An efficient and clean CuI-catalyzed chalcogenylation of aromatic azaheterocycles with dichalcogenides

Article abstract of DOI:10.1016/j.tet.2011.03.067

A highly efficient and environmentally friendly method for catalytic chalcogenylation of imidazopyridines, imidazopyrimidines, indoles, and pyrrolo[2,3-b]pyridines with dichalcogenides has been developed by using CuI as catalyst under air. The reactions proceed smoothly to give the desired products in moderate to excellent yields, without the presence of other additive.

Full text of DOI:10.1016/j.tet.2011.03.067

Tetrahedron 67 (2011) 3690e3697
Contents lists available at ScienceDirect
Tetrahedron
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An efficient and clean CuI-catalyzed chalcogenylation of aromatic azaheterocycles
with dichalcogenides
,b,
Zhen Li a, Jianquan Hong a, Xigeng Zhou a
*
a Department of Chemistry, Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Fudan University, Shanghai 200433, People’s Republic of China
b State Key Laboratory of Organometallic Chemistry, Shanghai 200032, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient and environmentally friendly method for catalytic chalcogenylation of imidazopyr-
idines, imidazopyrimidines, indoles, and pyrrolo[2,3-b]pyridines with dichalcogenides has been de-
veloped by using CuI as catalyst under air. The reactions proceed smoothly to give the desired products in
moderate to excellent yields, without the presence of other additive.
Received 17 January 2011
Received in revised form 20 March 2011
Accepted 22 March 2011
Available online 30 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Azaheterocycles
Dichalcogenides
Chalcogenylation
Copper(I) iodide
Air
1. Introduction
prevent from the reaction; further, some additives are often re-
quired in order to achieve optimal yields and selectivity, which also
Since the discovery of the potential utility of 3-sulfenylindoles
as pharmaceuticals in 1993,1 significant efforts have devoted to the
development of new sulfenyl-substituted indoles and related
compounds as well as their construction methods.2e11,12a,b Several
efficient strategies for synthesis of 3-sulfenylindoles have been
developed, including electrophilic substitution of indoles with
sulfur-containing electrophiles, such as sulfenyl chloride,2 N-thio-
phthalimides,3 and quinone mono-O,S-acetals,4 sulfoamination of
2-alkynylanilines with disulfides5 or arylsulfenyl chlorides,6 sul-
fanyl radical addition to alkynyl azides,7 nucleophilic substitution
of indole halides with metal mercaptides,8 coupling reactions of
indoles with disulfides and thiols in the presence of stoichiometric
strong base.9,10 Despite the synthetic utility of these trans-
formations, most of these processes require the use of the strong
bases, unavailable thiolating reagents or per-activated promoters,
which are limited by undesired byproducts and are not suitable for
sensitive substrates. In recent years, a few metal-catalyzed thio-
lations of heterocycles with thiols11 and disulfides12 have been
developed. These reactions have proven to be extremely efficient
for the synthesis of a wide variety of substituted sulfenylindoles
and other heterocycles. Nonetheless, these catalytic variants are
generally sensitive to the nature of heterocycles. For example, the
presence of the strong electron-withdrawing substituent should
limits the scope of these methods. On the other hand, despite the
medicinal importance of sulfenyl-substituted azaheterocycles,13,14
examples of discrete azaheterocycle species incorporating these
functionalities remain scarce.
Imidazopyridines15 and imidazopyrimidines16 are one impor-
tant class of alkaloids commonly found in natural products. Their
biological activities have resulted in them often being used as
building blocks in pharmaceutical compounds,17,18 as ligands for
transition metal catalysts.19 In contrast to the ever-growing litera-
ture on sulfenyl- or selenyl-substituted indoles, examples of imi-
dazopyridines and imidazopyrimidines incorporating these
functionalities remain very scarce.20 This is surprising, given the
expectation that the introduction of sulfenyl or selenyl groups on
the imidazole rings could impart markedly biological, chemical,
and/or physical properties of the compounds for final application.
There does not appear to be a large effort to expand upon this class
of compounds, which is probably due to the lack of viable synthetic
methodologies to access these compounds. Therefore, a new gen-
eral and flexible approach to different classes of chalcogenyl-
substituted heterocycles is highly desirable for the syntheses of
delicate designed products. As part of a continuing effort in our
laboratory toward the development of new methods for the ex-
peditious synthesis of biologically relevant carbo- and heterocyclic
compounds,21 we were interested in preparation of 3-chalcogeny-
limidazopyridines and 3-chalcogenylimidazopyrimidines by the
direct thiolation of a CeH bond. We herein describe a general and
* Corresponding author. Tel./fax: þ86 21 65643769; e-mail address: xgzhou@
fudan.edu.cn (X. Zhou).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.067

Z. Li et al. / Tetrahedron 67 (2011) 3690e3697
3691
efficient method for catalytic chalcogenylation of imidazopyridines,
imidazopyrimidines, indoles, and pyrrolo[2,3-b]pyridines with
dichalcogenides in the presence of CuI and air under the neutral
conditions.
