Copper-Catalyzed Aerobic Oxidative [3+2] Annulation for the Synthesis of 5-Amino/Imino-Substituted 1,2,4-Thiadiazoles through C-N/N-S Bond Formation

Article abstract of DOI:10.1021/acs.joc.8b01292

A copper-catalyzed aerobic oxidative annulation reaction of 2-aminopyridine/amidine with isothiocyanate has been reported. This strategy involving C-N/N-S bond formations provides various 5-amino/imino-substituted 1,2,4-thiadiazole derivatives under a Cu/O₂ catalytic system. This method has demonstrated high reactivity, mild reaction conditions, and a broad substrate scope. Furthermore, the synthetic utilities of the approach are demonstrated by further modifications.

Full text of DOI:10.1021/acs.joc.8b01292

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Article
Copper-Catalyzed Aerobic Oxidative [3+2] Annulation for Synthesis of 5-
Amino/Imino Substituted 1,2,4-Thiadiazoles through C-N/N-S Bond Formation
Wentao Yu, Yubing Huang, Jianxiao Li, Xiaodong Tang, Wanqing Wu, and Huanfeng Jiang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01292 • Publication Date (Web): 18 Jul 2018
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Copper-Catalyzed Aerobic Oxidative [3+2]
Annulation for Synthesis of 5-Amino/Imino
Substituted 1,2,4-Thiadiazoles through C-N/N-S Bond
Formation
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Wentao Yu, Yubing Huang, Jianxiao Li, Xiaodong Tang, Wanqing Wu*, and Huanfeng
Jiang*
Key Laboratory of Functional Molecular Engineering of Guangdong Province, Guangdong
Engineering Research Center for Green Fine Chemicals, School of Chemistry and Chemical
Engineering, South China University of Technology, Guangzhou 510640, China
Fax: (+86) 20ꢀ8711ꢀ2906; Eꢀmail: cewuwq@scut.edu.cn, jianghf@scut.edu.cn
Abstract:
A
copperꢀcatalyzed aerobic oxidative annulation reaction of
2ꢀaminopyridine/amidine with isothiocyanate has been reported. This strategy
involving CꢀN/NꢀS bond formations provides various 5ꢀamino/imino substituted
1,2,4ꢀthiadiazole derivatives under Cu/O2 catalytic system. This method has
demonstrated high reactivity, mild reaction conditions and a broad substrate scope.
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Furthermore, the synthetic utilities of the approach are demonstrated by further
modifications.
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INTRODUCTION
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1,2,4ꢀThiadiazole derivatives represent an important class of organic molecules. Most
of them have been extensively observed in many medicinal materials and biologically
active compounds, including antibacterial,1 inhibitory,2 and neuroprotective3 agents
(Figure 1).4,5 The development of efficient and practical methods to synthesize diverse
1,2,4ꢀthiadiazole is important. Traditionally, few syntheses of these valuable
molecules have been developed.6 In addition, several developments suffer from
certain limitations, such as prefunctionalized reactants, multistep protocols or harsh
reaction conditions, which lower the synthetic efficiency and generality. Therefore,
seeking for new synthetic strategies to construct molecules of this class has been
attracting great attention from organic chemists in recent years.7
Figure 1. Biologically Active 1,2,4ꢀThiadiazoles
It is a traditional strategy to use substrateꢀinduced tandem cyclization process for
the atomꢀeconomic construction of carbonꢀheteroatom and heteroatomꢀheteroatom
bonds. Compared with the extra directing group, these substrates either with nitrogen
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or sulfur atoms might preferentially bind to the transitionꢀmetal catalyst.8 To some
extent, it is easily operated, economical and environmentally friendly.
2ꢀaminopyridine/amidine have long been realized as one of the most widely used
commercial reagents in organic synthesis. In the past few decades, the
2ꢀaminopyridines acted as a directing group provided a basic block for the elegant
construction of five or sixꢀmembered nitrogenꢀcontaining heterocyclic compounds by
the formation of NꢀC9, NꢀN10, and NꢀO11 bonds.12 In 2013, our group also developed
an efficient method for the synthesis of 2ꢀhaloimidazopyridines from aminopyridines
and haloalkynes under Cu/O2 catalytic system, in which bidental nitrogen atoms of
2ꢀaminopyridine might coordinate with Cu, and then activated another substrate
(Scheme 1).13
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Scheme 1. Cyclization of 2ꢀAminopyridines
On the contrary, the NꢀS bond formation reaction using 2ꢀaminopyridine as
substrate remains challenging14 in despite of great progress of oxidative NꢀS bond
formation via copperꢀcatalyzed aerobic oxidation.15 Isothiocyanates are known to be
one of the most important intermediates and versatile building blocks.16 However,
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they are limited to the synthesis of thiourea intermediate in most cases, and their
sulfur atoms were usually discarded, rendering the transformations nonꢀatom
economic. Inspired by our previous work in copper/oxygen catalytic system17,18, we
speculated that the intermediate generated from 2ꢀaminopyridine and Cu could also
activate and direct the C=S group to form a new NꢀS bond. Herein, a copperꢀcatalyzed
aerobic oxidative cascade reaction of 2ꢀaminopyridine with isothiocyanate leading to
the formation of 1,2,4ꢀthiadiazole derivatives is reported.
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RESULTS AND DISCUSSION
We began our study by choosing 2ꢀaminopyridine (1) and isothiocyanate (2) as
o
model substrates in the presence of catalyst at 50 C (Table 1). To our delight, the
expected 1,2,4ꢀthiadiazole 3 was obtained in 42% yield with CH3CN as the solvent
under O2 balloon (entry 1). Then, different solvents were investigated (entries 1ꢀ4),
and the highest yield was achieved in DCE (entry 3). Subsequently, various copper
salts were employed as metal catalysts (entries 5ꢀ7), and CuI proved to be an ideal
choice among the tested catalysts. Moreover, various pyridine bases were tested in the
reaction, and the target product 3 was obtained in 83% yield when adding two
equivalents of 2,4ꢀdimethylpyridine (entries 8ꢀ10). Control experiments revealed that
copper and O2 atmosphere are both critical to this transformation (entries 11 and 12).
Table 1. Optimization of the reaction conditions a
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Entry a
Catalyst
Additive
Solvent
MeCN
DMSO
DCE
THF
Yield (%) b
1
2
CuI
CuI
ꢀ
42
8
ꢀ
3
CuI
ꢀ
55
4
CuI
ꢀ
15
5
CuBr2
CuBr
Cu(OTf)2
CuI
ꢀ
ꢀ
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
9
6
Trace
Trace
72
7
ꢀ
8
Pyridine
9
CuI
4ꢀCH3ꢀPyridine
2,4ꢀdimethylpyridine
2,4ꢀdimethylpyridine
2,4ꢀdimethylpyridine
65
10
11
12c
CuI
88 (83)
NR
NR
ꢀ
CuI
aReaction conditions: 1 (0.30 mmol), 2 (0.45 mmol), catalyst (20 mol %), and additives (0.6 mmol)
in 1.5 mL of solvent with O2 balloon at 50 oC for 12 h. bDetermined by GCꢀMS using dodecane as
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c
the internal standard. The value in parentheses is the isolated yield. NR = no reaction. Under N2
5
6
atmosphere.
