Catalyst-Free Regioselective C-3 Thiocyanation of Imidazopyridines

Article abstract of DOI:10.1021/acs.joc.5b01637

A direct and straightforward approach for highly regioselective thiocyanation of imidazoheterocycles through sp² C-H functionalization has been realized at room temperature. Various C-3 thiocyanated imidazopyridines are formed in moderate to go

Full text of DOI:10.1021/acs.joc.5b01637

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Catalyst-Free Regioselective C-3 Thiocyanation of Imidazopyridines
Daoshan Yang, Kelu Yan, Wei Wei, Guoqing Li, Shenglei Lu, Caixia Zhao, Laijin Tian, and Hua Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01637 • Publication Date (Web): 02 Oct 2015
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Catalyst-Free Regioselective C-3 Thiocyanation of
Imidazopyridines
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Daoshan Yang, Kelu Yan, Wei Wei, Guoqing Li, Shenglei Lu, Caixia Zhao, Laijin
Tian and Hua Wang*
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The Key Laboratory of LifeꢀOrganic Analysis and Key Laboratory of Pharmaceutical
Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical
Engineering, Qufu Normal University, Qufu 273165, Shandong, P. R. China.
*Eꢀmail: huawang_qfnu@126.com
ABSTRACT:
A direct and straightforward approach for highly regioselective thiocyanation of
imidazoheterocycles through sp2 CꢀH functionalization has been realized at room
temperature. Various Cꢀ3 thiocyanated imidazopyridines are formed in moderate to
good yield. The present method exhibits a mild and selective access to a variety of
imidazopyridine derivatives of pharmacological interest.
Aryl thiocyanates have shown diverse biological and pharmacological activities,
including antifungal, antiviral, and antibacterial etc.1 Additionally, aryl thiocyanates
are also versatile precursors for the synthesis of many sulfurcontaing aromatic
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compounds, such as sulfonic acids,2 sulfonyl chlorides,3 thiocarbamates,4 thioesters,5
and sulfonyl cyanides.6 Despite their potentially wide applications, unfortunately
synthetic methods remain rare. The traditional methods for the synthesis of aryl
thiocyanates typically involve coupling of diazonium salt with metal thiocyanates
under Sandmeyerꢀtype conditions,7 or the cyanation of organometallic8 and
organosulfur compounds.9 Although these methods have made various synthesis
contributions, the toxic and high cost of the reagent, unavailable starting materials,
and the undesired byꢀproducts could impede their wide applications. As an alternative,
the direct thiocyanation of readily available aryl halides is an appealing approach to
aryl thiocyanates. In 1996, Suzuki and coꢀworkers developed an elegant method for
the synthesis of arylthiocyanates from crossꢀcoupling of KCu(SCN)2 with aryl
iodides.10 In 2006, Guo et al. reported the coupling of aryl iodides with KSCN by
using CuI catalysis to provide the corresponding thiocyanation products.11 However,
the yields of these methods were low, and the substrates were mainly focus on aryl
iodides.
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Recently, exploring efficient, practical, and highly selective metalꢀfree
approaches for the direct functionalization of CꢀH bonds have become the hot topic of
intensive studies.12 Thus, the direct thiocyanation of C(sp2)ꢀH bonds would be more
economical and practical. Recently, a few of the direct thiocyanation transformations
have been reported, but these examples are mainly concentrated in indoles.13 As a
consequence, it is great significant and highly desirable to develop more efficient and
selective methods to prepare SCNꢀcontaining aryls or heterocycles that utilize
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inexpensive thiocyanation reagents through direct CꢀH functionalization under
metalꢀfree conditions.
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Figure 1. Representative Examples of C-3 Substituted Imidazopyridine
Compounds
Imidazoheterocycle motifs are well known to possess various useful biological
and medicinal activities. For example, they can be used as antibacterial,14 antiviral,15
antitumor,16 antiꢀinflammatory,17 and antimicrobial agents18. Additionally, some
commercially available drugs contain this core structure (Figure 1), such as A
(Zolimidin; to treat pepticulcer),19 B (minodronic acid; to treat osteoporosis),20
C
(Alpidem; a peripheral benzodiazepine receptor ligand),21 D (GSK812397; a potent
noncompetitive CXCR4 receptor antagonist).22 Consequently, extensive efforts have
been devoted to the discovery of efficient and useful methods for imidazoheterocycle
synthesis and functionalization.23 Besides that, to explore new methods for Cꢀ3
functionalization of imidazopyridines has made significant progress, but unfortunately
examples remain rather limited.24 In 2015, Hajra and coꢀworkers developed a
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silverꢀcatalyzed regioselective trifluoromethylation of imidazopyridines under mild
conditions.25 Recently, direct Cꢀ3 thiolation of imidazoheterocycles has been
extensively studied because of the importance of the 3ꢀthio substituted
imidazopyridines.26 For example, as shown in Figure 1, the compound E and F have
been considered as important intermediates for the synthesis of enviroxime analogues
which possess potent broad spectrum antiviral activities.27 In 2011, Zhou and
coꢀworkers developed an efficient CuIꢀcatalyzed Cꢀ3 thiolation of imidazopyridines
using alkyl/aryl disulfides as the thiol source.26a In 2013, Roychowdhury et al.
reported a metalꢀfree method for methylthiolation of imidazo[1,2ꢀa]pyridines using
DMSO/POCl3 complex.26b In 2014, Adimurthy’ group described an
N‑chlorosuccinimideꢀpromoted Cꢀ3 thiolation of imidazoheterocycles at room
temperature.24a In 2015, Hiebel et al. demonstrated an iodineꢀcatalyzed regioselective
sulfenylation of imidazoheterocycles in PEG400.26c Subsequently, Tang and Chen’
group demonstrated an iodineꢀcatalyzed thiolation of imidazoheterocycles with
disulfides in the presence of hydrogen peroxide.26d It is wellꢀknown that the biological
activity is mainly dependented on the nature of the functional groups. Incorporation of
thiocyanate into bioactive compounds could increases their medicinal activity. Thus,
synthesis of the new 3ꢀthiocyanatoimidazopyridines is highly desirable. Herein, we
report a novel, efficient, and direct catalystꢀfree Cꢀ3 thiocyanation of
imidazopyridines with simple and readily available KSCN as the sulfur source under
mild condtions.
