 121.4, 121.1 (d, JC-F = 2.8 Hz),
119.8, 112.4 (d, JC-F = 23.9 Hz), 111.6 (d, JC-F = 21.4 Hz), 111.3,
98.6 ppm; νmax(KBr)/cm-1 3336, 2934, 1627, 1442, 1324, 686; MS
(EI) m/z 121, 165, 196, 242, 287, 319; HRMS-ESI (m/z): calcd for
C20H14FNNaS, [M+Na]+: 342.0723, found 342.0729.
(dd, J = 15.2, 7.6 Hz, 3H), 7.40 (dd, J = 17.0, 8.0 Hz, 3H), 7.27 (t, J
= 7.6 Hz, 1H), 7.16 (dd, J = 14.2, 7.2 Hz, 3H), 7.05 (dd, J = 14.8, 7.6
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 140.7, 138.9, 135.9, 134.8,
131.2, 129.9, 129.3, 129.0, 128.9, 125.6, 124.8, 123.7, 121.4, 120.1,
111.2, 100.2 ppm; νmax(KBr)/cm-1 3327, 2923, 1624, 1448, 1320,
688; MS (EI) m/z 121, 150, 190, 223, 267, 303, 335; HRMS-ESI
(m/z): calcd for C20H14ClNNaS, [M+Na]+: 358.0428, found
358.0434.
3-(Phenylthio)-2-(thiophen-3-yl)-1H-indole (3l): Yield: 63% (47.5
1
mg), brown oil; H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.76 (s,
1H), 7.63 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 4.8 Hz, 1H), 7.44 - 7.29
(m, 2H), 7.24 - 7.19 (m, 1H), 7.12 (dt, J = 14.8, 7.6 Hz, 5H), 7.02 (t,
J = 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 138.9, 137.8, 135.6,
132.1, 131.3, 128.9, 126.5, 126.3, 125.7, 124.8, 123.8, 123.4, 121.3,
119.8, 111.1, 99.1 ppm; νmax(KBr)/cm-1 3344, 2935, 1627, 1438,
1401, 686; MS (EI) m/z 120, 136, 186, 229, 274, 307; HRMS-ESI
(m/z): calcd for C18H13NNaS2, [M+Na]+: 330.0382, found 330.0389.
3-((4-Fluorophenyl)thio)-2-phenyl-1H-indole (3e): Yield: 80% (51.0
mg), yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.72 (d,
J = 7.2 Hz, 2H), 7.61 (d, J = 7.6 Hz, 1H), 7.39 (dq, J = 14.4, 7.2 Hz,
4H), 7.26 (t, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.04 (dd, J =
8.8, 5.2 Hz, 2H), 6.84 (t, J = 8.8 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 160.8 (d, JC-F = 242.2 Hz), 141.9, 135.8, 134.1 (d, JC-F
=
3.0 Hz), 131.4, 131.0, 128.9, 128.8, 128.2, 127.5 (d, JC-F = 7.7 Hz),
123.5, 121.3, 119.8, 116.6 (d, JC-F = 21.9 Hz), 111.3, 99.9 ppm;
νmax(KBr)/cm-1 3324, 2920, 1625, 1441, 1327, 686; MS (EI) m/z
121, 165, 196, 223, 287, 319; HRMS-ESI (m/z): calcd for
C20H14FNNaS, [M+Na]+: 342.0723, found 342.0726.
2-(Cyclohex-1-en-1-yl)-3-(phenylthio)-1H-indole (3m): Yield: 71%
(47.5 mg), yellow oil; H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H),
1
7.54 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.24 - 6.92 (m,
8H), 6.35 (s, 1H), 2.61 - 2.52 (m, 2H), 2.24-2.17 (m, 2H), 1.77-1.70
(m, 2H), 1.68-1.62 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 143.9,
139.7, 135.0, 131.3, 130.2, 129.3, 128.7, 125.5, 124.4, 122.7, 120.8,
119.5, 110.8, 97.8, 27.4, 25.7, 22.6, 21.8 ppm; νmax(KBr)/cm-1 3424,
2938, 1630, 1601, 1445, 1321, 684; MS (EI) m/z 115, 154, 195, 228,
272, 305; HRMS-ESI (m/z): calcd for C20H19NNaS, [M+Na]+:
328.1130, found 328.1134.
3-((4-Chlorophenyl)thio)-2-phenyl-1H-indole (3f): Yield: 73% (48.9
mg), yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.70 (d,
J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.47 - 7.34 (m, 4H), 7.27 -
7.21 (m, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 6.99
(d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 142.2, 137.9,
135.9, 131.3, 130.9, 130.4, 128.9, 128.8, 128.6, 128.1, 126.8, 123.5,
121.4, 119.8, 111.3, 99.0 ppm; νmax(KBr)/cm-1 3327, 2930, 1625,
1446, 1321, 676; MS (EI) m/z 121, 150, 223, 267, 303, 335;
HRMS-ESI (m/z): calcd for C20H14ClNNaS, [M+Na]+: 358.0428,
found 358.0432.
