Copper(I)-Catalyzed Thiolation of C-H Bonds for the Synthesis of Sulfenyl Pyrroles and Indoles

Article abstract of DOI:10.1055/s-0037-1610295

A novel and convenient copper(I)-catalyzed thiolation of C-H bonds of pyrroles and indoles is developed for the synthesis of sulfenyl pyrroles and indoles. Dual C-H thiolation reactions are observed for pyrroles. A wide range of pyrroles and indoles undergo the C-H thiolation smoothly with various disulfides and diselenides to generate the corresponding heteroaryl thioethers in moderate to excellent yields.

Full text of DOI:10.1055/s-0037-1610295

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–G
paper
A
en
W. Xu et al.
Paper
Synthesis
Copper(I)-Catalyzed Thiolation of C–H Bonds for the Synthesis of
Sulfenyl Pyrroles and Indoles
Wei Xu
10 mol% CuI/Ligand
Yu-Yuan Hei
R1XXR1
R
+
XR1
R
N
H
X = S, Se
DG = directing group
R1X
Jian-Lan Song
N
H
DG
DG
Xin-Chen Zhan
Xing-Guo Zhang
Chen-Liang Deng*
22 examples
up to 97% yield
College of Chemistry and Materials Engineering,
Wenzhou University, Wenzhou 325035, P. R. of
China
dcl78@wzu.edu.cn
Received: 18.07.2018
Accepted after revision: 04.09.2018
Published online: 26.09.2018
chiometric amounts of copper salts were required in most
cases. In addition, only copper(II) salts were reported as
catalysts in most C–H activation reactions. For example,
Yu,8 Daugulis9 and Kambe10 reported on Cu(OAc)2-mediated
direct sp2 C–H thiolations of arenes bearing a directing
group with disulfides. While cuprous salts are rarely re-
ported as catalysts in C–H functionalizations of heterocyclic
compounds, the copper(I)-catalyzed C–H thiolation is espe-
cially challenging (Scheme 1). Alves described the CuI-cata-
lyzed sulfenylation of pyrroles, with only mono-sulfenyla-
tion products being obtained due to the pyrroles being
present in excess.7 Herein, we report a novel and conve-
nient CuI-catalyzed thiolation of pyrroles and indoles for
the synthesis of 2,5-disulfenyl pyrroles and 2-sulfenyl in-
doles under base-free conditions.
DOI: 10.1055/s-0037-1610295; Art ID: ss-2018-f0482-op
Abstract A novel and convenient copper(I)-catalyzed thiolation of C–H
bonds of pyrroles and indoles is developed for the synthesis of sulfenyl
pyrroles and indoles. Dual C–H thiolation reactions are observed for
pyrroles. A wide range of pyrroles and indoles undergo the C–H thiola-
tion smoothly with various disulfides and diselenides to generate the
corresponding heteroaryl thioethers in moderate to excellent yields.
Key words copper(I) iodide, ligands, thiolation, pyrroles, indoles
Nitrogen-containing heterocycles play important roles
in pharmaceuticals, materials, and agrochemicals.1 Among
these compounds, sulfenyl pyrroles and indoles are often
found in natural and bioactive products that can be applied
as therapeutics in many diseases, including cancer, obesity,
ulcers, and heart disease.2 Moreover, these N,S-containing
heterocycles have been employed as ligands in organic syn-
thesis.3 As a consequence, the development of convenient
and efficient methods for the preparation of these mole-
cules is highly desirable.
Recently, strategies for the preparation of multisubsti-
tuted indole and pyrrole derivatives have focused on transi-
tion-metal-catalyzed direct C–H functionalizations due to
the associated atom- and step-economic advantages.4 For
example, Li described an iron-catalyzed sulfenylation of in-
doles with disulfides. The employed catalytic system was
found to demonstrate good functional group tolerance.5 In
2015, Kambe and co-workers reported a palladium-cata-
lyzed chalcogenation of indoles, carbazole and 2-phen-
ylpyridine, which afforded excellent yields of the desired
products.4j As a typical representative, cheap and abundant
copper salts have attracted significant attention and have
been widely used as catalysts or promoters in many C–H
functionalizations.6,7 However, stoichiometric or semi-stoi-
Previous work
DG
DG
0.5–2.0 equiv Cu(OAc)2
RSSR
+
+
SR
H
This work
10 mol% CuI/ligand
RXXR
XR
H
X = S, Se
DG = directing group
N
N
H
RX
DG
DG
Scheme 1 Copper-mediated C–H thiolation
The reaction of 2-(1H-pyrrol-1-yl)pyridine (1a) with
PhSSPh (2a) was chosen as a model reaction to determine
the optimum conditions, and the results are summarized in
Table 1. Initially, the reaction was performed in the pres-
ence of CuI (10 mol%) and PPh3 (10 mol%) in DMSO at
120 °C for 24 hours, achieving a 56% yield of 2-[2,5-
bis(phenylthio)-1H-pyrrol-1-yl]pyridine (3a) (Table 1, entry
1). Encouraged by this result, further investigations were
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

B
W. Xu et al.
Paper
Synthesis
conducted by testing a series of ligands, and similar yields
were observed for PCy3, P(t-Bu)3 and DPPP (Table 1, entries
2–4). To our delight, product 3a was obtained in 86% yield
when 10 mol% of XPhos was used as the ligand (Table 1, en-
try 5). However, the yield of 3a decreased to 43% in the ab-
sence of a ligand (Table 1, entry 6). Subsequently, the effects
of several cuprous and cupric salts were tested. Lower
yields were obtained with CuBr and CuCl (Table 1, entries 7
and 8). No reaction took place when Cu(OAc)2 was applied
as the catalyst (Table 1, entry 9). These results suggested
that this thiolation of pyrrole did not proceed through a
copper(II)-catalyzed C–H activation pathway. In the ab-
sence of a copper catalyst, the reaction also failed (Table 1,
entry 10). Next, different solvents were screened, including
DMF, PrCN, THF and toluene, but all were completely inef-
fective (Table 1, entries 11–14). We believed that DMSO
might act as an auxiliary ligand to promote the C–H thiola-
tion. Thus we examined some other S-containing solvents.