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First, 2ꢀphenylimidazo[1,2ꢀa]pyridine (1a) and KSCN were used as the model
substrates to optimize the reaction conditions including the oxidant, solvent, and
temperature under ambient air. As shown in Table 1, seven oxidants, Oxone, TBHP,
O2, (NH4)2S2O8, Na2S2O8, H2O2, and K2S2O8 were investigated at 25°C in 2 mL
HOAc, and K2S2O8 was found to be the most effective oxidant (72%) (entries 1ꢀ7).
Furthermore, the solvents, including HOAc, DCE, CH3CN, H2O, DMF and
1,4ꢀdioxane were tested using K2S2O8 as the oxidant at 25 °C, and DCE provided the
highest yield (entries 6, 8ꢀ12). Additionally, different amounts of K2S2O8 were
attempted, and 1.5 equiv of K2S2O8 was more suitable for the present reaction
(compare entries 8, 13 and 14). Interestingly, the yield decreased when temperature
was elevated to 40oC (entry 15). We also investigated reactivity of other thiocyanates
such as NaSCN and NH4SCN, and KSCN showed the most effective activity in the
transformation (compare entries 8, 16 and 17). Notably, no target product was
observed in the absence of K2S2O8. After the optimization process for oxidant, solvent
and temperature, the various 3ꢀthiocyanatoimidazo[1,2ꢀa]pyridines were synthesized
under our standard conditions: 1.5 equiv of K2S2O8 as the oxidant, 2 equiv of KSCN
as the SCN sources, DCE as the solvent under air atmosphere at room temperature.
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Table 1. Optimization of the Reaction Conditions a
entry
1
2
oxidant
Oxone (1.5)
TBHP (1.5)
solvent
HOAc
HOAc
yield b (%)
63
trace
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O2 (1.5)
HOAc
HOAc
HOAc
HOAc
HOAc
DCE
CH3CN
H2O
0
68
65
72
trace
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74
trace
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66
72
Na2S2O8 (1.5)
(NH4)2S2O8 (1.5)
K2S2O8 (1.5)
H2O2
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K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.0)
K2S2O8 (2.0)
K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.5)
none
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DMF
1,4ꢀdioxane
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
80
58 c
78 d
74 e
0
a Reaction conditions: 1a (0.4mmol), 2a (2 equiv.), oxidant (1.5 equiv.), solvent (2 mL), rt, 18h.
b
c
TBHP = tertꢀbutyl hydroperoxide solution 5.5M in decane.
Isolated yield. Reaction
temperature (40oC). d NaSCN was used, e NH4SCN was used.
The scope and generality of substrates for the metalꢀfree regioselective Cꢀ3
thiocyanation of imidazopyridines was investigated under the optimized conditions,
with the results summarized in Table 2. To our delight, most of the tested substrates
afforded moderate to good yields. A variety of electronꢀdonating and
electronꢀwithdrawing groups at the any aryl ring of imidazopyridines could be well
tolerated, showing no obvious electronic effect in this transformation. Additionally,
the hindrance effect of this reaction was also not obvious, imidazopyridines bearing a
methyl group at different positions could efficiently reacted with KSCN to give the
corresponding products in good yields (3d, 3e, 3f, 3h, 3j, 3m and 3n). Notably, when
2ꢀfuran imidazo[1,2ꢀa]pyridines were used, the desired products of 3t and 3u were
obtained in 69% and 76% isolated yields, respectively. Furthermore, the application
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Table 2. Direct C-3 Thiocyanation of Different Imidazopyridines a,b
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a
Reaction conditions: substituted imidazopyridines (0.4 mmol), KSCN (0.8 mmol), K2S2O8 (0.6
mmol), DCE (2 mL), Reaction time (18 h). b Isolated yield.
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of our present protocol for thiocyanation of other heterocyclic and aromatic
compounds including imidazo[2,1ꢀb]thiazoles, indole, and N,Nꢀdimethylaniline were
explored (Table 3). Satisfactorily, these substrates also gave good yields of
thiocyanated products 5aꢀ5f in 72ꢀ87% yield. Some functional group could
compatible in the present reaction, including methyl, methoxy, CꢀCl bond and CꢀBr
bond which could be further transformed to other useful functional groups. The
structure of 3n was confirmed by Xꢀray crystallographic analysis (see Supporting
Information for details).
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Table 3. Substrates Scope of Heterocyclic and Aromatic Compounds a,b
a
Reaction conditions: substituted heterocyclic and aromatic compounds (0.4 mmol), KSCN
(0.8 mmol), K2S2O8 (0.6 mmol), DCE (2 mL), Reaction time (18 h). b Isolated yield.
The gramꢀscale applications for the present method was also explored. As shown
in Scheme 1, the proposed reaction between 1a and 2 was investigated under the
standard conditions which could give 1.2 g of 3a in 80 % yield, without any
significant loss of reactive efficiency. Thus, this simple and metalꢀfree protocol could
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be extended as an efficient and practical method to construct various potentially
bioactive Cꢀ3 substituted imidazopyridines.