2-Butyl-3-(phenylthio)-1H-indole (3n): Yield: 87% (48.9 mg),
1
yellow oil; H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.53 (d, J =
7.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.11
(q, J = 6.8 Hz, 3H), 7.02 (dd, J = 12.8, 7.2 Hz, 3H), 2.88 (t, J = 7.6
Hz, 2H), 1.84-1.41 (m, 2H), 1.33 (dq, J = 14.2, 7.2 Hz, 2H), 0.87 (t,
J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 145.5, 139.6, 135.5,
130.3, 128.7, 125.5, 124.5, 122.2, 120.7, 119.1, 110.8, 98.9, 31.7,
26.2, 22.4, 13.8 ppm; νmax(KBr)/cm-1 3361, 2923, 2847, 1632, 1316,
686; MS (EI) m/z 130, 172, 206, 238, 281; HRMS-ESI (m/z): calcd
for C18H19NNaS, [M+Na]+: 304.1130, found 304.1126.
3-((3,4-Dichlorophenyl)thio)-2-phenyl-1H-indole (3g): Yield: 71%
1
(52.4 mg), yellow oil; H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H),
7.69 (d, J = 7.6 Hz, 2H), 7.59 (d, J = 8.0 Hz, 1H), 7.50 - 7.36 (m,
4H), 7.29 (t, J = 7.6 Hz, 1H), 7.24 - 7.19 (m, 1H), 7.02 (s, 1H), 6.92
(s, 2H); 13C NMR (100 MHz, CDCl3) δ 143.5, 142.6, 135.9, 135.3,
131.0, 130.7, 129.1, 128.9, 128.1, 124.9, 123.7, 123.4, 121.6, 119.6,
111.4, 97.4 ppm; νmax(KBr)/cm-1 3324, 2926, 1621, 1436, 1324, 679;
MS (EI) m/z 107, 142, 177, 286, 321, 369; HRMS-ESI (m/z): calcd
for C20H13Cl2NNaS, [M+Na]+: 392.0038, found 392.0042.
2-Cyclopentyl-3-(phenylthio)-1H-indole (3o): Yield: 85% (49.8 mg),
yellow solid; mp = 73.4-74.5 °C; 1H NMR (400 MHz, CDCl3) δ 8.19
(s, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.18 - 7.07
(m, 4H), 7.06-6.94 (m, 3H), 3.57 (dd, J = 16.4, 8.0 Hz, 1H),
2.15-1.98 (m, 2H), 1.87-1.74 (m, 2H), 1.70-1.56 (m, 4H); 13C NMR
(100 MHz, CDCl3) δ 148.7, 139.8, 135.5, 130.5, 128.7, 125.5, 124.5,
122.2, 120.8, 119.0, 110.9, 98.4, 37.3, 33.4, 25.8 ppm;
νmax(KBr)/cm-1 3365, 2923, 1627, 1444, 1329, 684; MS (EI) m/z
108, 130, 155, 225, 260, 293; HRMS-ESI (m/z): calcd for
C19H19NNaS, [M+Na]+: 316.1130, found 316.1132.
3-(Phenylthio)-2-(p-tolyl)-1H-indole (3i): Yield: 89% (56.1 mg) ,
1
yellow oil; H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.61 (d, J =
7.2 Hz, 3H), 7.38 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 9.2 Hz, 3H), 7.16 -
7.06 (m, 5H), 7.01 (t, J = 6.4 Hz, 1H), 2.34 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 142.3, 139.4, 138.8, 135.8, 131.3, 129.5, 128.8,
128.6, 128.0, 125.6, 124.6, 123.2, 121.1, 119.9, 111.1, 99.0, 21.4
ppm; νmax(KBr)/cm-1 3033, 2931, 1620, 1460, 1406, 1014, 689; MS
(EI) m/z 121, 150, 204, 238, 267, 283, 315; HRMS-ESI (m/z): calcd
for C21H17NNaS, [M+Na]+: 338.0974, found 338.0973.
2-(Cyclohexylmethyl)-3-(phenylthio)-1H-indole (3p): Yield: 75%
1
(48.2 mg), yellow oil; H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H),
7.52 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.17 (t, J = 8.0 Hz,
1H), 7.10 (q, J = 6.8 Hz, 3H), 7.01 (dd, J = 14.0, 7.2 Hz, 3H), 2.75
(d, J = 6.8 Hz, 2H), 1.70-1.53 (m, 7H), 1.16-1.06 (m, 3H), 1.01-0.90
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 144.4, 139.6, 135.5, 130.3,
128.7, 125.6, 124.5, 122.2, 120.7, 119.2, 110.8, 99.7, 38.6, 34.3,
33.2, 26.3, 26.1 ppm; νmax(KBr)/cm-1 3344, 2930, 1622, 1435, 687;
MS (EI) m/z 130, 178, 204, 238, 288, 321; HRMS-ESI (m/z): calcd
for C21H23NNaS, [M+Na]+: 344.1443, found 344.1448.
