Iodine-promoted radical alkyl sulfuration of imidazopyridines with dialkyl azo compounds and elemental sulfur

Article abstract of DOI:10.1039/c8ob03191f

Dialkyl azo compounds were found to be effective alkyl radical sources for direct alkyl sulfuration with imidazopyridines using elemental sulfur under metal-free conditions. Iodine, an inexpensive and mild reagent, could promote alkyl sulfuration. A variety of quaternary cyanoalkyl radicals were successfully coupled with elemental sulfur. A subsequent C-H sulfuration of imidazopyridines afforded a diverse array of imidazopyridine derivatives bearing cyanoalkylthio groups. The cyano group could be modified and further underwent condensation with 2-aminothiazole to afford an interesting heterocyclic amide. Control experiments showed that iodine could greatly suppress the self-coupling of cyanoalkyl radicals, thus making the sulfuration proceed smoothly.

Full text of DOI:10.1039/c8ob03191f

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DOI: 10.1039/C8OB03191F
Journal Name
ARTICLE
Iodine-promoted Radical Alkyl Sulfuration of Imidazopyridines
with Dialkyl Azo Compounds and Elemental Sulfur
a
a
a
a
a
Received 00th January 20xx,
Accepted 00th January 20xx
Yong-Chao Gao, Zhuo-Bin Huang, Li Xu, Zhao-Dong Li,* Zhi-Sheng Lai, Ri-Yuan
Tang*ab
DOI: 10.1039/x0xx00000x
Dialkyl azo compounds were found to be effective alkyl radical sources for direct alkyl sulfuration with imidazopyridines
using elemental sulfur under metal-free conditions. Iodine, an inexpensive and mild reagent, could promote the alkyl
sulfuration. A variety of quaternary cyanoalkyl radicals were successfully coupled with elemental sulfur. A subsequent C-H
sulfuration of the imidazopyridines afforded a diverse array of imidazopyridine derivatives bearing cyanoalkylthio groups.
The cyano group could be modified and further underwent condensation with 2-aminothiazole to afford an interesting
heterocyclic amide. Control experiments showed that iodine could greatly suppress the self-coupling of cyanoalkyl radical,
thus made the sulfuration proceeded smoothly.
www.rsc.org/
copper-catalyzed cyanation of disulfides with AIBN. This provides
1
1d
an effective pathway for the preparation of thiocyanates. During
the development of this work, Lei and coauthors reported an
elegant method for the synthesis of alkylthionitrile derivatives via a
Introduction
Elemental sulfur is an inexpensive, nontoxic, odourless, stable, and
easily handled powder and is an ideal sulfur source for the synthesis
of sulfur-containing compounds. Coupling of two different
molecules using elemental sulfur through a C−H sulfuration
provides an economic and efficient route to a diverse range of
sulfur-containing compounds. The direct sulfuration of drug
skeletons using elemental sulfur enables access to biologically
useful molecules. Imidazopyridines are privileged scaffolds that
have been widely used in medicinal chemistry.
sulfuration of an imidazopyridine backbone using elemental sulfur
avoids the use of odorous and highly toxic thiols. In recent years,
an aryl sulfuration of imidazoheterocycles with elemental sulfur
copper-catalyzed radical coupling of aryl thiols with AIBN (Scheme
, eqn 1). Compared with Lei’s work, the coupling of cyanoalkyl
radical with elemental sulfur and imidazopyridines is challenging
because elemental sulfur is less reactive than thiol, and the
cyanoalkyl radical readily undergoes a self-coupling reaction. Thus,
the self-coupling of the cyanoalkyl radical must be inhibited for
selective cyanoalkyl sulfuration of imidazopyridines. We envisioned
that iodine may capture the cyanoalkyl radical to form an iodide
compound for next alkyl sulfuration and may be able to accelerate
the sulfuration. Based on these assumptions, we developed an
1
10b
1
12
2
3
-5,7
The C-H
9
6
-9
5g
iodine promoted alkylthionation of imidazopyridines with
elemental sulfur and dialkyl azo compounds involving a radical
process (Scheme 1, eqn 2).
7
and aryl iodides or aryl boric acid, has been developed. Recently,
our group has also developed an oxidative radical dual C−H
sulfuration of imidazopyridines with ethers or alkanes, and a
8
metal-free sulfuration with a diverse range of functionalized
haloalkanes using elemental sulfur. Although progress has been
9
Previous work
ref. 10b
Cu(OTf)2 (5 mol%)
Phen (20 mol%)
DCE, 80 oC, 12h
made, the C−H alkylthionation of imidazopyridines using elemental
sulfur has not been widely reported. The development of new
pharmaceutically useful alkyl reaction partners for the C−H
sulfuration of imidazopyridines is greatly desired. We envisaged
that dialkyl azo compounds (such as AIBN and related analogues)
bearing different functional groups would be attractive reaction
partners for such a transformation. AIBN is able to give cyanoalkyl
NC
N
ArSH
+
Ar
S
CN
(1)
(2)
N
CN
This work: metal-free double C-S bond formation using elemental sulfur
N
N
NC
I2
Ph
S
N
Ph
+
+
N
N
N
metal-free
CN
H
S
1
0
11
or cyano radicals, which are useful species for chemical
NC
transformations. For example, Cheng and coauthors developed a
Scheme 1. Sulfuration with dialkyl azo compounds.
Results and discussion
aDepartment of Applied Chemistry, College of Materials and Energy, South China
Agricultural University, Guangzhou 510642, China. E-mail: rytang@scau.edu.cn
Key Laboratory of Natural Pesticide & Chemical Biology, Ministry of Education, South
b
Our studies began with the three-component sulfuration of
China Agricultural University, Guangzhou 510642, China.
Electronic Supplementary Information (ESI) available:See DOI: 10.1039/x0xx00000x
imidazopyridine 1a with elemental sulfur and AIBN. Based on our
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
Page 2 of 7
ARTICLE
Journal Name
previous work,5d, 5g we envisioned that iodine may facilitate the
cleavage of the S-S bond in S to form a reactive sulfur species for
the sulfuration of imidazopyridines. Thus, the reaction was carried
out with two equivalents of iodine with different solvents (Table 1,
entries 1-7). Solvents, such as DMF, NMP, DMSO, and dioxane, were
not suitable (Table 1, entries 1-3 and 6). Reactions in DCE and
toluene gave the desired product 3 in 12% and 17% yield,
a
Reaction conditions: 1a (0.2 mmol), S (0.4 mmol, 2 equiv), 2a (0.2
View Article Online
o
DOI: 10.1 0b 39/C8OB03191F
8
mmol, 1 equiv), solvent (1 mL), at 100 C for 12 h. 2a (0.1 mmol,
0.5 equiv). 2a (0.4 mmol, 2 equiv).
