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

DOI: 10.1021/acs.joc.8b01292. Publication Date (Web): July 18, 2018. Copyright © 2018 American Chemical Society. Cite this:J. Org. Chem. XXXX, XXX, X...
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Article Cite This: J. Org. Chem. 2018, 83, 9334−9343

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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 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

J. Org. Chem. 2018.83:9334-9343. Downloaded from pubs.acs.org by UNIV OF SUSSEX on 08/17/18. For personal use only.

S Supporting Information *

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 1,2,4thiadiazole 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.

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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-thiadiazoles 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, investigation for new synthetic strategies to construct molecules of this class has been attracting great attention from organic chemists in recent years.7 It is a traditional strategy to use a 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 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 has 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 providing a basic block for the elegant construction of five- or six-membered nitrogen-containing heterocyclic compounds by the formation of N−C,9 N−N,10 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 a Cu/O2 catalytic system, in which bidental nitrogen atoms of 2-aminopyridine © 2018 American Chemical Society

might coordinate with Cu and then activate another substrate (Scheme 1).13 On the contrary, the N−S bond formation reaction using 2aminopyridine as the substrate remains challenging14 in spite of the 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 the thiourea intermediate in most cases, and their sulfur atoms were usually discarded, rendering the transformations nonatom economic. Inspired by our previous work in the copper/oxygen catalytic system,17,18 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.

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RESULTS AND DISCUSSION We began our study by choosing 2-aminopyridine (1) and isothiocyanate (2) as model substrates in the presence of a catalyst at 50 °C (Table 1). To our delight, the expected 1,2,4thiadiazole 3 was obtained in 42% yield with CH3CN as the solvent under an 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. Received: May 20, 2018 Published: July 18, 2018 9334

DOI: 10.1021/acs.joc.8b01292 J. Org. Chem. 2018, 83, 9334−9343

Article

The Journal of Organic Chemistry

Figure 1. Biologically active 1,2,4-thiadiazoles.

aminopyridines containing electron-poor groups gave desired products in moderate yields and higher yields after prolonging the reaction time (3da−3ia, 3fk, and 3ik). However, for the substrate with a 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-substituted aminopyridine was cycled with an excellent yield to deliver 3ka. Unfortunately, the sterically hindered C-6-substituted aminopyridine (3la) did not react with the 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 products in moderate yields (3ma−3oa). Interestingly, substituted isothiocyanates exhibited a similar effect on this transformation. The desired products were formed in 83 and 85% yields, respectively (3ab and 3ac). The isothiocyanates bearing electron-withdrawing groups, such as -halo, −CF3, and −COOMe at the phenyl ring, were obtained in yields ranging from 39 to 78% (3ad−3ah). Similarly, the substrates 2 possessing various degrees of steric bulkiness group, such as the 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 affecting 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 2aminopyridine (1) with phenylbenzamidines (4) to prepare other 1,2,4-thiadiazoles under the optimal reaction conditions. Gratifyingly, choosing the 2.0 equiv 2,4-dimethylpyridine to the 1.0 equiv NaOH, we were able to prepare substituted 1,2,4thiadiazoles 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-withdrawing substituents (5a−5g). Isonicotinimidamide hydrochloride could also obtain 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, and 5h, we usually detected the material recovery without other byproducts.

Scheme 1. Cyclization of 2-Aminopyridines

Table 1. Optimization of the Reaction Conditionsa

entrya

catalyst

1 2 3 4 5 6 7 8 9 10 11 12c

CuI CuI CuI CuI CuBr2 CuBr Cu(OTf)2 CuI CuI CuI CuI

additive

solvent

yield (%)b

pyridine 4-CH3-pyridine 2,4-dimethylpyridine 2,4-dimethylpyridine 2,4-dimethylpyridine

MeCN DMSO DCE THF DCE DCE DCE DCE DCE DCE DCE DCE

42 8 55 15 9 trace trace 72 65 88 (83) NR NR

a

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 an O2 balloon at 50 °C for 12 h. bDetermined by GC-MS using dodecane as the internal standard. The value in parentheses is the isolated yield. NR = no reaction. cUnder an N2 atmosphere.