2-(4-Methoxyphenyl)-3-(phenylthio)-1H-indole (3j): Yield: 83%
1
(54.9 mg), yellow oil; H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H),
7.71 - 7.56 (m, 3H), 7.36 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 7.6 Hz,
1H), 7.19 - 7.04 (m, 5H), 7.02 (t, J = 6.8 Hz, 1H), 6.90 (d, J = 8.0
Hz, 2H), 3.77 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.0, 142.2,
139.5, 135.8, 131.4, 129.5, 128.9, 125.6, 124.6, 123.9, 123.1, 121.1,
119.8, 114.3, 111.1, 98.4, 55.4 ppm; νmax(KBr)/cm-1 3031, 2925,
1628, 1435, 1021, 686; MS (EI) m/z 120, 165, 223, 254, 299, 316,
4-(3-(Phenylthio)-1H-indol-2-yl)butanenitrile (3q): Yield: 79% (47.5
mg) , yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 7.56 (d,
J = 7.6 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 5.6 Hz, 1H),
6

215, 241, 285, 304, 319; HRMS-ESI (m/z): calcd for C20H14FNNaS,
7.14 (t, J = 7.6 Hz, 3H), 7.03 (t, J = 9.0 Hz, 3H),A3.0C4C(t,EJ P= T7.2EHDz, MANUSCRIPT
2H), 2.28 (t, J = 6.8 Hz, 2H), 2.12-1.77 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 142.2, 139.1, 135.6, 130.2, 128.8, 125.1, 124.8,
122.8, 121.1, 119.4, 119.2, 111.1, 100.2, 25.5, 25.4, 16.5 ppm;
νmax(KBr)/cm-1 3412, 2938, 1716, 1442, 685; MS (EI) m/z 130, 205,
238, 259, 292; HRMS-ESI (m/z): calcd for C18H16N2NaS, [M+Na]+:
315.0926, found 315.0929.
[M+Na]+: 342.0723, found 342.0718.
6-Chloro-2-phenyl-3-(phenylthio)-1H-indole (3x): Yield: 84% (56.3
mg), yellow solid; mp = 114.7-115.5 °C; 1H NMR (400 MHz,
CDCl3) δ 8.50 (s, 1H), 7.71 (d, J = 7.2 Hz, 2H), 7.50 (d, J = 8.4 Hz,
1H), 7.46 - 7.32 (m, 4H), 7.17-7.10 (m, 3H), 7.08-7.01 (m, 3H); 13C
NMR (100 MHz, CDCl3) δ 142.6, 138.8, 136.2, 131.0, 129.8, 129.2,
129.0, 128.9, 128.8, 128.1, 125.7, 124.9, 121.9, 120.9, 111.2, 99.9
ppm; νmax(KBr)/cm-1 3366, 2927, 1634, 1445, 686; MS (EI) m/z 121,
150, 223, 267, 300, 335; HRMS-ESI (m/z): calcd for C20H14ClNNaS,
[M+Na]+: 358.0428, found 358.0432.
2-Phenyl-3-(phenylthio)-1H-indole (3r): Yield: 90% (54.2 mg) ,
1
yellow oil; H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.72 (d, J =
7.6 Hz, 2H), 7.62 (d, J = 7.6 Hz, 1H), 7.37 (dt, J = 21.2, 6.8 Hz, 4H),
7.25 (t, J = 7.6 Hz, 1H), 7.13 (dt, J = 15.6, 7.2 Hz, 5H), 7.03 (t, J =
6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 142.1, 139.3, 135.9,
131.5, 131.2, 128.8, 128.8, 128.7, 128.2, 125.6, 124.7, 123.4, 121.2,
120.0, 111.2, 99.5 ppm; νmax(KBr)/cm-1 3024, 2931, 1622, 1436,
1025, 687; MS (EI) m/z 121, 165, 197, 223, 268, 301.
5-Bromo-2-phenyl-3-(phenylthio)-1H-indole (3y): Yield: 80% (60.9
mg), yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 7.69 (s,
1H), 7.64 (d, J = 6.8 Hz, 2H), 7.32 (dd, J = 15.6, 7.2 Hz, 3H), 7.25
(d, J = 8.8 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.08 (t, J = 7.2 Hz, 2H),
6.98 (d, J = 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 143.3,
138.8, 134.5, 133.1, 130.9, 129.1, 128.9, 128.8, 128.1, 126.4, 125.6,
124.9, 122.5, 114.7, 112.7, 99.2 ppm; νmax(KBr)/cm-1 3412, 2946,
1630, 1439, 1343, 689; MS (EI) m/z 121, 150, 190, 223, 267, 300,
347, 381; HRMS-ESI (m/z): calcd for C20H14BrNNaS, [M+Na]+:
401.9923, found 401.9927.