c
With this metal-free C-H alkylthionation procedure in hand, the
substrate scope was investigated (Table 2). Initially, a variety of 2-
aryl imidazopyridines were subjected to reaction with AIBN
(products 3–15). Substituents on the benzene ring, including
3
respectively (Table 1, entries 4 and 5). To our delight, CH CN was
methyl, methoxy, fluoro, chloro, and cyano groups, were tolerated
to give their corresponding products in moderate to good yields
found to be the best solvent giving product 3 in 56% yield (Table 1,
entry 7). In the absence of iodine, the reaction still proceeded in
(
products 4–8). A substrate bearing a methyl group on the pyridine
ring provided good reactivity, giving the corresponding product 9 in
5% yield. Interestingly, a hydroxyl group was also tolerated to
CH
3
CN, but product 3 was obtained in only 18% yield (Table 1, entry
8
). Next, the influence of the amount of iodine on the reaction was
8
examined. The yield of product 3 decreased to 48% when 0.5
equivalents of iodine were used (Table 1, entry 9). The desired
product was obtained in 76% yield in the presence of 1 equivalent
of iodine (Table 1, entry 10), whereas the desired product 3 was
obtained in 70% yield when the amount of iodine was increased to
afford product 10 in 51% yield. Disubstituted methyl, methoxy and
chloro substrates were also amenable to the reaction conditions,
giving the desired products 11-14 in moderate to good yields. 2-
(
imidazo[1,2-a]pyridin-2-yl)phenol is an excellent fluorescent
1
3
molecule that is also suitable for such transformations. Other
1
.5 equivalents (Table 1, entry 11). No reaction occurred at room
o
AIBN analogues were also successfully reacted
(imidazo[1,2-a]pyridin-2-yl)phenol.
with
2-
temperature (Table 1, entry 12). Reaction at 100 C gave the best
yield of product. Deviation from a temperature of 100 C led to a
o
Table 2. Reaction scopea
decrease in yield of 3 (Table 1, entries 13 and 14) and a 3-iodo-2-
phenylimidazo[1,2-a]pyridine product was observed when the
reaction was conducted at 80 C. The product yield decreased to 54%
N
N
I2 (1equiv)
R2
R1
+
S
+
R
R2
R1
o
N
N
R
N
o
N
CH3CN,100 C
in the presence of 0.5 equivalent of 2a (Table 1, entry 15), whereas
the product yield increased to 83% when using 2 equivalents of 2a
S
R
1
2
N
N
N
N
(Table 1, entry 16).
O
F
N
N
N
N
Table 1. Screening of Optimal Conditionsa
S
S
S
S
NC
NC
NC
NC
N
3
, 83%
4, 85%
5, 74%
6, 82%
OH
N
I2
N
+
S
+
NC
N
N
CN
N
S
N
N
N
N
N
Cl
CN
NC
N
N
N
1
a
2a
3
S
S
S
S
NC
NC
NC
NC
10, 51%
Iodine
(equiv)
Solvent
(ml)
Temp
( C)
Yieldb
7
, 63%
8, 25%
9, 83%
o
Entry
(%)
N
N
N
N
O
O
Cl
N
N
N
N
1
2
3
4
5
6
7
8
9
I
I
I
I
I
I
I
2
2
2
2
2
2
2
(2)
(2)
(2)
(2)
(2)
(2)
(2)
DMF
NMP
DMSO
DCE
100
100
100
100
100
100
100
100
100
100
100
rt
0
0
O
O
S
S
S
S
NC
NC
NC
NC
14, 63%
1
1, 85%
12, 61%
13, 69%
0
HO
N
HO
N
HO
HO
N
N
N
N
N
12
17
Trace
56
18
48
76
70
0
N
S
S
CN
S
S
NC
PhMe
O
O
NC
1
5, 58%
16, 65%
17, 63%
18, 40%
Dioxane
N
N
N
N
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
3
CN
N
NC
N
N
N
CN
S
S
S
S
－
NC
O
O
I
I
2
(0.5)
19, 41%
20, 66%
21, 70%
22, 40%
S
S
N
S
1
1
1
1
1
0
1
2
3
4
I
2
(1)
N
N
N
N
N
N
N
2
(1.5)
S
F
S
S
S
NC
NC
NC
NC
I
2
(1)
(1)
(1)
(1)
(1)
2
3, trace
24, 46%
25, 37%
26, 38%
I
I
I
I
2
2
2
2
80
Trace
73
54
83
a
Reaction conditions: 1 (0.2 mmol), S (0.4 mmol, 2 equiv), 2
120
100
100
(0.4mmol, 2 equiv), I
00 C for 12 h.
2
(0.2 mmol, 1 equiv) in CH
3
CN (1 mL) at
o
1
1
5b
6c
1
To our delight, fluorescent molecules 15-18 could be prepared
in moderate yields. It is worth noting that these fluorescent
2
| J. Name., 2012, 00, 1-3
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Journal Name
ARTICLE
molecules bearing a cyano or an ester group can be subjected
to further transformations. Next, other AIBN analogues were
also subjected to reaction with 2-phenyl imidazopyridine and
their corresponding products 19-22 were obtained in
moderate yields. Although the cyanocyclohexyl group is
sterically demanding, reaction with the corresponding dialkyl
azo compound afforded product 20 in 66% yield. However, 2-
methyl imidazopyridine did not react successfully with this
compound possibly due to the conjugative effect of the
benzene ring being important for such transformations.
Imidazothiazoles were also employed under the optimal
reaction conditions, but their reactivity proved to be lower
than that of the imidazopyridines (products 24-26). An
electron-withdrawing group (e.g. cyano or nitro) on the
pyridine ring would greatly suppress the reaction, and only a
trace amount of product was observed.
Next, further modification of the cyano group of product 3 was
conducted. The hydrolysis of compound 3 was carried out to
afford the carboxylic acid 27 in 58% yield. The condensation of
compound 27 with 2-aminothiazole gave amide 28 in 56%
yield (scheme 2). Compound 28, which possesses an
imidazopyridine and a thiazole motif, is of great interest in
medicinal chemistry.
elemental sulfur did not produce the corresponding
heterocyclic disulfide, suggesting that elemental sulfur may
View Article Online
DOI: 10.1039/C8OB03191F
firstly react with AIBN (Eqn 1). The reaction of AIBN with
elemental sulfur did not produce the corresponding cyanoalkyl
disulfide, only 2-iodo-2-methylpropanenitrile 29 was observed
according to GC-MS. We speculated that 2-iodo-2-
methylpropanenitrile may be a reaction intermediate (Eqn 2).