conditions (Table 1, entries 1e6). We found that only copper(I) salts
were active for catalytic thiolation of 1a with 2a (Table 1, entries
1e3), while divalent copper(II) salts, such as Cu(OTf)2, CuBr2, and Cu
(OAc)2, were ineffective, although small amounts of 3aa were oc-
casionally observed (Table 1, entries 4e6). The catalytic activity of
monovalent copper(I) halide increases in order of CuI>CuBr>CuCl,
which is contrast to the observation in the FeX3/I2 cocatalyzed
thiolation of indoles with disulfides.12b To further optimize condi-
tions with CuI as catalyst, we examined the effect of other reaction
parameters. We quickly discovered that use of DMSO as solvent in
place of DMF provided significantly improved yield (Table 1, entry
7), whereas non-coordinating solvents, such as 1,2-dichloroethane
(DCE) and toluene, tend to shut down the reacting system (Table 1,
entries 9 and 10). After conducting reactions in different temper-
atures, we arrived at much improved condition in which 3aa was
obtained in 88% yield when the reaction was carried out at 110 ꢀC
(Table 1, entry 8). It was noteworthy that air was also crucial for
advancement of the reaction while the reaction under nitrogen (in
the absence of oxygen) produced only a moderate yield (49%) of the
product (Table 1, entry 11). In contrast to the observation in the CuI-
catalyzed thiolation of benzoxazole with 2a,12c wherein the addi-
tives of 2,20-bipyridine and Cs2CO3 were required for a satisfactory
yield, in the present case the presence of 2,20-bipyridine as the
ligand led to the decrease of the yield (Table 1, entry 12), and the
presence of base also had an adverse effect on the reaction (Table 1,
entry 13). The reaction was completed in 15 h at 110 ꢀC and part of
the product was decomposed in an extended reaction time (24 h)
and/or at higher temperature (140 ꢀC) (Table 1, entry 14). Moreover,
the yield decreased to 63% (Table 1, entry 15) with the lower cat-
alyst loading (5 mol %). The further investigation result indicated
that no desired product could be formed in the absence of Cu-
catalyst (Table 1, entry 16).
2. Results and discussion
The reaction of 2-phenylimidazo[1,2-a]pyridine (1a) with
diphenyl disulfide (2a) was investigated to explore the optimal
conditions, and the results are summarized in Table 1. Initially,
a series of copper salts, including CuCl, CuBr, CuI, Cu(OTf)2, CuBr2,
and Cu(OAc)2 were screened under otherwise similar reaction
Table 1
Optimization of reaction conditions for the formation of 3aaa
Entry
[Cu]
Solvent
Temp (ꢀC)
Yield (%)e
1
2
3
4
5
6
7
8
CuCl
CuBr
CuI
Cu(OTf)2
CuBr2
Cu(OAc)2
CuI
CuI
CuI
CuI
CuI
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMSO
DCE
Toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
80
80
80
80
80
8
37
50
0
26
11
73
88
trace
27
49
81
71
76
63
0
80
80
110
110
110
110
110
110
140
110
110
9
10
11b
12c
13
14
15d
16
CuI
CuI/Cs2CO3
CuI
With the optimal protocol in hand, we subsequently explored
the scope with respect to the imidazopyridines and imidazopyr-
imidines under the optimized conditions, and the results are shown
in Table 2. The reaction of diphenyl disulfide 2a with various imi-
dazopyridines gave the corresponding 3-sulfenylimidazopyridines
3aae3ia in good to excellent yields (Table 2, entries 1e9). In gen-
eral, the imidazopyridines bearing electron-donating groups were
more reactive than those with electron-withdrawing groups (Table
CuI
a
Reaction conditions: 1a (0.20 mmol), 2a (0.10 mmol), [Cu] (0.02 mmol,
10 mol %), and solvent (2.0 mL) under air atmosphere for 15 h.
b
Under N2 atmosphere.
c
2,20-Bipyridine (0.04 mmol, 20 mol %) was added.
d
CuI (0.01 mmol, 5 mol %) was added.
Isolated yield.
e
Table 2
CuI-catalyzed direct CeH chalcogenylation of 1 with dichalcogenide 2a
Entry
1
1: R1; R2; R3; X
1a: H; H; H; CH
2: RY
Product
Yield (%)c
88
2a: C6H5S
2
3
4
1b: H; Me; H; CH
1c: H; H; Cl; CH
1d: Me; H; H; CH
2a
2a
2a
95
89
97
(continued on next page)

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Z. Li et al. / Tetrahedron 67 (2011) 3690e3697
Table 2 (continued )
Entry
5
1: R1; R2; R3; X
1e: Cl; H; H; CH
2: RY
Product
Yield (%)c
94
2a
6
1f: Cl; Me; H; CH
2a
91
7
1g: Me; H; Cl; CH
1h: Me; Me; H; CH
1i: Cl; H; Cl; CH
1j: H; H; H; N
2a
2a
2a
2a
81
98
65
76
8
9
10
11
12
1k: Cl; H; H; N
2a
70
89
1a
2b: p-MeC6H4S
13
1a
2c: p-ClC6H4S
96
14
15
16
1a
1a
1a
2d:p-BrC6H4S
93
92
89
2e: p-NO2C6H4S
2f: a-naphthyl
17b
18b
19
1a
1a
1a
2g:EtS
42
80
93
2h:n-BuS
2i:C6H5Se
20
21
22
1h
1i
2i
2i
2i
95
61
66
1j
a
Reaction conditions: 1a (0.20 mmol), 2 (0.10 mmol), CuI (0.02 mmol, 10 mol %), DMSO (2.0 mL), at 110 ꢀC under air atmosphere for 10e18 h.