5-Methyl-2-phenyl-3-(phenylthio)-1H-indole (3s): Yield: 87% (54.8
mg), yellow solid; mp = 116.8 - 118.2 °C; 1H NMR (400 MHz,
CDCl3) δ 8.40 (s, 1H), 7.70 (d, J = 7.2 Hz, 2H), 7.45-7.32 (m, 4H),
7.29 (d, J = 8.4 Hz, 1H), 7.14 (t, J = 7.2 Hz, 2H), 7.11-7.00 (m, 4H),
2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 142.2, 139.6, 134.2,
131.6, 130.7, 128.9, 128.8, 128.6, 128.1, 125.5, 125.1, 124.6, 119.5,
110.9, 98.7, 21.5 ppm; νmax(KBr)/cm-1 3036, 2938, 1626, 1449,
1415, 689; MS (EI) m/z 121, 165, 204, 223, 238, 267, 282, 315;
HRMS-ESI (m/z): calcd for C21H17NNaS, [M+Na]+: 338.0974,
found 338.0969.
2-Phenyl-3-(phenylthio)-5-(trifluoromethyl)-1H-indole (3z): Yield:
1
70% (51.7 mg), yellow solid; mp = 247.4-248.5 °C; H NMR (400
MHz, CDCl3) δ 8.72 (s, 1H), 7.94 (s, 1H), 7.72 (d, J = 7.2 Hz, 2H),
7.47 (s, 2H), 7.43-7.32 (m, 3H), 7.15 (t, J = 7.2 Hz, 2H), 7.11-7.00
(m, 3H); 13C NMR (100 MHz, CDCl3) δ 143.8, 138.6, 137.2, 130.9,
130.7, 129.2, 129.0, 128.9, 128.2, 125.4 (q, JC-F = 226.0 Hz), 123.7
(q, JC-F = 63.0 Hz), 120.2 (q, JC-F = 6.0 Hz), 111.7 (q, JC-F = 8.0 Hz),
111.6, 100.7 ppm; νmax(KBr)/cm-1 3392, 2934, 1626, 1451, 684; MS
(EI) m/z 121, 150, 188, 267, 337, 369; HRMS-ESI (m/z): calcd for
C21H14F3NNaS, [M+Na]+: 392.0691, found 392.0697.
6-Methyl-2-phenyl-3-(phenylthio)-1H-indole (3t): Yield: 89% (56.1
mg), yellow solid; mp = 129.7-130.7 °C; 1H NMR (400 MHz,
CDCl3) δ 8.39 (s, 1H), 7.69 (d, J = 7.2 Hz, 2H), 7.46-7.32 (m, 4H),
7.28 (d, J = 8.0 Hz, 1H), 7.14 (t, J = 7.6 Hz, 2H), 7.11-6.99 (m, 5H),
2.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 142.2, 139.6, 134.2,
131.6, 130.7, 128.8, 128.8, 128.6, 128.1, 125.5, 125.1, 124.6, 119.5,
110.9, 98.6, 21.5 ppm; νmax(KBr)/cm-1 3365, 2934, 1612, 1438,
1401, 675; MS (EI) m/z 128, 151, 178, 242, 257, 315; HRMS-ESI
(m/z): calcd for C21H17NNaS, [M+Na]+: 338.0974, found 338.0980.
Methyl 2-phenyl-3-(phenylthio)-1H-indole-5-carboxylate (3za):
Yield: 64% (45.9 mg), yellow solid; mp = 253.5-253.9 °C; 1H NMR
(400 MHz, CDCl3) δ 8.39 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.77 (d, J
= 7.2 Hz, 2H), 7.44 (dd, J = 19.6, 12.0 Hz, 4H), 7.17 (t, J = 7.2 Hz,
2H), 7.08 (d, J = 7.2 Hz, 3H), 3.90 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 167.8, 143.5, 138.9, 138.4, 131.0, 130.9, 129.1, 128.9,
128.8, 128.1, 125.6, 124.9, 124.8, 123.5, 122.7, 110.9, 51.9 ppm;
νmax(KBr)/cm-1 3363, 2940, 1634, 1440, 1326, 686; MS (EI) m/z
121, 163, 223, 267, 299, 327, 359; HRMS-ESI (m/z): calcd for
C22H17NNaO2S, [M+Na]+: 382.0872, found 382.0872.