As expected, tetramethylene sulfoxide (TMSO) and dibutyl
sulfoxide afforded 3a in 65% and 35% yields, respectively
(Table 1, entries 15 and 16). These results demonstrated
that sulfoxide played a critical role as both a solvent and a
promoter. The reaction performed under O2 resulted in a
69% yield of the desired product (Table 1, entry 17). Howev-
er, only a trace amount of product 3a was obtained when
the reaction was carried out under an N2 atmosphere (Table
1, entry 18).
With optimized reaction conditions in hand, we next
explored the scope of substrates 1 and 2 (Scheme 2). Initial-
ly, the electronic and steric effects of the sulfides were eval-
uated. The results showed that sulfides bearing electron-
donating and electron-withdrawing groups on the aromatic
Table 1 Optimization of the Reaction Conditionsa
Y
Y
10 mol% CuI
10 mol% X-Phos
RX
XR
N
N
PhS
SPh
[Cu]/ligand
+
RXXR
N
N
+
PhSSPh
Y
N
Y
N
DMSO, 120 °C
solvent, 120 °C, 24 h
N
N
X = S, Se, Y = CH, N
1a–c
2b–n
3b–p
1a
2a
3a
R
R
R
R
Entry
[Cu]
Ligand
Solvent
DMSO
Yieldb
1
2
CuI
CuI
CuI
CuI
CuI
CuI
PPh3
56
62
60
56
86
43
23
12
NR
NR
NR
NR
NR
NR
65
35
69
trace
S
S
N
S
S
N
PCy3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
R = Me, 3b, 65%
R = MeO, 3c, 52%
R = NO2, 3d, 93%
R = Cl, 3e, 97%
R = F, 3f, 88%
N
N
3
P(t-Bu)3
DPPPc
XPhosd
–
R = Cl, 3g, 82%
R = F, 3h, 80%
4
Cl
5
Cl
R
R
S
6
Cl
7
CuBr
CuCl
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
S
S
N
N
Cl
S
8
N
R = Cl, 3i, 67%
R = F, 3j, 70%
3k, 40%
N
9
Cu(OAc)2
–
10
11
12
13
14
15e
16
17f
18g
S
S
CuI
S
S
Et–S
S–Et
CuI
PrCN
N
N
CuI
THF
N
N
CuI
toluene
TMSO
3l, 54%
3m,25%
CuI
CuI
dibutyl sulfoxide
DMSO
N
CuI
S
S
S
Se
Se
N
N
N
CuI
DMSO
N
N
N
N
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), [Cu] (10 mol%), ligand
(10 mol%), solvent (2 mL), 120 °C, air atmosphere, 24 h.
b Yield of isolated product; NR = no reaction.
c DPPP = 1,3-bis(diphenylphosphino)propane.
d XPhos = 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.
e TMSO = tetramethylene sulfoxide.
3n, 48%
3o, 36%
3p, 23%
Scheme 2 CuI-catalyzed dual thiolation of pyrroles. Reagents and con-
ditions: 1 (0.2 mmol), 2 (0.4 mmol), CuI (10 mol%), XPhos (10 mol%),
DMSO (2 mL), 120 °C, air atmosphere, 24 h. Yields are those of isolated
products
f Reaction under O2.
g Reaction under N2
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

C
W. Xu et al.
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Synthesis
ring were well-tolerated. For example, sulfides with elec-
tron-donating groups such as p-Me and p-MeO on the phe-
nyl ring facilitated the reaction to give products 3b,c in 65%
and 52% yields, respectively. Phenyl sulfides with electron-
withdrawing groups such as p-NO2, p-Cl and p-F reacted
smoothly with 1a to form products 3d–f in excellent yields.
m-Cl- and m-F-substituted phenyl sulfides afforded prod-
ucts 3g and 3h in 82% and 80% yield, respectively. The inhi-
bition effect of steric hindrance on the aromatic ring was
observed, with lower yields being obtained for o-substitut-
ed phenyl sulfides (67% and 70% for 3i and 3j). The struc-
ture of product 3i was further confirmed by X-ray crystal
analysis (see the Supporting Information). Furthermore,
3,5-dichlorophenyl disulfide (2k) gave the target product
3k in 40% yield. A heterocyclic sulfide was also a suitable
substrate for the reaction, affording 3l in 54% yield. Impor-
tantly, the reaction of alkyl sulfide 2m with 1a proceeded
smoothly, albeit furnishing a lower yield of 25% of 3m. Grat-
ifyingly, a diselenide also reacted successfully to produce 3n
in 48% yield. Pyrimidine-substituted substrate 1b gave the
corresponding thiolated product 3o in a moderate 36%
yield. It is noteworthy that mono-thiolated product 3p was
afforded in 23% yield when 2-(1H-imidazol-1-yl)pyridine
(1c) was used as the substrate.
patible with the transformation leading to products 5b–e.
However, the reaction was sluggish when 1-(pyrimidin-2-
yl)-1H-indole (4f) was used as the substrate, with only a
37% yield of product 5f isolated.
To further demonstrate the synthetic application of this
methodology, removal of the directing group was required
to give medicinally useful N-unblocked indoles. As expect-
ed, the pyridinyl group on 2-phenylsulfenyl indole 5a was
readily removed by treatment with CH3ONa in DMSO
(Scheme 4).10
SPh
CH3ONa (2 equiv)
SPh
N
DMSO (2 mL), 120 °C, 12 h
N
H
N
5a
5aa, 80%
Scheme 4 Removal of the directing group
To probe the thiolation mechanism, several control ex-
periments were conducted under standard conditions.