Disulfide (0.20 mmol) was added.
Isolated yield based on substrate 1.
b
c

Z. Li et al. / Tetrahedron 67 (2011) 3690e3697
3693
2, entries 8 and 9). For the reaction with substituted imidazopyr-
imidines 1j and 1k, the corresponding thiolation products 3ja and
3ka were also obtained in satisfactory yields (Table 2, entries 10 and
11). We also examined the scope with respect to disulfides. All the
diaryl disulfides 2be2f with an electron-rich, electron-neutral, or
electron-deficient substituent were screened, such as p-methyl,
conditions described above are effective for the transformation of
a number of different substrate combinations. The thiolation re-
actions of electron-rich (Table 3, entry 6), electron-neutral (Table 3,
entries 2 and 3), and electron-deficient (Table 3, entries 7 and 8)
N-alkylated indoles proceeded with good to excellent yields. In
general, the N-alkylated indoles were more reactive than those
without the substituent at the nitrogen atom. For example, starting
materials 4a and 4d, which do not bear a protecting group at the
nitrogen atom, provide the desired products 5aa and 5da in only
moderate yields (Table 3, entries 1 and 4). This trend contrasts with
that of previously described FeF3/I2-catalyzed reactions of indoles
with disulfides, wherein the introduction of protecting groups at
the N atom of indole rings results in the decrease of yields.12b To our
delight, benzyl (Bn) protected pyrrolo[2,3-b]pyridine (4i) could also
undergo the thiolation with 2a in the presence of CuI and air, giving
the desired coupling product in 85% yield (Table 3, entry 9).
Moreover, it has been found that the Bn-protected indole is also
a suitable substrate for the selenylation reaction (Table 3, entry 10).
Reaction with dialkyl disulfide was also successful (Table 3, entry
11). Noticeably, the substrate bearing a carboxylate group at the
2-position of indole ring also gave the desired product in a satis-
factory yield (Table 3, entry 12).12b The structure of 5ha was de-
termined by X-ray diffraction analysis (Fig. 2).26 Finally,
sulfenylation of the 3-substituted indoles with disulfide was eval-
uated under the standard reaction conditions. It was found that 4k
and 4l reacted with 2a to give the 2-sulfenylated products (Table 3,
entries 13 and 14), indicating that the regioselectivity of sulfeny-
lation is controllable. Consistent with the above observation in
3-sulfenylation, the N-protected indole 4l provided the product in
a higher yield compared with N-unprotected 4k.
p-chloride, p-bromide, and a-naphthyl afforded the corresponding
thioethers 3abe3ad and 3af in excellent yields (Table 2, entries
12e14 and 16). It is noted that (p-O2NC6H4S)2 (2e), which is inactive
in thiolation of benzoxazoles,12c displayed a high reactivity and
reacted smoothly with 1a to give the desired product in 92% yield
(Table 2, entry 15). The structure of 3ae was verified by X-ray dif-
fraction analysis (Fig. 1).26 Moreover, it was found that dialkyl
disulfides 2g and 2h were also suitable substrates for the thiolation
of imidazopyridine 1a (Table 2, entries 17 and 18). Replacement of
disulfide 2a with diselenide 2i as partner provided the desired
products 3ai and 3hie3ji in good to excellent yields (Table 2, en-
tries 19e22).
A plausible mechanism for the copper-catalyzed chalcogenyla-
tion of azaheterocycles with dichalcogenides is illustrated in
Scheme 1.22,2f Initially, CuI reacts with 2 to form a RYþ cation (I) as
observed previously.22aꢁc Then the regioselectively electrophilic
attack of I on imidazole ring results in the formation of substituted
imidazolenium (II), which deprotonates to give the corresponding
chalcogenated products 3 and the copper catalyst is regenerated.
Clearly, the steric and electronic factors are favorable to the attack
of RYþ cation on the carbon atom at the 3-position, and the aza-
heterocycles bearing electron-donating groups are more reactive
than those with electron-withdrawing groups. At the same time,
the oxidation of the in situ generated RYH by air reproduces
dichalcogenides 2.
Fig. 1. Molecular structure of 3ae.