5,7-Dimethyl-2-phenyl-3-(phenylthio)-1H-indole (3u): Yield: 83%
(54.6 mg), yellow solid; mp = 156.1 - 157.7 °C; 1H NMR (400 MHz,
CDCl3) δ 8.33 (s, 1H), 7.73 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 7.2 Hz,
2H), 7.35 (d, J = 7.2 Hz, 1H), 7.27 (s, 1H), 7.17-7.08 (m, 4H), 7.03
(t, J = 6.8 Hz, 1H), 6.90 (s, 1H), 2.50 (s, 3H), 2.37 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ142.0, 139.6, 133.7, 131.7, 131.2, 130.9, 128.8,
128.7, 128.6, 128.2, 125.8, 125.5, 124.5, 120.0, 117.2, 99.2, 21.5,
16.4 ppm; νmax(KBr)/cm-1 3354, 2930, 1638, 1330, 683; MS (EI) m/z
115, 150, 237, 281, 296, 313, 329; HRMS-ESI (m/z): calcd for
C22H19NNaS, [M+Na]+: 352.1130, found 352.1137.
5,7-Dichloro-2-phenyl-3-(phenylthio)-1H-indole (3zb): Yield: 71%
1
(52.4 mg), yellow solid; mp = 116.9-118.8 °C; H NMR (400 MHz,
CDCl3) δ 8.69 (s, 1H), 7.75 (d, J = 7.2 Hz, 2H), 7.51 (s, 1H), 7.47 -
7.36 (m, 3H), 7.25 (s, 1H), 7.17 (t, J = 7.6 Hz, 2H), 7.06 (t, J = 8.0
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 144.2, 138.3, 133.2, 131.7,
130.5, 129.4, 129.0, 128.9, 128.2, 127.1, 125.7, 125.1, 122.9, 118.3,
117.0, 100.7 ppm; νmax(KBr)/cm-1 3326, 2941, 1633, 1438, 686; MS
(EI) m/z 150, 257, 301, 337, 369; HRMS-ESI (m/z): calcd for
C20H13Cl2NNaS, [M+Na]+: 392.0038, found 392.0037.
5-Methoxy-2-phenyl-3-(phenylthio)-1H-indole (3v): Yield: 77%
(50.9 mg), yellow solid; mp = 145.2 - 146.4 °C; 1H NMR (400 MHz,
CDCl3) δ 8.49 (s, 1H), 7.68 (d, J = 7.6 Hz, 2H), 7.41 - 7.30 (m, 3H),
7.26 (d, J = 8.4 Hz, 1H), 7.18 - 6.99 (m, 6H), 6.89 (d, J = 8.8 Hz,
1H), 3.75 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.3, 142.7,
139.3, 132.2, 131.5, 130.8, 128.9, 128.8, 128.6, 128.1, 125.5, 124.7,
113.8, 112.2, 101.2, 98.9, 55.8 ppm; νmax(KBr)/cm-1 3352, 2927,
1611, 1422, 676; MS (EI) m/z 107, 152, 183, 199, 277, 331;
HRMS-ESI (m/z): calcd for C21H17NNaOS, [M+Na]+: 354.0923,
found 354.0928.
Acknowledgements
The authors are grateful to the National Natural Science
Foundation of China (Grant 21602032) for financial support.
5-Fluoro-2-phenyl-3-(phenylthio)-1H-indole (3w): Yield: 81% (51.6
mg), yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.62 (d,
J = 7.2 Hz, 2H), 7.29 (dd, J = 16.0, 7.6 Hz, 3H), 7.24-7.14 (m, 2H),
7.06 (t, J = 7.2 Hz, 2H), 6.96 (dd, J = 14.8, 7.6 Hz, 3H), 6.88 (t, J =
8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 158.8 (d, J = 235.7 Hz),
143.8, 138.8, 132.2 (d, J = 2.5 Hz), 132.1, 131.1, 129.0, 128.9,
References and notes
1. (a) Silvestri, R.; Martino, G. D.; Regina, G. L.; Artico, M.; Massa, S.;
Vargiu, L.; Mura, M.; Loi, A. G.; Marceddu, T.; Colla, P. L. J. Med. Chem.
2003, 46, 2482; (b) Barbuceanu, S.-F.; Almajan, G. L.; Saramet, I.;
Draghici, C.; Tarcomnicu, A. I.; Bancescu, G. Eur. J. Med. Chem. 2009, 44,
4752; (c) Hartz, R. A.; Arvanitis, A. G.; Arnold, C.; Rescinito, J. P.; Hung,
K. L.; Zhang, G.; Wong, H.; Langley, D. R.; Gilligan, P. J.; Trainor, G. L.
Bioorg. Med. Chem. Lett. 2006, 16, 934; (d) Williams, T. M.; Ciccarone, T.