Firstly, when two equivalents of TEMPO (2,2,6,6-tetrameth-
yl-1-piperidinyloxy) or BHT (2,6-di-tert-butyl-4-methyl-
phenol), two radical inhibitors, were added to the reaction,
no target product was detected by GC-MS analysis, which
implied that the reaction might be a radical process
(Scheme 5, eq 1). Next, the reaction of 1a with PhSSPh was
quenched after running for 2 hours under standard condi-
tions. A mono-substituted product, 2-[2-(phenylthio)-1H-
pyrrol-1-yl]pyridine (3aa), was isolated in 30% yield
(Scheme 5, eq 2). Finally, treatment of 3aa with PhSSPh un-
der the standard reaction conditions afforded 3a in 85%
yield (Scheme 5, eq 3). These results indicated that the dual
thiolation of pyrrole might proceed through two stepwise
C–H activations.
When the catalytic system was applied to indoles, the
reaction also occurred smoothly, affording the target com-
pounds in moderate to excellent yields (Scheme 3). For ex-
ample, N-pyridine indole 4a reacted with 2a successfully
under the optimized conditions to furnish 5a in 77% yield.
During the investigation of the electronic effects on the in-
doles, both electron-donating (3-Me, 5-Me) and electron-
withdrawing groups (5-Cl and 6-F) were found to be com-
SPh
R
R
10 mol% CuI
10 mol% X-Phos
N
N
PhSSPh
standard conditions
N
+
N
N
DMSO, 120 °C
Y = CH, N
PhSSPh
no reaction
(eq 1)
(eq 2)
Y
Y
Py
TEMPO (2 equiv)
or BHT (2 equiv)
1a
4a–f
2a
5a–f
Me
Me
SPh
standard conditions
2 h
N
N
SPh
SPh
PhSSPh
N
SPh
Py
1a
Py
N
N
3aa, 30%
N
N
N
SPh
PhS
SPh
standard conditions
Py = pyridin-2yl
N
N
Py
PhSSPh
(eq 3)
5a, 77%
5b, 75%
5c, 91%
Py
3aa
Cl
3a, 85%
SPh
SPh
SPh
Scheme 5 Control experiments
N
N
N
N
F
N
N
N
Based on previous reports5–8 and our present observed
results, a possible mechanism has been proposed as out-
lined in Scheme 6. Initially, substrate 1a combines with CuI
and XPhos to generate Cu complex A. The Cu complex then
undergoes ligand exchange with DMSO to give intermediate
B, which was monitored by HRMS analysis (see the Sup-
5d, 81%
5e, 50%
5f, 37%
Scheme 3 CuI-catalyzed thiolation of indoles 4. Reagents and condi-
tions: 1 (0.2 mmol), 2 (0.4 mmol), CuI (10 mol%), XPhos (10 mol%),
DMSO (2 mL), 120 °C, air atmosphere, 24 h. Yields are those of isolated
products
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

D
W. Xu et al.
Paper
Synthesis
porting Information). Subsequently, under oxidation by ox-
ygen, complex B, through a one-electron oxidation pathway
with a PhS radical, affords intermediate C.6c,11 This interme-
diate furnishes product 3aa through a reduction process
and regenerates the Cu(I) species.6e,10 Finally, 3aa is con-
verted into the target molecule 3a via C–N bond rotation
and a second C–H thiolation.
ous layer had been extracted with EtOAc, the combined organic layers
were dried over anhydrous Na2SO4 and evaporated under vacuum.
The residue was purified by flash column chromatography (hex-
ane/EtOAc) to afford the product 3a.
Yield: 64.5 mg (86%); light yellow oil.
1H NMR (500 MHz, CDCl3): δ = 8.44 (d, J = 4.5 Hz, 1 H), 7.52 (t, J = 7.5
Hz, 1 H), 7.20–7.14 (m, 5 H), 7.08 (t, J = 7.5 Hz, 2 H), 6.99 (d, J = 7.5 Hz,
4 H), 6.89 (d, J = 7.5 Hz, 1 H), 6.75 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 150.4, 148.7, 137.8, 137.0, 128.7,
127.1, 125.7, 124.1, 123.4, 123.2, 120.1.
CuI/X-Phos
HI
Me
Me
N
N
N
CuI
CuI X-Phos
ligand exchange
S O
LRMS (EI, 70 eV): m/z (%) = 360 (100), 251 (98), 218 (19), 174 (18), 78
(27).
HRMS (ESI): m/z [M + H]+ calcd for C21H17N2S2: 361.0828; found:
361.0838.
N
N
N
B
detected by HRMS
1a
A
O2
PhS
PhSSPh
2-[2,5-Bis(p-tolylthio)-1H-pyrrol-1-yl]pyridine (3b)
SPh
Me
SPh
N
Yield: 48.2 mg (65%); light yellow oil.
N
CuIII
N
C–N rotation
repeat
reduction
Cu(I)
1H NMR (500 MHz, CDCl3): δ = 8.47 (dd, J = 5.0 Hz, J = 1.5 Hz, 1 H),
7.56 (td, J = 1.5 Hz, J = 7.5 Hz, 1 H), 7.21 (dd, J = 7.5 Hz, J = 5.0 Hz, 1 H),
6.97 (d, J = 8.0 Hz, 4 H), 6.94 (d, J = 8.0 Hz, 1 H), 6.90 (d, J = 8.0 Hz, 4 H),
6.69 (s, 2 H), 2.26 (s, 6 H).
S
3a
N
Me
O
3aa
C
Scheme 6 Proposed mechanism
13C NMR (125 MHz, CDCl3): δ = 150.5, 148.6, 137.0, 135.7, 134.1,
129.5, 127.6, 124.6, 123.5, 123.2, 119.6, 20.9.
HRMS (ESI): m/z [M + H]+ calcd for C23H21N2S2: 389.1141; found:
389.1145.
In summary, we have developed an efficient and conve-
nient protocol for the synthesis of sulfenyl pyrrole and in-
dole derivatives by CuI-catalyzed thiolation using disulfides
as the sulfur source. A number of pyrroles and indoles were
tolerated under the optimized reaction conditions, furnish-
ing the corresponding products in moderate to excellent
yields. Importantly, the reaction proceeds via a copper(I)-
catalyzed C–H thiolation process rather than by way of a
traditional stoichiometric copper(II)-mediated C–H thiola-
tion.