Having demonstrated the viability of the CuI-catalyzed thio-
lation of imidazopyridines and imidazopyrimidines with dichal-
cogenides, we decided to extend the new conditions to the
thiolation of indoles. As shown in Table 3, the new reaction
Table 3
CuI-catalyzed direct CeH chalcogenylation of indoles and pyrrolo[2,3-b]pyridine with dichalcogenidea
Entry
1
4: R1; R2; R3; R4; R5; X
4a: H; H; H; H; H; CH
2: RY
Product
Yield (%)c
67
2a: C6H5S
2
4b: H; H; H; H; Me; CH
2a
84
(continued on next page)

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Z. Li et al. / Tetrahedron 67 (2011) 3690e3697
Table 3 (continued )
Entry
4: R1; R2; R3; R4; R5; X
4c: H; H; H; H; Bn; CH
2: RY
Product
Yield (%)c
93
3
2a
4
5
6
4d: Me; H; H; H; H; CH
4e: Me; H; H; H; Me; CH
4f: H; OMe; H; H; Bn; CH
2a
2a
2a
41
80
96
7
8
4g: Bn; H; H; Cl; H; CH
4h: H; H; H; F; Bn; CH
2a
2a
98
92
9
4i: H; H; H; H; Bn; N
2a
2i
85
84
10
4f
11b
12
4g
2h
2a
72
67
4j: CO2Et; H; H; H; H; CH
13
2a
2a
40
83
14
a
Reaction conditions: 1 (0.20 mmol), 2 (0.10 mmol), CuI (0.02 mmol, 10 mol %), DMSO (2.0 mL), at 110 ꢀC under air atmosphere for 10e18 h.
Compound 2h (0.20 mmol) was added.
Isolated yield based on substrate 4.
b
c

Z. Li et al. / Tetrahedron 67 (2011) 3690e3697
3695
ꢀ
technique,
l
¼0.71073 A). The intensity data were integrated by
means of the SAINT program. SADABS was used to perform area-
detector scaling and absorption corrections. The structures were
solved by direct methods and were refined against F2 using all re-
flections with the aid of the SHELXTL package. All non-hydrogen
atoms were found from the difference Fourier syntheses and re-
fined anisotropically. The H atoms were included in calculated
positions with isotropic thermal parameters related to those of the
supporting carbon atoms but were not included in the refinement.
All calculations were performed using the Bruker Smart program.
4.2. General procedure for chalcogenylation of
azaheterocycles with dichalcogenides
Fig. 2. X-ray structure of 5ha.
A mixture of azaheterocycles 1 or 4 (0.20 mmol), dichalcoge-
nides 2 (0.10 mmol), and CuI (0.020 mmol, 10 mol %) in DMSO
(2.0 mL) was stirred at 110 ꢀC under air atmosphere for 10e18 h
until complete consumption of staring material as monitored by
TLC. The solution was then cooled to room temperature, diluted
with ethyl acetate (10 mL), washed with H2O (3ꢂ10 mL), dried over
Na2SO4, filtered, and evaporated under vacuum. The crude product
was purified by column chromatography on silica gel (eluting with
PE/EA¼25/1 to 4/1) to afford the desired products 3 or 5.
H2O
CuI
RYYR
2
O2
[RYCuI]-
RY+
(I)
RYH
X
N
4.2.1. 7-Methyl-2-phenyl-3-(phenylthio)H-imidazo[1,2-a]pyridine
(3ba). 1H NMR (400 MHz, CDCl3):
d
¼8.18 (d, J¼7.2 Hz, 2H), 8.10 (d,
Ph
3
+ CuI
X
N
1
N
J¼6.9 Hz, 1H), 7.47 (s, 1H), 7.41 (t, J¼7.6 Hz, 2H), 7.34 (t, J¼7.4 Hz,
1H), 7.18 (t, J¼7.5 Hz, 2H), 7.10 (t, J¼7.4 Hz, 1H), 6.97 (d, J¼7.7 Hz,
2H), 6.65 (d, J¼6.9 Hz, 1H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3):
Ph
N
+
[RYCuI]-
H
Y = S, Se
X = CH, N
RY
II
( )
d
¼151.3, 147.5, 138.0, 135.6, 133.5, 129.5, 128.5, 128.4, 128.3, 126.0,
125.5, 123.7, 116.2, 115.7, 105.5, 21.5. HR-MS (ESI): calcd for
Scheme 1. The possible reaction mechanism.
C20H16N2S (MþþH): 317.1112, found: 317.1115.
4.2.2. 6-Chloro-2-phenyl-3-(phenylthio)H-imidazo[1,2-a]pyridine
3. Conclusion
(3ca). 1H NMR (400 MHz, CDCl3):
d
¼8.30 (s, 1H), 8.19 (d, J¼7.2 Hz,
2H), 7.65 (d, J¼9.3 Hz, 1H), 7.42 (t, J¼7.3 Hz, 2H), 7.36 (t, J¼7.2 Hz,
1H), 7.26 (d, J¼9.4 Hz, 1H), 7.21 (t, J¼7.5 Hz, 2H), 7.13 (t, J¼7.3 Hz,
In summary, we have developed an efficient and atom eco-
nomical method for synthesis of various chalcogenyl-substituted
azaheterocycles, such as 3-chalcogenylimidazopyridines, 3-chal-
cogenylimidazopyrimidines, 3-chalcogenylindoles, and 3-chalco-
genylpyrrolo[2,3-b]pyridines, by CuI-catalyzed chalcogenylation of
the corresponding azaheterocycles with dichalcogenides. The
simplicity, economy, high efficiency, and use of environmentally
benign reagents render this method useful and competitive to the
conventional approaches. Efforts to extend the applications of the
transformation in organic synthesis as well as screen for biological
activity of these types of compounds are currently underway in our
laboratory.