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Scheme 1. Synthesis of 3a on Gram Scale
To gain insight into the reaction mechanism further, a wellꢀknown radical
scavenger TEMPO (2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy) was added into the reaction
system, the thiocyanation reaction was suppressed, which indicated that a free radical
pathway might be involved in the present reaction.
Based on the priliminary results above and previous related literature,25, 28 two
plausible pathways for this present reaction were proposed (Scheme 2). In path I,
SCN radical A was first generated by the oxidation of KSCN. Subsequently, the
radical A reacted with the imidazopyridines 1 to give the alkyl radical intermediate C,
which could be stabilized by the adjacent nitrogen atom and phenyl. Subsequently, the
radical intermediate C was further oxidized to the carbocation D by K2S2O8. Finally,
elimination of H+ from the intermediate carbocation D afforded the desired product 3.
As a complementary mechanism, oxidation of KSCN by K2S2O8 generated an
electrophile thiocyanogen (SCN)2 B. Subsequently, electrophilic addition of the
electrophile B to 1 also gave the same intermediate carbocation D as shown in path II,
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Scheme 2. Further investigations on the more detailed mechanism are in progress in
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our laboratory.
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Scheme 2. Proposed mechanism for the Direct Transformation.
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KSCN
path I
path II
2
+
(SCN)2
SCN
A
B
K2S2O8
1
1
R2
R2
N
N
K2S2O8
+
R1
R1
N
N
H
H
NCS
NCS
D
C
H+
R2
N
R1
N
SCN
3
In summary, we have disclosed the first example of catalystꢀfree highly
regioselective Cꢀ3 thiocyanation of imidazopyridines under mild conditions. The
transformation proceed in good yields, and tolerated a wide range of functional
groups. Tentative experiments suggested that this reaction was likely to proceed via a
radical pathway. The present protocol provided a new avenue to formation of
potentially bioactive imidazopyridine derivatives, and it would gain much more
attention in synthetic and pharmaceutical chemistry.
EXPERIMENTAL SECTION
General.
All commercially available reagent and chemicals were purchased from chemical
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suppliers and used as received without further purification. Mass analyses and HRMS
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were obtained by ESI on a TOF mass analyzer. 1H NMR and C NMR spectra were
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recorded in CDCl3 with TMS as internal standard (400 MHz H, 100 MHz 13C) at
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room temperature. Column chromatography was performed on silica gel (200ꢀ300
mesh).
General experimental procedures.
A 25 mL Schlenk tube was charged with imidazopyridines (0.4 mmol), KSCN (77.5
mg, 0.8 mmol), K2S2O8 (161.9 mg, 0.6 mmol), DCE (2 mL). The tube was sealed and
then the mixture was stirred under air at room temperature for 18 h. After completion
of the reaction (TLC), H2O (5 mL) was added, the mixture was extracted with ethyl
acetate or dichloromethane (3×4 mL). The combined organic layers was concentrated
by a rotary evaporator, and the residue was purified by column chromatography on
silica gel to provide the desired products (3). The same procedure starting from
imidazothiazoles led to compounds (5).
2-Phenyl-3-thiocyanatoimidazo[1,2-a]pyridine (3a). Eluent petroleum ether/ethyl
acetate (5:1). White solid, 83 mg, 83% yield, mp 121–122 oC. (Petroleum ether/ethyl
acetate = 2:1, Rf= 0.5). 1H NMR (CDCl3, 400 MHz, ppm) δ 8.48 (d, 1H, J = 8.0 Hz),
8.08 (d, 2H, J = 8.0 Hz), 7.79 (d, 1H, J = 8.0 Hz), 7.56 (t, 2H, J = 8.0 Hz), 7.49 (t, 2H,
13
J = 8.0 Hz), 7.16 (t, 1H, J = 8.0 Hz). C NMR (CDCl3, 100 MHz, ppm) δ 153.1,
148.0, 132.0, 129.5, 128.8, 128.7, 128.0, 124.4, 118.3, 114.4, 108.1, 94.7. HRMS m/z
calcd. for C14H10N3S [M+H]+: 252.0595 found: 252.0597. IR (KBr): 3068, 2154,
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1633, 1496, 1469, 1443 cm−1.
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2-(4-Methoxyphenyl)-3-thiocyanatoimidazo[1,2-a]pyridine (3b). Eluent petroleum
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ether/ethyl acetate (5:1). White solid, 87 mg, 77% yield, mp 160–162 C. (Petroleum
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ether/ethyl acetate = 2:1, Rf= 0.4). 1H NMR (CDCl3, 400 MHz, ppm) δ 8.43 (d, 1H, J
= 8.0 Hz), 8.05 (d, 2H, J = 8.0 Hz), 7.74 (d, 1H, J = 8.0 Hz), 7.45 (t, 1H, J = 8.0 Hz),
13
7.12ꢀ7.05 (m, 3H), 3.89 (s, 3H). C NMR (CDCl3, 100 MHz, ppm) δ 160.7, 152.9,
147.9, 130.1, 127.9, 124.5, 124.3, 118.0, 114.2, 114.1, 108.2, 93.7, 55.4. HRMS m/z
calcd. for C15H12N3OS [M+H]+: 282.0701 found: 282.0705. IR (KBr): 2901, 2152,
1608, 1534, 1454, 1406 cm−1.