The reaction still proceeded in the absence of iodine when 2-
iodo-2-methylpropanenitrile 29 was used in place of AIBN,
giving product 3 in 56% yield (Eqn 3). AIBN is a good radical
initiator and the reaction may proceed via a radical process. To
confirm this hypothesis, 3 equivalents of 2,2,6,6-tetramethyl-
1-piperidyloxy (TEMPO, a radical trapping agent) were added
to the reaction. Both of the reactions using AIBN and 2-iodo-2-
methylpropanenitrile were completely suppressed (Eqns 4 and
5). These results demonstrate that both AIBN and 2-iodo-2-
methylpropanenitrile release a cyanoalkyl radical at high
temperature. To elucidate the role of iodine in the reaction,
the transformation of AIBN in the presence/absence of iodine
at elevated temperature, was studied (Eqn 6). In the absence
of iodine, AIBN was transformed into 2,2,3,3-
tetramethylsuccinonitrile. In the presence of iodine, only a
trace amount of 2,2,3,3-tetramethylsuccinonitrile was
observed
according
to
GC-MS,
and
2-iodo-2-
N
N
Ph
Ph
Ph
NH2
N
EDCI(3equiv),
-DMAP(20mol%)
N
N
H2SO4 (75%) H2SO4 (50%)
85 oC, 2h
115 oC, 2h
N
H
methylpropanenitrile was formed. These results suggest that
iodine is able to inhibit the self-coupling of the cyanoalkyl
radical, and the newly formed 2-iodo-2-methylpropanenitrile
acts as a relay radical intermediate for the sulfuration.
4
N
+
N
S
N
S
S
S
DCM, 6h, rt
O
S
NC
HOOC
3
27, 58%
28, 56%
Scheme 2 Modification of the cyano group.
Based on our results and previous reports concerning C-H
alkylthionation using elemental sulfur,8 possible reaction
mechanisms have been proposed (Scheme 4). When heated,
AIBN decomposes to the cyanoalkyl radical A, which can react
with iodine to form 2-iodo-2-methylpropanenitrile. This
process is reversible at elevated temperature. The subsequent
transformation may proceed via one of two pathways:
Intermediate A may react with sulphur and iodine to afford an
active species B, which then undergoes an electrophilic
addition with imidazopyridine to form a carbenium ion D.
Finally, the carbenium ion D undergoes hydrogen elimination
to afford the desired product 3 (Path 1). Alternatively, radical
A may react with sulphur to form a cyanoalkyl sulfur radical C,
which then undergoes a radical addition with imidazopyridine
to form a radical E. A subsequent hydrogen elimination gives
product 3 (Path 2). Both the carbenium ion D and radical E can
be stabilized by the conjugative effect of the benzene ring.
,9
N
N
I2
ph
+
S
ph
(1)
N
CH CN,100oC,12h
N
3
1a
S
2
no observed
NC
N
N
I2
CN
+
S
S
S
CN
(2)
(3)
CN
+
o
CH3CN,100 C,12h
NC
I
2a
no observed observed on GCMS
N
I
N
ph
+
S
+
ph
N
NC
CH3CN,100 C,12h
o
N
S
1a
29 (2 equiv)
NC
3
, 56%
I2 (1 equiv)
N
TEMPO (3 equiv)
N
ph
+
S
+
2a
ph
(4)
N
CH3CN,100 C,12h
o
N
S
1
a
recovery: 52%
NC
3
, trace
I2 (1 equiv)
N
I
TEMPO (3 equiv)
N
ph
+
S
+
ph
(5)
N
NC
CH3CN,100 C,12h
o
N
CN
Path 1
I
N
S
I2
Ph
CN
CN
1a
1
a
29 (2 equiv)
I2
I
N
S
N
H
S
NC
NC
S
B
C
Ph
CN
N
N
CN
D
N
3
, trace
CN
S
A
CN
1a
N
Ph
CN
3
NC
N
N
I2 (1 equiv)
CN
S
N
NC
CN
+
CN (6)
Path 2
NC
CN
H
S
CH3CN,
00 C, 12h
CH3CN,
100 C, 12h
I
o
o
E
1
observed
observed
trace
Scheme 4 Possible reaction mechanisms.
Scheme 3 Control experiments.
In order to elucidate the reaction mechanism, the control
experiments shown in Scheme 3 were conducted. In the
presence of iodine, the reaction of imidazopyridine 1a with
Conclusion
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ARTICLE
Journal Name
In summary, a metal-free iodine promoted alkylthionation
reaction of imidazopyridines and dialkyl azo compounds using
elemental sulfur has been developed. Iodine was able to
inhibit the self-coupling of the cyanoalkyl radical, and the 2-
iodo-2-methylpropanenitrile intermediate formed in-situ acts
as a relay cyanoalkyl radical allow for efficient transformation.
completed, the solvent was removed under vacuo. The residue was
dissolved in ethyl acetate and washed with water and then brine,
dried over Na SO , filtered and concentrated under vacuo. The
2 4
resulting residue was purified by flash column chromatography
using hexanes and EtOAc as the eluent.
View Article Online
DOI: 10.1039/C8OB03191F
Analytical data for products
In the presence of iodine,
a variety of vulcanized
2
-methyl-2-((2-phenylimidazo[1,2-a]pyridin-3-
imidazopyridines were successfully synthesized, which are
difficult to prepare via other means involving odorous thiols.
We believe that these imidazoheterocycles bearing
cyanoalkylthio groups are of great interest to medicinal
chemists.
yl)thio)propanenitrile (3): yield (48.7 mg, 83%); Yellow solid, mp
o
-1
1
24.8 – 126.4 C; vmax/cm 2985, 2233 (CN), 1463, 1381, 706, 697;
δH (600 MHz; CDCl ; Me Si) 8.81 (1H, d, J = 6.8 Hz, Ar), 8.18 (2H, d,
J = 7.3 Hz, Ar), 7.68 (1H, d, J = 9.0 Hz, Ar), 7.46 (2H, t, J = 7.4 Hz, Ar),
3
4
7
6
Me
.39 (1H , t, J = 7.4 Hz, Ar), 7.36 (1H, t, J = 7.5 Hz, Ar), 6.96 (1H, t, J =
.6 Hz, Ar), 1.62 (3H, s, Me), 1.29 (3H, s, Me); δC (151 MHz; CDCl
Si) 153.6, 147.7, 133.5, 129.0, 128.7, 128.3, 127.5, 125.4, 122.9,
17.8, 113.0, 106.0, 41.5, 27.3, 27.1; HRMS (ESI) m/z calcd for
H N
17 16 3
2
3
;
4
Experimental
1
C
+
+
S (M+H) 294.10594, found 294.10620.
-methyl-2-((2-(p-tolyl)imidazo[1,2-a]pyridin-3-
yl)thio)propanenitrile (4): yield (52.2 mg, 85%); Yellow solid, mp
General remarks
1H and 13C NMR spectra were measured on a Bruker Avance-
1
13
Ⅲ
600 instrument (600MHz for H, 151 MHz for C NMR
spectroscopy) using CDCl or DMSO-d as the solvent.