1H), 6.99 (d, J¼7.8 Hz, 2H); 13C NMR (100 MHz, CDCl3):
¼152.2,
d
145.5, 134.6, 133.0, 129.7, 128.9, 128.6, 128.3, 128.1, 126.4, 125.7,
122.5, 121.6, 118.1, 107.4. HR-MS (ESI): calcd for C19H13ClN2S
(MþþH): 337.0566, found: 337.0564.
4.2.3. 3-(Phenylthio)-2-p-tolylH-imidazo[1,2-a]pyridine (3da). 1H
NMR (400 MHz, CDCl3):
d
¼8.23 (d, J¼6.7 Hz, 1H), 8.11 (d, J¼8.1 Hz,
2H), 7.70 (d, J¼9.0 Hz, 1H), 7.29 (d, J¼7.0 Hz, 1H), 7.23 (d, J¼7.3 Hz,
2H), 7.17 (t, J¼7.6 Hz, 2H), 7.09 (t, J¼7.6 Hz, 1H), 6.98 (d, J¼7.3 Hz,
2H), 6.80 (t, J¼6.7 Hz, 1H), 2.36 (s, 1H); 13C NMR (100 MHz, CDCl3):
d
¼151.6, 147.1, 138.6, 135.3, 130.5, 129.5, 129.2, 128.3, 126.7, 126.1,
125.6, 124.5, 117.6, 113.080, 105.9, 21.4. HR-MS (ESI): calcd for
4. Experimental section
4.1. General methods
C20H16N2S (MþþH): 317.1112, found: 317.1113.
4.2.4. 2-(4-Chlorophenyl)-3-(phenylthio)H-imidazo[1,2-a]pyridine
(3ea). 1H NMR (400 MHz, CDCl3):
d¼8.24 (d, J¼6.4 Hz, 1H), 8.17 (d,
All reactions were carried out in test tubes under air atmo-
sphere. 1H NMR spectra were recorded on a Bruker AVANCE ECA-
400 MHz spectrometer. Chemical shifts (in ppm) were referenced
to tetramethylsilane (
NMR spectra were obtained by the same NMR spectrometers and
J¼8.4 Hz, 2H), 7.70 (d, J¼8.9 Hz, 1H), 7.38 (d, J¼7.4 Hz, 2H), 7.31 (t,
J¼9.0 Hz, 1H), 7.19 (t, J¼7.1 Hz, 2H), 7.12 (t, J¼7.7 Hz, 1H), 6.97 (d,
J¼7.3 Hz, 2H), 6.86e6.82 (m, 1H); 13C NMR (100 MHz, CDCl3):
d
¼0 ppm) in CDCl3 as an internal standard. 13
C
d
¼150.2, 147.1, 134.9, 134.6, 131.9, 129.6, 129.6, 128.7, 127.0, 126.3,
125.6, 124.6, 117.7, 113.3, 106.5. HR-MS (ESI): calcd for C19H13ClN2S
were calibrated with CDCl3
(d
¼77.00 ppm). High-resolution mass
(MþþH): 337.0566, found: 337.0551.
spectra (HR-MS) were recorded using ESI ionization sources. Sub-
strates 1,23 2,24 and 425 were prepared according to the reported
methods. Methylsulfinylmethane (DMSO) was distilled under ni-
trogen from calcium hydride. Copper(I) iodide was purchased from
SigmaeAldrich. X-ray diffraction data for 3ae and 5ha (CCDC
4.2.5. 2-(4-Chlorophenyl)-7-methyl-3-(phenylthio)H-imidazo[1,2-a]
pyridine (3fa). 1H NMR (400 MHz, CDCl3):
d¼8.15 (d, J¼8.5 Hz, 2H),
8.10 (d, J¼6.9 Hz, 1H), 7.46 (s, 1H), 7.37 (d, J¼8.5 Hz, 2H), 7.18 (t,
J¼7.6 Hz, 2H), 7.11 (t, J¼7.2 Hz, 1H), 6.96 (d, J¼7.9 Hz, 2H), 6.67 (d,
J¼7.0 Hz, 1H), 2.41 (s, 3H); 13C NMR (100 MHz, CDCl3):
¼150.0,
d
ˇ
784894, 784,895) were collected on a SMART APEX CCD diffrac-
tometer (graphite-monochromated Mo K
a
radiation, W
f
-u
-scan
147.5, 138.3, 135.2, 134.5, 132.0, 129.5, 128.6, 126.2, 125.5, 123.7,

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Z. Li et al. / Tetrahedron 67 (2011) 3690e3697
116.2, 115.9, 105.7, 21.5. HR-MS (ESI): calcd for C20H15ClN2S
2H), 8.25 (d, J¼8.5 Hz, 2H), 7.41 (d, J¼8.6 Hz, 2H), 7.19e7.17 (m, 3H),
7.10e7.08 (m, 2H), 6.94e6.92 (m, 1H); 13C NMR (100 MHz, CDCl3):
(MþþH): 351.0722, found: 351.0704.