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Under the optimized reaction conditions, the substrate scope of
2ꢀaminopyridines and isothiocyanates was explored as shown in Table 2. The
reactions of electronꢀrich 2ꢀaminopyridines afforded the products in excellent
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yields (3aa
containing electronꢀpoor groups gave desired products in moderate yields and
higher yields after prolonging reaction time (3da 3ia 3fk 3ik). However, for
ꢀ3ca, 3bk, 3ck). On the contrary, the reactions of 2ꢀaminopyridines
ꢀ
,
,
the substrate with strong electronꢀwithdrawing group, the reaction did not occur
and the material was recovered (3ja). Then, the steric hindrance effects in
aromatics were examined. The Cꢀ3
Table 2. Substrate scope of N
ꢀfused 1,2,4ꢀthiadiazoles a
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R1
CuI (20 mol %)
2.4-dimethylpyridine (2.0 equiv)
R1
N
N
R2 NCS
+
DCE, 50 oC, O2
N
NH2
S
N
6
R2
7
8
9
1
2
3
X
3aa, X=H, 83%
X
3ba, X=CH3, 86%
3ca, X=OCH3, 91%
3da, X=F, 75%
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N
N
N
N
S
N
3iab, X=Br,46%
3jac, X=CN, n.r.
N
N
S
N
S
N
N
S
3ea, X=Cl, 68%
3fab, X=Br, 65%
N
N
3gab, X=CF3, 38%
3hab, X=C(CO)OMe, 35%
3ka, 92%
3lac, n.r.
S
3ab, X=CH3, 83%
3ac, X=OCH3, 85%
3ad, X=F, 78%
N
N
N
N
N
N
S
N
N
S
N
S
N
S
N
3ae, X=Cl, 72%
N
3af, X=Br, 58%
3agb, X=CF3, 45%
3ahb, X=C(CO)OMe, 39%
3ma, 75%
3na, 68%
3oa, 42%
X
Br
X
3ak, X=H. 86%
N
N
N
N
N
S
N
S
3bk, X=CH3, 90%
3ck, X=OCH3, 93%
3fkb, X=Br, 53%
S
N
N
N
N
N
S
N
3ikb, 44%
3ai, 59%
3aj, trace
N
N
S
N
N
N
N
N
N
N
N
N
S
N
S
S
S
N
N
N
3al, 72%
3am, 47%
3an, trace
3ao, 83%
3ap, 42%
N
N
N
N
N
N
S
S
S
N
N
N
3ar, 94%
3aq, 62%
3as, 90%
aReaction conditions: 1 (0.30 mmol), 2 (0.45 mmol), CuI (0.060 mmol), and 2,4ꢀdimethylpyridine
(0.60 mmol), in 1.5 mL of solvent at 50 oC under O2 balloon for 12 h. Isolated yields. b24 h. cn.r. =
no reaction.
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substituted aminopyridine was cycled with excellent yield to deliver 3ka.
Unfortunately, the sterically hindered Cꢀ6 substituted aminopyridine (3la) did not
react with isothiocyanate substrate. The other variants such as 2ꢀaminoquinoline
2ꢀamino(iso)quinolines, and 2ꢀamino(benzo)thiazoles could also react with 2 to give
the corresponding product in moderate yields (3ma-3oa). Interestingly, substituted
isothiocyanates exhibited similar effect on this transformation. The desired products
were formed in 83% and 85% yields respectively (3ab, 3ac). The isothiocyanates
bearing electronꢀwithdrawing groups, such as ꢀhalo, ꢀCF3, ꢀCOOMe at the phenyl ring
were obtained in yields ranging from 39% to 78% (3adꢀ3ah). Similarly, substrates 2
possessing various degrees of steric bulkiness group, such as 2,4,6ꢀtrimethylphenyl
group (3aj) and tertiary amino group (3an), were detected only in trace amounts.
Other substituted isothiocyanates such as Nꢀethyl (3ak), Nꢀpropyl (3al), Nꢀisopropyl
(3am), Nꢀcyclopropyl (3ao), Nꢀcyclopentyl (3ap), Nꢀnapththyl (3aq), Nꢀbenzyl (3ar)
and Nꢀpropenyl (3as) isothiocyanate were tolerated under the optimized reaction
conditions. The structure of 3ak was determined by Xꢀray singleꢀcrystal analysis (see
the Supporting Information for details). By comparing the NMR spectra of the
compound secured by the crystal structure, the regioselectivity of the remaining
compounds was determined. These results indicated the steric and electronic effects
affected the product formation.
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Considering a successful oxidative cyclization process for the synthesis of
Nꢀfused 1,2,4ꢀthiadiazoles, we sought to further extend the scope of this practical
approach by replacing 2ꢀaminopyridine (1) with phenylbenzamidines (4) to prepare
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other 1,2,4ꢀthiadiazoles under the optimal reaction conditions. Gratifyingly, choosing
the 2.0 equivalent 2,4ꢀdimethylpyridine to 1.0 equivalent NaOH, we were able to
prepare substituted 1,2,4ꢀthiadiazoles very efficiently. As shown in Table 3, for
amidine hydrochlorides, no significant substituent effect was observed, and excellent
yields were obtained for both electronꢀdonating and electronꢀwithꢀdrawing
substituents (5a-5g). Isonicotinimidamide hydrochloride could also obtained the
corresponding product (5h). It also should be noted that isothiocyanates with various
groups, including ꢀethyl, ꢀtertꢀbutyl, cyclopropyl, and propenyl, were all tolerated
under the reaction conditions, and the desired 5ꢀaminoꢀ1,2,4ꢀthiadiazole products
were obtained in good yields (5i-5m). Meanwhile, for the substrates with low yields,
such as 3ia, 3ag, 3ah, 5h, we usually detected the material recovery without other
byꢀproducts.
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Table 3. Substrate scope of 5ꢀaminoꢀ1,2,4ꢀthiadiazoles a
aReaction conditions: 4 (0.30 mmol), 2 (0.45 mmol), CuI (0.060 mmol), and NaOH (0.30 mmol),
in 1.5 mL of solvent at 50 oC under O2 balloon for 12 h. Isolated yield
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The obtained Nꢀfused 1,2,4ꢀthiadiazole products bearing various active
functional groups were easily converted into a wide range of derivatives using
classical organic transformations (Scheme 2). Product 3fa, possessing C(sp2)ꢀBr
bonds, underwent SuzukiꢀMiyaura and Sonogashira coupling reactions to afford the
corresponding arylated and alkenylated products in good yields. In addition, a newly
formed product 5k could also be smoothly transformed into the corresponding
2ꢀaminoꢀ1,2,4ꢀthiadiazole derivatives,19 which are useful synthons and versatile
skeletons in organic synthetic chemistry.
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Scheme 2. Transformations of 3fa, 5k
To understand more insight into the reaction mechanism, we conducted several
experiments
(Scheme
3).
When
the
radical
scavenger
TEMPO
(2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy, free radical) and 1,1ꢀdiphenylethene were
added to the reaction, the reaction proceeded with 77% or 44% isolated yields,
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demonstrating that a radical mechanism should be ruled out. Although the product 9
was obtained when 2ꢀaminopyridine (1) was reacted with phenyl isothiocyanate (2) in
the absence of copper, it did not produce 3 under the standard conditions, which
indicated that the product 9 is not the reaction intermediate.
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Scheme 3. Control Experiments
Based on the above results, a possible mechanism is proposed in Scheme 4.