Chemical shifts for H and C NMR were referred to internal
Me Si (0 ppm) as the standard. The following abbreviations (or
o
-1
1
57.4 – 159.7 C; vmax/cm 2973, 2861, 2228 (CN), 1460, 1362, 828;
δH (600 MHz; CDCl ; Me Si) 8.80 (1H, d, J = 6.8 Hz, Ar), 8.10 (2H, d,
J = 7.4 Hz, Ar), 7.67 (1H, d, J = 8.9 Hz, Ar), 7.34 (1H, t, J = 7.8 Hz, Ar),
.27 (2H, d, J = 7.6 Hz,Ar), 6.94 (1H, t, J = 6.8 Hz, Ar), 2.41 (3H, s,
Me), 1.62 (3H, s, Me), 1.30 (3H, s, Me); δC (151 MHz; CDCl ; Me Si)
53.6, 147.7, 138.6, 130.6, 129.1, 128.8, 127.5, 125.4, 123.0, 117.6,
12.9, 105.6, 41.5, 27.4, 27.03, 21.4; HRMS (ESI) m/z calcd for
3
13
6
3
4
1
4
7
combinations thereof) were used to explain chemical shift (δ
ppm), multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet), integration, and coupling constants (J)
in hertz (Hz). IR spectra were measured on a Nicolet IS10. Mass
spectra were measured on an Agilent GC-MS-5975C Plus
spectrometer (EI). LCMS (ESI) analysis was measured on an AB
Sciex API3200. HRMS (ESI) analysis was measured on a Thermo
Scientific LTQ Orbitrap XL.
Typical experimental procedure for the alkyl sulfuration of
imidazopyridines: To a 15-mL tube with a Teflon cap, equipped
8
with a magnetic stirring bar was charged with 1a (0.2 mol), S (0.4
mmol), AIBN (0.4 mmol) in MeCN (0.5 mL). The reaction mixture
was stirred at 100 °C for 12 hours. After the reaction finished, the
mixture was extracted with ethyl acetate, the combined organic
3
4
1
1
C
+
+
18 18
H N
3
S (M+H) 308.12159, found 308.12178.
-((2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)thio)-2-
methylpropanenitrile (5): yield (47.8 mg, 74%); Yellow solid, mp
2
o
-1
1
19.1 – 120.3 C; vmax/cm 2970, 2854, 2225 (CN), 1457, 1387, 805;
δH (600 MHz; CDCl ; Me Si) 8.79 (1H, d, J = 6.8 Hz, Ar), 8.16 (2H, d,
J = 8.8 Hz, Ar), 7.66 (1H, d, J = 8.9 Hz, Ar), 7.37 – 7.31 (1H, m, Ar),
.99 (2H, d, J = 8.8 Hz, Ar), 6.94 (1H, t, J = 6.8 Hz, Ar), 3.86 (3H, s,
OMe), 1.63 (3H, s, Me), 1.31 (3H, s, Me); δC (151 MHz; CDCl ; Me Si)
60.1, 153.3, 147.6, 130.3, 127.5, 126.0, 125.4, 123.0, 117.5, 113.8,
12.9, 105.2, 55.3, 41.5, 27.4, 27.2; HRMS (ESI) m/z calcd for
3
4
6
3
4
1
1
C
+
+
18 18
H N
3
OS (M+H) 324.11651, found 324.11682.
-((2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)thio)-2-
methylpropanenitrile (6): yield (51.0 mg, 82%); Yellow solid, mp
layers were dried over anhydrous Na
2 4
SO and evaporated under
2
vacuum. The residue was purified by flash column chromatography
(petroleum ether / ethyl acetate) to afford the desired product.
o
-1
1
29.2 – 131.3 C; vmax/cm 2228 (CN), 1461, 1390, 1391, 1003, 840;
δH (600 MHz; CDCl ; Me Si) 8.79 (1H, d, J = 6.9 Hz, Ar), 8.22 – 8.15
2H , m,), 7.66 (1H, d, J = 9.0 Hz, Ar), 7.40 – 7.33 (1H ,m, Ar), 7.17 –
Experimental procedure for the synthesis of compound 27: To a
3
4
5
0-mL flask with a reflux condensing tube, equipped with a
magnetic stirring bar was charged with compound 3 (1 mmol) and
SO (5 mL, 75%), the reaction mixture was stirred at 85 °C for 3
(
7
1
.11 (2H, m, Ar), 6.96 (1H, td, J = 6.8, 1.0 Hz, Ar), 1.62 (3H, s, Me),
.31 (3H, s, Me); δC (151 MHz; CDCl ; Me Si) 163.1(d, JC-F = 248.9
H
2
4
3
4
hours. Water (2.5 g) was then added to the reaction mixture, and
the reaction was stirred at 115°C for 2 hours. After the reaction
finished, the mixture was extracted with ethyl acetate, the
Hz, 1C), 162.3, 152.5, 147.7, 130.8 (d, JC-F = 8.2 Hz, 1C), 129.6 (d, JC-
F
= 3.5 Hz, 1C) 127.7, 125.4, 122.7, 117.7, 115.5 (d, JC-F = 21.4 Hz,
1
C), 113.2, 105.8, 41.7, 27.4, 27.0; HRMS (ESI) m/z calcd for
2 4
combined organic layers were dried over anhydrous Na SO and
+
+
C
17
H15FN
3
S (M+H) 312.09652, found 312.09680.
-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)thio)-2-
methylpropanenitrile (7): yield (41.2 mg, 63%); Yellow solid, mp
evaporated under vacuum. The residue was purified by flash
column chromatography (petroleum ether / ethyl acetate) to afford
the desired product 27.
2
o
-1
1
6
52.1 – 153.5 C; vmax/cm 2978, 2931, 2228 (CN), 1454, 1371,837,
11; δH (600 MHz; CDCl ; Me Si) 8.80 (1H, d, J = 6.8 Hz, Ar), 8.16
Experimental procedure for the synthesis of compound 28: To a
3
4
2
5-mL flask with a rubber stopper, equipped with a magnetic
(
7
(
2H ,d, J = 7.4 Hz, Ar), 7.67 (1H, d, J = 8.9 Hz, Ar), 7.44 (2H, d, J =
.4Hz, Ar), 7.37 (1H, t, J = 7.8 Hz, Ar), 6.98 (1H, t, J = 6.8 Hz, Ar), 1.64
3H, s, Me), 1.32 (3H,s, Me); δC (151 MHz; CDCl ; Me Si) 152.2,
stirring bar was charged with compound 27 (1 mmol), thiazol-2-
amine (2 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDCI) (3 mmol), 4-Dimethylaminopyridine (4-DMAP)
3
4
1
47.7, 134.7, 132.0, 130.2, 128.6, 127.8, 125.4, 122.7, 117.8, 113.2,
(0.2 mmol), and DCM (5 mL) were added. The reaction mixture was
stirred at room temperature for 6 hours. After the reaction was
4
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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Page 5 of 7
O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
Journal Name
ARTICLE
1
3
06.1, 41.7, 27.3; HRMS (ESI) m/z calcd for C17
28.06697, found 328.06723.