2-{2,5-Bis[(4-methoxyphenyl)thio]-1H-pyrrol-1-yl}pyridine (3c)
Yield: 47.4 mg (52%); light yellow oil.
1H NMR (500 MHz, CDCl3): δ = 8.49 (dd, J = 5.0 Hz, J = 1.5 Hz, 1 H),
7.59 (td, J = 1.5 Hz, J = 7.5 Hz, 1 H), 7.25–7.22 (m, 1 H), 6.97–6.94 (m, 4
H), 6.92 (d, J = 7.5 Hz, 1 H), 6.71–6.68 (m, 4 H), 6.60 (s, 2 H), 3.73 (s, 6
H).
13C NMR (125 MHz, CDCl3): δ = 158.5, 150.6, 148.6, 137.0, 130.4,
127.7, 125.5, 123.7, 123.1, 118.6, 114.4, 55.3.
HRMS (ESI): m/z [M + H]+ calcd for C23H21O2N2S2: 421.1039; found:
421.1049.
Chemicals were either purchased or purified by standard techniques.
All reactions were conducted under air an atmosphere using standard
Schlenk techniques. Column chromatography was performed using
EM silica gel 60 (300–400 mesh). Melting points were obtained using
a SGW X-4 apparatus. 1H NMR and 13C NMR spectra were measured at
room temperature on a Bruker ADVANCE-500 MHz spectrometer (1H:
500 MHz, 13C: 125 MHz) using CDCl3 as the solvent and TMS as an in-
ternal standard. Chemical shifts (δ) are given in ppm relative to TMS
and the coupling constants J are given in Hz. Low-resolution mass
spectra (LRMS) were obtained using a Shimadazu GC-MS 2010 plus
spectrometer. High-resolution mass spectra (HRMS) were recorded
on an ESI-Q-TOF mass spectrometer.
2-{2,5-Bis[(4-nitrophenyl)thio]-1H-pyrrol-1-yl}pyridine (3d)
Yield: 89.4 mg (93%); light yellow oil.
1H NMR (500 MHz, CDCl3): δ = 8.33–8.32 (m, 1 H), 8.03–8.00 (m, 4 H),
7.64 (td, J = 2.0 Hz, J = 7.5 Hz, 1 H), 7.24–7.22 (m, 1 H), 7.07–7.04 (m, 5
H), 6.89 (d, J = 2.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 149.6, 149.0, 147.4, 145.6, 137.6,
125.9, 124.0, 123.9, 123.0, 122.3, 121.7.
HRMS (ESI): m/z [M + H]+ calcd for C21H15O4N4S2: 451.0529; found:
451.0538.
2-{2,5-Bis[(4-chlorophenyl)thio]-1H-pyrrol-1-yl}pyridine (3e)
2-[2,5-Bis(phenylthio)-1H-pyrrol-1-yl]pyridine (3a); Typical Pro-
cedure
Yield: 84.7 mg (97%); light yellow oil.
1H NMR (500 MHz, CDCl3): δ = 8.44 (d, J = 4.0 Hz, 1 H), 7.58 (td, J = 1.5
Hz, J = 7.5 Hz, 1 H), 7.23 (dd, J = 5.0 Hz, J = 7.5 Hz, 1 H), 7.09 (t, J = 7.5
Hz, 2 H), 7.06–7.04 (m, 2 H), 6.94 (t, J = 1.5 Hz, 2 H), 6.90 (d, J = 7.5 Hz,
1 H), 6.87–6.85 (m, 2 H), 6.79 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 150.1, 148.9, 139.9, 137.2, 134.6,
129.8, 126.6, 125.9, 125.0, 123.6, 123.5, 123.3, 120.7.
Under an air atmosphere, a reaction tube was charged with 2-(1H-
pyrrol-1-yl)pyridine (1a) (0.2 mmol), diphenyldisulfane (2a) (0.4
mmol), CuI (10 mol%), XPhos (2-dicyclohexylphosphino-2′,4′,6′-tri-
isopropylbiphenyl) (10 mol%) and DMSO (2 mL). The vessel was
sealed and heated at 120 °C (oil bath temperature) for 24 h and then
cooled to room temperature. The reaction mixture was washed with
saturated Na2S2O3 (2 × 15 mL) and then brine (15 mL). After the aque-
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W. Xu et al.
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Synthesis
HRMS (ESI): m/z [M + H]+ calcd for C21H15Cl2N2S2: 429.0048; found:
429.0064.
1H NMR (500 MHz, CDCl3): δ = 8.43–8.42 (m, 1 H), 7.61 (td, J = 7.5 Hz,
J = 1.5 Hz, 1 H), 7.23–7.21 (m, 1 H), 7.10–7.06 (m, 2 H), 7.02 (d, J = 7.5
Hz, 1 H), 6.97 (t, J = 7.5 Hz, 2 H), 6.92–6.87 (m, 4 H), 6.76 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 159.2 (d, JC–F = 243.8 Hz), 150.1, 148.7,
137.2, 129.9, 127.6 (d, JC–F = 7.5 Hz), 124.8 (d, JC–F = 16.3 Hz), 124.4 (d,
JC–F = 2.5 Hz), 123.4, 123.2, 122.6, 120.5, 115.2 (d, JC–F = 21.3 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C21H15F2N2S2: 397.0639; found:
397.0648.
2-{2,5-Bis[(4-fluorophenyl)thio]-1H-pyrrol-1-yl}pyridine (3f)
Yield: 70.2 mg (88%); light yellow oil.