Intermediate A is initially generated by the coordination of copper to the substrate
with the aid of base.9f, 10a, 13,20 When the copper salt was coordinated to the substrate
aminopyridine, it may enhance the nucleophilic reactivity of nitrogen atom at pyridine.
Meanwhile, electronꢀrich sulfur atom at isothiocyanate might also bind to the metal
copper species. The use of electronꢀpoor and steric hindered substrates gives inferior
results which is consistent with this process. Then, migratory insertion of
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isothiocyanate occurs to form the intermediate B.13 Next, CuI species is oxidized to a
putative CuII intermediate C.7b,21,22 Finally, reductive elimination affords the desired
product.23 Meanwhile, the Cu0 can be oxidized by O2 to regenerate the CuI species.
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NH
CuI
[CuIX],Base
HX, HB
N
NH+
CuI
N
R
S
N
NH2
S
N
C
R
B
A
-H+
O2
N
N
S
N
N
CuII
Cu0
S
N
N
R
R
C
O2
Cu0
CuI
Scheme 4. Possible reaction mechanism
CONCLUSION
In conclusion, we have developed a Cuꢀcatalyzed aerobic oxidative [3+2]
annulation of 2ꢀaminopyridine/amidine with isothiocyanate. A plausible mechanism
of the transformation is described. This method is useful for synthesizing various
Nꢀfused 1,2,4ꢀthiadiazoles. Meanwhile, the use of molecular oxygen as the oxidant
makes the overall chemical transformation sustainable and practical.
EXPERIMENTAL SECTION
General Information. All reactions were carried out in 10 mL tubes under O2 balloon.
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TLC was performed by using commercially prepared 100ꢀ400 mesh silica gel plates
(GF254) and visualization was effected at 254 nm. Unless otherwise noted, all reagents
were purchased as reagent grade and used without further purification. Melting points
were measured with a micromelting point apparatus. NMR spectra were recorded in
CDCl3, or DMSOꢀd6 on a 400 MHz spectrometer. Chemical shifts were reported in
parts per million (δ) relative to TMS (0.00 ppm) for 1H NMR data and CDCl3 (77.00
ppm), or DMSOꢀd6 (40.00 ppm) for 13C NMR data. IR spectra were obtained either as
potassium bromide pellets or as liquid films between two potassium bromide pellets
with an infrared Fourier spectrometer. Highꢀresolution mass spectra (ESI) were
obtained with a LCMSꢀITꢀTOF mass spectrometer.
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General Procedure for Preparation of N-Fused 1,2,4-Thiadiazoles:
2ꢀAminopyridine (0.3 mmol), isothiocyanate (0.45 mmol), CuI (20 mol %) and
2,4ꢀdimethylpyridine (0.6 mmol) were mixed in 1.5 mL DCE to stir under O2 balloon
o
at 50 C. Upon completion, the reaction mixture was washed by saturated NaCl
aqueous solution (2×10 mL) and then extracted with ethyl acetate (2×10 mL), and the
organic layers were combined, dried over anhydrous MgSO4, filtered, and
concentrated under reduced pressure. The residue was separated by column
chromatography (petroleum ether/ethyl acetate 20:1) to give the pure products.
(Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)-aniline (3aa):7f yellow solid
(57 mg, 83 %), mp = 124 ꢀ 125 oC; 1H NMR (400 MHz, CDCl3) δ 8.22 (d, J = 7.2 Hz,
1H), 7.40 (m, 2H), 7.23 ꢀ 7.09 (m, 4H), 7.05 (d, J = 9.4 Hz, 1H), 6.45 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 159.1, 151.5, 148.5, 133.3, 129.5, 126.0, 124.2, 121.0,
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119.3, 109.6 ppm; vmax(KBr)/cmꢀ1 3114, 3031, 2926, 1580, 1164, 757, 696; MS (EI,
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70 eV): m/z (%) = 227 [M]+, 169, 124, 78, 51.
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(Z)-N-(7-Methyl-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-aniline
(3ba):7f
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o
yellow solid (62 mg, 86 %), mp = 105 ꢀ 106 C; 1H NMR (400 MHz, CDCl3) δ 8.11
(d, J = 7.3 Hz, 1H), 7.38 (m, 2H), 7.12 (m, 3H), 6.80 (s, 1H), 6.29 (d, J = 7.3 Hz, 1H),
2.25 (s, 3H).; 13C NMR (101 MHz, CDCl3) δ 159.2, 151.7, 148.5, 144.7, 129.4, 124.8,
124.0, 121.0, 116.7, 112.3 ppm; vmax(KBr)/cmꢀ1 3052, 2923, 1578, 1443, 944, 758,
681; m/z (%) = 241 [M]+, 138, 92, 77, 65.
(Z)-N-(7-Methoxy-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-aniline
(3ca):
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yellow solid (70 mg, 91 %), mp = 157 ꢀ 158 C; H NMR (400 MHz, CDCl3) δ 8.10
(d, J = 7.7 Hz, 1H), 7.38 (m, 2H), 7.12 (m, 3H), 6.22 (m, 2H), 3.81 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 163.7, 158.8, 152.7, 148.4, 129.4, 126.1, 124.1, 121.1, 106.6,
93.9, 55.8 ppm; vmax(KBr)/cmꢀ1 3077, 2924, 1645, 1546, 1230, 766, 692; MS (EI, 70
eV): m/z (%) = 257 [M]+, 154, 135, 108, 77; HRMSꢀESI (m/z): calcd for C13H12ON3S,
[M+H]+ : 258.0696, found 258.0696.
(Z)-N-(7-Fluoro-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-aniline
(3da):
yellow solid (55 mg, 75 %); mp = 115 ꢀ 116 oC; 1H NMR (400 MHz, CDCl3) δ 8.30 ꢀ
8.21 (m, 1H), 7.40 (m, 2H), 7.14 (m, 3H), 6.74 ꢀ 6.63 (m, 1H), 6.44 ꢀ 6.34 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 166.1 (d, J = 262 Hz), 158.0, 151.3 (d, J = 15.3 Hz),
148.1, 129.6, 128.1 (d, J = 11.9 Hz), 124.5, 121.0, 103.6 (d, J = 30.8 Hz), 101.7 (d, J
= 23.9 Hz) ppm; vmax(KBr)/cmꢀ1 3067, 2923, 1656, 1597, 1177, 950, 758; HRMSꢀESI
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(m/z): calcd for C12H9N3FS, [M+H]+ : 246.0496, found 246.0494.
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(Z)-N-(7-Chloro-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-aniline
(3ea):
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yellow solid (53 mg, 68 %), mp = 120 ꢀ 122 C; H NMR (400 MHz, CDCl3) δ 8.16
(d, J = 7.6 Hz, 1H), 7.40 (m, 2H), 7.14 (m, 3H), 7.07 (s, 1H), 6.44 (d, J = 7.6 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 157.9, 150.4, 148.1, 141.1, 129.6, 126.2, 124.5, 121.0,
117.5, 111.8 ppm; vmax(KBr)/cmꢀ1 3100, 2923, 1604, 1529, 1449, 756, 677;
HRMSꢀESI (m/z): calcd for C12H9N3ClS, [M+H]+ : 262.0200, found 262.0200.