H
15ClN
3
S+ (M+H)+
= 2.3 Hz, Ar), 6.63 (1H, dd, J = 7.5, 2.5 Hz, Ar), 3.88 (3H, s, OMe), 3.86
(3H, s, OMe), 1.61 (3H, s, Me), 1.30 (3H, s, Me). δC (151 MHz; CDCl ;
3
View Article Online
DOI: 10.1039/C8OB03191F
4
-(3-((2-cyanopropan-2-yl)thio)imidazo[1,2-a]pyridin-2-
Me
4
Si) 160.0, 159.9, 153.2, 149.2, 130.0, 126.1, 125.7, 123.0, 113.7,
-1
yl)benzonitrile (8): yield (15.9 mg, 25%); Yellow oil; vmax/cm 2925,
854, 2227 (CN), 1463, 1342, 850; δH (600 MHz; CDCl ; Me Si) 8.77
1H, d, J = 6.8 Hz, Ar), 8.35 (2H, d, J = 8.3 Hz, Ar), 7.73 (2H ,d, J = 8.2
Hz, Ar), 7.68 (1H, d, J = 9.0 Hz, Ar), 7.38 (1H, t, J = 7.9 Hz, Ar), 6.99
1H, t, J = 6.8 Hz, Ar), 1.62 (3H, s, Me), 1.33 (3H, s, Me);δC (151 MHz;
CDCl3; Me4Si) 151.0, 147.8, 138.0, 132.1, 129.4, 128.2, 125.4,
107.5, 103.7, 95.1, 55.7, 55.3, 41.6, 27.4, 26.8; HRMS (ESI) m/z calcd
for C19H N O S (M+H) 354.12707, found 354.12753.
20 3 2
2-((2-(4-chlorophenyl)-6-methoxyimidazo[1,2-a]pyridin-3-
yl)thio)-2-methylpropanenitrile (14): yield (45.0 mg, 63%);Yellow
solid, mp 177.7 – 178.3 C; vmax/cm 2985, 2223 (CN), 1454, 1368,
757, 688; δH (600 MHz; CDCl ; Me Si) 8.55 (1H, d, J = 7.5 Hz, Ar),
+
+
2
(
3
4
o
-1
(
3
4
1
22.3, 118.8, 118.00, 113.7, 112.1, 107.2, 42.0, 27.3; HRMS (ESI)
8.14 (2H, d, J = 7.7 Hz, Ar), 7.41 (2H, d, J = 8.2 Hz, Ar), 6.92 (1H, s,
Ar), 6.65 (1H, d, J = 7.4 Hz, Ar), 3.88 (3H, s, OMe), 1.61 (3H, s, Me),
+
+
m/z calcd for C18
15 4
H N S (M+H) 319.10119, found 319.10153.
2
-methyl-2-((8-methyl-2-phenylimidazo[1,2-a]pyridin-3-
3 4
1.30 (3H, s, Me); δC (151 MHz; CDCl ; Me Si) 160.2, 152.1, 149.3,
yl)thio)propanenitrile (9): yield (51.0 mg, 83%); White solid, mp
134.5, 132.1, 130.0, 128.5, 125.8, 122.8, 108.0, 104.7, 95.2, 55.7,
o
-1
+
+
9
1.1 – 92.8 C; vmax/cm 2974, 2759, 2225 (CN), 1471, 1386, 706;
δH (600 MHz; CDCl ; Me Si) 8.67 (1H, d, J = 6.8 Hz, Ar), 8.15 (2H , d,
J = 7.2 Hz, Ar), 7.46 (2H, t, J = 7.6 Hz, Ar), 7.38 (1H, t, J = 7.4 Hz, Ar),
.15 (1H, d, J = 6.9 Hz, Ar), 6.88 (1H, t, J = 6.9 Hz, Ar), 2.68 (3H, s, Ar-
Me), 1.60 (3H, s, Me), 1.27 (3H, s, Me); δC (151 MHz; CDCl ; Me Si)
53.2, 148.0, 133.8, 129.2, 128.5, 128.3, 127.7, 126.2, 123.2, 122.9,
13.0, 106.2, 41.5, 27.4, 27.2, 16.7; HRMS (ESI) m/z calcd for
41.7, 27.4, 26.9; HRMS (ESI) m/z calcd for C18
358.07754, found 358.07788.
3
H17ClN OS (M+H)
3
4
2-((2-(-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl)thio)-2-
methylpropanenitrile (15): yield (35.9 mg, 58%); Yellow solid, mp
7
o
-1
3
4
138.6 – 139.1 C; vmax/cm 3438 (OH), 2964, 2851, 2233 (CN), 1455,
1385, 757; δH (600 MHz; CDCl ; Me Si) 12.91 (1H, s, OH), 8.89 (1H,
1
1
C
3
4
d, J = 6.9 Hz, Ar), 8.71 (1H, dd, J = 7.9, 1.2 Hz, Ar), 7.64 (1H, d, J = 8.9
Hz, Ar), 7.45 – 7.42 (1H, m, Ar), 7.31 – 7.27 (1H, m, Ar), 7.07 – 7.02
(2H, m, Ar), 6.90 (1H, t, J = 7.6 Hz, Ar), 1.73 (3H, s, Me), 1.46 (3H, s,
+
+
18
H
2
18
N
3
S (M+H) 308.12159, found 308.12183.
-((8-(hydroxymethyl)-2-phenylimidazo[1,2-a]pyridin-3-
yl)thio)-2-methylpropanenitrile (10): yield (33.0 mg, 51%); Yellow
3 4
Me) ; δC (151 MHz; CDCl ; Me Si) 158.6, 151.1, 145.4, 131.0, 128.5,
o
-1
solid, mp 137.2 – 137.9 C; vmax/cm 3430 (OH), 2978, 2930, 2863,
225 (CN), 1462, 1487, 1355, 706; δH (600 MHz; CDCl ; Me Si) 8.7
1H, d, J = 6.8, Ar), 8.16 (2H, d, J = 7.2 Hz, Ar), 7.44 (2H, t, J = 7.5 Hz,
Ar), 7.38 (1H, t, J = 7.3 Hz, Ar), 7.26 (1H, d, J = 6.7 Hz, Ar), 6.92 (1H,
t, J = 6.9 Hz, Ar), 5.06 (2H, s, CH ), 4.47 (1H , s, OH), 1.61 (3H, s, Me),
.29 (3H , s, Me); δC (151 MHz; CDCl ; Me Si) 152.7, 146.5, 133.2,
29.9, 129.0, 128.8, 128.4, 124.4, 122.8, 113.1, 106.5, 62.0, 41.6,
128.1, 125.3, 122.8, 118.4, 118.1, 116.8, 115.9, 113.7, 104.9, 41.9,
+
+
2
(
3
4
27.5, 27.1; HRMS (ESI) m/z calcd for C17
16 3
H N OS (M+H)
310.10086, found 310.10114.