2-(4-Chlorophenyl)-3-thiocyanatoimidazo[1,2-a]pyridine (3c). Eluent petroleum
o
ether/ethyl acetate (5:1). White solid, 96 mg, 84% yield, mp 158–161 C. (Petroleum
ether/ethyl acetate = 2:1, Rf= 0.4). 1H NMR (CDCl3, 400 MHz, ppm) δ 8.45 (d, 1H, J
= 8.0 Hz), 8.03 (d, 2H, J = 8.0 Hz), 7.77 (d, 1H, J = 8.0 Hz), 7.52ꢀ7.48 (m, 3H), 7.15
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(t, 1H, J = 8.0 Hz). C NMR (CDCl3, 100 MHz, ppm) δ 151.8, 147.9, 135.6, 130.5,
130.0, 129.0, 128.2, 124.4, 118.3, 114.6, 107.8, 94.8. HRMS m/z calcd. for
C14H9ClN3S [M+H]+: 286.0206 found: 286.0202. IR (KBr): 3029, 2151, 1634, 1515,
1497, 1459 cm−1.
8-Methyl-2-phenyl-3-thiocyanatoimidazo[1,2-a]pyridine (3d). Eluent petroleum
ether/ethyl acetate (10:1). White solid, 92 mg, 87% yield, mp 131–133 oC. (Petroleum
ether/ethyl acetate = 5:1, Rf= 0.6). 1H NMR (CDCl3, 400 MHz, ppm) δ 8.31 (d, 1H, J
= 8.0 Hz), 8.10 (d, 2H, J = 8.0 Hz), 7.56 (t, 2H, J = 8.0 Hz), 7.48 (d, 1H, J = 8.0 Hz),
7.27 (d, 1H, J = 8.0 Hz), 7.05 (t, 1H, J = 8.0 Hz), 2.72 (s, 3H). 13C NMR (CDCl3, 100
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MHz, ppm) δ 152.6, 148.3, 132.3, 129.3, 128.9, 128.7, 128.6, 126.7, 122.1, 114.4,
108.3, 94.9, 16.7. HRMS m/z calcd. for C15H12N3S [M+H]+: 266.0752 found:
266.0741. IR (KBr): 2919, 2153, 1627, 1559, 1490, 1463 cm−1.
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8-Methyl-3-thiocyanato-2-p-tolylimidazo[1,2-a]pyridine (3e). Eluent petroleum
ether/ethyl acetate (10:1). White solid, 88 mg, 79% yield, mp 137–139 oC. (Petroleum
ether/ethyl acetate = 5:1, Rf= 0.5). 1H NMR (CDCl3, 400 MHz, ppm) δ 8.31 (d, 1H, J
= 8.0 Hz), 7.99 (d, 2H, J = 8.0 Hz), 7.36 (d, 2H, J = 8.0 Hz), 7.25 (d, 1H, J = 8.0 Hz),
7.02 (t, 1H, J = 8.0 Hz), 2.71 (s, 3H), 2.46 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm)
δ 152.7, 148.2, 139.3, 129.6, 129.4, 128.8, 128.4, 126.6, 122.1, 114.2, 108.4, 94.5,
21.4, 16.7. HRMS m/z calcd. for C16H14N3S [M+H]+: 280.0908 found: 280.0911. IR
(KBr): 2964, 2143, 1631, 1488, 1473 cm−1.
7-Methyl-2-phenyl-3-thiocyanatoimidazo[1,2-a]pyridine (3f). Eluent petroleum
ether/ethyl acetate (5:1). White solid, 100 mg, 94% yield, mp 123–124 oC. (Petroleum
ether/ethyl acetate = 2:1, Rf= 0.4). 1H NMR (CDCl3, 400 MHz, ppm) δ 8.36 (d, 1H, J
= 8.0 Hz), 8.07 (d, 2H, J = 8.0 Hz), 7.58ꢀ7.54 (m, 3H), 7.50 (d, 1H, J = 8.0 Hz), 7.00
13
(d, 1H, J = 8.0 Hz), 2.53 (s, 3H). C NMR (CDCl3, 100 MHz, ppm) δ 153.3, 148.6,
139.8, 132.3, 129.4, 128.8, 128.7, 123.5, 117.0, 116.9, 108.2, 21.5. HRMS m/z calcd.
for C15H12N3S [M+H]+: 266.0752 found: 266.0741. IR (KBr): 2949, 2157, 1644, 1465,
1440, 1463 cm−1.
2-(4-Methoxyphenyl)-7-methyl-3-thiocyanatoimidazo[1,2-a]pyridine (3g). Eluent
o
petroleum ether/ethyl acetate (5:1). White solid, 90 mg, 76% yield, mp 126–128 C.
1
(Petroleum ether/ethyl acetate = 3:1, Rf= 0.4). H NMR (CDCl3, 400 MHz, ppm) δ
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8.33 (d, 1H, J = 8.0 Hz), 8.04 (d, 2H, J = 8.0 Hz), 7.52 (s, 1H), 7.08 (d, 1H, J = 8.0
Hz), 6.98 (d, 1H, J = 8.0 Hz), 3.91 (s, 3H), 2.52 (s, 3H). 13C NMR (CDCl3, 100 MHz,
ppm) δ 160.6, 153.1, 148.4, 139.4, 130.1, 124.7, 123.5, 116.7, 116.6, 114.2, 108.4,
92.9, 55.4, 21.4. HRMS m/z calcd. for C16H14N3OS [M+H]+: 296.0858 found:
296.0852. IR (KBr): 2953, 2154, 1665, 1608, 1471, 1439 cm−1.
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7-Methyl-3-thiocyanato-2-m-tolylimidazo[1,2-a]pyridine (3h). Eluent petroleum
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ether/ethyl acetate (5:1). White solid, 84 mg, 75% yield, mp 153–155 C. (Petroleum
ether/ethyl acetate = 2:1, Rf= 0.5). 1H NMR (CDCl3, 400 MHz, ppm) δ 8.34 (d, 1H, J
= 8.0 Hz), 7.87ꢀ7.85 (m, 2H), 7.54 (s, 1H), 7.44 (t, 1H, J = 8.0 Hz), 7.29 (d, 1H, J =
13
8.0 Hz), 6.97 (d, 1H, J = 8.0 Hz), 2.52 (s, 3H), 2.48 (s, 3H). C NMR (CDCl3, 100
MHz, ppm) δ 153.3, 148.3, 139.4, 138.5, 132.0, 130.1, 129.4, 128.6, 125.9, 123.5,
116.9, 116.8, 108.3, 93.7, 21.5, 21.4. HRMS m/z calcd. for C16H14N3S [M+H]+:
280.0908 found: 280.0911. IR (KBr): 2973, 2151, 1645, 1453, 1406 cm−1.
2-(3-Bromophenyl)-7-methyl-3-thiocyanatoimidazo[1,2-a]pyridine (3i). Eluent
petroleum ether/ethyl acetate (5:1). White solid, 111 mg, 81% yield, mp 165–167 oC.
1
(Petroleum ether/ethyl acetate = 2:1, Rf= 0.5). H NMR (CDCl3, 400 MHz, ppm) δ
8.34 (d, 1H, J = 8.0 Hz), 8.23 (s, 1H), 8.02 (d, 1H, J = 8.0 Hz), 7.61 (d, 1H, J = 8.0
Hz), 7.54 (s, 1H), 7.41 (t, 1H, J = 8.0 Hz), 7.01 (d, 1H, J = 8.0 Hz), 2.53 (s, 3H). 13C
NMR (CDCl3, 100 MHz, ppm) δ 151.4, 148.3, 139.8, 134.2, 132.3, 131.6, 130.2,
127.2, 123.5, 122.9, 117.3, 116.9, 107.9, 94.2, 21.5. HRMS m/z calcd. for
C15H11BrN3S [M+H]+: 343.9857 found: 343.9855, 345.9833. IR (KBr): 2961, 2162,
1638, 1594, 1561, 1489 cm−1.
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6-Methyl-3-thiocyanato-2-p-tolylimidazo[1,2-a]pyridine (3j). Eluent petroleum
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7
o
ether/ethyl acetate (5:1). White solid, 83 mg, 74% yield, mp 164–165 C. (Petroleum
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ether/ethyl acetate = 2:1, Rf= 0.6). 1H NMR (CDCl3, 400 MHz, ppm) δ 8.25 (s, 1H),
7.97 (d, 2H, J = 8.0 Hz), 7.68 (d, 1H, J = 8.0 Hz), 7.37ꢀ7.32 (m, 3H), 2.50 (s, 3H),
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2.46 (s, 3H). C NMR (CDCl3, 100 MHz, ppm) δ 153.0, 147.0, 139.4, 130.9, 129.4,
129.3, 128.6, 124.4, 122.2, 117.5, 108.3, 93.7, 21.4, 18.6. HRMS m/z calcd. for
C16H14N3S [M+H]+: 280.0908 found: 280.0911. IR (KBr): 2962, 2154, 1640, 1613,
1507, 1462 cm−1.
2-(4-Chlorophenyl)-6-methyl-3-thiocyanatoimidazo[1,2-a]pyridine (3k). Eluent
o
petroleum ether/ethyl acetate (5:1). White solid, 90 mg, 75% yield, mp 151–153 C.
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(Petroleum ether/ethyl acetate = 2:1, Rf= 0.4). H NMR (CDCl3, 400 MHz, ppm) δ
8.25 (s, 1H), 8.03 (d, 2H, J = 8.0 Hz), 7.68 (d, 1H, J = 8.0 Hz), 7.52 (d, 2H, J = 8.0
Hz), 7.36 (d, 1H, J = 8.0 Hz), 2.51 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm) δ 151.6,
147.0, 135.5, 131.3, 130.6, 129.9, 129.0, 124.8, 122.2, 117.6, 108.0, 94.2, 18.5.
HRMS m/z calcd. for C15H11ClN3S [M+H]+: 300.0362 found: 300.0361. IR (KBr):
2970, 2155, 1598, 1539, 1503, 1407 cm−1.
2-(4-Bromophenyl)-6-methyl-3-thiocyanatoimidazo[1,2-a]pyridine (3l). Eluent
petroleum ether/ethyl acetate (5:1). White solid, 110 mg, 80% yield, mp 183–185 oC.
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(Petroleum ether/ethyl acetate = 3:1, Rf= 0.5). H NMR (CDCl3, 400 MHz, ppm) δ
8.23 (s, 1H), 7.95 (d, 2H, J = 8.0 Hz), 7.68ꢀ7.65 (m, 3H), 7.35 (d, 1H, J = 8.0 Hz),
13
2.50 (s, 3H). C NMR (CDCl3, 100 MHz, ppm) δ 151.6, 147.0, 131.9, 131.3, 131.1,
130.1, 124.8, 123.8, 122.2, 117.6, 108.0, 94.2, 18.5. HRMS m/z calcd. for
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C15H11BrN3S [M+H]+: 343.9857 found: 343.9855, 345.9833. IR (KBr): 2924, 2155,
1537, 1502, 1455, 1402 cm−1.