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(Z)-N-(7-Bromo-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-aniline
(3fa):
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yellow solid (59 mg, 65 %), mp = 130 ꢀ 132 C; H NMR (400 MHz, CDCl3) δ 8.09
(d, J = 7.5 Hz, 1H), 7.40 (m, 2H), 7.29 (s, 1H), 7.14 (m, 3H), 6.56 (d, J = 7.6 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 157.8, 150.4, 147.9, 129.5, 129.4, 125.9, 124.4, 121.0,
120.9, 113.9 ppm; vmax(KBr)/cmꢀ1 3065, 2924, 1600, 1532, 926, 759, 680; HRMSꢀESI
(m/z): calcd for C12H9N3BrS, [M+H]+ : 305.9695, found 305.9694.
(Z)-N-(7-Trifluromethyl-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-aniline
(3ga): yellow solid (34 mg, 38 %); mp = 144 ꢀ 145 oC; 1H NMR (400 MHz, CDCl3) δ
8.29 (d, J = 7.5 Hz, 1H), 7.41 (m, 2H), 7.34 (s, 1H), 7.15 (m, 3H), 6.53 (d, J = 7.5 Hz,
1H); 13C NMR (100 MHz, CDCl3) δ 157.6, 149.7, 147.9, 135.4 (q, J = 34.0 Hz),
129.6, 127.7, 124.7, 123.5, 120.9, 117.8 (q, J = 5.2 Hz), 104.9 (q, J = 2.6 Hz) ppm;
v
max(KBr)/cmꢀ1 3114, 2922, 1596, 1527, 1117, 760, 671; MS (EI, 70 eV): m/z (%) =
295 [M]+, 192, 148, 126, 77. HRMSꢀESI (m/z): calcd for C13H9N3F3S, [M+H]+ :
296.0464, found 296.0462.
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(Z)-N-(6-Methoxyformyl-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-aniline
(3ha): yellow solid (30 mg, 35 %), mp = 142 ꢀ 144 oC; 1H NMR (400 MHz, CDCl3) δ
8.22 (d, J = 7.5 Hz, 1H), 7.74 (s, 1H), 7.40 (m, 2H), 7.14 (m, 3H), 6.94 (d, J = 7.5 Hz,
1H), 3.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.4, 158.1, 151.0, 148.2, 135.0,
129.6, 126.2, 124.5, 122.4, 120.9, 108.1, 53.0 ppm; vmax(KBr)/cmꢀ1 3103, 2924, 1709,
1572, 1249, 1085, 751, 683; HRMSꢀESI (m/z): calcd for C14H12O2N3S, [M+H]+ :
286.0645, found 286.0644.
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(Z)-N-(6-Bromo-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-aniline
(3ia):7f
yellow solid (42 mg, 46 %); mp = 147 ꢀ 149 oC; 1H NMR (400 MHz, CDCl3) δ 8.70 (s,
1H), 7.73 (m, 2H), 7.53 (m, 1H), 7.47 (m, 3H), 7.28 (d, J = 9.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 157.4, 149.5, 147.8, 136.6, 129.5, 125.8, 124.4, 120.9, 119.8,
104.0 ppm; vmax(KBr)/cmꢀ1 3077, 1578, 1230, 1142, 884, 755, 667; MS (EI, 70 eV):
m/z (%) = 304 [M]+, 307, 207, 204, 156, 135, 89, 73.
(Z)-N-(8-Methyl-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-aniline
(3ka):
yellow solid (66 mg, 92 %); mp = 83 ꢀ 84 oC; 1H NMR (400 MHz, CDCl3) 8.10 (d, J
= 7.2 Hz, 1H), 7.39 (m, 2H), 7.20 ꢀ 7.07 (m, 3H), 6.97 (d, J = 6.2 Hz, 1H), 6.37 (m,
1H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.6, 152.1, 148.5, 130.7, 129.4,
128.7, 124.0, 123.7, 121.0, 109.6, 16.6 ppm; vmax(KBr)/cmꢀ1 3076, 2925, 1581, 1517,
1193, 1067, 894, 757; HRMSꢀESI (m/z): calcd for C13H12N3S, [M+H]+ : 242.0746,
found 242.0746.
(Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]quinolin-3-ylidene)amine (3ma): yellow solid
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(62 mg, 75 %), mp = 133 ꢀ 134 oC; 1H NMR (400 MHz, CDCl3) δ 9.89 (d, J = 8.6 Hz,
1H), 7.62 ꢀ 7.54 (m, 1H), 7.51 (d, J = 6.8 Hz, 1H), 7.43 (m, 2H), 7.36 (t, J = 8.6 Hz,
2H), 7.16 (m, 3H), 6.90 (d, J = 9.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 163.2,
152.0, 150.8, 136.0, 134.2, 130.1, 129.8, 127.7, 125.3, 124.4, 123.3, 120.4, 118.5,
117.7 ppm; vmax(KBr)/cmꢀ1 3067, 2924, 1620, 1550, 1442, 1292, 1226, 752, 686;
HRMSꢀESI (m/z): calcd for C16H12N3S, [M+H]+ : 278.0746, found 278.0746.
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(Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]isoquinolin-3-ylidene)amine (3na): yellow
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solid (56mg, 68 %), mp = 172 ꢀ 173 C; H NMR (400 MHz, CDCl3) δ 8.43 (d, J =
7.9 Hz, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.67 ꢀ 7.61 (m, 1H), 7.56 (m, 2H), 7.41 (m, 2H),
7.21 ꢀ 7.10 (m, 3H), 6.74 (d, J = 7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 159.4,
150.4, 148.8, 131.8, 129.6, 128.5, 126.9, 125.2, 124.2, 121.0, 111.0 ppm;
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max(KBr)/cmꢀ12921, 2851, 1572, 1399, 1269, 1004, 757, 677; HRMSꢀESI (m/z):
calcd for C16H12N3S, [M+H]+ : 278.0746, found 278.0748.
(Z)-N-(3H-[1,2,4]Thiadiazolo[3,3-a]quinolin-3-ylidene)amine (3oa): yellow solid
o
(29 mg, 42 %), mp = 79 ꢀ 80 C; 1H NMR (400 MHz, CDCl3) δ 7.43 ꢀ 7.34 (m, 3H),
13
7.16 ꢀ 7.05 (m, 3H), 6.58 (d, J = 4.8 Hz, 1H); C NMR (100 MHz, CDCl3) δ 157.3,
155.8, 148.4, 129.5, 124.4, 120.8, 117.3, 111.2 ppm; vmax(KBr)/cmꢀ1 3109, 2921, 2851,
1575, 1353, 1191, 1079, 913, 822, 757; HRMSꢀESI (m/z): calcd for C10H8N3S2,
[M+H]+ : 234.0154, found 234.0156.
(Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]thiazoles-3-ylidene)-4-methylaniline (3ab):7f
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1
yellow solid (60 mg, 83 %), mp = 104 ꢀ 106 C; H NMR (400 MHz, CDCl3) δ 8.21
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(d, J = 7.1 Hz, 1H), 7.19 (m, 3H), 7.10 ꢀ 6.97 (m, 3H), 6.45 (m, 1H), 2.36 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 158.5, 151.5, 145.9, 133.8, 133.3, 130.1, 126.1, 120.9,
119.3, 109.4, 20.9 ppm; vmax(KBr)/cmꢀ1 3115, 3030, 2975, 1574, 1171, 822, 751; MS
(EI, 70 eV): m/z (%) = 241 [M]+, 183, 124, 91, 78.