2-((2-(2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl)thio)-2-
2
methylbutanenitrile (16): yield (42.0 mg, 65%); A mixture of
o
1
1
2
3
4
conformational isomerism. Yellow solid, mp 103.7 – 104.2 C;
-1
v
max/cm 3451 (OH), 2976, 2938, 2855, 2229 (CN), 1451, 1390, 757;
+
+
7.2; HRMS (ESI) m/z calcd for C18
18
H N
3
OS (M+H) 324.11651,
δH (600 MHz; CDCl ; Me Si) 12.92 (1H, s, OH), 8.89 (1H, d, J = 6.1
3
4
found 324.11673.
-methyl-2-((6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridin-3-
yl)thio)propanenitrile (11): yield (54.6 mg, 85%); Yellow solid, mp
Hz, Ar), 8.70 (1H, t, J = 8.5 Hz, Ar), 7.63 (1H, d, J = 8.9 Hz, Ar), 7.43
(1H, t, J = 7.8 Hz, Ar), 7.29 (1H, t, J = 7.5 Hz, Ar), 7.07 – 7.03 (2H, m,
2
Ar), 6.90 (1H, q, J = 7.5 Hz, Ar), 2.07 – 1.77 (2H, q, CH
(3H, s, Me), 1.27/0.95 (3H, t, J = 7.3 Hz, Me); δC (151 MHz; CDCl
Me Si) 158.6, 151.1, 145.3, 130.9, 128.5, 128.2, 128.1, 125.3, 122.0,
2
), 1.63/1.38
o
-1
1
7
65.3 – 166.3 C; vmax/cm 2978, 2864, 2225 (CN), 1457, 1390, 814,
06; δH (600 MHz; CDCl ; Me Si) 8.59 (1H, s, Ar), 8.09 (2H, d, J = 7.4
3
;
3
4
4
Hz, Ar), 7.57 (1H, d, J = 9.0 Hz, Ar), 7.26 (2H, d, J = 7.7 Hz, Ar), 7.19
1H, d, J = 9.1 Hz, Ar), 2.41 (6H, s, Ar-Me), 1.63 (3H, s, Me), 1.30 (3H,
s, Me); δC (151 MHz; CDCl ; Me Si) 153.3, 146.6, 138.5, 130.7,
30.5, 129.0, 128.8, 123.2, 123.0, 122.8, 116.9, 105.2, 41.4, 27.2,
121.7, 118.5, 118.4, 118.0, 116.7, 115.9, 113.7, 104.6, 104.4, 47.5,
47.2, 32.8, 33.2, 25.0, 23.8,10.0, 9.6; HRMS (ESI) m/z calcd for
(
+
+
3
4
C
18
H
18
N
3
OS (M+H) 324.11651, found 324.11676.
2-((2-(2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-yl)thio)-2,4-
dimethylpentanenitrile (17): yield (44.2 mg, 63%); A mixture of
1
2
+
+
20 3
1.4, 18.4; HRMS (ESI) m/z calcd for C19H N S (M+H) 322.13724,
-1
found 322.13742.
-((2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridin-3-
yl)thio)-2-methylpropanenitrile (12): yield (41.1 mg, 61%); Yellow
conformational isomerism. Yellow oil; vmax/cm 3630 (OH), 2957,
2925, 2854, 2226 (CN), 1456, 1390, 757; δH (600 MHz; CDCl
Me Si) 12.89 (1H, s, OH), 8.92–8.85 (1H, m, Ar), 8.70 – 8.68 (1H, m,
2
3
;
4
o
-1
solid, mp 130.8 – 131.9 C; vmax/cm 2974, 2238 (CN), 1462, 1368,
83; δH (600 MHz; CDCl ; Me Si) 8.63 (1H, d, J = 6.9 Hz, Ar), 8.14
2H, d, J = 8.5 Hz, Ar), 7.39 (1H, s, Ar), 6.97 (2H, d, J = 8.5 Hz, Ar),
Ar), 7.63 (1H, d, J = 8.8 Hz, Ar), 7.42 (1H, t, J = 7.9 Hz, Ar), 7.29 (1H,
t, J = 7.7 Hz, Ar), 7.09 – 7.01 (2H, m, Ar), 6.92 – 6.88 (1H, m, Ar), 2.09
7
3
4
(
(1H, m, CH), 1.92/1.79 (2H, dd, J = 6.1 Hz, CH
Me), 1.12/0.84 (6H, d, J = 6.7 Hz, 2Me); δC (151 MHz; CDCl
2
), 1.64/1.41 (3H, s,
; Me Si)
6
1
1
1
C
.75 (1H, d, J = 7.0 Hz, Ar), 3.85 (3H, s, OMe), 2.42 (3H, s, Ar-Me),
3
4
.61 (3H, s, Me), 1.29 (3H, s, Me); δC (151 MHz; CDCl ; Me Si) 159.9,
3
4
158.6, 158.4, 151.2, 151.1, 145.3, 130.9, 128.5, 128.3, 128.1, 125.4,
125.1, 122.7, 122.2, 118.5, 118.3, 118.0, 117.8, 116.7, 116.6, 115.9,
113.6, 104.6, 48.1, 47.9, 46.1, 45.7, 26.2, 26.0, 25.4, 23.8, 23.6;
53.2, 148.0, 138.7, 130.2, 126.2, 124.5, 123.1, 116.0, 115.4, 113.7,
04.4, 55.3, 41.5, 27.4, 26.9, 21.4; HRMS (ESI) m/z calcd for
+
+
+
+
19
H
2
20
N
3
OS (M+H) 338.13216, found 338.13254.