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6-Methyl-3-thiocyanato-2-o-tolylimidazo[1,2-a]pyridine (3m). Eluent petroleum
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ether/ethyl acetate (5:1). White solid, 82 mg, 73% yield, mp 113–115 C. (Petroleum
ether/ethyl acetate = 2:1, Rf= 0.5). 1H NMR (CDCl3, 400 MHz, ppm) δ 8.25 (s, 1H),
13
7.69 (d, 2H, J = 8.0 Hz), 7.43ꢀ7.33 (m, 5H), 2.52 (s, 3H), 2.39 (s, 3H). C NMR
(CDCl3, 100 MHz, ppm) δ 154.7, 146.8, 137.6, 131.6, 130.8, 130.7, 130.6, 129.2,
125.6, 124.5, 122.3, 117.7, 108.3, 96.1, 20.2, 18.4. HRMS m/z calcd. for C16H14N3S
[M+H]+: 280.0908 found: 280.0911. IR (KBr): 2929, 2151, 1536, 1502, 1458, 1414
cm−1.
2-(3-Chlorophenyl)-6-methyl-3-thiocyanatoimidazo[1,2-a]pyridine (3n). Eluent
petroleum ether/ethyl acetate (5:1). White solid, 108 mg, 90% yield, mp 187–188 oC.
1
(Petroleum ether/ethyl acetate = 2:1, Rf= 0.5). H NMR (CDCl3, 400 MHz, ppm) δ
8.26 (s, 1H), 8.08 (s, 1H), 7.99 (d, 1H, J = 8.0 Hz), 7.69 (d, 1H, J = 8.0 Hz), 7.51ꢀ7.45
(m, 2H), 7.37 (d, 1H, J = 8.0 Hz), 2.51 (s, 3H). 13C NMR (CDCl3, 100 MHz, ppm) δ
151.2, 147.0, 134.8, 133.9, 131.3, 129.9, 129.4, 128.7, 126.7, 124.9, 122.3, 117.7,
107.9, 94.5, 18.5. HRMS m/z calcd. for C15H11ClN3S [M+H]+: 300.0362 found:
300.0361. IR (KBr): 2971, 2154, 1539, 1502, 1406 cm−1.
2-(3-Bromophenyl)-6-methyl-3-thiocyanatoimidazo[1,2-a]pyridine (3o). Eluent
petroleum ether/ethyl acetate (5:1). White solid, 118 mg, 86% yield, mp 169–171 oC.
1
(Petroleum ether/ethyl acetate = 2:1, Rf= 0.5). H NMR (CDCl3, 400 MHz, ppm) δ
8.26ꢀ8.24 (m, 2H), 8.03 (d, 1H, J = 8.0 Hz), 7.69 (d, 1H, J = 8.0 Hz), 7.61 (d, 1H, J =
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8.0 Hz), 7.42 (t, 1H, J = 8.0 Hz), 7.37 (d, 1H, J = 8.0 Hz), 2.52 (s, 3H). C NMR
(CDCl3, 100 MHz, ppm) δ 151.1, 147.0, 134.2, 132.3, 131.6, 131.3, 130.2, 127.2,
124.9, 122.9, 122.2, 117.7, 107.8, 94.6, 18.5. HRMS m/z calcd. for C15H11BrN3S
[M+H]+: 343.9857 found: 343.9855, 345.9833. IR (KBr): 2922, 2159, 1593, 1561,
1499, 1466 cm−1.
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6-Chloro-2-phenyl-3-thiocyanatoimidazo[1,2-a]pyridine (3p). Eluent petroleum
ether/ethyl acetate (10:1). White solid, 91 mg, 80% yield, mp 183–184 oC. (Petroleum
ether/ethyl acetate = 4:1, Rf= 0.5). 1H NMR (CDCl3, 400 MHz, ppm) δ 8.51 (s, 1H),
8.07 (d, 2H, J = 8.0 Hz), 7.74 (d, 1H, J = 8.0 Hz), 7.59ꢀ7.51 (m, 3H), 7.47 (d, 1H, J =
8.0 Hz). 13C NMR (CDCl3, 100 MHz, ppm) δ 153.7, 146.3, 131.6, 129.7, 129.5, 128.8,
128.7, 123.0, 122.5, 118.7, 107.6, 95.7. HRMS m/z calcd. for C14H9ClN3S [M+H]+:
286.0206 found: 286.0201. IR (KBr): 3018, 2156, 1519, 1493, 1466, 1443 cm−1.
6-Chloro-2-(4-chlorophenyl)-3-thiocyanatoimidazo[1,2-a]pyridine (3q). Eluent
petroleum ether/ethyl acetate (10:1). White solid, 103 mg, 81% yield, mp 201–203 oC.
1
(Petroleum ether/ethyl acetate = 5:1, Rf= 0.4). H NMR (CDCl3, 400 MHz, ppm) δ
8.50 (s, 1H), 8.03 (d, 2H, J = 8.0 Hz), 7.72 (d, 1H, J = 8.0 Hz), 7.53 (d, 2H, J = 8.0
13
Hz), 7.48 (d, 1H, J = 8.0 Hz). C NMR (CDCl3, 100 MHz, ppm) δ 152.5, 146.3,
136.0, 130.0, 129.9, 129.7, 129.1, 123.2, 122.5, 118.7, 107.3, 95.7. HRMS m/z calcd.
for C14H8Cl2N3S [M+H]+: 319.9816 found: 319.9821. IR (KBr): 2987, 2164, 1523,
1489, 1405 cm−1.