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 an O2 atmosphere are both critical to this transformation (entries 11 and 12). 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, and 3ck). On the contrary, the reactions of 29335

DOI: 10.1021/acs.joc.8b01292 J. Org. Chem. 2018, 83, 9334−9343

Article

The Journal of Organic Chemistry Table 2. Substrate Scope of N-Fused 1,2,4-Thiadiazolesa

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 °C under an O2 balloon for 12 h. Isolated yields. b24 h. cn.r. = no reaction.

a

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. 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, 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. On the basis of 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 9336

DOI: 10.1021/acs.joc.8b01292 J. Org. Chem. 2018, 83, 9334−9343

Article

The Journal of Organic Chemistry Table 3. Substrate Scope of 5-Amino-1,2,4-thiadiazolesa

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 °C under an O2 balloon for 12 h. Isolated yield. a

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Scheme 2. Transformations of 3fa and 5k

EXPERIMENTAL SECTION

General Information. All reactions were carried out in 10 mL tubes under an O2 balloon. 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 of DCE with stirring under an O2 balloon at 50 °C. Upon completion, the reaction mixture was washed with 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 °C. 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, 119.3, 109.6 ppm. IR (KBr) vmax (cm−1): 3114, 3031, 2926, 1580, 1164, 757, 696. EIMS (70 eV) m/ z: [M]+ 227, 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 °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. IR (KBr) vmax (cm−1): 3052, 2923, 1578, 1443, 944, 758, 681. EIMS (70 eV) m/z: [M]+ 241, 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 °C. 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. IR (KBr) v max (cm−1): 3077, 2924, 1645, 1546, 1230, 766,

base.9f,10a,13,20 When the copper salt is coordinated to the substrate aminopyridine, it may enhance the nucleophilic reactivity of the nitrogen atom at pyridine. Meanwhile, the electron-rich sulfur atom at isothiocyanate might also bind to the metal copper species. The use of electron-poor and sterichindered substrates gives inferior results, which is consistent with this process. Then, migratory insertion of isothiocyanate occurs to form the intermediate B.13 Next, the 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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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 Nfused 1,2,4-thiadiazoles. Meanwhile, the use of molecular oxygen as the oxidant makes the overall chemical transformation sustainable and practical. 9337

DOI: 10.1021/acs.joc.8b01292 J. Org. Chem. 2018, 83, 9334−9343

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The Journal of Organic Chemistry Scheme 3. Control Experiments

(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 °C. 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). 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. IR (KBr) vmax (cm−1): 3065, 2924, 1600, 1532, 926, 759, 680. HRMS-ESI ( m/z): [M + H]+ calcd for C12H9N3BrS, 305.9695; found, 305.9694. (Z)-N-(7-Trifluoromethyl-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3ylidene)-aniline (3ga). Yellow solid (34 mg, 38%). mp 144−145 °C. 1 H 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. IR (KBr) vmax (cm−1): 3114, 2922, 1596, 1527, 1117, 760, 671. EIMS (70 eV) m/z: [M]+ 295, 192, 148, 126, 77. HRMSESI (m/z): [M + H]+ calcd for C13H9N3F3S, 296.0464; found, 296.0462. (Z)-N-(6-Methoxyformyl-3H-[1,2,4]thiadiazolo[4,3-a]pyridin-3ylidene)-aniline (3ha). Yellow solid (30 mg, 35%). mp 142−144 °C. 1 H 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. IR (KBr) vmax (cm−1): 3103, 2924, 1709, 1572, 1249, 1085, 751, 683. HRMSESI ( m/z): [M + H]+ calcd for C14H12O2N3S, 286.0645; found, 286.0644. (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 °C. 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. IR (KBr) vmax (cm−1): 3077, 1578, 1230, 1142, 884, 755, 667. EIMS (70 eV) m/z: [M]+ 304, 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 °C. 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). 13 C 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. IR (KBr) vmax (cm−1):