-((6-methoxy-2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-
yl)thio)-2-methylpropanenitrile(13): yield (48.7 mg, 69%); Yellow
HRMS (ESI) m/z calcd for C20
22 3
H N OS (M+H) 352.14781, found
352.14819.
methyl
2-((2-(2-hydroxyphenyl)imidazo[1,2-a]pyridin-3-
o
-1
solid, mp 152.5 – 153.7 C; vmax/cm 2977, 2835, 2225 (CN), 1465,
yl)thio)-2-methylpropanoate (18) : yield (27.4 mg, 40%); Orange
o
-1
1
8
350, 821; δH (600 MHz; CDCl
.15 (2H, d, J = 8.8 Hz, Ar), 6.97 (2H, d, J = 8.8 Hz, Ar), 6.93 (1H, d, J
3
; Me
4
Si) 8.56 (1H, d, J = 7.5 Hz, Ar),
solid, mp 120.2 – 121.4 C; vmax/cm 3437 (OH), 2983, 1729, 1454,
1383, 695; δH (600 MHz; CDCl
3
; Me
4
Si) 13.00 (1H, s, OH), 8.79 (1H,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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O rP gl ea na si ce &d Bo i on mo to al e dc juu l sa tr mC ha er mg i ins ts ry
Page 6 of 7
ARTICLE
Journal Name
d, J = 8.0 Hz, Ar), 8.59 (1H, d, J = 6.9 Hz, Ar), 7.62 (1H, d, J = 8.9 Hz,
Ar), 7.38 (1H, t, J = 7.9 Hz, Ar), 7.28 (1H, s, Ar), 7.04 (1H, d, J = 8.2
Hz, Ar), 6.98 (1H, t, J = 6.8 Hz, Ar), 6.91 (1H, t, J = 7.5 Hz, Ar), 3.24
2-((6-(4-fluorophenyl)imidazo[2,1-b]thiazol-5-yl)thio)-2-
View Article Online
DOI: 10.1039/C8OB03191F
methylpropanenitrile (25): yield (23.5 mg, 37%);Yellow solid, mp
o
-1
136.7 – 137.5 C; vmax/cm 2925, 2853, 2229 (CN), 1458, 1335, 1291
, 708, 684; δH (600 MHz; CDCl ; Me Si) 8.12 – 8.06 (2H, m, Ar), 7.80
(1H, d, J = 4.5 Hz, Ar), 7.13 – 7.07 (2H, m, Ar), 6.90 (1H, d, J = 4.5 Hz,
Ar), 1.48 (6H, s, Me); δC (151 MHz; CDCl ; Me Si) 161.3 (d, JC-F
(
3H, s, Me), 1.48 (3H, s, Me), 1.41 (3H, s, Me); δC (151 MHz; CDCl
Me Si) 173.5, 158.4, 150.2, 144.6, 130.5, 128.2, 127.4, 124.7, 118.5,
17.7, 116.6, 116.4, 113.2, 107.2, 54.0, 52.2, 25.6, 25.1; HRMS (ESI)
3
;
3
4
4
1
3
4
=
+
+
m/z calcd for C18
19
H N
2
O
3
S (M+H) 343.11109, found 343.11142.
249.1 Hz, 1C), 153.9, 152.7, 130.1 (d, JC-F = 7.6 Hz, 1C), 122.8, 119.2,
115.3 (d, JC-F = 21.1 Hz, 1C), 113.0, 106.9, 41.8, 27.0; HRMS (ESI) m/z
methyl
2-methyl-2-((2-phenylimidazo[1,2-a]pyridin-3-
+
+
yl)thio)propanoate (19): yield (26.7 mg, 41%); White solid, mp 82.3
3 2
calcd for C15H13FN S (M+H) 318.05294, found 318.05331.
o
-1
–
84.7 C; vmax/cm 2965, 2852, 1725 (CO), 1463, 1380, 701, 692; δH
2-methyl-2-((2-(p-tolyl)benzo[d]imidazo[2,1-b]thiazol-3-
(
7
7
600 MHz; CDCl ; Me Si) 8.50 (1H, d, J = 6.9 Hz, Ar), 8.25 (2H, d, J =
.2 Hz, Ar), 7.65 (1H, d, J = 8.9 Hz, Ar), 7.44 (2H, t, J = 7.7 Hz, Ar),
.35 (1H, t, J = 7.4 Hz, Ar), 7.30 – 7.27 (1H, m, Ar), 6.91 – 6.87 (1H,
3
4
yl)thio)propanenitrile (26): yield (27.6 mg, 38%);Yellow solid, mp
o
-1
127.1 – 128.2 C; vmax/cm 2922, 2852, 2229 (CN), 1479, 1368, 810 ,
800; δH (600 MHz; CDCl ; Me Si) 8.72 (1H, d, J = 8.3 Hz, Ar), 8.01
3
4
m, Ar), 3.16 (3H, s, Me), 1.33 (6H, Me); δC (151 MHz; CDCl
3
; Me
73.7, 152.5, 147.0, 133.9, 128.9, 128.4, 128.3, 126.6, 124.9, 117.6,
12.6, 108.1, 53.6, 52.1, 25.2; HRMS (ESI) m/z calcd for
4
Si)
(2H, d, J = 8.2 Hz, Ar), 7.70 (1H, d, J = 7.7 Hz, Ar), 7.50 (1H, t, J = 7.8
Hz, Ar), 7.37 (1H, t, J = 7.4 Hz, Ar), 7.24 (2H, d, J = 8.0 Hz, Ar), 2.40
1
1
C
(3H, s, Me), 1.61 (3H, s, Me), 1.35 (3H, s, Me); δC (151 MHz; CDCl
Me Si) 156.1, 151.8, 138.4, 133.8, 130.5, 130.0, 129.1, 128.5, 126.2,
125.1, 124.1, 121.7, 115.0, 108.9, 42.9, 27.3, 21.4; HRMS (ESI) m/z
3
;
+
+
18
H
1
19
N
2
O
2
S (M+H) 327.11617, found 327.11646.
-((2-phenylimidazo[1,2-a]pyridin-3-yl)thio)cyclohexane-1-
carbonitrile (20): yield (44.0 mg, 66%); White solid, mp 159.5 –
4
+
+
18 3 2
calcd for C20H N S (M+H) 364.09367, found 364.09393.