1H NMR (500 MHz, CDCl3): δ = 8.43 (dd, J = 5.0 Hz, J = 1.5 Hz, 1 H),
7.57 (td, J = 8.0 Hz, J = 1.5 Hz, 1 H), 7.23–7.21 (m, 1 H), 7.14–7.10 (m, 2
H), 6.92 (d, J = 8.0 Hz, 1 H), 6.80 (s, 2 H), 6.79–6.75 (m, 4 H), 6.69 (dt,
J = 9.0 Hz, J = 2.0 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 162.8 (d, JC–F = 247.5 Hz), 150.1, 148.8,
140.3 (d, JC–F = 7.5 Hz), 137.2, 130.0 (d, JC–F = 8.8 Hz), 123.5 (d, JC–F = 2.5
Hz), 123.2, 122.3 (d, JC–F = 2.5 Hz), 120.7, 113.8 (d, JC–F = 23.8 Hz),
112.7 (d, JC–F = 21.3 Hz).
2-{2,5-Bis[(3,5-dichlorophenyl)thio]-1H-pyrrol-1-yl}pyridine (3k)
Yield: 41.6 mg (40%); light yellow oil.
1H NMR (500 MHz, CDCl3): δ = 8.44 (d, J = 3.5 Hz, 1 H), 7.66 (td, J = 7.5
Hz, J = 1.5 Hz, 1 H), 7.28 (dd, J = 7.5 Hz, J = 5.0 Hz, 1 H), 7.07 (t, J = 1.5
Hz, 2 H), 6.95 (d, J = 7.5 Hz, 1 H), 6.83 (d, J = 1.5 Hz, 4 H), 6.82 (s, 2 H).
LRMS (EI, 70 eV): m/z (%) = 396 (26), 395 (100), 268 (77), 174 (12), 78
(18).
13C NMR (125 MHz, CDCl3): δ = 149.9, 149.0, 141.3, 137.4, 135.2,
126.0, 124.8, 123.8, 123.2, 122.9, 121.3.
HRMS (ESI): m/z [M + H]+ calcd for C21H15F2N2S2: 397.0639; found:
397.0645.
HRMS (ESI): m/z [M + H]+ calcd for C21H13Cl4N2S2: 496.9269; found:
496.9267.
2-{2,5-Bis[(3-chlorophenyl)thio]-1H-pyrrol-1-yl}pyridine (3g)
Yield: 66.9 mg (82%); light yellow oil.
2-[2,5-Bis(thiophen-3-ylthio)-1H-pyrrol-1-yl]pyridine (3l)
1H NMR (500 MHz, CDCl3): δ = 8.43 (d, J = 3.5 Hz, 1 H), 7.57 (t, J = 7.5
Hz, 1 H), 7.23–7.21 (m, 1 H), 7.12 (dd, J = 7.5 Hz, J = 14.0 Hz, 2 H), 6.93
(d, J = 7.5 Hz, 1 H), 6.80–6.75 (m, 6 H), 6.69 (d, J = 7.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 163.8, 161.8, 150.1, 148.8, 140.31,
140.26, 137.2, 130.0, 129.9, 122.33, 122.31, 120.7, 113.9, 113.7, 112.8,
112.6.
Yield: 45.5 mg (54%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 8.61 (dd, J = 5.0 Hz, J = 1.5 Hz, 1 H),
7.78 (td, J = 7.5 Hz, J = 1.5 Hz, 1 H), 7.38–7.36 (m, 1 H), 7.21–7.19 (m, 3
H), 6.80 (dd, J = 5.0 Hz, J = 3.5 Hz, 2 H), 6.72 (dd, J = 3.5 Hz, J = 1.5 Hz, 2
H), 6.55 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 150.3, 148.8, 137.3, 134.7, 131.6,
128.8, 127.1, 126.3, 123.8, 123.3, 117.8.
HRMS (ESI): m/z [M + H]+ calcd for C21H15Cl2N2S2: 429.0048; found:
429.0062.
LRMS (EI, 70 eV): m/z (%) = 372 (28), 371 (52), 256 (100), 255 (19), 78
(23).
2-{2,5-Bis[(3-fluorophenyl)thio]-1H-pyrrol-1-yl}pyridine (3h)
HRMS (ESI): m/z [M + H]+ calcd for C17H13N2S4: 372.9956; found:
372.9956.
Yield: 71.0 mg (80%); light yellow oil.
1H NMR (500 MHz, CDCl3): δ = 8.44 (d, J = 5.0 Hz, 1 H), 7.57 (td, J = 7.5
Hz, J = 1.5 Hz, 1 H), 7.22 (dd, J = 7.5 Hz, J = 5.0 Hz, 1 H), 7.14–7.10 (m, 2
H), 6.92 (d, J = 7.5 Hz, 1 H), 6.80 (s, 2 H), 6.79–6.75 (m, 4 H), 6.69 (dt,
J = 9.0 Hz, J = 1.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 162.8 (d, JC–F = 247.5 Hz), 150.1, 148.8,
140.3 (d, JC–F = 7.5 Hz), 137.2, 130.0 (d, JC–F = 8.8 Hz), 123.5, 123.2,
2-[2,5-Bis(ethylthio)-1H-pyrrol-1-yl]pyridine (3m)
Yield: 13.5 mg (25%); light yellow oil.
1H NMR (500 MHz, CDCl3): δ = 8.63 (d, J = 4.5 Hz, 1 H), 7.86 (td, J = 7.5
Hz, J = 1.5 Hz, 1 H), 7.38 (dd, J = 7.5 Hz, J = 4.5 Hz, 1 H), 7.31 (d, J = 7.5
Hz, 1 H), 6.47 (s, 2 H), 2.48 (dd, J = 14.5 Hz, J = 7.5 Hz, 4 H), 1.08 (t, J =
7.5 Hz, 6 H).
13C NMR (125 MHz, CDCl3): δ = 151.5, 148.7, 137.4, 125.4, 124.2,
123.3, 117.9, 31.1, 14.4.
122.3 (d, JC–F = 3.8 Hz), 120.7, 113.7 (d, JC–F = 23.8 Hz), 112.7 (d, JC–F
=
21.3 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C21H15F2N2S2: 397.0639; found:
397.0647.
LRMS (EI, 70 eV): m/z (%) = 264 (100), 235 (70), 207 (16), 174 (48), 78
(34).