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(Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)-4-methoxyaniline (3ac):7f
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yellow solid (65 mg, 85 %), mp = 126 ꢀ 127 C; H NMR (400 MHz, CDCl3) δ 8.20
(d, J = 7.2 Hz, 1H), 7.18 (m, 1H), 7.09 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 9.4 Hz, 1H),
6.94 (d, J = 8.8 Hz, 2H), 6.44 (m, 1H), 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
157.9, 156.3, 151.6, 141.5, 133.3, 126.1, 122.1, 119.3, 114.7, 109.4, 55.4 ppm;
v
max(KBr)/cmꢀ1 2927, 1599, 1503, 1231, 1003, 823, 744; MS (EI, 70 eV): m/z (%) =
257 [M]+, 242, 150, 124, 78.
(Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)-4-fluoroaniline
(3ad):7f
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yellow solid (57 mg, 78 %), mp = 149 ꢀ 151 C; H NMR (400 MHz, CDCl3) δ 8.18
(d, J = 7.2 Hz, 1H), 7.20 (m, 1H), 7.07 (m, 5H), 6.47 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 160.0 (d, J = 128.4 Hz), 158.2, 151.6, 144.7, 133.4, 126.0, 122.4 (d, J = 8.1
Hz), 119.4, 116.2 (d, J = 22.4 Hz), 109.7 ppm; vmax(KBr)/cmꢀ1 3038, 2927, 1609, 1509,
1320, 1098, 821, 746; MS (EI, 70 eV): m/z (%) = 245 [M]+, 187, 124, 78, 51.
(Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)-4-chloroaniline
(3ae):7f
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yellow solid (56 mg, 72 %), mp = 144 ꢀ 145 C; H NMR (400 MHz, CDCl3) δ 8.20
(d, J = 7.2 Hz, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.22 (m, 1H), 7.07 (d, J = 8.4 Hz, 3H),
6.49 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 159.7, 151.6, 147.0, 133.4, 129.5, 129.1,
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(Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)-4-bromoaniline
(3af):
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yellow solid (53 mg, 58 %), mp = 128 ꢀ 130 C; H NMR (400 MHz, CDCl3) δ 8.18
(d, J = 7.2 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.21 (m, 1H), 7.04 (m, 3H), 6.48 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 159.6, 151.5, 147.5, 133.3, 132.5, 125.9, 122.8,
119.4, 116.8, 109.8 ppm; vmax(KBr)/cmꢀ1 2924, 2856, 1599, 1196, 819, 751;
HRMSꢀESI (m/z): calcd for C12H9N3BrS, [M+H]+ : 305.9695, found 305.9695.
(Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)-4-trifluoromethylaniline
(3ag):7f yellow solid (40 mg, 45 %), mp = 150 ꢀ 152 oC; 1H NMR (400 MHz, CDCl3)
δ 8.20 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 8.4 Hz, 3H), 7.08 (d,
J = 9.5 Hz, 1H), 6.50 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 160.6, 151.5, 133.4,
126.7 (q, J = 3.7 Hz), 125.9, 125.8, 125.6, 124.3 (q, J = 270 Hz), 121.2, 119.4, 110.1
ppm; vmax(KBr)/cmꢀ1 3101, 2922, 1578, 1519, 1328, 1102, 836, 743; MS (EI, 70 eV):
m/z (%) = 295 [M]+, 278, 145, 124, 78.
(Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)-4-methoxyformylaniline
(3ah): yellow solid (33 mg, 39 %); mp = 130 ꢀ 132 oC; 1H NMR (400 MHz, CDCl3) δ
8.19 (d, J = 7.2 Hz, 1H), 8.04 (d, J = 8.6 Hz, 2H), 7.23 ꢀ 7.12 (m, 3H), 7.06 (d, J = 9.5
Hz, 1H), 6.53 ꢀ 6.43 (m, 1H), 3.89 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.6,
160.3, 152.5, 151.4, 133.3, 131.2, 125.8, 125.4, 120.9, 119.3, 110.1, 51.8 ppm;
v
max(KBr)/cmꢀ1 2923, 2850, 1697, 1569, 1275, 1107, 845, 750; HRMSꢀESI (m/z):
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(Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)-2-methylaniline
(3ai):
8
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yellow solid (43 mg, 59 %), mp = 85 ꢀ 86 oC; 1H NMR (400 MHz, CDCl3) δ 8.20 (d,
J = 7.2 Hz, 1H), 7.28 ꢀ 7.15 (m, 3H), 7.04 (m, 3H), 6.45 (m, 1H), 2.29 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 158.6, 151.7, 147.4, 133.2, 131.3, 130.9, 126.9, 126.0,
124.3, 119.4, 117.7, 109.5, 17.8 ppm; vmax(KBr)/cmꢀ1 3090, 2925, 1609, 1320, 1252,
745; HRMSꢀESI (m/z): calcd for C13H12N3S, [M+H]+ : 242.0746, found 242.0744.
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(Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)ethyl-1-amine (3ak): yellow
solid (46 mg, 86 %), mp = 78 ꢀ 79 oC; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.2
Hz, 1H), 7.12 (m, 1H), 6.94 (d, J = 9.5 Hz, 1H), 6.38 ꢀ 6.27 (m, 1H), 3.19 (q, J = 7.2
Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.7, 152.3, 133.3,
125.9, 119.3, 108.8, 49.2, 15.4 ppm; vmax(KBr)/cmꢀ1 3073, 2960, 2856, 1627, 1520,
1366, 755; HRMSꢀESI (m/z): calcd for C8H10N3S, [M+H]+ : 180.0590, found
180.0590.
(Z)-N-(7-Methyl-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)ethyl-1-amine
o
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(3bk): yellow solid (53 mg, 90 %), mp = 94 ꢀ 95 C; H NMR (400 MHz, CDCl3) δ
7.82 (d, J = 7.3 Hz, 1H), 6.69 (s, 1H), 6.16 (dd, J = 7.3, 1.2 Hz, 1H), 3.15 (q, J = 7.2
Hz, 2H), 2.20 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.7,
152.5, 144.6, 124.7, 116.6, 111.9, 49.1, 21.3, 15.4 ppm; vmax(KBr)/cmꢀ1 3066, 2962,
2858, 1628, 1533, 1361, 843, 766; HRMSꢀESI (m/z): calcd for C9H12N3S, [M+H]+ :
194.0746, found 194.0745.
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(Z)-N-(7-Methoxy-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)ethyl-1-amine
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o
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(3ck): pale green solid (58 mg, 93 %), mp = 120 ꢀ 122 C; H NMR (400 MHz,
CDCl3) δ 7.85 (d, J = 7.7 Hz, 1H), 6.16 (s, 1H), 6.09 (d, J = 7.7 Hz, 1H), 3.78 (s, 3H),
3.16 (d, J = 6.9 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
163.7, 158.3, 153.4, 125.9, 105.6, 93.8, 55.6, 49.1, 15.4 ppm; vmax(KBr)/cmꢀ1 3047,
2969, 1632, 1547, 1449, 1228, 834, 733; HRMSꢀESI (m/z): calcd for C9H12ON3S,
[M+H]+ : 210.0696, found 210.0696.