o
-1
1
60.1 C; vmax/cm 2932, 2854, 2227 (CN), 1462, 702, 693; δH (600
MHz; CDCl ; Me Si) 8.82 (1H, d, J = 6.9 Hz, Ar), 8.17 (2H, d, J = 7.6
Hz, Ar), 7.67 (1H, d, J = 9.0 Hz, Ar), 7.46 (2H, t, J = 7.7 Hz, Ar), 7.39
1H, t, J = 7.4 Hz, Ar), 7.34 (1H, t, J = 7.7 Hz, Ar), 6.95 (1H, t, J = 6.1
Hz, Ar), 2.38 – 1.55 (8H, m, CH ), 1.24 – 1.06 (2H, m, CH ); δC (151
MHz; CDCl ; Me Si) 153.6, 147.7, 133.6, 129.1, 128.6, 128.3, 127.4,
25.6, 121.5, 117.7, 112.9, 105.0, 48.1, 36.0, 24.5, 23.2; HRMS (ESI)
2-methyl-2-((2-phenylimidazo[1,2-a]pyridin-3-
3
4
yl)thio)propanoic acid (27): yield (181.0 mg, 58%); Yellow solid, mp
o
-1
207.1 – 208.8 C; vmax/cm 2993, 2919, 1704 (COOH), 1471, 1384,
1442, 708; δH (600 MHz; DMSO; Me Si) 12.70 (1H, s, COOH), 8.62
(
4
2
2
(1H, dt, J = 6.8, 1.2 Hz, Ar), 8.34 – 8.23 (2H, m, Ar), 7.67 (1H, d, J =
8.9 Hz, Ar), 7.47 (2H, t, J = 7.6 Hz, Ar), 7.44 – 7.41 (1H, m, Ar), 7.41
– 7.36 (1H, m, Ar), 7.05 (1H, td, J = 6.8, 1.2 Hz, Ar), 1.24 (6H, d, J =
3
4
1
+
+
m/z calcd for C20
-methyl-2-((2-phenylimidazo[1,2-a]pyridin-3-
yl)thio)butanenitrile (21): yield (43.0 mg, 70%); Cyan oil; vmax/cm-1
973, 2924, 2852, 2228 (CN), 1489, 1463, 1385, 695; δH (600 MHz;
CDCl ; Me Si) 8.78 (1H, d, J = 6.8 Hz, Ar), 8.15 (2H, d, J = 7.6 Hz, Ar),
H
20
N
3
S (M+H) 334.13724, found 334.13742.
118.8 Hz, Me); δC (151 MHz; DMSO; Me
4
Si) 174.9, 151.4, 146.8,
2
134.3, 128.7, 128.7, 128.6, 127.7, 125.8, 117.5, 113.4, 108.0, 54.0,
+
+
25.6; HRMS (ESI) m/z calcd for C17
17 2 2
H N O S (M+H) 313.10052,
2
found 313.10086.
2-methyl-2-((2-phenylimidazo[1,2-a]pyridin-3-yl)thio)-N-
3
4
7
7
–
1
1
C
.65 (1H, d, J = 8.9 Hz, Ar), 7.43 (2H, t, J = 7.6 Hz, Ar), 7.36 (1H, t, J =
.4 Hz, Ar), 7.31 (1H, t, J = 7.9 Hz, Ar), 6.92 (1H, t, J = 6.8 Hz, Ar), 1.92
(thiazol-2-yl)propanamide (28): yield (220.7 mg, 56%);White solid,
o
-1
mp 221.9 – 223.0 C; vmax/cm 3435 (NH), 2974, 2930, 1463, 1384,
708, 694; δH (600 MHz; CDCl ; Me Si) 9.16 (1H, s, NH), 8.42 (1H, d,
1.43/1.22 – 0.69 (8H, m, CH
2
, 2Me); δC (151 MHz; CDCl
3
; Me
4
Si)
3
4
53.8, 147.7, 133.5, 129.1, 128.6, 128.3, 127.5, 125.5, 122.0, 117.7,
13.0, 105.6, 47.1, 32.7, 25.0, 9.8; HRMS (ESI) m/z calcd for
J = 6.8 Hz, Ar), 8.11 (2H, d, J = 7.6 Hz, Ar), 7.61 (1H, d, J = 8.9 Hz, Ar),
7.32 (3H, t, J = 7.7 Hz, Ar), 7.22 (2H, q, J = 7.1 Hz, Ar), 6.89 (1H, d, J
= 2.8 Hz, Ar), 6.70 (1H, t, J = 6.8 Hz, Ar), 1.47 (6H, s, Me); δC (151
+
+
18
H
2
18
N
3
S (M+H) 308.12159, found 308.12186.
,4-dimethyl-2-((2-phenylimidazo[1,2-a]pyridin-3-
yl)thio)pentanenitrile (22): yield (26.8 mg, 40%); Brown oil;
3 4
MHz; CDCl ; Me Si) 170.6, 153.1, 147.3, 137.1, 133.3, 129.9, 128.8,
128.3, 128.2, 126.8, 124.7, 117.7, 113.8, 112.9, 106.9, 54.5, 25.0;
-1
+
+
v
max/cm 2944, 2884, 2859, 2274 (CN), 1479, 1384, 724; δH (600
MHz; CDCl ; Me Si) 8.78 (1H, s, Ar), 8.13 (2H, d, J = 7.6 Hz, Ar), 7.63
1H, d, J = 8.9 Hz, Ar), 7.42 (2H, t, J = 7.5 Hz, Ar), 7.35 (1H, t, J = 7.2
Hz, Ar), 7.31 – 7.26 (1H, m, Ar), 6.93 – 6.86 (1H, m, Ar), 2.08–0.66
12H, m, CH, CH , 3CH ); δC (151 MHz; CDCl ; Me Si) 153.8, 147.7,
33.6, 129.1, 128.6, 128.3, 127.5, 125.6, 122.7, 117.7, 113.0, 105.7,
7.8, 45.3, 26.0, 25.1, 23.7, 23.6; HRMS (ESI) m/z calcd for
HRMS (ESI) m/z calcd for C20
19 4 2
H N OS (M+H) 395.09948, found
3
4
395.09967.
(
(
2
3
3
4
Conflicts of interest
1
4
C
“There are no conflicts to declare”.
+
+
20 22
H N
3
S (M+H) 336.15289, found 336.15308.
-methyl-2-((6-phenylimidazo[2,1-b]thiazol-5-
yl)thio)propanenitrile (24): yield (27.5 mg, 46%);Yellow solid , mp
2
Acknowledgments
o
-1
1
04.9 – 106.0 C; vmax/cm 2925, 2854, 2230 (CN), 1465,1369, 789
δH (600 MHz; CDCl ; Me Si) 8.10 (2H, d, J = 7.8 Hz, Ar), 7.84 (1H, d,
J = 4.4 Hz, Ar), 7.42 (2H, t, J = 7.5 Hz, Ar), 7.35 (1H, t, J = 7.3 Hz, Ar),
.91 (1H, d, J = 4.4 Hz, Ar), 1.48 (6H, s, Me); δC (151 MHz; CDCl
Me Si) 154.9, 152.6, 133.5, 128.3, 128.3, 128.2, 123.0, 119.3, 112.9,
We gratefully thank the South China Agricultural University and
Science Technology Program Project of Guangdong Province (No.
2016B020204005) for their financial support.
;
3
4
6
3
;
4
+
+
1
3
07.1, 41.6, 26.9; HRMS (ESI) m/z calcd for C15
00.06237, found 300.06265.
14
H N
S
3 2
(M+H)
Notes and references
1
A review on the application of elemental sulfur in organic
6
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
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This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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