d
¼151.7, 150.7, 135.1, 133.2, 131.6, 130.1, 130.0, 129.7, 128.7, 128.5,
4.2.6. 6-Chloro-3-(phenylthio)-2-p-tolylH-imidazo[1,2-a]pyridine
127.3, 109.6, 101.9. HR-MS (ESI): calcd for C19H12Cl2N2Se (MþþH):
(3ga). 1H NMR (400 MHz, CDCl3):
d
¼8.29 (s, 1H), 8.09 (d, J¼8.1 Hz,
418.9621, found: 418.9620.
2H), 7.63 (d, J¼9.4 Hz, 1H), 7.23 (d, J¼7.6 Hz, 3H), 7.19 (d, J¼7.7 Hz,
2H), 7.12 (t, J¼7.2 Hz, 1H), 6.99 (d, J¼7.2 Hz, 2H), 2.36 (s, 3H); 13C
4.2.14. 2-Phenyl-3-(phenylselanyl)imidazo[1,2-a]pyrimidine
NMR (100 MHz, CDCl3):
d
¼152.3, 145.4, 138.9, 134.7, 130.1, 129.6,
(3ji). 1H NMR (400 MHz, CDCl3):
d
¼8.60e8.56 (m, 2H), 8.28 (d,
129.3, 128.2, 127.9, 126.3, 125.7, 122.4, 121.5, 118.0, 106.9, 21.4. HR-
J¼7.1 Hz, 2H), 7.44 (t, J¼7.9 Hz, 2H), 7.38 (t, J¼6.9 Hz, 1H), 7.17e7.15
MS (ESI): calcd for C20H15ClN2S (MþþH): 351.0722, found: 351.0714.
(m, 3H), 7.11e7.08 (m, 2H), 6.91e6.88 (m, 1H); 13C NMR (100 MHz,
CDCl3):
d
¼153.0, 151.5, 150.8, 133.2, 133.1, 130.0, 129.9, 129.0, 129.0,
4.2.7. 7-Methyl-3-(phenylthio)-2-p-tolylH-imidazo[1,2-a]pyridine
128.5, 128.4, 127.1, 109.5, 101.7. HR-MS (ESI): calcd for C18H13N3Se
(3ha). 1H NMR (400 MHz, CDCl3):
d
¼8.08 (d, J¼8.2 Hz, 3H), 7.46 (s,
(MþþH): 352.0353, found: 352.0354.
1H), 7.23 (t, J¼8.0 Hz, 2H), 7.17 (t, J¼7.7 Hz, 2H), 7.09 (t, J¼7.7 Hz,
1H), 6.97 (d, J¼7.3 Hz, 2H), 6.64 (d, J¼6.9 Hz, 1H), 2.39 (s, 3H), 2.36
4.2.15. 1-Benzyl-4-methoxy-3-(phenylthio)-1H-indole (5fa). 1H NMR
(s, 3H); 13C NMR (100 MHz, CDCl3):
d¼151.4, 147.5, 138.4, 137.9,
(400 MHz, CDCl3):
d
¼7.30e7.23 (m, 4H), 7.16 (t, J¼8.3 Hz, 5H), 7.10 (t,
135.7, 130.7, 129.4, 129.2, 128.2, 125.9, 125.5, 123.7, 116.1, 115.6, 105.1,
21.4, 21.4. HR-MS (ESI): calcd for C21H18N2S (MþþH): 331.1269,
found: 331.1262.
J¼6.1 Hz, 3H), 7.02 (m, J¼6.8 Hz, 1H), 6.90 (d, J¼8.2 Hz, 1H), 6.50 (d,
J¼7.8 Hz, 1H), 5.21 (s, 2H), 3.66 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
¼154.9, 141.0, 139.2, 136.8, 133.4, 129.0, 128.5, 128.0, 127.0, 126.4,
124.6, 123.8, 119.4, 103.5, 101.5, 101.3, 55.6, 50.5. HR-MS (ESI): calcd
4.2.8. 6-Chloro-2-(4-chlorophenyl)-3-(phenylthio)H-imidazo[1,2-a]
for C22H19NOS (MþþH): 346.1265, found: 346.1263.
pyridine (3ia). 1H NMR (400 MHz, CDCl3):
d
¼8.66e8.64 (m, 1H),
8.52 (d, J¼6.7 Hz, 1H), 8.29 (d, J¼8.6 Hz, 2H), 7.40 (d, J¼8.6 Hz, 2H),
4.2.16. 1-Benzyl-5-chloro-3-(phenylthio)-1H-indole (5ga). 1H NMR
7.22 (t, J¼7.7 Hz, 2H), 7.15 (t, J¼7.0 Hz, 1H), 6.98 (d, J¼7.3 Hz, 2H),
(400 MHz, CDCl3):
d
¼7.58 (s, 1H), 7.37 (s, 1H), 7.28 (t, J¼7.3 Hz, 3H),
6.96e6.93(m, 1H); 13C NMR (100 MHz, CDCl3):
d¼151.9,151.5, 150.0,
7.18e7.04 (m, 9H), 5.26 (s, 2H); 13C NMR (100 MHz, CDCl3):
d
¼139.1,
135.3, 133.9, 132.2, 131.2, 129.8, 129.7, 128.8, 126.7, 125.9, 109.6,
105.6. HR-MS (ESI): calcd for C19H12Cl2N2S (MþþH): 371.0176,
found: 371.0163.
