Copper-Catalyzed Aerobic Oxidative [3+2] Annulation for Synthesis of

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Copper-Catalyzed Aerobic Oxidative [3+2] Annulation for Synthesis of 5Amino/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 Downloaded from http://pubs.acs.org on July 19, 2018

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The Journal of Organic Chemistry

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*

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) 20-8711-2906; E-mail: [email protected], [email protected]

Abstract:

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 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.

INTRODUCTION 1,2,4-Thiadiazole 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 1,2,4-thiadiazole 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 1,2,4-Thiadiazoles

It is a traditional strategy to use substrate-induced tandem cyclization process for the atom-economic construction of carbon-heteroatom and heteroatom-heteroatom bonds. Compared with the extra directing group, these substrates either with nitrogen


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or sulfur atoms might preferentially bind to the transition-metal catalyst.8 To some extent,

it

is

easily

operated,

economical

and

environmentally

friendly.

2-aminopyridine/amidine have long been realized as one of the most widely used commercial reagents in organic synthesis. In the past few decades, the 2-aminopyridines acted as a directing group provided a basic block for the elegant construction of five or six-membered nitrogen-containing heterocyclic compounds by the formation of N-C9, N-N10, and N-O11 bonds.12 In 2013, our group also developed an efficient method for the synthesis of 2-haloimidazopyridines from aminopyridines and haloalkynes under Cu/O2 catalytic system, in which bidental nitrogen atoms of 2-aminopyridine might coordinate with Cu, and then activated another substrate (Scheme 1).13

Scheme 1. Cyclization of 2-Aminopyridines

On the contrary, the N-S bond formation reaction using 2-aminopyridine as substrate remains challenging14 in despite of great progress of oxidative N-S bond formation via copper-catalyzed aerobic oxidation.15 Isothiocyanates are known to be one of the most important intermediates and versatile building blocks.16 However,



they are limited to the synthesis of thiourea intermediate in most cases, and their sulfur atoms were usually discarded, rendering the transformations non-atom economic. Inspired by our previous work in copper/oxygen catalytic system17,18, we speculated that the intermediate generated from 2-aminopyridine and Cu could also activate and direct the C=S group to form a new N-S bond. Herein, a copper-catalyzed aerobic oxidative cascade reaction of 2-aminopyridine with isothiocyanate leading to the formation of 1,2,4-thiadiazole derivatives is reported.

RESULTS AND DISCUSSION We began our study by choosing 2-aminopyridine (1) and isothiocyanate (2) as model substrates in the presence of catalyst at 50 oC (Table 1). To our delight, the expected 1,2,4-thiadiazole 3 was obtained in 42% yield with CH3CN as the solvent under O2 balloon (entry 1). Then, different solvents were investigated (entries 1-4), and the highest yield was achieved in DCE (entry 3). Subsequently, various copper salts were employed as metal catalysts (entries 5-7), 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 2,4-dimethylpyridine (entries 8-10). 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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a

Entry a

Catalyst

Additive

Solvent

Yield (%) b

1

CuI

-

MeCN

42

2

CuI

-

DMSO

8

3

CuI

-

DCE

55

4

CuI

-

THF

15

5

CuBr2

-

DCE

9

6

CuBr

-

DCE

Trace

7

Cu(OTf)2

-

DCE

Trace

8

CuI

Pyridine

DCE

72

9

CuI

4-CH3-Pyridine

DCE

65

10

CuI

2,4-dimethylpyridine

DCE

88 (83)

11

-


DCE

NR

12c

CuI


DCE

NR

Reaction 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 GC-MS using dodecane as



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the internal standard. The value in parentheses is the isolated yield. NR = no reaction. cUnder N2 atmosphere.

Under

the

optimized

reaction

conditions,

the

substrate

scope

of

2-aminopyridines and isothiocyanates was explored as shown in Table 2. The reactions of electron-rich 2-aminopyridines afforded the products in excellent yields (3aa-3ca, 3bk, 3ck). On the contrary, the reactions of 2-aminopyridines containing electron-poor groups gave desired products in moderate yields and higher yields after prolonging reaction time (3da-3ia, 3fk, 3ik). However, for the substrate with strong electron-withdrawing group, the reaction did not occur and the material was recovered (3ja). Then, the steric hindrance effects in aromatics were examined. The C-3 Table 2. Substrate scope of N-fused 1,2,4-thiadiazoles a


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CuI (20 mol %) R1 2.4-dimethylpyridine (2.0 equiv)

R1 NH2

N

R2 NCS

+

1 X

DCE, 50 oC, O2

N

N R2

2

N S

3

3aa, X=H, 83% X 3ba, X=CH3, 86% 3ca, X=OCH3, 91% N N 3da, X=F, 75% S 3ea, X=Cl, 68% N 3fab, X=Br, 65% b 3ga , X=CF3, 38% 3hab, X=C(CO)OMe, 35%

N

N

N N 3iab, X=Br,46% S 3jac, X=CN, n.r.

N

N

N S

N

N S

3lac, n.r.

3ka, 92% S

N N

N

N S

N

N

N S

N

N S

N N

3ma, 75%

3na, 68%

3oa, 42%

3ab, X=CH3, 83% 3ac, X=OCH3, 85% N 3ad, X=F, 78% S 3ae, X=Cl, 72% 3af, X=Br, 58% 3agb, X=CF3, 45% 3ahb, X=C(CO)OMe, 39% X Br

X N N

N S

N N

N S

N N

3ai, 59%

N N

N N

N

N S

3aq, 62% a

N

N S

3am, 47%

N N

N S

3ar, 94%

N N

N S

3ikb, 44%

3aj, trace

N S

3al, 72%

3ak, X=H. 86% 3bk, X=CH3, 90% N 3ck, X=OCH , 93% 3 S 3fkb, X=Br, 53%

N N

N S

N

3an, trace

N N

N

N S

3ao, 83%

N N

N S

3ap, 42%

N S

3as, 90%

Reaction conditions: 1 (0.30 mmol), 2 (0.45 mmol), CuI (0.060 mmol), and 2,4-dimethylpyridine

(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.



substituted aminopyridine was cycled with excellent yield to deliver 3ka. Unfortunately, the sterically hindered C-6 substituted aminopyridine (3la) did not react with isothiocyanate substrate. The other variants such as 2-aminoquinoline 2-amino(iso)quinolines, and 2-amino(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 electron-withdrawing groups, such as -halo, -CF3, -COOMe at the phenyl ring were obtained in yields ranging from 39% to 78% (3ad-3ah). Similarly, substrates 2 possessing various degrees of steric bulkiness group, such as 2,4,6-trimethylphenyl group (3aj) and tertiary amino group (3an), were detected only in trace amounts. Other substituted isothiocyanates such as N-ethyl (3ak), N-propyl (3al), N-isopropyl (3am), N-cyclopropyl (3ao), N-cyclopentyl (3ap), N-napththyl (3aq), N-benzyl (3ar) and N-propenyl (3as) isothiocyanate were tolerated under the optimized reaction conditions. The structure of 3ak was determined by X-ray single-crystal 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. Considering a successful oxidative cyclization process for the synthesis of N-fused 1,2,4-thiadiazoles, we sought to further extend the scope of this practical approach by replacing 2-aminopyridine (1) with phenylbenzamidines (4) to prepare