6-Chloro-3-thiocyanato-2-o-tolylimidazo[1,2-a]pyridine (3r). Eluent petroleum
ether/ethyl acetate (10:1). White solid, 87 mg, 73% yield, mp 149–152 oC. (Petroleum
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ether/ethyl acetate = 5:1, Rf= 0.4). 1H NMR (CDCl3, 400 MHz, ppm) δ 8.51 (s, 1H),
7.74 (d, 1H, J = 8.0 Hz), 7.49 (d, 1H, J = 8.0 Hz), 7.43ꢀ7.35 (m, 4H), 2.38 (s, 3H). 13C
NMR (CDCl3, 100 MHz, ppm) δ 155.7, 146.2, 137.6, 131.0, 130.8, 130.6, 129.6,
129.3, 125.7, 123.0, 122.5, 118.8, 107.6, 97.8, 20.1. HRMS m/z calcd. for
C15H11ClN3S [M+H]+: 300.0362 found: 300.0361. IR (KBr): 3018, 2154, 1518, 1489,
1460, 1415 cm−1.
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6-Bromo-2-(3-chlorophenyl)-3-thiocyanatoimidazo[1,2-a]pyridine (3s). Eluent
petroleum ether/ethyl acetate (10:1). White solid, 107 mg, 74% yield, mp 177–178 oC.
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(Petroleum ether/ethyl acetate = 5:1, Rf= 0.3). H NMR (CDCl3, 400 MHz, ppm) δ
8.61 (s, 1H), 8.09 (s, 1H), 8.00ꢀ7.97 (m, 1H), 7.69 (d, 1H, J = 8.0 Hz), 7.59 (d, 1H, J
13
= 8.0 Hz), 7.51ꢀ7.49 (m, 2H). C NMR (CDCl3, 100 MHz, ppm) δ 151.9, 146.4,
135.0, 133.3, 131.9, 130.1, 129.8, 128.8, 126.8, 124.6, 119.0, 109.7, 107.2, 95.9.
HRMS m/z calcd. for C14H8BrClN3S [M+H]+: 363.9311 found: 363.9315, 365.9291.
IR (KBr): 2988, 2160, 1595, 1566, 1492, 1405 cm−1.
2-(Furan-2-yl)-3-thiocyanatoimidazo[1,2-a]pyridine (3t). Eluent petroleum
o
ether/ethyl acetate (5:1). White solid, 67 mg, 69% yield, mp 174–176 C. (Petroleum
ether/ethyl acetate = 1:1, Rf= 0.4). 1H NMR (CDCl3, 400 MHz, ppm) δ 8.43 (d, 1H, J
= 4.0 Hz), 7.35 (d, 1H, J = 8.0 Hz), 7.67 (s, 1H), 7.48 (t, 1H, J = 8.0 Hz), 7.24 (d, 1H,
J = 4.0 Hz), 7.13 (t, 1H, J = 8.0 Hz), 6.62 (s, 1H). 13C NMR (CDCl3, 100 MHz, ppm)
δ 148.2, 147.1, 144.1, 128.2, 124.2, 118.2, 114.5, 111.9, 111.4, 107.7, 93.5. HRMS
m/z calcd. for C12H8N3OS [M+H]+: 242.0388 found: 242.0391. IR (KBr): 2959, 2156,
1633, 1512, 1494, 1429 cm−1.
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2-(Furan-2-yl)-7-methyl-3-thiocyanatoimidazo[1,2-a]pyridine
(3u).
Eluent
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petroleum ether/ethyl acetate (5:1). White solid, 78 mg, 76% yield, mp 178–180 C.
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(Petroleum ether/ethyl acetate = 1:1, Rf= 0.3). H NMR (CDCl3, 400 MHz, ppm) δ
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8.27 (d, 1H, J = 8.0 Hz), 7.65 (s, 1H), 7.67 (s, 1H), 7.47 (s, 1H), 7.19 (d, 1H, J = 4.0
13
Hz), 6.94 (d, 1H, J = 8.0 Hz), 6.61 (dd, 1H, J = 4.0 Hz), 2.48 (s, 3H). C NMR
(CDCl3, 100 MHz, ppm) δ 148.5, 147.2, 144.3, 143.9, 139.8, 123.3, 117.1, 116.6,
111.8, 111.2, 107.9, 92.6, 21.4. HRMS m/z calcd. for C13H10N3OS [M+H]+: 256.0545
found: 256.0544. IR (KBr): 3094, 2151, 1644, 1611, 1515, 1432 cm−1.
2-(p-tolyl)-3-(thiocyanato)benzo[d]imidazo[2,1-b]thiazole (5a). Eluent petroleum
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ether/ethyl acetate (10:1). White solid, 101 mg, 79% yield, mp 126–128 C.
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(Petroleum ether/ethyl acetate = 5:1, Rf= 0.5). H NMR (CDCl3, 400 MHz, ppm) δ
8.48 (d, 1H, J = 8.0 Hz), 7.90 (d, 2H, J = 8.0 Hz), 7.77 (d, 1H, J = 8.0 Hz), 7.58 (t, 1H,
J = 8.0 Hz), 7.45 (t, 1H, J = 4.0 Hz), 7.32 (d, 2H, J = 8.0 Hz), 2.44 (s, 3H). 13C NMR
(CDCl3, 100 MHz, ppm) δ 155.7, 152.6, 139.4, 132.9, 130.2, 129.4, 128.3, 126.9,
125.6, 124.5, 113.8, 112.6, 108.9, 97.6, 21.4. HRMS m/z calcd. for C17H12N3S2
[M+H]+: 322.0473 found: 322.0479. IR (KBr): 2963, 2157, 1478, 1408cm−1.
2-(4-methoxyphenyl)-3-(thiocyanato)benzo[d]imidazo[2,1-b]thiazole (5b). Eluent
petroleum ether/ethyl acetate (10:1). White solid, 97 mg, 72% yield, 186ꢀ188.