2-{2,5-Bis[(2-chlorophenyl)thio]-1H-pyrrol-1-yl}pyridine (3i)
HRMS (ESI): m/z [M + H]+ calcd for C13H17N2S2: 265.0828; found:
265.0828.
Yield: 58.8 mg (69%); white solid; mp 92–94 °C.
1H NMR (500 MHz, CDCl3): δ = 8.38 (d, J = 4.5 Hz, 1 H), 7.56 (td, J = 1.5
Hz, J = 7.5 Hz, 1 H), 7.19–7.16 (m, 3 H), 7.10 (t, J = 7.5 Hz, 2 H), 7.02–
7.00 (m, 3 H), 6.85 (d, J = 7.5 Hz, 2 H), 6.82 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 149.9, 148.8, 137.3, 137.2, 130.7,
129.2, 128.0, 127.0, 126.5, 123.5, 123.1, 122.9, 121.2.
2-[2,5-Bis(phenylselanyl)-1H-pyrrol-1-yl]pyridine (3n)
Yield: 48.5 mg (48%); light yellow oil.
1H NMR (500 MHz, CDCl3): δ = 8.46 (dd, J = 5.0 Hz, J = 1.5 Hz, 1 H),
7.55 (td, J = 7.5 Hz, J = 1.5 Hz, 1 H), 7.22 (dd, J = 7.5 Hz, J = 5.0 Hz, 1 H),
7.18–7.15 (m, 10 H), 6.92 (d, J = 7.5 Hz, 1 H), 6.70 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 151.8, 148.5, 137.0, 133.2, 130.0,
129.0, 126.5, 123.11, 123.09, 121.2, 119.3.
LRMS (EI, 70 eV): m/z (%) = 430 (61), 429 (21), 428 (76), 285 (100),
250 (26), 174 (43).
HRMS (ESI): m/z [M + H]+ calcd for C21H15Cl2N2S2: 429.0048; found:
429.0058.
HRMS (ESI): m/z [M + H]+ calcd for C21H17N2Se2: 456.9717; found:
456.9726.
2-{2,5-Bis[(2-fluorophenyl)thio]-1H-pyrrol-1-yl}pyridine (3j)
Yield: 54.6 mg (70%); light yellow solid; mp 72–74 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

F
W. Xu et al.
Paper
Synthesis
2-[2,5-Bis(phenylthio)-1H-pyrrol-1-yl]pyrimidine (3o)
1H NMR (500 MHz, CDCl3): δ = 8.59 (d, J = 3.5 Hz, 1 H), 8.15 (d, J = 8.0
Hz, 1 H), 8.01 (s, 1 H), 7.83 (td, J = 1.5 Hz, J = 8.0 Hz, 1 H), 7.50 (d, J =
8.0 Hz, 1 H), 7.45 (s, 1 H), 7.22–7.19 (m, 6 H), 7.12–7.08 (m, 1 H), 2.45
(s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 151.8, 149.0, 138.5, 134.2, 131.9,
131.7, 131.3, 128.7, 126.2, 125.6, 124.9, 120.5, 119.6, 114.4, 113.2,
105.8, 21.3.
Yield: 26.0 mg (36%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 8.66 (d, J = 5.0 Hz, 2 H), 7.19–7.15 (m, 5
H), 7.10–7.09 (m, 1 H), 7.08–7.06 (m, 5 H), 6.66 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 157.9, 156.7, 137.8, 128.7, 127.5,
125.8, 124.5, 120.1, 119.7.
LRMS (EI, 70 eV): m/z (%) = 361 (26), 360 (100), 351 (90), 147 (10), 77
(6).
HRMS (ESI): m/z [M + H]+ calcd for C20H16N3S2: 362.0780; found:
HRMS (ESI): m/z [M + H]+ calcd for C20H17N2S: 317.1107; found:
317.1105.
362.0798.
5-Chloro-2-(phenylthio)-1-(pyridin-2-yl)-1H-indole (5d)
Yield: 55.3 mg (81%); light yellow solid; mp 83–85 °C.
2-[5-(Phenylthio)-1H-imidazol-1-yl]pyridine (3p)
1H NMR (500 MHz, CDCl3): δ = 8.59 (s, 1 H), 8.23 (d, J = 9.0 Hz, 1 H),
7.99 (s, 1 H), 7.85 (t, J = 9.0 Hz, 1 H), 7.60 (d, J = 1.5 Hz, 1 H), 7.46 (d, J =
9.0 Hz, 1 H), 7.30 (dd, J = 1.5 Hz, J = 9.0 Hz, 1 H), 7.25–7.22 (m, 1 H),
7.21–7.17 (m, 4 H), 7.11 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 151.5, 149.1, 138.7, 137.8, 134.3,
132.8, 132.3, 128.9, 128.0, 126.5, 125.4, 124.4, 121.0, 119.4, 115.0,
114.4, 106.2.
Yield: 12.0 mg (23%); light yellow oil.
1H NMR (500 MHz, CDCl3): δ = 8.48 (dd, J = 5.0 Hz, J = 1.5 Hz, 1 H),
7.76 (td, J = 7.5 Hz, J = 1.5 Hz, 1 H), 7.53 (s, 1 H), 7.48 (d, J = 7.5 Hz, 1
H), 7.25–7.19 (m, 6 H), 7.17–7.14 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 149.7, 148.9, 139.1, 138.3, 133.6,
130.4, 130.1, 129.1, 127.3, 122.8, 121.9, 118.3.
HRMS (ESI): m/z [M + H]+ calcd for C19H14ClN2S: 337.0561; found:
337.0566.
LRMS (EI, 70 eV): m/z (%) = 253 (13), 252 (54), 251 (100), 118 (26), 78
(23).
HRMS (ESI): m/z [M + H]+ calcd for C14H12N3S: 254.0747; found:
254.0752.
6-Fluoro-2-(phenylthio)-1-(pyridin-2-yl)-1H-indole (5e)
Yield: 32.2 mg (50%); light yellow oil.