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other 1,2,4-thiadiazoles under the optimal reaction conditions. Gratifyingly, choosing the 2.0 equivalent 2,4-dimethylpyridine to 1.0 equivalent NaOH, we were able to prepare substituted 1,2,4-thiadiazoles very efficiently. As shown in Table 3, for amidine hydrochlorides, no significant substituent effect was observed, and excellent yields were obtained for both electron-donating and electron-with-drawing substituents (5a-5g). Isonicotinimidamide hydrochloride could also obtained the corresponding product (5h). It also should be noted that isothiocyanates with various groups, including -ethyl, -tert-butyl, cyclopropyl, and propenyl, were all tolerated under the reaction conditions, and the desired 5-amino-1,2,4-thiadiazole 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 by-products. Table 3. Substrate scope of 5-amino-1,2,4-thiadiazoles a

a

Reaction 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 N-fused 1,2,4-thiadiazole 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 Suzuki-Miyaura 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 2-amino-1,2,4-thiadiazole derivatives,19 which are useful synthons and versatile skeletons in organic synthetic chemistry.

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

(2,2,6,6-tetramethyl-1-piperidinyloxy, free radical) and 1,1-diphenylethene 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 2-aminopyridine (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.

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, electron-rich sulfur atom at isothiocyanate might also bind to the metal copper species. The use of electron-poor 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.

[CuIX],Base N

NH CuI

N

N

S

NH2 HX, HB

S

N R

C R N A

B O2

N N R

NH+ CuI

N S

-H+

N Cu0

N R

S

N CuII

C Cu0

O2

CuI

Scheme 4. Possible reaction mechanism

CONCLUSION In conclusion, we have developed a Cu-catalyzed aerobic oxidative [3+2] annulation of 2-aminopyridine/amidine with isothiocyanate. A plausible mechanism of the transformation is described. This method is useful for synthesizing various N-fused 1,2,4-thiadiazoles. 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 100-400 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 DMSO-d6 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 DMSO-d6 (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. High-resolution mass spectra (ESI) were obtained with a LCMS-IT-TOF mass spectrometer.

General

Procedure

for

Preparation

of

N-Fused

1,2,4-Thiadiazoles:

2-Aminopyridine (0.3 mmol), isothiocyanate (0.45 mmol), CuI (20 mol %) and 2,4-dimethylpyridine (0.6 mmol) were mixed in 1.5 mL DCE to stir under O2 balloon at 50 oC. 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)/cm-1 3114, 3031, 2926, 1580, 1164, 757, 696; MS (EI, 70 eV): m/z (%) = 227 [M]+, 169, 124, 78, 51.

(Z)-N-(7-Methyl-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-aniline

(3ba):7f

yellow solid (62 mg, 86 %), mp = 105 - 106 oC; 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)/cm-1 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):

yellow solid (70 mg, 91 %), mp = 157 - 158 oC; 1H 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)/cm-1 3077, 2924, 1645, 1546, 1230, 766, 692; MS (EI, 70 eV): m/z (%) = 257 [M]+, 154, 135, 108, 77; HRMS-ESI (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); 13

C 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)/cm-1 3067, 2923, 1656, 1597, 1177, 950, 758; HRMS-ESI


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(m/z): calcd for C12H9N3FS, [M+H]+ : 246.0496, found 246.0494. (Z)-N-(7-Chloro-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-aniline

(3ea):

yellow solid (53 mg, 68 %), mp = 120 - 122 oC; 1H 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); 13

C 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)/cm-1 3100, 2923, 1604, 1529, 1449, 756, 677; HRMS-ESI (m/z): calcd for C12H9N3ClS, [M+H]+ : 262.0200, found 262.0200. (Z)-N-(7-Bromo-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-aniline

(3fa):

yellow solid (59 mg, 65 %), mp = 130 - 132 oC; 1H 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); 13

C 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)/cm-1 3065, 2924, 1600, 1532, 926, 759, 680; HRMS-ESI (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);

13

C 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; vmax(KBr)/cm-1 3114, 2922, 1596, 1527, 1117, 760, 671; MS (EI, 70 eV): m/z (%) = 295 [M]+, 192, 148, 126, 77. HRMS-ESI (m/z): calcd for C13H9N3F3S, [M+H]+ : 296.0464, found 296.0462.



Page 16 of 42

(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)/cm-1 3103, 2924, 1709, 1572, 1249, 1085, 751, 683; HRMS-ESI (m/z): calcd for C14H12O2N3S, [M+H]+ : 286.0645, found 286.0644. (3ia):7f

(Z)-N-(6-Bromo-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-aniline

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);

13

C 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)/cm-1 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)/cm-1 3076, 2925, 1581, 1517, 1193, 1067, 894, 757; HRMS-ESI (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);

13

C 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)/cm-1 3067, 2924, 1620, 1550, 1442, 1292, 1226, 752, 686; HRMS-ESI (m/z): calcd for C16H12N3S, [M+H]+ : 278.0746, found 278.0746. (Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]isoquinolin-3-ylidene)amine

(3na):

yellow

solid (56mg, 68 %), mp = 172 - 173 oC; 1H 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; vmax(KBr)/cm-12921, 2851, 1572, 1399, 1269, 1004, 757, 677; HRMS-ESI (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 (29 mg, 42 %), mp = 79 - 80 oC; 1H NMR (400 MHz, CDCl3) δ 7.43 - 7.34 (m, 3H), 7.16 - 7.05 (m, 3H), 6.58 (d, J = 4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 157.3, 155.8, 148.4, 129.5, 124.4, 120.8, 117.3, 111.2 ppm; vmax(KBr)/cm-1 3109, 2921, 2851, 1575, 1353, 1191, 1079, 913, 822, 757; HRMS-ESI (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

yellow solid (60 mg, 83 %), mp = 104 - 106 oC; 1H NMR (400 MHz, CDCl3) δ 8.21



Page 18 of 42

(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)/cm-1 3115, 3030, 2975, 1574, 1171, 822, 751; MS (EI, 70 eV): m/z (%) = 241 [M]+, 183, 124, 91, 78.

(Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)-4-methoxyaniline

(3ac):7f

yellow solid (65 mg, 85 %), mp = 126 - 127 oC; 1H 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; vmax(KBr)/cm-1 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

yellow solid (57 mg, 78 %), mp = 149 - 151 oC; 1H 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)/cm-1 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

yellow solid (56 mg, 72 %), mp = 144 - 145 oC; 1H 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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126.0, 122.4, 119.4, 109.9 ppm; vmax(KBr)/cm-1 3296, 2924, 1587, 1248, 756, 652; MS (EI, 70 eV): m/z (%) = 261 [M]+, 169, 137, 124, 78.

(Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)-4-bromoaniline

(3af):

yellow solid (53 mg, 58 %), mp = 128 - 130 oC; 1H 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)/cm-1 2924, 2856, 1599, 1196, 819, 751; HRMS-ESI (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);

13

C 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)/cm-1 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);

13

C 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; vmax(KBr)/cm-1 2923, 2850, 1697, 1569, 1275, 1107, 845, 750; HRMS-ESI (m/z):



Page 20 of 42

calcd for C14H12O2N3S, [M+H]+ : 286.0645, found 286.0645. (Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)-2-methylaniline

(3ai):

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)/cm-1 3090, 2925, 1609, 1320, 1252, 745; HRMS-ESI (m/z): calcd for C13H12N3S, [M+H]+ : 242.0746, found 242.0744. (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)/cm-1 3073, 2960, 2856, 1627, 1520, 1366, 755; HRMS-ESI (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 (3bk): yellow solid (53 mg, 90 %), mp = 94 - 95 oC; 1H 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)/cm-1 3066, 2962, 2858, 1628, 1533, 1361, 843, 766; HRMS-ESI (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 (3ck): pale green solid (58 mg, 93 %), mp = 120 - 122 oC; 1H 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);

13

C 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)/cm-1 3047, 2969, 1632, 1547, 1449, 1228, 834, 733; HRMS-ESI (m/z): calcd for C9H12ON3S, [M+H]+ : 210.0696, found 210.0696.

(Z)-N-(7-Bromo-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)ethyl-1-amine (3fk): yellow solid (41 mg, 53 %), mp = 93 - 94 oC; 1H 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);

13

C NMR (100 MHz, CDCl3) δ 157.5, 151.3, 129.5,

125.9, 121.0, 113.2, 49.3, 15.4 ppm; vmax(KBr)/cm-1 3357, 3072, 2920, 2851, 1636, 1527, 1348, 762; HRMS-ESI (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).;

13

C NMR (100 MHz, CDCl3) δ 156.9, 150.1, 136.4,

125.6, 119.7, 102.9, 49.0, 15.3 ppm; vmax(KBr)/cm-1 3076, 2962, 2855, 1632, 1521, 1316, 1120, 804, 662; HRMS-ESI (m/z): calcd for C8H9N3BrS, [M+H]+ : 257.9695, found 257.9695.



(Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)propan-1-amine

Page 22 of 42

(3al):7f

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)/cm-1 3092, 2951, 1631, 1530, 1138, 878, 748; MS (EI, 70 eV): m/z (%) = 193 [M]+, 164, 124, 78.

(Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)propan-2-amine

(3am):7f

brown liquid (27 mg, 47 %); 1H 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)/cm-1 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);

13


161.2, 152.1, 133.1, 125.7, 119.2, 108.8, 35.9, 6.9 ppm; vmax(KBr)/cm-1 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)/cm-1 3098, 2925, 1627, 1535, 1322, 1255, 880, 747; HRMS-ESI (m/z): calcd for C12H16N3S, [M+H]+ : 234.1059, found 234.1059. (Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)naphthyl-1-amine

(3aq):

yellow solid (52 mg, 62 %), mp = 120 - 122 oC; 1H 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);

13


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)/cm-1 3046, 2923, 1582, 1389, 1255, 869, 753; HRMS-ESI (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);

13

C 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; vmax(KBr)/cm-1 3032, 2813, 1624, 1528, 1327, 874, 739; HRMS-ESI (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),



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)/cm-1 3071, 2923, 2792, 1625, 1522, 1326, 1207, 988, 912, 752; HRMS-ESI (m/z): calcd for C9H10N3S, [M+H]+ : 192.0590, found 192.0589. 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 (0.30 mmol) were mixed in 1.5 mL DCE to stir under O2 balloon at 50 oC. 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 = 170 - 171 oC; 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)/cm-1 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, 1H), 2.36 (s, 3H); 13C NMR (100 MHz, DMSO) δ 179.5, 169.1, 140.4, 140.3, 130.7, ACS Paragon Plus Environment

Page 24 of 42

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129.9, 129.8, 128.0, 123.3, 118.1, 21.5 ppm; vmax(KBr)/cm-1 3227, 3136, 3077, 2921, 1601, 1563, 1441, 1343, 749, 695; MS (EI, 70 eV): m/z (%) = 267 [M]+, 149, 117, 91, 77, 65.

N-Phenyl-3-(4-methoxyphenyl)-1,2,4-thiadiazol-5-amine (5c): yellow solid (78mg, 92 %); mp = 117 - 118 oC; 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)/cm-1 3221, 3133, 3078, 2964, 1657, 1608, 1447, 1296, 1025, 829, 757, 698; HRMS-ESI (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)/cm-1 3233, 2919, 1650, 1510, 998, 755; HRMS-ESI (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,



129.3, 123.5, 118.2 ppm; vmax(KBr)/cm-1 3236, 3085, 2969, 1663, 1440, 1007, 838, 751; MS (EI, 70 eV): m/z (%) = 287 [M]+, 169, 150, 137, 110, 77, 65. 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)/cm-1 2920, 1656, 1435, 1006, 824, 758; MS (EI, 70 eV): m/z (%) = 333 [M]+, 331, 215, 181, 150, 134, 102, 77, 65. 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; vmax(KBr)/cm-1 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)/cm-1 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 =


Page 26 of 42

Page 27 of 42 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


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)/cm-1 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.

N-Ethyl-3-phenyl-1,2,4-thiadiazol-5-amine (5j): yellow solid (50 mg, 81 %); mp = 150 - 151 oC; 1H 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)/cm-1 3242, 2976, 1572, 1463, 1345, 1026, 820, 707; HRMS-ESI (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 %); 1

H 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)/cm-1 3252, 3055, 2972, 1552, 1349, 1215, 1026, 820, 706; HRMS-ESI (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 %); mp = 175 - 177 oC; 1H 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)/cm-1 3213, 1656, 1563, 1460, 1344, 1007, 825, 762, 705; HRMS-ESI (m/z): calcd for C11H12N3S,



Page 28 of 42

[M+H]+ : 218.0746, found 218.0747.