Scheme 4. Possible Reaction Mechanism

692. EIMS (70 eV) m/z: [M]+ 257, 154, 135, 108, 77. HRMS-ESI (m/z): [M + H]+ calcd for C13H12ON3S, 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 °C. 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. IR (KBr) vmax (cm −1): 3067, 2923, 1656, 1597, 1177, 950, 758. HRMS-ESI ( m/z): [M + H]+ calcd for C12H9N3FS, 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 °C. 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). 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. IR (KBr) vmax (cm−1): 3100, 2923, 1604, 1529, 1449, 756, 677. HRMS-ESI ( m/z): [M + H]+ calcd for C12H9N3ClS, 262.0200; found, 262.0200. 9338

DOI: 10.1021/acs.joc.8b01292 J. Org. Chem. 2018, 83, 9334−9343

Article

The Journal of Organic Chemistry

(q, J = 3.7 Hz), 125.9, 125.8, 125.6, 124.3 (q, J = 270 Hz), 121.2, 119.4, 110.1 ppm. IR (KBr) vmax (cm−1): 3101, 2922, 1578, 1519, 1328, 1102, 836, 743. EIMS (70 eV) m/z: [M]+ 295, 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 °C. 1 H 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. IR (KBr) vmax (cm−1): 2923, 2850, 1697, 1569, 1275, 1107, 845, 750. HRMS-ESI (m/z): [M + H]+ calcd for C14H12O2N3S, 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 °C. 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. IR (KBr) vmax (cm−1): 3090, 2925, 1609, 1320, 1252, 745. HRMS-ESI (m/z): [M + H]+ calcd for C13H12N3S, 242.0746; found, 242.0744. (Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)ethyl1-amine (3ak). Yellow solid (46 mg, 86%). mp 78−79 °C. 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. IR (KBr) vmax (cm−1): 3073, 2960, 2856, 1627, 1520, 1366, 755. HRMS-ESI ( m/z): [M + H]+ calcd for C8H10N3S, 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 °C. 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. IR (KBr) vmax (cm−1): 3066, 2962, 2858, 1628, 1533, 1361, 843, 766. HRMS-ESI (m/z): [M + H]+ calcd for C9H12N3S, 194.0746; found, 194.0745. (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 °C. 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). 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. IR (KBr) vmax (cm−1): 3047, 2969, 1632, 1547, 1449, 1228, 834, 733. HRMS-ESI (m/z): [M + H]+ calcd for C9H12ON3S, 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 °C. 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). 13C NMR (100 MHz, CDCl3, δ): 157.5, 151.3, 129.5, 125.9, 121.0, 113.2, 49.3, 15.4 ppm. IR (KBr) vmax (cm−1): 3357, 3072, 2920, 2851, 1636, 1527, 1348, 762. HRMS-ESI ( m/z): [M + H]+ calcd for C8H9N3BrS, 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 °C. 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. IR (KBr) vmax (cm−1): 3076, 2962, 2855, 1632, 1521, 1316, 1120, 804, 662. HRMS-ESI (m/z): [M + H]+ calcd for C8H9N3BrS, 257.9695; found, 257.9695. (Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)propan-1amine (3al).7f Yellow solid (42 mg, 72%). mp 55−56 °C. 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. IR (KBr) vmax (cm−1): 3092, 2951, 1631, 1530, 1138, 878, 748. EIMS (70 eV) m/z: [M]+ 193, 164, 124, 78. (Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)propan-2amine (3am).7f brown liquid (27 mg, 47%). 1H NMR (400 MHz,