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(Z)-N-(7-Bromo-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)ethyl-1-amine
o
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(3fk): yellow solid (41 mg, 53 %), mp = 93 ꢀ 94 C; H NMR (400 MHz, CDCl3) δ
7.81 (d, J = 7.5 Hz, 1H), 7.17 (s, 1H), 6.42 (d, J = 7.5 Hz, 1H), 3.17 (q, J = 7.2 Hz,
2H), 1.31 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 157.5, 151.3, 129.5,
125.9, 121.0, 113.2, 49.3, 15.4 ppm; vmax(KBr)/cmꢀ1 3357, 3072, 2920, 2851, 1636,
1527, 1348, 762; HRMSꢀESI (m/z): calcd for C8H9N3BrS, [M+H]+ : 257.9695, found
257.9694.
(Z)-N-(6-Bromo-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)ethyl-1-amine
(3ik): yellow solid (33 mg, 44 %), mp = 112 ꢀ 114 oC; 1H NMR (400 MHz, CDCl3) δ
8.07 (s, 1H), 7.11 (d, J = 9.8 Hz, 1H), 6.83 (d, J = 9.8 Hz, 1H), 3.17 (q, J = 7.2 Hz,
2H), 1.32 (t, J = 7.2 Hz, 3H).; 13C NMR (100 MHz, CDCl3) δ 156.9, 150.1, 136.4,
125.6, 119.7, 102.9, 49.0, 15.3 ppm; vmax(KBr)/cmꢀ1 3076, 2962, 2855, 1632, 1521,
1316, 1120, 804, 662; HRMSꢀESI (m/z): calcd for C8H9N3BrS, [M+H]+ : 257.9695,
found 257.9695.
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(Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)propan-1-amine
(3al):7f
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yellow solid (42 mg, 72 %), mp = 55 ꢀ 56 oC; 1H NMR (400 MHz, CDCl3) δ 7.93 (d,
J = 7.2 Hz, 1H), 7.15 ꢀ 7.05 (m, 1H), 6.93 (d, J = 9.5 Hz, 1H), 6.31 (m, 1H), 3.09 (m,
2H), 1.73 (dd, J = 14.3, 7.2 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 158.5, 152.2, 133.2, 125.9, 119.2, 108.7, 56.6, 23.8, 12.0 ppm;
vmax(KBr)/cmꢀ1 3092, 2951, 1631, 1530, 1138, 878, 748; MS (EI, 70 eV): m/z (%) =
193 [M]+, 164, 124, 78.
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(Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)propan-2-amine
(3am):7f
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brown liquid (27 mg, 47 %); H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.2 Hz, 1H),
7.17 ꢀ 7.03 (m, 1H), 6.91 (d, J = 9.5 Hz, 1H), 6.29 (m, 1H), 3.13 (m, 1H), 1.23 (q, J =
6.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 157.0, 152.2, 133.3, 126.1, 119.2, 108.5,
56.3, 22.9 ppm; vmax(KBr)/cmꢀ1 3098, 2958, 1627, 1535, 1330, 1143, 747; MS (EI, 70
eV): m/z (%) = 193 [M]+, 178, 124, 78, 51.
(Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)cyclopropanamine (3ao):7f
yellow solid (48 mg, 84 %), mp = 75 ꢀ 76 oC; 1H NMR (400 MHz, CDCl3) δ 7.84 (d,
J = 7.2 Hz, 1H), 7.09 (m, 1H), 6.93 (d, J = 9.5 Hz, 1H), 6.30 (m, 1H), 2.47 ꢀ 2.35 (m,
1H), 0.81 (t, J = 5.9 Hz, 2H), 0.69 ꢀ 0.55 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
161.2, 152.1, 133.1, 125.7, 119.2, 108.8, 35.9, 6.9 ppm; vmax(KBr)/cmꢀ1 3091, 2934,
1621, 1527, 966, 744; MS (EI, 70 eV): m/z (%) = 191 [M]+, 163, 138, 124, 78, 51.
(Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)cyclohexylamine
(3ap):
yellow liquid (29 mg, 42 %); 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 7.2 Hz, 1H),
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7.08 (m, 1H), 6.90 (d, J = 9.4 Hz, 1H), 6.28 (m, 1H), 2.78 (m, 1H), 1.89 ꢀ 1.75 (m,
4H), 1.63 (d, J = 10.7 Hz, 1H), 1.47 ꢀ 1.28 (m, 5H); 13C NMR (100 MHz, CDCl3) δ
156.8, 152.2, 133.3, 126.2, 119.1, 108.5, 64.4, 32.8, 25.7, 24.7 ppm; vmax(KBr)/cmꢀ1
3098, 2925, 1627, 1535, 1322, 1255, 880, 747; HRMSꢀESI (m/z): calcd for
C12H16N3S, [M+H]+ : 234.1059, found 234.1059.
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(Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)naphthyl-1-amine
(3aq):
o
1
yellow solid (52 mg, 62 %), mp = 120 ꢀ 122 C; H NMR (400 MHz, CDCl3) δ 8.40
(m, 2H), 7.89 ꢀ 7.82 (m, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.56 ꢀ 7.41 (m, 3H), 7.20 (m,
2H), 7.08 (d, J = 9.5 Hz, 1H), 6.54 ꢀ 6.45 (m, 1H); 13C NMR (100 MHz, CDCl3) δ
159.3, 151.5, 144.9, 134.5, 133.3, 128.9, 127.8, 126.4, 126.0, 125.9, 125.3, 124.2,
123.6, 119.4, 112.8, 109.8 ppm; vmax(KBr)/cmꢀ1 3046, 2923, 1582, 1389, 1255, 869,
753; HRMSꢀESI (m/z): calcd for C16H12N3S, [M+H]+ : 278.0746, found 278.0747.
(Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)benzylamine (3ar): yellow
solid (68 mg, 94 %), mp = 84 ꢀ 86 oC; 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.2
Hz, 1H), 7.40 (d, J = 7.4 Hz, 2H), 7.33 (m, 2H), 7.25 (m, 1H), 7.10 (m, 1H), 6.95 (d, J
= 9.5 Hz, 1H), 6.32 (m, 1H), 4.35 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 159.8,
152.2, 139.3, 133.2, 128.3, 127.6, 126.9, 125.9, 119.2, 108.9, 57.7 ppm;
v
max(KBr)/cmꢀ1 3032, 2813, 1624, 1528, 1327, 874, 739; HRMSꢀESI (m/z): calcd for
C13H12N3S, [M+H]+ : 242.0746, found 242.0745.
(Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)propenylamine
(3as):
yellow solid (52 mg, 90 %); mp = 65 ꢀ 66 oC; 1H NMR (400 MHz, CDCl3) δ 7.97 (d,
J = 7.2 Hz, 1H), 7.11 (m, 1.4 Hz, 1H), 6.94 (d, J = 9.5 Hz, 1H), 6.40 ꢀ 6.27 (m, 1H),
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6.07 ꢀ 5.90 (m, 1H), 5.32 (m, 1H), 5.16 (m, 1H), 3.79 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 159.9, 152.1, 134.4, 133.2, 125.8, 119.2, 116.1, 108.9, 56.4 ppm;
vmax(KBr)/cmꢀ1 3071, 2923, 2792, 1625, 1522, 1326, 1207, 988, 912, 752; HRMSꢀESI
(m/z): calcd for C9H10N3S, [M+H]+ : 192.0590, found 192.0589.