N-Propenyl-3-phenyl-1,2,4-thiadiazol-5-amine (5m): yellow liquid (53 mg, 88 %); 1

H 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);

13

C

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)/cm-1 3227, 3015, 2922, 1566, 1463, 1343, 1009, 926, 818, 771, 707; HRMS-ESI (m/z): calcd for C11H12N3S, [M+H]+ : 218.0746, found 218.0744. (Z)-N-(7-Phenyl-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3-ylidene)-aniline (6): yellow solid (139 mg, 92 %); mp = 208-209 oC; 1H 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);

13


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)/cm-1 3352, 3057, 2926, 1732, 1583, 1259, 754; HRMS-ESI (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): yellow solid (149 mg, 95 %); mp = 137-139 oC; 1H 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);

13

C 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)/cm-1 3052, 2925, 2206, 1580, 1367, 1295, 1080, 954, 756, 684; HRMS-ESI (m/z): calcd for C20H14N3S, [M+H]+ : 328.0903, found 328.0902.


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3-phenyl-1,2,4-thiadiazol-5-amine (8):7c yellow solid ( 33 mg, 62 %); mp = 135-136 o

C; 1H NMR (400 MHz, DMSO) δ

Hz, 3H);

13

8.13 - 8.06 (m, 2H), 8.04 (s, 2H), 7.46 (d, J = 5.8

C NMR (100 MHz, DMSO) δ 184.0, 168.9, 133.7, 130.2, 129.0, 127.8

ppm; vmax(KBr)/cm-1 3294, 3139, 2923, 1622, 1523, 1461, 1350, 756, 701; MS (EI, 70 eV): m/z (%) = 177 [M]+, 135, 108, 103, 91, 77, 51.

Supporting Information Copies of 1H and

13

C NMR spectra data for all compounds. X-ray 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

(21420102003

21672072),

and

National

Natural Guangdong

Science Province

Foundation Science

of

China

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 1,2,4-Thiadiazole Heterocycles. Bioorg. Med. Chem. 2006, 14, 1644-1652. (b) Iizawa, Y.; Okonogi, K.; Hayashi, R.; ACS Paragon Plus Environment


Iwahi, T.; Yamazaki, T.; Imada, A. Therapeutic Effect of Cefozopran (SCE-2787), a New Parenteral Cephalosporin, against Experimental Infections in Mice. Antimicrob. Agents Chemother. 1993, 37, 100-105.

(2)

(a) Huang, D.; Luthi, U.; Kolb, P.; Edler, K.; Cecchini, M.; Audetat, S.; Barberis,

A.; Caflisch. A. Discovery of Cell-Permeable Non-Peptide Inhibitors of β-Secretase by High-Throughput Docking and Continuum Electrostatics Calculations. J. Med. Chem. 2005, 48, 5108-5111. (b) Gurjar, A. S.; Andrisano, V.; Simone, A. D.; Velingkar, V. S. Design, Synthesis, in Silico and in Vitro Screening of 1,2,4-Thiadiazole Analogues as Non-Peptide Inhibitors of Beta-secretase. Bioorg. Chem. 2014, 57, 90-98.

(3)

Perlovich, G. L.; Proshin, A. N.; Volkova, T. V.; Petrova, L. N.; Bachurin, S. O.

Novel 1,2,4-Thiadiazole Derivatives as Potent Neuroprotectors: Approach to Creation of Bioavailable Drugs. Mol. Pharmaceutics 2012, 9, 2156-2167.

(4)

(a) Kumar, D.; Maruthi-Kumar, N.; Chang, K.-H.; Gupta, R.; Shah, K. Synthesis

and In-vitro Anticancer Activity of 3,5-Bis(indolyl)-1,2,4-thiadiazoles. Bioorg. Med. Chem. Lett. 2011, 21, 5897-5900. (b) Romagnoli, R.; Baraldi, P. G.; Carrion, M. G.; Cruz-Lopez, O.; Preti, D.; Tabrizi, M. A.; Fruttarolo, F.; Heilmann, J.; Bermejo, J.; Estevez, F. Hybrid Molecules Containing Benzo[4,5]imidazo-[1,2-d][1,2,4]thiadiazole and a-Bromoacryloyl Moieties as Potent Apoptosis Inducers on Human Myeloid Leukaemia Cells. Bioorg. Med. Chem. Lett. 2007, 17, 2844-2848. (c) Leung-Toung, R.; Wodzinska, J.; Li, W.; Lowrie, J.; Kukreja, R.; Desilets, D.; Karimian, K.; Tam, T.


Page 30 of 42

Page 31 of 42 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


F. 1,2,4-Thiadiazole: A Novel Cathepsin B Inhibitor. Bioorg. Med. Chem. 2003, 11, 5529-5537. (d) van den Nieuwendijk, A. M. C. H.; Pietra, D.; Heitman, L.; Goblyos, A.; IJzerman, A. P. Synthesis and Biological Evaluation of 2,3,5-Substituted [1,2,4]Thiadiazoles as Allosteric Modulators of Adenosine Receptors. J. Med. Chem. 2004, 47, 663-672. (e) Leung-Toung, R.; Tam, T. F.; Wodzinska, J. M.; Zhao, Y.; Lowrie,

J.;

Simpson,

C.

D.;

Karimian,

K.;

Spino,

M.

3-Substituted

Imidazo[1,2-d][1,2,4]-thiadiazoles: A Novel Class of Factor XIIIa Inhibitors. J. Med. Chem. 2005, 48, 2266-2269. (f) Martinez, A.; Alonso, M.; Castro, A.; Perez, C.; Moreno, F. J. First Non-ATP Competitive Glycogen Synthase Kinase 3 β (GSK-3β) Inhibitors: Thiadiazolidinones (TDZD) as Potential Drugs for the Treatment of Alzheimer’s Disease. J. Med. Chem. 2002, 45, 1292-1299. (g) Unangst, P. C.; Shrum, G. P.; Connor, D. T.; Dyer, R. D.; Schrier, D. J. Novel 1,2,4-Oxadiazeles and 1,2,4-Thiadiazoles as Dual 5-Lipoxygenase and Cyclooxygenase Inhibitors. J. Med. Chem. 1992, 35, 3691-3698.

(5)

(a) Yamanaka, T.; Ohki, H.; Ohgaki, M.; Okuda, S.; Toda, A.; Kawabata, K.;.

Inoue, S.; Misumi, K.; Itoh, K.; Satoh, K. Processing of Ditital Images. U.S. Patent US 2005004094 A1, 2005. (b) Kharimian, K.; Tam, T. F.; Leung-Toung, R. C.; Li, W. Thiadiazole Compounds Useful as Inhibitors of H/K Atpase. PCT Int. Appl. WO 9951584 A1, 1999. (c) Johnstone, C.; Mckerrecher, D.; Pike, K. G.; Waring, M. J. Preparation of N-Heteroaryl Aryloxy-substituted Benzamide Derivatives for Use as Glk Activators in the Treatment of Diabetes. PCT Int. Appl. WO 2005121110 A1, 2005.