2-(Phenylthio)-1-(pyridin-2-yl)-1H-indole (5a)
1H NMR (500 MHz, CDCl3): δ = 8.60 (d, J = 4.0 Hz, 1 H), 8.11 (dd, J = 2.0
Hz, J = 8.5 Hz, 1 H), 7.95 (s, 1 H), 7.85 (td, J = 2.0 Hz, J = 8.5 Hz, 1 H),
7.52 (dd, J = 5.5 Hz, J = 8.5 Hz, 1 H), 7.45 (d, J = 8.0 Hz, 1 H), 7.23 (dd,
J = 5.5 Hz, J = 8.5 Hz, 1 H), 7.20–7.19 (m, 4 H), 7.12–7.09 (m, 1 H), 6.99
(td, J = 2.0 Hz, J = 8.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 161.0 (d, JC–F = 237.5 Hz), 151.7, 149.0,
138.7, 137.9, 136.0, 135.9, 131.6 (d, JC–F = 2.5 Hz), 128.8, 127.2, 126.5,
125.3, 120.8, 120.7 (d, JC–F = 10.0 Hz), 114.1, 110.7 (d, JC–F = 25.0 Hz),
106.9, 101.1, 100.9.
Yield: 56.8 mg (77%); light yellow oil.
1H NMR (500 MHz, CDCl3): δ = 8.59 (d, J = 4.0 Hz, 1 H), 8.26 (d, J = 8.0
Hz, 1 H), 8.02 (s, 1 H), 7.83 (t, J = 8.0 Hz, 1 H), 7.64 (d, J = 8.0 Hz, 1 H),
7.50 (d, J = 8.0 Hz, 1 H), 7.37 (t, J = 8.0 Hz, 1 H), 7.25–7.17 (m, 6 H),
7.09 (t, J = 8.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 151.8, 149.0, 138.6, 138.2, 135.9,
131.8, 131.0, 128.7, 126.4, 125.1, 124.0, 122.1, 120.7, 120.0, 114.7,
113.4, 106.5.
LRMS (EI, 70 eV): m/z (%) = 320 (23), 319 (100), 318 (45), 286 (16),
LRMS (EI, 70 eV): m/z (%) = 302 (25), 301 (100), 300 (41), 268 (20),
241 (15).
223 (12).
HRMS (ESI): m/z [M + H]+ calcd for C19H14FN2S: 321.0856; found:
HRMS (ESI): m/z [M + H]+ calcd for C19H15N2S: 303.0951; found:
321.0855.
303.0951.
2-(Phenylthio)-1-(pyrimidin-2-yl)-1H-indole (5f)10
3-Methyl-2-(phenylthio)-1-(pyridin-2-yl)-1H-indole (5b)
Yield: 47.5 mg (37%); yellow solid.
Yield: 44.2 mg (75%); light yellow oil.
1H NMR (500 MHz, CDCl3): δ = 8.84 (d, J = 8.5 Hz, 1 H), 8.70 (d, J = 4.5
Hz, 2 H), 8.58 (s, 1 H), 7.57 (d, J = 7.5 Hz, 1 H), 7.40–7.37 (m, 1 H),
7.24–7.22 (m, 3 H), 7.18 (t, J = 7.5 Hz, 2 H), 7.10–7.06 (m, 2 H).
1H NMR (500 MHz, CDCl3): δ = 8.58 (d, J = 4.0 Hz, 1 H), 7.73 (t, J = 8.0
Hz, 1 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.53 (d, J = 8.0 Hz, 1 H), 7.31–7.28 (m,
2 H), 7.25–7.22 (m, 2 H), 7.16–7.13 (m, 2 H), 7.07–7.04 (m, 1 H), 6.97–
6.96 (m, 2 H), 2.49 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 158.2, 157.3, 137.7, 136.0, 131.6,
13C NMR (125 MHz, CDCl3): δ = 151.0, 149.0, 138.2, 137.6, 137.2,
128.9, 128.3, 126.3, 125.4, 124.4, 123.7, 123.0, 122.1, 122.0, 120.7,
119.3, 111.6, 10.0.
131.4, 128.8, 126.8, 125.2, 124.5, 122.8, 119.8, 116.7, 116.5, 108.5.
LRMS (EI, 70 eV): m/z (%) = 303 (24), 302 (100), 301 (48), 300 (9), 269
(16).
HRMS (ESI): m/z [M + H]+ calcd for C18H14N3S: 304.0903; found:
304.0902.
LRMS (EI, 70 eV): m/z (%) = 316 (100), 287 (17), 207 (22), 156 (16), 78
(14).
HRMS (ESI): m/z [M + H]+ calcd for C20H17N2S: 317.1107; found:
317.1110.
2-[2-(Phenylthio)-1H-pyrrol-1-yl]pyridine (3aa)7
Yield: 15.1 mg (30%); yellow oil.
5-Methyl-2-(phenylthio)-1-(pyridin-2-yl)-1H-indole (5c)
1H NMR (500 MHz, CDCl3): δ = 8.45 (d, J = 4.5 Hz, 1 H), 7.68–7.65 (m, 1
H), 7.57–7.56 (m, 1 H), 7.52 (d, J = 8.5 Hz, 1 H), 7.19–7.15 (m, 3 H),
7.07–7.06 (m, 1 H), 6.75 (d, J = 7.5 Hz, 2 H), 6.76–6.75 (m, 1 H), 6.44–
6.42 (m, 1 H).
Yield: 73.1 mg (91%); light yellow oil.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

G
W. Xu et al.
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Synthesis
13C NMR (125 MHz, CDCl3): δ = 151.3, 148.8, 139.3, 137.8, 129.1,
127.7, 126.1, 126.0, 125.5, 123.5, 122.0, 119.1, 117.3, 110.4.
H.; Black, R. M. WO2004/019869 A2, 2004. (f) Aktiebolag, A.
US5877192A, 1998. (g) Lafon, L. L. US4927855A, 1990.
(h) Rinehart, K. L.; Sakai, R. US2004/59112A1, 2004.