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General Procedure for Preparation of 5-Amino/Imino-1,2,4-Thiadiazoles:
benzamidines. (0.3 mmol), isothiocyanate (0.45 mmol), CuI (20 mol %) and NaOH
o
(0.30 mmol) were mixed in 1.5 mL DCE to stir under O2 balloon at 50 C. Upon
completion, the reaction mixture was washed by saturated NaCl aqueous solution
(2×10 mL) and then extracted with ethyl acetate (2×10 mL), and the organic layers
were combined, dried over anhydrous MgSO4, filtered, and concentrated under
reduced pressure. The residue was separated by column chromatography (petroleum
ether/ethyl acetate 5:1) to give the pure products.
N,3-Diphenyl-1,2,4-thiadiazol-5-amine (5a):15e yellow solid (64 mg, 85 %); mp =
o
170 ꢀ 171 C; 1H NMR (400 MHz, DMSO) δ 11.05 (s, 1H), 8.20 (d, J = 6.9 Hz, 2H),
7.66 (d, J = 8.0 Hz, 2H), 7.55 ꢀ 7.46 (m, 3H), 7.43 (m, 2H), 7.09 (m, 1H); 13C NMR
(100 MHz, DMSO) δ 179.6, 169.0, 140.4, 133.3, 130.6, 129.8, 129.2, 128.0, 123.3,
118.2 ppm; vmax(KBr)/cmꢀ1 3233, 3080, 2922, 1559, 1447, 1346, 1023, 755, 698; MS
(EI, 70 eV): m/z (%) = 253 [M]+, 150, 135, 103, 91, 77, 65.
N-Phenyl-3-(4-methyphenyl)-1,2,4-thiadiazol-5-amine (5b):15e yellow solid (64 mg,
86 %); mp = 178 ꢀ 180 oC; 1H NMR (400 MHz, DMSO) δ 11.02 (s, 1H), 8.07 (d, J =
8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.43 (m, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.09 (m,
13
1H), 2.36 (s, 3H); C NMR (100 MHz, DMSO) δ 179.5, 169.1, 140.4, 140.3, 130.7,
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129.9, 129.8, 128.0, 123.3, 118.1, 21.5 ppm; vmax(KBr)/cmꢀ1 3227, 3136, 3077, 2921,
1601, 1563, 1441, 1343, 749, 695; MS (EI, 70 eV): m/z (%) = 267 [M]+, 149, 117, 91,
77, 65.
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N-Phenyl-3-(4-methoxyphenyl)-1,2,4-thiadiazol-5-amine (5c): yellow solid (78mg,
o
92 %); mp = 117 ꢀ 118 C; 1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 8.10 (d, J =
8.8 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.40 (m, 2H), 7.05 (m, 3H), 3.80 (s, 3H); 13C
NMR (100 MHz, DMSO) δ 179.4, 168.8, 161.2, 140.4, 129.9, 129.7, 126.1, 123.3,
118.1, 114.5 ppm; vmax(KBr)/cmꢀ1 3221, 3133, 3078, 2964, 1657, 1608, 1447, 1296,
1025, 829, 757, 698; HRMSꢀESI (m/z): calcd for C15H14N3OS, [M+H]+ : 284.0852,
found 284.0848.
N-Phenyl-3-(4-fluroxyphenyl)-1,2,4-thiadiazol-5-amine (5d): yellow solid (67 mg,
82 %); mp = 150 ꢀ 152 oC; 1H NMR (400 MHz, DMSO) δ 11.05 (s, 1H), 8.22 (m, 2H),
7.65 (d, J = 8.0 Hz, 2H), 7.42 (m, 2H), 7.33 (m, 2H), 7.09 (m, 1H); 13C NMR (100
MHz, DMSO) δ 179.7, 168.0, 163.7 (d, J = 246 Hz), 140.3, 130.4 (d, J = 8.7 Hz),
129.9, 129.9, 123.4, 118.2, 116.2 (d, J = 21.7 Hz) ppm; vmax(KBr)/cmꢀ1 3233, 2919,
1650, 1510, 998, 755; HRMSꢀESI (m/z): calcd for C14H11FN3S, [M+H]+ : 272.0652,
found 272.0647.
N-Phenyl-3-(4-chlorophenyl)-1,2,4-thiadiazol-5-amine (5e):15e yellow solid (67 mg,
78 %); mp = 187 ꢀ 189 oC; 1H NMR (400 MHz, DMSO) δ 11.08 (s, 1H), 8.17 (d, J =
8.5 Hz, 2H), 7.65 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.43 (m, 2H), 7.10 m,
1H); 13C NMR (100 MHz, DMSO) δ 179.7, 167.9, 140.3, 135.3, 132.0, 129.9, 129.8,
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129.3, 123.5, 118.2 ppm; vmax(KBr)/cmꢀ1 3236, 3085, 2969, 1663, 1440, 1007, 838,
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751; MS (EI, 70 eV): m/z (%) = 287 [M]+, 169, 150, 137, 110, 77, 65.
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N-Phenyl-3-(4-bromophenyl)-1,2,4-thiadiazol-5-amine (5f):15e yellow solid (71 mg,
72 %); mp = 235 ꢀ 237 oC; 1H NMR (400 MHz, DMSO) δ 11.04 (s, 1H), 8.06 (d, J =
8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 7.38 (m, 2H), 7.06 (m,
1H); 13C NMR (100 MHz, DMSO) δ 179.8, 168.0, 140.2, 132.4, 132.3, 130.0, 129.9,
124.2, 123.5, 118.2 ppm; vmax(KBr)/cmꢀ1 2920, 1656, 1435, 1006, 824, 758; MS (EI,
70 eV): m/z (%) = 333 [M]+, 331, 215, 181, 150, 134, 102, 77, 65.
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N-Phenyl-3-(4-nitrophenyl)-1,2,4-thiadiazol-5-amine (5g):15e yellow solid (59 mg,
66 %); mp = 188 ꢀ 190 oC; 1H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 8.32 (m, 4H),
7.62 (d, J = 8.0 Hz, 2H), 7.42 (m, 2H), 7.10 (m, 1H); 13C NMR (100 MHz, DMSO) δ
179.9, 167.0, 148.5, 140.1, 138.5, 129.9, 129.1, 124.5, 123.6, 118.3 ppm;
v
max(KBr)/cmꢀ1 3441, 2926, 1604, 1560, 1522, 1341, 1025, 822, 760; MS (EI, 70 eV):
m/z (%) = 298 [M]+, 180, 150, 134, 118, 90, 77, 65.
N-Phenyl-3-(4-pyridyl)-1,2,4-thiadiazol-5-amine (5h):15e yellow solid (29 mg,
38 %); mp = 213 ꢀ 215 oC; 1H NMR (400 MHz, DMSO) δ 11.15 (s, 1H), 8.75 (d, J =
5.7 Hz, 2H), 8.05 (d, J = 5.9 Hz, 2H), 7.66 (d, J = 7.9 Hz, 2H), 7.44 (m, 2H), 7.12 (m,
1H); 13C NMR (100 MHz, DMSO) δ 180.1, 167.0, 151.0, 140.1, 139.7, 129.9, 123.6,
121.9, 118.3 ppm; vmax(KBr)/cmꢀ1 3437, 2917, 1659, 1461, 1354, 1000, 824, 766; MS
(EI, 70 eV): m/z (%) = 254 [M]+, 150, 135, 118, 104, 91, 77.