(d)

Burk,

G.

A.


Mixan,

C.

E.


Page 32 of 42

Antimicrobial-bis[(5-nitro-2-thiazolyl)thio]isothiazoles and -Thiadiazoles. U.S. Patent US

4209522

A,

1980.

(e)

Katz.

L.

E.

Selected

5-Hydrazino-3-trichloromethyl-1,2,4-thiadiazoles and Their Use as Foliar Fungicides. U.S. Patent US 4263312 A, 1981. (f) Gay. W. A. Thiolcarbamate Derivatives of 3-Trihalomethyl-1,2,4-thiadiazoles and Their Use as Herbicides. U.S. Patent US 4207089 A, 1980.

(6)

(a) Potts, K. T.; Kane, J. M. Synthesis of Ring-Fused 1,2,4-Thiadiazoles.

Synthesis 1986, 12, 1027-1029. (b) Potts, K. T.; Armbruster, R. Bridgehead Nitrogen Heterocycles.

V.

Some

3H-[1,2,4]Thiadiazolo[4,3-a]pyridines

Derived

from

2-Trichloromethylthioaminopyridine. J. Org. Chem. 1971, 36, 1846-1848. (c) Hennrich, G.; Sonnenschein, H.; Resch-Genger, U. Fluorescent Anion Receptors with Iminoylthiourea Binding Sites-selective Hydrogen Bond Mediated Recognition of CO32-, HCO3- and HPO42-. Tetrahedron Lett. 2001, 42, 2805-2808. (d) Patil, P. C.; Bhalerao, D. S.; Dangate, P. S.; Akamanchi, K. G. IBX/TEAB-mediated Oxidative Dimerization of Thioamides: Synthesis of 3,5-Disubstituted 1,2,4-Thiadiazoles. Tetrahedron Lett. 2009, 50, 5820-5822. (e) Mayhoub, A. S.; Kiselev, E.; Cushman, M. An Unexpected Synthesis of 3,5-Diaryl-1,2,4-Thiadiazoles from Thiobenzamides and Methyl Bromocyanoacetate. Tetrahedron Lett. 2011, 52, 4941-4943. (f) Cheng, D.; Luo, R.; Zheng, W.; Yan, J. Highly Efficient Oxidative Dimerization of Thioamides to 3,5-Disubstituted 1,2,4-Thiadiazoles Mediated by DDQ. Synth. Commun. 2012, 42, 2007-2013. (g) Leung-Toung, R.; Tam, T. F.; Zhao, Y.; Simpson, C. D.; Li, W.; Desilets,

D.;

Karimian,

K.

Synthesis

of


3-Substituted

Bicyclic

Page 33 of 42 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Imidazo[1,2-d][1,2,4]thiadiazoles

and

Tricyclic

Benzo[4,5]imidazo[1,2-d][1,2,4]thiadiazoles. J. Org. Chem. 2005, 70, 6230-6241.

(7)

(a) Noei, J.; Khosropour, A. R. A Novel Process for the Synthesis of

3,5-Diaryl-1,2,4-Thiadiazoles from Aryl Nitriles. Tetrahedron Lett. 2013, 54, 9-11. (b) Kim, H.-Y.; Kwak, S. H.; Lee, G.-H.; Gong, Y.-D. Copper-Catalyzed Synthesis of 3-Substituted-5-amino-1,2,4-thiadiazoles via Intramolecular N-S Bond Formation. Tetrahedron 2014, 70, 8737-8743. (c) Wehn, P. M.; Harrington, P. E.; Eksterowicz, J. E. Facile Synthesis of Substituted 5-Amino- and 3-Amino-1,2,4-thiadiazoles from a Common Precursor Org. Lett., 2009, 11, 5666-5669. (d) Niu, P.; Kang, J.; Tian, X.; Song, L.; Liu, H.; Wu, J.; Yu, W.; Chang, J. Synthesis of 2-Amino-1,3,4-oxadiazoles and 2-Amino-1,3,4-thiadiazoles via Sequential Condensation and I2-Mediated Oxidative C-O/C-S Bond Formation. J. Org. Chem. 2015, 80, 1018-1024. (e) Frija, L. M. T.; Pombeiro, A. J. L.; Kopylovich, M. N. Building 1,2,4-Thiadiazole: Ten Years of Progress. Eur. J. Org. Chem. 2017, 19, 2670-2682. (f) Tumula, N.; Jatangi, N.; Palakodety, R. K.; Balasubramanian, S.; Nakka, M. I2-Catalyzed Oxidative N-S Bond Formation: Metal-Free Regiospecific Synthesis of N-Fused and 3,4-Disubstituted 5-Imino-1,2,4-thiadiazoles. J. Org. Chem. 2017, 82, 5310-5316. (g) Wang, B.; Meng, Y.; Zhou, Y.; Ren, L.; Wu, J.; Yu, W.; Chang, J. Synthesis of 5-Amino and 3,5-Diamino Substituted 1,2,4-Thiadiazoles by I2-Mediated Oxidative N-S Bond Formation. J. Org. Chem. 2017, 82, 5898-5903. (h) Mariappan, A.; Rajaguru, K.; Chola, N. M.; Muthusubramanian, S.; Bhuvanesh, N. Hypervalent Iodine(III) Mediated

Synthesis

of

3-Substituted

5-Amino-1,2,4-thiadiazoles


through


Page 34 of 42

Intramolecular Oxidative S-N Bond Formation. J. Org. Chem. 2016, 81, 6573-6579. (i) Jatangi, N.; Tumula, N.; Palakodety, R. K.; Nakka, M. I2-Mediated Oxidative C-N and N-S Bond Formation in Water: A Metal-Free Synthesis of 4,5-Disubstituted/N-Fused 3-Amino-1,2,4-triazoles and 3-Substituted 5-Amino-1,2,4-thiadiazoles. J. Org. Chem 2018, 83, 5715-5723.

(8)

Shang, M.; Wang, M.-M.; Saint-Denis, T. G.; Li, M.-H.; Dai, H.-X.; Yu, J.-Q.

Copper-Mediated Late-Stage Functionalization of Heterocycle-Containing Molecules. Angew. Chem. Int. Ed. 2017, 56, 5317-5321.