LRMS (EI, 70 eV): m/z (%) = 252 (100), 251 (36), 174 (19), 78 (38), 51
(3) (a) Mellah, M.; Voituriez, A.; Schulz, E. Chem. Rev. 2007, 107,
5133. (b) Jiang, C.; Covell, D. J.; Stepan, A. F.; Plummer, M. S.;
White, M. C. Org. Lett. 2012, 14, 1386. (c) Chen, J.; Lang, F.;
Zhang, X.; Cun, L.; Zhu, J.; Deng, J.; Liao, J. J. Am. Chem. Soc. 2010,
132, 4552.
(21).
HRMS (ESI): m/z [M + H]+ calcd for C15H12N2S: 253.0721; found:
253.0801.
2-(Phenylthio)-1H-indole (5aa)4b
(4) For Co-, Pd-, Ru- and Rh-catalyzed C–H activation of heterocy-
cles see: Cobalt: (a) Wang, S.; Hou, J.-T.; Feng, M.-L.; Zhang, X.-
Z.; Chen, S.-Y.; Yu, X. Q. Chem. Commun. 2016, 52, 2709.
(b) Gensch, T.; Klauk, F. J. R.; Glorius, F. Angew. Chem. Int. Ed.
2016, 55, 11287. (c) Yu, D.-G.; Gensch, T.; de Azambuja, F.;
Vásquez-Céspedes, S.; Glorius, F. J. Am. Chem. Soc. 2014, 136,
17722. (d) Suzuki, Y.; Sun, B.; Sakata, K.; Yoshino, T.; Matsunaga,
S.; Kanai, M. Angew. Chem. Int. Ed. 2015, 54, 9944. Palladium:
(e) Li, C.; Zhu, W.; Shu, S.; Wu, X.; Liu, H. Eur. J. Org. Chem. 2015,
3743. (f) Tu, D.; Cheng, X.; Gao, Y.; Yang, P.; Ding, Y.; Jiang, C.
Org. Biomol. Chem. 2016, 14, 7443. (g) Xu, S.; Huang, X.; Hong,
X.; Xu, B. Org. Lett. 2012, 14, 4614. Ruthenium: (h) Kumar, G. S.;
Kapur, M. Org. Lett. 2016, 18, 1112. (i) Liang, L.; Fu, S.; Lin, D.;
Zhang, X.-Q.; Deng, Y.; Jiang, H.; Zeng, W. J. Org. Chem. 2014, 79,
9472. (j) Qiu, R.; Reddy, V. P.; Iwasaki, T.; Kambe, N. J. Org. Chem.
2015, 80, 367. Rhodium: (k) Yang, L.; Zhang, G.; Huang, H. Adv.
Synth. Catal. 2014, 356, 1509. (l) Li, T.; Wang, Z.; Zhang, M.;
Zhang, H.-J.; Wen, T.-B. Chem. Commun. 2015, 51, 6777. (m) Jia,
J.; Shi, J.; Zhou, J.; Liu, X.; Song, Y.; Xu, H. E.; Yi, W. Chem.
Commun. 2015, 51, 2925.
Yield: 36.0 mg (80%); white solid.
1H NMR (500 MHz, CDCl3): δ = 8.50 (d, J = 3.5 Hz, 1 H), 8.13 (d, J = 8.5
Hz, 1 H), 7.77–7.76 (m, 1 H), 7.66 (d, J = 3.5 Hz, 1 H), 7.59 (d, J = 8.5 Hz,
1 H), 7.43 (d, J = 8.5 Hz, 1 H), 7.23–7.09 (m, 4 H), 6.65 (d, J = 3.5 Hz, 1
H).
13C NMR (125 MHz, CDCl3): δ = 149.0, 138.4, 135.1, 130.5, 125.9,
123.1, 121.1, 120.0, 114.6, 112.9, 105.5.
LRMS (EI, 70 eV): m/z (%) = 225 (100), 224 (42), 193 (22), 148 (22),
121 (19), 112 (13), 77 (41), 51 (28).
Funding Information
We thank the National Natural Science Foundation of China (Nos.
21102104, 21502065) and the Natural Science Foundation of Zhejiang
Province (Nos. LY14B020011, LR15B020002) for their financial sup-
port.
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Supporting Information
(6) For Cu-catalyzed C–H functionalization of heterocycles, see:
(a) Le, J.; Gao, Y.; Ding, Y.; Jiang, C. Tetrahedron Lett. 2016, 57,
1728. (b) Kou, X.; Zhao, M.; Qiao, X.; Zhu, Y.; Tong, X.; Shen, Z.
Chem. Eur. J. 2013, 19, 16880. (c) Zhang, H.-J.; Su, F.; Wen, T.-B.
J. Org. Chem. 2015, 80, 11322. (d) Zhao, J.; Cheng, X.; Le, J.; Yang,
W.; Xue, F.; Zhang, X.; Jiang, C. Org. Biomol. Chem. 2015, 13,
9000. (e) Pan, C.; Jin, H.; Xu, P.; Liu, X.; Cheng, Y.; Zhu, C. J. Org.
Chem. 2013, 78, 9494. (f) Nishino, M.; Hirano, K.; Satoh, T.;
Miura, M. Angew. Chem. Int. Ed. 2012, 51, 6993.
(7) For Cu-catalyzed thiolation of pyrrole, see: Alves, D.; Lara, R. G.;
Contreira, M. E.; Radatz, C. S.; Duarte, L. F. B.; Perin, G. Tetrahe-
dron Lett. 2012, 53, 3364.
(8) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc.
2006, 128, 6790.
(9) Tran, L. D.; Popov, I.; Daugulis, O. J. Am. Chem. Soc. 2012, 134,
18237.
(10) Zhu, L.; Cao, X.; Qiu, R.; Iwasaki, T.; Reddy, V. P.; Xu, X.; Yin,
S.-F.; Kambe, N. RSC Adv. 2015, 5, 39358.
(11) Tu, H.-Y.; Hu, B.-L.; Deng, C.-L.; Zhang, X.-G. Chem. Commun.
2015, 51, 15558.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610295.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G