N-Phenyl-3-ethyl-1,2,4-thiadiazol-5-amine (5i):7b yellow solid (47 mg, 83 %); mp =
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108 ꢀ 110 oC; 1H NMR (400 MHz, DMSO) δ 10.86 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H),
7.37 (m, 2H), 7.04 (m, 1H), 2.39 (s, 3H); 13C NMR (100 MHz, DMSO) δ 179.4, 169.8,
140.4, 129.7, 123.1, 118.0, 19.5 ppm; vmax(KBr)/cmꢀ1 3257, 3196, 3073, 2965, 1608,
1554, 1446, 1321, 1043, 816, 756; MS (EI, 70 eV): m/z (%) = 191 [M]+, 150, 122,
118, 91, 77, 73.
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N-Ethyl-3-phenyl-1,2,4-thiadiazol-5-amine (5j): yellow solid (50 mg, 81 %); mp =
o
1
150 ꢀ 151 C; H NMR (400 MHz, DMSO) δ 8.52 (s, 1H), 8.10 (m, 2H), 7.53 ꢀ 7.34
(m, 3H), 3.35 (q, 2H), 1.22 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, DMSO) δ 183.4,
169.0, 133.7, 130.2, 129.0, 128.0, 40.6, 14.6 ppm; vmax(KBr)/cmꢀ1 3242, 2976, 1572,
1463, 1345, 1026, 820, 707; HRMSꢀESI (m/z): calcd for C10H12N3S, [M+H]+ :
206.0746, found 206.0749.
N-tert-Butyl-3-phenyl-1,2,4-thiadiazol-5-amine (5k): yellow liquid (50 mg, 72 %);
1H NMR (400 MHz, DMSO) δ 8.33 (s, 1H), 8.10 (m, 2H), 7.45 (d, J = 7.3 Hz, 3H),
1.44 (s, 9H); 13C NMR (100 MHz, DMSO) δ 181.1, 168.6, 133.8, 130.1, 129.0, 127.9,
53.7, 28.6 ppm; vmax(KBr)/cmꢀ1 3252, 3055, 2972, 1552, 1349, 1215, 1026, 820, 706;
HRMSꢀESI (m/z): calcd for C12H16N3S, [M+H]+ : 234.1059, found 234.1060.
N-Cylclopropyl-3-phenyl-1,2,4-thiadiazol-5-amine (5l): yellow solid (42 mg, 65 %);
o
1
mp = 175 ꢀ 177 C; H NMR (400 MHz, DMSO) δ 9.04 (s, 1H), 8.07 (m, 2H), 7.45
(m, 3H), 2.65 (s, 1H), 0.78 (m, 2H), 0.69 ꢀ 0.54 (m, 2H); 13C NMR (100 MHz, DMSO)
δ 186.0, 169.5, 133.6, 130.3, 129.0, 127.8, 27.2, 7.1 ppm; vmax(KBr)/cmꢀ1 3213, 1656,
1563, 1460, 1344, 1007, 825, 762, 705; HRMSꢀESI (m/z): calcd for C11H12N3S,
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[M+H]+ : 218.0746, found 218.0747.
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N-Propenyl-3-phenyl-1,2,4-thiadiazol-5-amine (5m): yellow liquid (53 mg, 88 %);
1H NMR (400 MHz, DMSO) δ 8.69 (s, 1H), 8.10 (m, 2H), 7.45 (m, 3H), 5.94 (m, 1H),
5.30 (dd, J = 17.2, 1.5 Hz, 1H), 5.18 (dd, J = 10.3, 1.3 Hz, 1H), 4.01 (s, 2H); 13C
NMR (100 MHz, DMSO) δ 183.6, 168.9, 134.3, 133.6, 130.2, 129.0, 128.0, 117.0,
47.8 ppm; vmax(KBr)/cmꢀ1 3227, 3015, 2922, 1566, 1463, 1343, 1009, 926, 818, 771,
707; HRMSꢀESI (m/z): calcd for C11H12N3S, [M+H]+ : 218.0746, found 218.0744.
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(Z)-N-(7-Phenyl-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-aniline (6): yellow
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solid (139 mg, 92 %); mp = 208ꢀ209 C; H NMR (400 MHz, CDCl3) δ 8.25 (d, J =
7.4 Hz, 1H), 7.55 (d, J = 7.5 Hz, 2H), 7.41 (m, 3H), 7.34 (m, 2H), 7.17 (d, J = 3.7 Hz,
1H), 7.13 ꢀ 7.03 (m, 3H), 6.72 (d, J = 7.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
159.4, 152.0, 148.3, 145.9, 136.9, 129.7, 129.6, 129.2, 126.7, 125.9, 124.3, 121.1,
115.2, 110.2 ppm; vmax(KBr)/cmꢀ1 3352, 3057, 2926, 1732, 1583, 1259, 754;
HRMSꢀESI (m/z): calcd for C18H14N3S, [M+H]+ : 304.0903, found 304.0902.
(Z)-N-(7-Phenylethynl-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-aniline (7):
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yellow solid (149 mg, 95 %); mp = 137ꢀ139 C; H NMR (400 MHz, CDCl3) δ 8.13
(d, J = 7.4 Hz, 1H), 7.55 (d, J = 7.4 Hz, 2H), 7.41 (d, J = 11.1 Hz, 5H), 7.20 ꢀ 7.10 (m,
4H), 6.48 (d, J = 7.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 158.3, 150.9, 148.2,
131.9, 129.4, 129.4, 128.6, 128.4, 125.3, 124.2, 121.6, 121.4, 121.0, 111.8, 95.9, 86.4
ppm; vmax(KBr)/cmꢀ1 3052, 2925, 2206, 1580, 1367, 1295, 1080, 954, 756, 684;
HRMSꢀESI (m/z): calcd for C20H14N3S, [M+H]+ : 328.0903, found 328.0902.
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The Journal of Organic Chemistry
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3-phenyl-1,2,4-thiadiazol-5-amine (8):7c yellow solid ( 33 mg, 62 %); mp = 135ꢀ136
oC; 1H NMR (400 MHz, DMSO) δ 8.13 ꢀ 8.06 (m, 2H), 8.04 (s, 2H), 7.46 (d, J = 5.8
Hz, 3H); 13C NMR (100 MHz, DMSO) δ 184.0, 168.9, 133.7, 130.2, 129.0, 127.8
ppm; vmax(KBr)/cmꢀ1 3294, 3139, 2923, 1622, 1523, 1461, 1350, 756, 701; MS (EI, 70
eV): m/z (%) = 177 [M]+, 135, 108, 103, 91, 77, 51.
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Supporting Information
1
Copies of H and 13C NMR spectra data for all compounds. Xꢀray crystallographic
data for 3ak. This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgments
The authors thank the National Key Research and Development Program of China
(2016YFA0602900), the National Natural Science Foundation of China
(21420102003 and 21672072), Guangdong Province Science Foundation
(2017B090903003) and the Fundamental Research Funds for the Central Universities
(2017ZD062) for financial support.
References
(1) (a) Castro, A.; Castano, T.; Encinas, A.; Porcal, W.; Gil, C. Advances in the
Synthesis and Recent Therapeutic Applications of 1,2,4ꢀThiadiazole Heterocycles.
Bioorg. Med. Chem. 2006, 14, 1644ꢀ1652. (b) Iizawa, Y.; Okonogi, K.; Hayashi, R.;
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