(9)

(a) Xie, Y.; Wu, J.; Che, X.; Chen, Y.; Huang. H.; Deng, G.-J. Efficient

Pyrido[1,2-a]benzimidazole Formation from 2-Aminopyridines and Cyclohexanones under Metal-free Conditions. Green Chem. 2016, 18, 667-671. (b) Manna, S.; Matcha, K.; Antonchick, A. P. Metal-Free Annulation of Arenes with 2-Aminopyridine Derivatives: The Methyl Group as a Traceless Non-Chelating Directing Group. Angew. Chem. Int. Ed., 2014, 53, 8163-8166. (c) Mukhopadhyay, S.; Dighe, S. U.; Kolle, S.; Shukla, P. K.; Batra, S. NaNO2/I2-Mediated Regioselective Synthesis of Nitrosoimidazoheterocycles from Acetophenones by a Domino Process. Eur. J. Org. Chem. 2016, 22, 3836-3844. (d) Qian, G.; Liu, B.; Tan, Q.; Zhang, S.; Xu, B. Hypervalent Iodine(III) Promoted Direct Synthesis of Imidazo[1,2-a]pyrimidines. Eur. J. Org. Chem. 2014, 22, 4837-4843. (e) Wang, H.; Wang, Y.; Liang, D.; Liu, L.; Zhang,

J.;

Zhu,

Q.

Copper-Catalyzed

Intramolecular

Dehydrogenative

Aminooxygenation: Direct Access to Formyl-Substituted Aromatic N-Heterocycles. Angew. Chem. Int. Ed., 2011, 50, 5678-5678. (f) Rasheed, S.; Nageswar Rao, D.; Das, ACS Paragon Plus Environment

Page 35 of 42 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


P. Copper-Catalyzed Inter- and Intramolecular C-N Bond Formation:Synthesis of Benzimidazole-Fused Heterocycles. J. Org. Chem. 2015, 80, 9321-9327. (g) Zhao, D.; Hu, J.; Wu, N.; Huang, X.; Qin, X.; Lan, J.; You, J. Regiospecific Synthesis of 1,2-Disubstituted (Hetero)aryl Fused Imidazoles with Tunable Fluorescent Emission. Org. Lett. 2011, 13, 6516-6519.

(10)

(a) Ueda, S.; Nagasawa, H. J. Am. Chem. Soc. Facile Synthesis of

1,2,4-Triazoles via a Copper-Catalyzed Tandem Addition-Oxidative Cyclization. 2009, 131, 15080-15081. (b) Ma, Y.; Wei, S.; Lan, J.; Wang, J.; Xie, R.; You, J. Pyrido[1,2-a][1,2,4]triazol-3-ylidenes as a New Family of Stable Annulated N-Heterocyclic Carbenes: Synthesis,

Reactivity,

and Their Application in

Coordination Chemistry and Organocatalysis. J. Org. Chem. 2008, 73, 8256-8264. (c) Pandurangan, K.; Aletti, A. B.; Montroni, D.; Kitchen, J. A.; Martínez-Calvo, M.; Blasco, S.; Gunnlaugsson, T.; Scanlan, E. M. Supramolecular Anion Recognition Mediates

One-Pot

Synthesis

of

3-Amino-[1,2,4]-triazolo

Pyridines

from

Thiosemicarbazides. Org. Lett. 2017, 19, 1068-1071. (d) Bergamini, G.; Bell, K.; Shimamura, S.; Werner, T.; Cansfield, A.; Müller, K.; Perrin, J.; Rau, C.; Ellard, K.; Hopf, C.; Doce, C.; Leggate, D.; Mangano, R.; Mathieson, T.; Mahony, A.; Plavec, I.; Rharbaoui, F.; Reinhard, F.; Savitski, M. M.; Ramsden, N.; Hirsch, E.; Drewes, G.; Rausch, O.; Bantscheff, M.; Neubauer, G. A Selective Inhibitor Reveals pl3Kγ Dependence of TH17 Cell Differentiation. Nat. Chem. Biol. 2012, 8, 576-582. (e) Ishimoto, K.; Nagata, T.; Murabayashi, M.; Ikemoto, T. Oxidative Cyclization of 1-(pyridin-2-yl)Guanidine

Derivatives:

a


Synthesis

of


[1,2,4]Triazolo[1,5-a]pyridin-2-amines

and

an

Unexpected

Page 36 of 42

Synthesis

of

[1,2,4]Triazolo[4,3-a]pyridin-3-amines. Tetrahedron 2015, 71, 407-418. (f) Filak, L.; Riedl, Z.; Egyed, O.; Czugler, M.; Hoang, C. N.; Schantl, J. G.; Hajos, G. A New Synthesis of the Linearly Fused [1,2,4]Triazolo[1,5-b]isoquinoline Ring. Observation of an Unexpected Dimroth Rearrangement. Tetrahedron 2008, 64, 1101-1113. (g) Palko, R.; Egyed, O.; Riedl, Z.; Rokob, T. A.; Hajos, G. Rearrangement of Aryl- and Benzylthiopyridinium Imides with Participation of a Methyl Substituent. J. Org. Chem. 2011, 76, 9362-9369.

(11)

Clarkson, R.; Dowell, R. I.; Taylor, P. J. The Reversible Cation-Anion

Isomerisation of 2-Imino-2H-pyrido[1,2-b][1,2,4]thia(oxa)diazole Hydrobromide. Tetrahedron Lett. 1982, 23, 485-488.

(12)

(a) Renard, B.-L.; Boucherle, B.; Maurin, B.; Molina, M.-C.; Norez, C.; Becq,

F.; ellor, J.; Merriman, G. D.; Rataj, H.; Reid, G. Direct Synthesis of 3,4-Dihydro-2H-pyrido[1,2-a]pyrimidines,

by

Addition

Reactions

with

2-Aminopyridines. Tetrahedron Lett. 1996, 37, 2615-2618. (b) Chen, J.; Natte, K.; Spannenberg, A.; Neumann, H.; Langer, P.; Beller, M.; Wu, X.-F. Base-Controlled Selectivity in the Synthesis of Linear and Angular Fused Quinazolinones by a Palladium-Catalyzed Carbonylation/Nucleophilic Aromatic Substitution Sequence. Angew. Chem. Int. Ed. 2014, 53, 7579-7583. (c) Xu, T.; Alper, H. Synthesis of Pyrido[2,1-b]quinazolin-11-ones and Dipyrido[1,2-a:2’,3’-d]pyrimidin-5-ones by Pd/DIBPP-Catalyzed Dearomatizing Carbonylation. Org. Lett. 2015, 17, 1569-1572. (d) Chen, J.; Feng, J. -B.; Natte, K.; Wu, X.-F. Palladium-Catalyzed Carbonylative ACS Paragon Plus Environment

Page 37 of 42 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Cyclization of Arenes by C-H Bond Activation with DMF as the Carbonyl Source. Chem. Eur. J. 2015, 21, 16370-16373. (e) Sun, J.; Tan, Q.; Yang, W.; Liu, B.; Xu, B. Copper-Catalyzed Aerobic Oxidative Annulation and Carbon-Carbon Bond Cleavage of Arylacetamides: Domino Synthesis of Fused Quinazolinones. Adv. Synth. Catal. 2014, 356, 388-394. (f) Sinan, M.; Panda, M.; Ghosh, A.; Dhara, K.; Fanwick, P. E.; Chattopadhyay, D. J.; Goswami, S. Mild Synthesis of a Family of Planar Triazinium Cations via Proton-Assisted Cyclization of Pyridyl Containing Azo Compounds and Studies on DNA Intercalation. J. Am. Chem. Soc. 2008, 130, 5185-5193.