128.8, 128.1, 125.7, 124.9, 112.1 (d, JC-F = 9.4 Hz), 111.8 (d, JC-F
=
26.4 Hz), 105.0 (d, JC-F = 24.1 Hz), 99.6 (d, JC-F = 4.5 Hz) ppm;
νmax(KBr)/cm-1 3352, 2931, 1623, 1454, 689; MS (EI) m/z 139, 183,
7

2011, 353, 1474; (d) Chen, D.; Cao, Y.; Yuan, Z.; Cai, H.; Zheng, R.;
M.; MacTough, S. C.; Rooney, C. S.; Balani, S. K.; CAondCraC, J.EHP.; ETmEiniD, E.MANUSCRIPT
A.; Goldman, M. E.; Greenlee, W. J.; Kauffman, L. R.; O’Brien, J. A.;
Sardana, V. V.; Schleif, W. A.; Theoharides, A. D.; Anderson, P. S. J. Med.
Chem. 1993, 36, 1291;
2. (a) Tietze, L. T.; Brasche, G.; Gericke, K. M. Domino Reactions in
Organic Synthesis; Wiley-VCH: Weinheim, Germany, 2006; (b) Xu, P.;
Wang, W. Catalytic Cascade Reactions; John Wiley & Sons, Inc.:
Hoboken, NJ, 2013; (c) Müller, T. J. J. Metal Catalyzed Cascade Reactions;
Springer: New York, 2006.
Kong, L.; Zhu, G. J. Org. Chem. 2011, 76, 4071; (e) Chen, X.; Chen, D.;
Lu, Z.; Kong, L.; Zhu, G. J. Org. Chem., 2011, 76, 6338; (f) DeKorver, K.
A.; Walton, M. C.; North, T. D.; Hsung, R. P. Org. Lett., 2011, 13, 4862;
(g) Li, Y.; Liu, X.; Jiang, H.; Feng, Z. Angew. Chem., Int. Ed., 2010, 49,
3338; (h) Li, Y.; Liu, X.; Jiang, H.; Liu, B.; Chen, Z.; Zhou, P. Angew.
Chem., Int. Ed., 2011, 50, 6341; (i)Wu, W.; Jiang, H. Acc. Chem. Res.,
2014, 47, 2483.
12. (a) Li, N.; Lian, X.-L.; Li, Y.-H.; Wang, T.-Y.; Han, Z.-Y.; Zhang, L.;
Gong, L.-Z. Org. Lett. 2016, 18, 4178; (b) Lu, B.; Luo, Y.; Liu, L.; Ye, L.;
Wang, Y.; Zhang, L. Angew. Chem. Int. Ed. 2011, 50, 8358; (c) Liu, Q.;
Chen, P.; Liu, G. ACS Catal. 2013, 3, 178; (d) Li, N.; Wang, T.-Y.; Han,
Z.-Y.; Gong, L.; Zhang, L. Chem. Eur. J. 2015, 21, 3585.
13. For selected examples, see: (a) Zhao, L.; Lu, X. Angew. Chem., Int. Ed.
2002, 41, 4343; (b) Song, J.; Shen, Q.; Xu, F.; Lu, X. Org. Lett. 2007, 9,
2947; (c) Han, X.; Lu, X. Org. Lett. 2010, 12, 3336; (d) Xia, G.; Han, X.;
Lu, X. Org. Lett. 2014, 16, 2058; (e) Zhang, J.; Han, X.; Lu, X. Synlett.
2015, 26, 1744.
14. (a) Stokes, B. J.; Liu, S.; Driver, T. G. J. Am. Chem. Soc. 2011, 133, 4702;
(b) Stokes, B. J.; Dong, H.; Leslie, B. E.; Pumphrey, A. L; Driver, D. G. J.
Am. Chem. Soc. 2007, 129, 7500; (c) Harrison, J. G.; Gutierrez, O.; Jana,
N.; Driver, T. G.; Dean J. Tantillo, D. J. J. Am. Chem. Soc. 2016, 138,
487; (d) Nguyen, Q.; Ke S., K.; Driver, T. G. J. Am. Chem. Soc. 2012, 134,
7262; (e) Nguyen, Q.; Nguyen, T.; Driver, T. G. J. Am. Chem. Soc. 2013,
135, 620; (f) Jana, N.; Zhou, F.; Driver, T. G. J. Am. Chem. Soc. 2015, 137,
6738; (g) Chen Kong, C.; Jana, N.; Jones, C.; Driver, T. G. J. Am. Chem.
Soc. 2016, 138, 13271; (h) Mazumdar, W.; Jana, N.; Thurman, B. T.;
Wink, D. J.; Driver, T. G. J. Am. Chem. Soc. 2017, 139, 5031; (i) Jana, N.;
Driver, T. G. Org. Biomol. Chem. 2015, 13, 9720.