3076, 2925, 1581, 1517, 1193, 1067, 894, 757. HRMS-ESI ( m/z): [M + H]+ calcd for C13H12N3S, 242.0746; found, 242.0746. (Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]quinolin-3-ylidene)amine (3ma). Yellow solid (62 mg, 75%). mp 133−134 °C. 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. IR (KBr) vmax (cm−1): 3067, 2924, 1620, 1550, 1442, 1292, 1226, 752, 686. HRMS-ESI ( m/z): [M + H]+ calcd for C16H12N3S, 278.0746; found, 278.0746. (Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]isoquinolin-3-ylidene)amine (3na). Yellow solid (56 mg, 68%). mp 172−173 °C. 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. IR (KBr) vmax (cm−1): 2921, 2851, 1572, 1399, 1269, 1004, 757, 677. HRMS-ESI ( m/z): [M + H]+ calcd for C16H12N3S, 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 °C. 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. IR (KBr) vmax (cm−1): 3109, 2921, 2851, 1575, 1353, 1191, 1079, 913, 822, 757. HRMS-ESI (m/ z): [M + H]+ calcd for C10H8N3S2, 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 °C. 1H NMR (400 MHz, CDCl3, δ): 8.21 (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. IR (KBr) vmax (cm−1): 3115, 3030, 2975, 1574, 1171, 822, 751. EIMS (70 eV) m/z: [M]+ 241, 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 °C. 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. IR (KBr) vmax (cm−1): 2927, 1599, 1503, 1231, 1003, 823, 744. EIMS (70 eV) m/ z: [M]+ 257, 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 °C. 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. IR (KBr) vmax (cm−1): 3038, 2927, 1609, 1509, 1320, 1098, 821, 746. EIMS (70 eV) m/ z: [M]+ 245, 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 °C. 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, 126.0, 122.4, 119.4, 109.9 ppm. IR (KBr) vmax (cm −1): 3296, 2924, 1587, 1248, 756, 652. EIMS (70 eV) m/z: [M]+ 261, 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 °C. 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. IR (KBr) vmax (cm−1): 2924, 2856, 1599, 1196, 819, 751. HRMS-ESI (m/z): [M + H]+ calcd for C12H9N3BrS, 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 °C. 1 H 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 9339

DOI: 10.1021/acs.joc.8b01292 J. Org. Chem. 2018, 83, 9334−9343

Article

The Journal of Organic Chemistry 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). 13 C NMR (100 MHz, CDCl3, δ): 157.0, 152.2, 133.3, 126.1, 119.2, 108.5, 56.3, 22.9 ppm. IR (KBr) vmax (cm−1): 3098, 2958, 1627, 1535, 1330, 1143, 747. EIMS (70 eV) m/z: [M]+ 193, 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 °C. 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. IR (KBr) vmax (cm−1): 3091, 2934, 1621, 1527, 966, 744. EIMS (70 eV) m/z: [M]+ 191, 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), 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. IR (KBr) vmax (cm−1): 3098, 2925, 1627, 1535, 1322, 1255, 880, 747. HRMS-ESI ( m/z): [M + H]+ calcd for C12H16N3S, 234.1059; found, 234.1059. (Z)-N-(3H-[1,2,4]Thiadiazolo[4,3-a]pyridin-3-ylidene)naphthyl-1amine (3aq). Yellow solid (52 mg, 62%). mp 120−122 °C. 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). 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. IR (KBr) vmax (cm−1): 3046, 2923, 1582, 1389, 1255, 869, 753. HRMS-ESI (m/z): [M + H]+ calcd for C16H12N3S, 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 °C. 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. IR (KBr) vmax (cm−1): 3032, 2813, 1624, 1528, 1327, 874, 739. HRMS-ESI ( m/z): [M + H]+ calcd for C13H12N3S, 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 °C. 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. IR (KBr) vmax (cm−1): 3071, 2923, 2792, 1625, 1522, 1326, 1207, 988, 912, 752. HRMS-ESI (m/z): [M + H]+ calcd for C9H10N3S, 192.0590; found, 192.0589. General Procedure for Preparation of 5-Amino/Imino-1,2,4Thiadiazoles. Benzamidines. (0.3 mmol), isothiocyanate (0.45 mmol), CuI (20 mol %), and NaOH (0.30 mmol) were mixed in 1.5 mL of DCE with stirring under an O2 balloon at 50 °C. Upon completion, the reaction mixture was washed with saturated NaCl aqueous solution (2 × 10 mL) and then extracted with ethyl acetate (2 × 10 mL). 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 °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. IR (KBr) vmax (cm−1): 3233, 3080, 2922, 1559, 1447, 1346, 1023, 755, 698. EIMS (70 eV) m/z: [M]+ 253, 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 °C. 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, 129.9, 129.8, 128.0, 123.3, 118.1, 21.5 ppm. IR (KBr) vmax (cm−1): 3227, 3136, 3077, 2921, 1601, 1563, 1441, 1343, 749, 695. EIMS (70 eV) m/z: [M]+ 267, 149, 117, 91, 77, 65. N-Phenyl-3-(4-methoxyphenyl)-1,2,4-thiadiazol-5-amine (5c). Yellow solid (78 mg, 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. IR (KBr) vmax (cm−1): 3221, 3133, 3078, 2964, 1657, 1608, 1447, 1296, 1025, 829, 757, 698. HRMS-ESI (m/ z): [M + H]+ calcd for C15H14N3OS, 284.0852; found, 284.0848. N-Phenyl-3-(4-fluoroxyphenyl)-1,2,4-thiadiazol-5-amine (5d). Yellow solid (67 mg, 82%). mp 150−152 °C. 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. IR (KBr) vmax (cm−1): 3233, 2919, 1650, 1510, 998, 755. HRMS-ESI (m/z): [M + H]+ calcd for C14H11FN3S, 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 °C. 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. IR (KBr) vmax (cm−1): 3236, 3085, 2969, 1663, 1440, 1007, 838, 751. EIMS (70 eV) m/z: [M]+ 287, 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 °C. 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. IR (KBr) vmax (cm−1): 2920, 1656, 1435, 1006, 824, 758. EIMS (70 eV) m/z: [M]+ 333, 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 °C. 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. IR (KBr) vmax (cm−1): 3441, 2926, 1604, 1560, 1522, 1341, 1025, 822, 760. EIMS (70 eV) m/z: [M]+ 298, 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 °C. 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. IR (KBr) vmax (cm−1): 3437, 2917, 1659, 1461, 1354, 1000, 824, 766. EIMS (70 eV) m/z: [M]+ 254, 150, 135, 118, 104, 91, 77. N-Phenyl-3-ethyl-1,2,4-thiadiazol-5-amine (5i).7b Yellow solid (47 mg, 83%). mp 108−110 °C. 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. IR (KBr) vmax (cm−1): 3257, 3196, 3073, 2965, 1608, 1554, 1446, 1321, 1043, 816, 756. EIMS (70 eV) m/z: [M]+ 191, 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 °C. 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. IR (KBr) vmax (cm−1): 3242, 2976, 1572, 1463, 1345, 1026, 820, 707. HRMS-ESI (m/z): [M + H]+ calcd for C10H12N3S, 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, 9340