(13)

Gao, Y.; Yin, M.; Wu, W.; Huang, H.; Jiang, H. Copper-Catalyzed

Intermolecular Oxidative Cyclization of Halo-alkyne: Synthesis of 2-Halo-substituted Imidazo[1,2-a]pyridines, Imidazo[1,2-a]pyrazines and Imidazo[1,2-a]pyrimidines. Adv. Synth. Catal. 2013, 355, 2263-2273.

(14)

(a) Mitchell, J. A.; Reid, D. H. Studies of Heterocyclic Compounds. Part 28.1

Condensation

of

3-Substituted

5-Phenyl-1,2-dithiolylium

Salts

with

2-Amino-N-heterocycles. J. Chem. Soc., Perkin Trans. 1, 1982, 0, 499-507. (b) Tian, L.;

Song,

J.;

Wang,

J.;

Liu,

B.

Synthesis

and

Bioactivity

of

N-Cyclopropanecarboxyl-N’-pyridin-2-yl Thiourea Derivatives and Related Fused Ring Compounds. Chin. Chem. Lett. 2009, 20, 288-291. (c) Adhami, F.; Safavi, M.; Ehsani, M.; Ardestani, S. K.; Emmerling, F.; Simyari, F. Synthesis, Crystal Structure, and Cytotoxic Activity of Novel Cyclic Systems in [1,2,4]Thiadiazolo[2,3-a]-pyridine Benzamide Derivatives and Their Copper(II) Complexes. Dalton Trans. 2014, 43, 7945-7957. (d) Vercek, B.; Stanovnik, B.; Tisler, M. Synthesis and Reactivity of ACS Paragon Plus Environment


Page 38 of 42

1,2,4-Thiadiazolo-[2,3-a]pyridines and Some Related Systems. Heterocycles 1978, 11, 313-318. (e) Wang, Z.; Xie, H.; Xiao, F.; Guo, Y.; Huang, H.; Deng, G.-J. Palladium-Catalyzed

3-Aryl-5-acyl-1,2,4-thiadiazole

Formation

from

Ketones,

Amidines, and Sulfur Powder. Eur. J. Org. Chem. 2017, 12, 1604-1607. (f) Xie, H.; Cai, J.; Wang, Z.; Huang, H.; Deng, G.-J. A Three-Component Approach to 3,5-Diaryl-1,2,4-thiadiazoles under Transition-Metal-Free Conditions. Org. Lett. 2016, 18, 2196-2199.

(15)

(a) Zhi, H.; Yu, J.-T.; Cheng, J. Copper-catalyzed N-Thioetherification of

Sulfoximines Using Disulfides. Chem. Commun., 2016, 52, 11908-11911. (b) Wang, Z.; Kuninobu, Y.; Kanai, M. Copper-Catalyzed Intramolecular N-S Bond Formation by Oxidative Dehydrogenative Cyclization. J. Org. Chem. 2013, 78, 7337-7342. (c) Lee, C.; Wang, X.; Jiang, H.-Y. Copper-Catalyzed Oxidative N-S Bond Formation for the Synthesis of N-Sulfenylimines. Org. Lett. 2015, 17, 1130-1133. (d) Chen, F.-J.; Liao, G.; Li, X.; Wu, J.; Shi, B.-F. Cu(II)-Mediated C-S/N-S Bond Formation via C-H Activation: Access to Benzoisothiazolones Using Elemental Sulfur. Org. Lett. 2014, 16, 5644-5647. (e) Durust, Y.; Yildirim, M.; Aycan, A. An Efficient One-pot Synthesis of 5-(Substituted amino)-1,2,4-thia- and -Oxa-diazoles. J. Chem. Ress. 2008, 4, 235-239.

(16)

(a) Abdel-Wahab, B. F.; Shaaban, S.; El-Hiti, G. A. Synthesis of

Sulfur-Containing

Heterocycles

via

Ring

Enlargement.

Mol

Divers

2018,

https://doi.org/10.1007/s11030-017-9810-3. (b) Comas, H.; Bernardinelli, G.; Swinnen, D. A Straightforward, One-Pot Protocol for the Synthesis of Fused ACS Paragon Plus Environment

Page 39 of 42 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


3-Aminotriazoles. J. Org. Chem. 2009, 74, 5553-5558. (c) Menet, C. J.; Fletcher, S. R.; Lommen, G. V.; Geney, R.; Blanc, J.; Smits, K.; Jouannigot, N.; Deprez, P.; van der Aar, E. M.; Clement-Lacroix, P.; Lepescheux, L.; Galien, R.; Vayssiere, B.; Nelles, L.; Christophe, T.; Brys, R.; Uhring, M.; Ciesielski, F.; Rompaey, L. V. Triazolopyridines as Selective JAK1 Inhibitors: From Hit Identficationto GLPG0634. J. Med. Chem. 2014, 57, 9323-9343. (d) Tang, X.; Zhu, Z.; Qi, C.; Wu, W.; Jiang, H. Copper-Catalyzed Coupling of Oxime Acetates with Isothiocyanates: A Strategy for 2-Aminothiazoles. Org. Lett. 2016, 18, 180-183. (e) Wang, P.; Tang, S.; Lei, A. Electrochemical Intramolecular Dehydrogenative C-S Bond Formation for the Synthesis of Benzothiazoles. Green Chem. 2017, 19, 2092-2095. (f) Zhang, X.; Wang, T.-L.; Huo, C.-D.; Wang, X.-C.; Quan, Z.-J. Base-Controlled Chemoselectivity Reaction of Vinylanilines with Isothiocyanates for Synthesis of Quinolino-2-thione and 2-Aminoquinoline Derivatives. Chem. Commun., 2018, 54, 3114-3117.

(17)

(a) Elwell, C. E.; Gagnon, N. L.; Neisen, B. D.; Dhar, D.; Spaeth, A. D.; Yee, G.