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(Petroleum ether/ethyl acetate = 5:1, Rf= 0.4). H NMR (CDCl3, 400 MHz, ppm) δ
8.50 (d, 1H, J = 8.0 Hz), 7.97 (d, 2H, J = 8.0 Hz), 7.79 (d, 1H, J = 8.0 Hz), 7.60 (t, 1H,
J = 8.0 Hz), 7.47 (t, 1H, J = 4.0 Hz), 7.06 (d, 2H, J = 8.0 Hz), 3.91 (s, 3H). 13C NMR
(CDCl3, 100 MHz, ppm) δ 160.5, 155.6, 152.6, 132.9, 130.1, 129.8, 126.9, 125.6,
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124.5, 124.3, 114.2, 113.8, 109.0, 97.0, 55.4. HRMS m/z calcd. for C17H12N3OS2
[M+H]+: 338.0422 found: 338.0426. IR (KBr): 2934, 2159, 1608, 1574, 1526, 1453
cm−1.
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2-(4-Bromophenyl)-3-(thiocyanato)benzo[d]imidazo[2,1-b]thiazole (5c). Eluent
petroleum ether/ethyl acetate (10:1). White solid, 115 mg, 75% yield, mp 173–175 oC.
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(Petroleum ether/ethyl acetate = 5:1, Rf= 0.6). H NMR (CDCl3, 400 MHz, ppm) δ
8.50 (d, 1H, J = 8.0 Hz), 7.89 (d, 2H, J = 8.0 Hz), 7.81 (d, 1H, J = 8.0 Hz), 7.66 (d,
2H, J = 8.0 Hz), 7.60 (t, 1H, J = 8.0 Hz), 7.49 (t, 1H, J = 8.0 Hz). 13C NMR (CDCl3,
100 MHz, ppm) δ 154.3, 152.9, 132.6, 132.0, 130.7, 130.2, 129.8, 127.1, 126.0, 124.6,
123.8, 113.9, 108.4, 98.2. HRMS m/z calcd. for C16H9BrN3S2 [M+H]+: 385.9421
found: 385.9419, 387.9400. IR (KBr): 2962, 2158, 1478, 1396 cm−1.
2-(3-Chlorophenyl)-3-(thiocyanato)benzo[d]imidazo[2,1-b]thiazole (5d). Eluent
petroleum ether/ethyl acetate (10:1). White solid, 105 mg, 77% yield, mp 176ꢀ177.
1
(Petroleum ether/ethyl acetate = 5:1, Rf= 0.4). H NMR (CDCl3, 400 MHz, ppm) δ
8.52 (d, 1H, J = 8.0 Hz), 8.01 (s, 1H), 7.92 (d, 1H, J = 8.0 Hz), 7.81 (d, 1H, J = 8.0
Hz), 7.61 (t, 1H, J = 8.0 Hz), 7.52ꢀ7.43 (m, 3H). 13C NMR (CDCl3, 100 MHz, ppm) δ
153.8, 152.9, 134.8, 133.5, 132.8, 130.3, 130.0, 129.3, 128.4, 127.1, 126.3, 126.0,
124.6, 114.0, 108.4, 98.6. HRMS m/z calcd. for C16H9ClN3S2 [M+H]+: 341.9926
found: 341.9921. IR (KBr): 3067, 2157, 1569, 1479, 1465, 1409 cm−1.
3-thiocyanato-1H-indole (5e).13a Eluent petroleum ether/ethyl acetate (10:1). White
solid, 57 mg, 82% yield, mp 72ꢀ74. (Petroleum ether/ethyl acetate = 3:1, Rf= 0.2). 1H
NMR (CDCl3, 400 MHz, ppm) δ 8.81 (br, 1H), 7.83 (dd, 1H, J = 8.0 Hz), 7.46 (d, 1H,
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J = 8.0 Hz), 7.45ꢀ7.43 (m, 1H), 7.35ꢀ7.32 (m, 2H). 13C NMR (CDCl3, 100 MHz, ppm)
δ 136.1, 131.1, 127.7, 123.9, 121.9, 118.7, 112.2, 112.1, 92.0. HRMS m/z calcd. for
C9H7N2S [M+H]+: 175.0330 found: 175.0321.
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N,N-dimethyl-4-thiocyanatoaniline (5f).29 Eluent petroleum ether/ethyl acetate
(10:1). White solid, 62 mg, 87% yield, mp 73ꢀ75. (Petroleum ether/ethyl acetate = 3:1,
Rf= 0.5). 1H NMR (CDCl3, 400 MHz, ppm) δ 7.44 (d, 2H, J = 8.0 Hz), 6.70 (d, 2H, J
13
= 4.0 Hz), 3.01 (s, 6H). C NMR (CDCl3, 100 MHz, ppm) δ 151.7, 134.4, 113.2,
112.6, 106.5, 40.1. HRMS m/z calcd. for C9H11N2S [M+H]+: 179.0643 found:
179.0631.
ASSOCIATED CONTENT
Supporting Information
13
1H and C NMR spectra for all compounds and ORTEP structures of compound 3n,
spectroscopic data for 3n; Xꢀray results (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* Eꢀmail: huawang_qfnu@126.com
Notes
The authors declare no competing financial interest.
ACKNOWLEGEMENTS
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The authors gratefully acknowledge the financial support from the National Natural
Science Foundation of China (Nos. 21302110, 21302109 and 21375075), the Scientic
Research Foundation of Qufu Normal University (BSQD 2012021), the Taishan
Scholar Foundation of Shandong Province, the Project of Shandong Province Higher
Educational Science and Technology Program (J13LD14), and the Natural Science
Foundation of Shandong Province (ZR2013BQ017). We thank Pengfei Sun in this
group for reproducing the results of 3a and 5c.
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