136.2, 135.9, 135.6, 131.3, 129.1, 128.9, 128.2, 127.0, 125.9, 125.1,
123.3, 119.4, 111.6, 101.4, 50.8. HR-MS (ESI): calcd for C21H16ClNS
(MþþH): 350.0770, found: 350.0746.
4.2.9. 2-(4-Chlorophenyl)-3-(phenylthio)imidazo[1,2-a]pyrimidine
4.2.17. 1-Benzyl-6-fluoro-3-(phenylthio)-1H-indole (5ha). 1H NMR
(3ka). 1H NMR (400 MHz, CDCl3):
d
¼8.30 (d, J¼1.6 Hz, 1H), 8.15 (d,
(400 MHz, CDCl3):
d
¼7.51e7.48 (m, 1H), 7.35 (s, 1H), 7.34e7.26 (m,
J¼8.6 Hz, 2H), 7.64 (d, J¼9.5 Hz, 1H), 7.39 (d, J¼8.5 Hz, 2H), 7.28 (d,
J¼9.5 Hz, 1H), 7.22 (t, J¼7.6 Hz, 2H), 7.16 (t, J¼7.2 Hz, 1H), 6.98 (d,
3H), 7.17e7.13 (m, 4H), 7.09e7.02 (m, 3H), 6.98 (d, J¼9.6 Hz, 1H),
6.88 (t, J¼8.8 Hz, 1H), 5.24 (s, 2H); 13C NMR (100 MHz, CDCl3):
J¼7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d¼150.9, 145.4, 134.9,
d¼161.6, 159.2, 139.2, 137.3, 136.2, 134.9, 129.1, 128.8, 128.2, 127.0,
134.3,131.4,129.7,129.5,128.8,128.4,126.6,125.7,122.5,121.8,118.1,
107.4. HR-MS (ESI): calcd for C18H12ClN3S (MþþH): 338.0518,
found: 338.0504.
126.4, 125.9, 125.0, 121.0, 120.9, 109.8, 109.5, 102.0, 97.1, 96.8, 50.7.
HR-MS (ESI): calcd for C21H16FNS (MþþH): 334.1065, found:
334.1053.
4.2.10. 3-(Naphthalen-1-ylthio)-2-phenylH-imidazo[1,2-a]pyridine
4.2.18. 1-Benzyl-3-(phenylthio)-1H-pyrrolo[2,3-b]pyridine (5ia). 1H
(3af). 1H NMR (400 MHz, CDCl3):
d
¼8.25 (t, J¼8.7 Hz, 3H),
NMR (400 MHz, CDCl3):
1H), 7.44 (s, 1H), 7.33e7.27 (m, 3H), 7.22e7.02 (m, 8H), 5.51 (s, 2H);
13C NMR (100 MHz, CDCl3):
d¼8.39 (d, J¼6.2 Hz, 1H), 7.86 (d, J¼7.8 Hz,
7.76e7.67 (m, 3H), 7.55 (d, J¼6.5 Hz, 1H), 7.44e7.36 (m, 6H), 7.31 (t,
J¼8.8 Hz, 1H), 7.16 (d, J¼8.6 Hz, 1H), 6.80 (t, J¼6.8 Hz, 1H); 13C NMR
d
¼148.4, 144.1, 143.1, 138.9, 137.0, 134.1,
(100 MHz, CDCl3):
d
¼151.6, 147.3, 133.9, 133.4, 132.7, 131.8, 129.3,
128.9,128.0,127.6,126.0,125.1,122.1,117.0,115.9,100.6, 48.2. HR-MS
128.7, 128.5, 128.5, 127.8, 127.1, 126.9, 125.873, 124.6, 123.9, 123.5,
117.81, 113.2, 106.2. HR-MS (ESI): calcd for C23H16N2S (MþþH):
353.1112, found: 353.1103.
(ESI): calcd for C20H16N2S (MþþH): 317.1112, found: 317.1119.