M.; Tolman, W. B. Copper-Oxygen Complexes Revisited: Structures, Spectroscopy, and Reactivity. Chem. Rev. 2017, 117, 2059-2107. (b) Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski, M. C. Aerobic Copper-Catalyzed Organic Reactions. Chem. Rev. 2013, 113, 6234-6458. (c) Zhang, C.; Tang, C.; Jiao, N. Recent Advances in Copper-Catalyzed Dehydrogenative Functionalization via a Single Electron Transfer (SET) Process. Chem. Soc. Rev. 2012, 41, 3464-3484. (d) Zhu, X.; Chiba, S. Copper-Catalyzed Oxidative Carbon-Heteroatom Bond Formation: a Recent Update. Chem. Soc. Rev. 2016, 45, 4504-4523. (e) Greene, J. F.; Hoover, J. M.; Mannel, D. S.;



Root, T. W.; Stahl, S. S. Continuous-Flow Aerobic Oxidation of Primary Alcohols with a Copper(I)/TEMPO Catalyst. Org. Process Res. Dev. 2013, 17, 1247-1251. (f) Tang, X.; Wu, W.; Zeng, W.; Jiang, H. Copper-Catalyzed Oxidative Carbon-Carbon and/or Carbon-Heteroatom Bond Formation with O2 or Internal Oxidants. Acc. Chem. Res. 2018, 51, 1092-1105.

(18)

(a) Li, X.; Liu, X.; Chen, H.; Wu, W.; Qi, C.; Jiang, H. Copper-Catalyzed

Aerobic Oxidative Transformation of Ketone-Derived N-Tosyl Hydrazones : An Entry to Alkynes. Angew. Chem. Int. Ed. 2014, 53, 14485-14489. (b) Tang, X.; Huang, L.; Qi, C.; Wu, W.; Jiang, H. An Efficient Synthesis of Polysubstituted Pyrroles via Copper-Catalyzed Coupling of Oxime Acetates with Dialkyl Acetylenedicarboxylates under Aerobic Conditions. Chem. Commun. 2013, 49, 9597-9599. (c) Li, X.; Huang, L.; Chen, H.; Wu, W.; Huang, H.; Jiang, H. Copper-Catalyzed Oxidative [2 + 2 + 1] Cycloaddition: Regioselective Synthesis of 1,3-Oxazoles from Internal Alkynes and Nitriles. Chem. Sci. 2012, 3, 3463-3467. (d) Huang, L.; Jiang, H.; Qi, C.; Liu, X. Copper-Catalyzed Intermolecular Oxidative [3 + 2] Cycloaddition between Alkenes and Anhydrides: A New Synthetic Approach to γ-Lactones. J. Am. Chem. Soc. 2010, 132, 17652-17654. (e) Huang, Y.; Li, X.; Yu, Y.; Zhu, C.; Wu, W.; Jiang, H. Copper-Mediated [3 + 2] Oxidative Cyclization Reaction of N-Tosylhydrazones and β‑Ketoesters: Synthesis of 2,3,5-Trisubstituted Furans. J. Org. Chem. 2016, 81, 5014-5020.

(19)

(a) Watson, D. J.; Dowdy, E. D.; Li, W.; Wang, J.; Polniaszek, R. Electronic

Effects in the Acid-promoted Deprotection of N-2,4-Dimethoxybenzyl Maleimides. ACS Paragon Plus Environment

Page 40 of 42

Page 41 of 42 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Tetrahedron Lett. 2001, 42, 1827-1830. (b) Schleicher, K. D.; Jamison, T. F. Nickel-Catalyzed Synthesis of Acrylamides from α-Olefins and Isocyanates. Org. Lett. 2007, 9, 875-878.

(20)

(a) Wdowik, T.; Chemler, S. R. Direct Synthesis of 2-Formylpyrrolidines,

2-Pyrrolidinones

and

Aminooxygenation

2-Dihydrofuranones

and

Dioxygenation

via of

Aerobic

Copper-Catalyzed

4-Pentenylsulfonamides

and

4-Pentenylalcohols. J. Am. Chem. Soc. 2017, 139, 9515-9518. (b) Zhang, C.; Jiao, N. Dioxygen

Activation

under

Ambient

Conditions:

Cu-Catalyzed

Oxidative

Amidation-Diketonization of Terminal Alkynes Leading to r-Ketoamides. J. Am. Chem. Soc. 2010, 132, 28-29. (c) Giri, R.; Hartwig, J. F. Cu(I)-Amido Complexes in the Ullmann Reaction: Reactions of Cu(I)-Amido Complexes with Iodoarenes with and without Autocatalysis by CuI. J. Am. Chem. Soc. 2010, 132, 15860-15863. (d) Toh, K. K.; Biswis, A.; Wang, Y.-F.; Tan, Y. Y.; Chiba, S. Copper-Mediated Oxidative Transformation

of

N-Allyl

Enamine

Carboxylates

toward

Synthesis

of

Azaheterocycles. J. Am. Chem. Soc. 2014, 136, 6011-6020.

(21)

Taniguchi, N. Copper-Catalyzed Formation of Sulfur-Nitrogen Bonds by

Dehydrocoupling of Thiols with Amines. Eur. J. Org. Chem. 2010, 14, 2670-2673.

(22)

Wang, Z.; Kuninobu, Y.; Kanai, M. Copper-Catalyzed Intramolecular N-S

Bond Formation by Oxidative Dehydrogenative Cyclization. J. Org. Chem. 2013, 78, 7337-7342.

(23)

(a) Alvarado, J.; Fournier, J.; Zakarian, A. Synthesis of Functionalized



Dihydrobenzofurans by Direct Aryl C-O Bond Formation under Mild Conditions. Angew. Chem. Int. Ed. 2016, 55, 11625-11628. (b) Huffman, L. M.; Casitas, A.; Font, M.; Canta, M.; Costas, M.; Ribas, X.; Stahl, S. S. Observation and Mechanistic Study of Facile C-O Bond Formation between a Well-Defined Aryl-Copper(III) Complex and Oxygen Nucleophiles. Chem. Eur. J. 2011, 17, 10643-10650. (c) Yao, B.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. Room-Temperature Aerobic Formation of a Stable Aryl-Cu(III) Complex and Its Reactions with Nucleophiles: Highly Efficient and Diverse Arene C-H Functionalizations of Azacalix[1]arene[3]pyridine. Chem. Commun. 2009, 0, 2899-2901. (d) Suess, A. M.; Ertem, M. Z.; Cramer, C. J.; Stahl, S. S. Divergence between Organometallic and Single-Electron-Transfer Mechanisms in Copper(II)-Mediated Aerobic C-H Oxidation. J. Am. Chem. Soc. 2013, 135, 9797-9804.


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Copper-Catalyzed Aerobic Oxidative [3+2] Annulation for Synthesis of

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