15. For selected examples on Mn(III)-catalyzed oxidative cascade reactions:
(a) Wang, Y.-F.; Toh, K. K.; Pei Jian Ng, E.; Chiba. S. J. Am. Chem. Soc.
2011, 133, 6411; (b) Wang, Y.-F.; Chiba, S. J. Am. Chem. Soc. 2009, 131,
12570; (c) Wang, D.; Ren, R.; Zhu, C. J. Org. Chem. 2016, 81, 8043; (d)
Ren, R.; Zhu, C. Synlett. 2016, 27, 1139; (e) Ren, R.; Wu, Z.; Xu, Y.; Zhu,
C. Angew. Chem. Int. Ed. 2016, 55, 2866; (f) Ren, R.; Zhao, H.; Huan, C.;
Zhu, C. Angew. Chem. Int. Ed. 2015, 54, 12692.
16. (a) Chiba, S.; Cao, Z. Y.; El Bialy, S. A. A.; Narasaka, K. Chem. Lett.
2006, 35, 18; (b) Booker-Milburn, K. I.; Jones, J. L.; Sibley, G. E. M.;
Cox, R.; Meadows, J. Org. Lett. 2003, 5, 1107; (c) Booker-Milburn, K. I.;
Barker, A.; Brailsford, W.; Cox, B.; Mansley, T. E. Tetrahedron 1998, 54,
15321; (d) Snider, B. B.; Kwon, T. J. Org. Chem. 1992, 57, 2399.
17. Montevecchi, P. C.; Navavvhia, M. L.; Spagnolo, P. Eur. J. Org. Chem.
1998, 1219.
18. The exact role of LiBr in this transformation is not clear at this stage, we
postulated that it might act as a base to facilatate the oxidation of sulfonyl
hydrazine to the corresponding sulfide radical. For related references: (a) Su,
Y.; Sun, X.; Wu, G.; Jiao, N. Angew. Chem. Int. Ed. 2013, 52, 9808; (b) Yang,
F.-L.; Tian, S.-K. Tetrahedron Lett. 2017, 58, 487. For the references on the
generation of sulfenyl halides for the further transformations: (c) Ge, W.; Wei,
Y. Green Chem., 2012, 14, 2066; (d) N. Taniguchi, J. Org. Chem., 2006, 71,
7874; (e) Du, H.-A.; Tang, R.-Y.; Deng, C.-L.; Liu, Y.; Li, J.-H.; Zhang,
X.-G. Adv. Synth. Catal., 2011, 353, 2739.
3. (a) Merino, E.; Nevado, C. Chem. Soc. Rev. 2014, 43, 6598; (b) Sibi, M. P.;
Manyem, S.; Zimmerman, J. Chem. Rev. 2003, 103, 3263.
4. For selected examples, see: (a) Wu, W.; Yi, S.; Huang, W.; Luo, D.; Jiang,
H. Org. Lett. 2017, 19, 2825; (b) Chen, F.; Meng, Q.; Han, S.-Q.; Han, B.
Org. Lett. 2016, 18, 3330; (c) Hu, M.; Fan, J.-H.; Liu, Y.; Ouyang, X.-H.;
Song, R.-J.; Li, J.-H. Angew.Chem. Int. Ed. 2015, 54, 9577; (d) Cheng,
J.-K.; Loh, T.-P. J. Am. Chem. Soc. 2015, 137, 42; (e) Bunescu, A.; Wang,
Q.; Zhu, J. Angew. Chem. Int. Ed. 2015, 54, 3132; (f) Lu, Q.; Zhang, J.;
Zhao, G.; Qi, Y.; Wang, H.; Lei, A. J. Am. Chem. Soc., 2013, 135, 11481;
(g) Sun, X.; Li, X.; Song, S.; Zhu, Y.; Liang, Y.-F.; Jiao, N. J. Am. Chem.
Soc., 2015, 137, 6059; (h) Lin, J.-S.; Dong, X.-Y.; Li, T.-T.; Jiang, N.-C.;
Tan, B.; Liu, X.-Y. J. Am. Chem. Soc. 2016, 138, 9357; (i) Giese, B.
Angew. Chem. Int. Ed. Engl., 1983, 22, 753; (j) Yuan, Z.; Wang, H.-Y.;
Mu, X.; Chen, P.; Guo, Y.-L.; Liu, G. J. Am. Chem. Soc., 2015, 137, 2468.
5. For reviews on transition-metal-catalyzed C-S bond formations, see: (a)
Beletskaya, I. P.; Ananikov, V. P. Chem. Rev. 2011, 111, 1596; (b)
Hartwig, J. F. Nature 2008, 455, 314; (c) Kubas, G. J. Acc. Chem. Res.
1994, 27, 183.
6. (a) Artico, M.; Silvestri, R.; Pagnozzi, E.; Bruno, B. Novellino, E.;
Greco, G.; Massa, S.; Ettorre, A.; Loi, A. G.; Scintu, F.; Coll, P. L. J. Med.