4.2.19. 1-Benzyl-4-methoxy-3-(phenylselanyl)-1H-indole
NMR (400 MHz, CDCl3):
¼7.35 (d, J¼8.4 Hz, 2H), 7.24e7.22 (m, 2H),
7.15e7.06 (m, 8H), 6.88 (d, J¼8.2 Hz, 1H), 6.50 (d, J¼7.8 Hz, 1H), 5.20
(s, 2H), 3.72 (s, 3H); 13C NMR (100 MHz, CDCl3):
(5fi). 1H
d
4.2.11. 2-Phenyl-3-(phenylselanyl)H-imidazo[1,2-a]pyridine
(3ai). 1H NMR (400 MHz, CDCl3):
d
¼8.31 (d, J¼6.8 Hz, 1H), 8.16 (d,
d¼154.8, 139.1,
J¼7.5 Hz, 2H), 7.70 (d, J¼9.0 Hz, 1H), 7.42 (t, J¼7.3 Hz, 2H), 7.35 (t,
J¼7.5 Hz, 1H), 7.26 (t, J¼6.9 Hz, 1H), 7.16e7.12 (m, 3H), 7.10e7.07 (m,
137.0, 135.1, 133.2, 129.9, 128.9, 128.9, 127.9, 127.0, 125.8, 123.6,
119.8, 103.4, 101.2, 95.7, 55.5, 50.5. HR-MS (ESI): calcd for
C22H19NOSe (MþþH): 394.0710, found: 394.0688.
2H), 6.79 (t, J¼6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3):
¼151.8,
d
147.8, 133.8, 130.9, 129.7, 128.8, 128.5, 128.4, 128.3, 126.7, 126.6,
125.7,117.5,113.1,102.9. HR-MS (ESI): calcd for C19H14N2Se (MþþH):
351.0400, found: 351.0390.
4.2.20. 1-Benzyl-3-(butylthio)-5-chloro-1H-indole (5gh). 1H NMR
(400 MHz, CDCl3):
d
¼7.73 (s, 1H), 7.30e7.27 (m, 2H), 7.23 (s, 1H),
7.17e7.06 (m, 6H), 5.24 (s, 2H), 2.66 (t, J¼7.4 Hz, 2H), 1.54e1.47 (m,
4.2.12. 7-Methyl-3-(phenylselanyl)-2-p-tolylH-imidazo[1,2-a]pyri-
2H), 1.43e1.34 (m, 2H), 0.86 (t, J¼7.2 Hz, 2H); 13C NMR (100 MHz,
dine (3hi). 1H NMR (400 MHz, CDCl3):
d
¼8.16 (d, J¼6.9 Hz,1H), 8.04
CDCl3):
d
¼136.6, 135.3, 134.5, 131.6, 129.0, 128.0, 126.8, 123.3,
(t, J¼8.1 Hz, 2H), 7.45 (s,1H), 7.22 (d, J¼8.0 Hz, 2H), 7.15e7.12 (m, 3H),
122.8, 119.2, 111.3, 104.9, 50.5, 36.4, 32.0, 21.7, 13.8. HR-MS (ESI):
7.08e7.06 (m, 2H), 6.62 (d, J¼6.9 Hz,1H), 2.39 (s, 3H), 2.36 (s, 3H); 13C
calcd for C19H20ClNS (MþþH): 330.1083, found: 330.1070.
NMR (100 MHz, CDCl3):
d
¼151.8,148.1,138.2,137.6,131.3,131.1,129.7,
129.1, 128.6, 128.1, 126.6, 124.7, 116.0, 115.5, 101.6, 21.4. HR-MS (ESI):
Acknowledgements
calcd for C21H18N2Se (MþþH): 379.0713, found: 379.0709.
We thank the NNSF of China, 973 program (2009CB825300),
Shanghai Science and Technology Committee (No. 08dj1400100),
the Research Fund for the Doctoral Program of Higher Education of
4.2.13. 6-Chloro-2-(4-chlorophenyl)-3-(phenylselanyl)H-imidazo
[1,2-a]pyridine (3ii). 1H NMR (400 MHz, CDCl3):
d¼8.63e8.58 (m,

Z. Li et al. / Tetrahedron 67 (2011) 3690e3697
3697
G.; Xin, Z.; Wang, X.; Wang, R.; McNally, T.; Camp, H.; Beutel, B. A.; Sham, H. L.
J. Med. Chem. 2006, 49, 3770; (d) Tandon, V. K.; Yadav, D. B.; Singh, R. V.;
Chaturvedi, A. K.; Shukla, P. K. Bioorg. Med. Chem. Lett. 2005, 15, 5324; (e)
Llauger, L.; He, H.; Kim, J.; Aguirre, J.; Rosen, N.; Peters, U.; Davies, P.; Chiosis, G.
J. Med. Chem. 2005, 48, 2892.
China, and Shanghai Leading Academic Discipline Project for
financial support (B108).
Supplementary data
14. For selected recent examples on medicinal 3-sulfenyl indoles: (a) Silvestri, R.; De
ꢁ
Martino, G.; La Regina, G.; Artico, M.; Massa, S.; Vargiu, L.; Mura, M.; Loi, A. G.;
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2011.03.067. These data include MOL files and
InChIKeys of the most important compounds described in this
article.
Marceddu, T.; La Colla, P. J. Med. Chem. 2003, 46, 2482; (b) Avis, I.; Martinez, A.;
Tauler, J.; Zudaine, E.; Mayburd, A.; Abu-Ghazaleh, R.; Obndrey, F.; Mulshine, J. L.
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