Chem. 2000, 43, 1886; (b) Nugent, R. A.; Schlachter, S. T.; Murphy, M. J.;
Cleek, G. J.; Poel, T. J.; Wishka, D. G.; Graber, D. R.; Yagi, Y.; Keiser,
B. J.; Olmsted, R. A.; Kopta, L. A.; Swaney, S. M.; Poppe, S. M.;
Morris, J.; Tarpley, W. G.; Thomas, R. C. J. Med. Chem. 1998, 41, 3793;
(c) Regina, G. La.; Coluccia, A.; Brancale, A.; Piscitelli, F.; Famiglini,
V.; Cosconati, S.; Maga, G.; Samuele, A.; Gonzalez, E.; Clotet, B.;
Schols, D.; Esté, J. A.; Novellino, E.; Silvestri, R. J. Med. Chem.
2012, 55, 6634.
7. (a) Boyer, J.; Arnoult, E.; Médebielle, M.; Guillemont, J.; Unge, J.;
Jochmans, D. J. Med. Chem. 2011, 54, 7974; (b) Ling, C.; Fu, L.; Gao, S.;
Chu, W.; Wang, H.; Huang, Y.; Chen, X.; Yang, Y. J. Med. Chem. 2014,
57, 4772.
8. (a) Guo, Y.-J.; Tang, R.-Y.; Li, J.-H.; Zhong, P.; Zhang, X.-G. Adv. Synth.
Catal. 2009, 351, 2615; (b) Li, Z.; Hong, L.; Liu, R.; Shen, J.; Zhou, X.
Tetrahedron Lett. 2011, 52, 1343; (c) Tao, L.-M.; Liu, W.-Q.; Zhou, Y.; Li,
A.-T. J. Chem. Res. 2012, 36, 644; (d) Yang, F. L.; Tian, S. K. Angew.
Chem., Int. Ed. 2013, 52, 4929; (e) Li, X.; Xu, Y.; Wu, W.; Jiang, C.; Qi,
C.; Jiang, H. Chem. -Eur. J. 2014, 20, 7911; (f) Li, J.; Li, C.; Yang, S.; An,
Y.; Wu, W.; Jiang, H. J. Org. Chem. 2016, 81, 2875.
9. (a) Stoll, A. H.; Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2006,
45, 606; (b) Chen, X.; Hao, X.-S.;Goodhue, C. E.; Yu, J.-Q. J. Am. Chem.
Soc. 2006, 128, 6790; (c) Zhao, X.; Dimitrijevic, E.; Dong, V. M. J. Am.
Chem. Soc. 2009, 131, 3466; (d) Martinek, M.; Korf, M.; Srogl, J. Chem.
Commun. 2010, 46, 4387; (e) Sahoo, S. K.; Banerjee, A.; Chakraborty,
S.;Patel, B. K. ACS Catal. 2012, 2, 544; (f) Wu, Z.; Song, H.; Cui,X.; Pi,
C.; Du, W.; Wu, Y. Org. Lett. 2013, 15, 1270; (g) Timpa, S. D.; Pell, C. J.;
Ozerov, O. V. J. Am. Chem. Soc. 2014, 136, 14772; (h) Mao, J.; Jia, T.;
Frensch, G.; Walsh, P. J. Org. Lett. 2014, 16, 5304.
10. (a) Li, X.; Huang, L.; Chen, H.; Wu, W.; Huang, H.; Jiang, H. Chem.
Sci. 2012, 3, 3463; (b) Jiang, H.; Li, X.; Pan, X.; Zhou, P. Pure Appl. Chem.
2012, 84, 411; (c) Li, X.; He, L.; Chen, H.; Wu, W.; Jiang, H. J. Org.
Chem. 2013, 78, 3636; (d) Li, X.; Liu, X.; Chen, H.; Wu, W.; Qi, C.; Jiang,
H. Angew. Chem. Int. Ed. 2014, 53, 14485; (e) Huang, L.; Jiang, H.; Qi, C.;
Liu, X. J. Am. Chem. Soc. 2010, 132, 17652; (f) Yuan, G.; Zheng, J.; Gao,
X.; Li, X.; Huang, L.; Chen, H.; Jiang, H. Chem. Commun. 2012, 48, 7513.
11. For selected examples, see: (a) Shi, W.; Luo, Y.; Luo, X.; Chao, L.;
Zhang, H.; Wang, J.; Lei, A. J. Am. Chem. Soc. 2008, 130, 14713; (b)
Besseliévre, F.; Piguel, S. Angew. Chem., Int. Ed. 2009, 48, 9553; (c)
Chen, D.; Chen, X.; Lu, Z.; Cai, H.; Shen, J.; Zhu, G. Adv. Synth. Catal.
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