DOI: 10.1021/acs.joc.8b01292 J. Org. Chem. 2018, 83, 9334−9343

Article

The Journal of Organic Chemistry 28.6 ppm. IR (KBr) vmax (cm−1): 3252, 3055, 2972, 1552, 1349, 1215, 1026, 820, 706. HRMS-ESI (m/z): [M + H]+ calcd for C12H16N3S, 234.1059; found, 234.1060. N-Cylclopropyl-3-phenyl-1,2,4-thiadiazol-5-amine (5l). Yellow solid (42 mg, 65%). mp 175−177 °C. 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. IR (KBr) vmax (cm−1): 3213, 1656, 1563, 1460, 1344, 1007, 825, 762, 705. HRMSESI (m/z): [M + H]+ calcd for C11H12N3S, 218.0746; found, 218.0747. 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. IR (KBr) vmax (cm−1): 3227, 3015, 2922, 1566, 1463, 1343, 1009, 926, 818, 771, 707. HRMS-ESI (m/z): [M + H]+ calcd for C11H12N3S, 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 °C. 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). 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. IR (KBr) vmax (cm−1): 3352, 3057, 2926, 1732, 1583, 1259, 754. HRMS-ESI (m/z): [M + H]+ calcd for C18H14N3S, 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 °C. 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). 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. IR (KBr) vmax (cm−1): 3052, 2925, 2206, 1580, 1367, 1295, 1080, 954, 756, 684. HRMS-ESI (m/z): [M + H]+ calcd for C20H14N3S, 328.0903; found, 328.0902. 3-Phenyl-1,2,4-thiadiazol-5-amine (8).7c Yellow solid (33 mg, 62%). mp 135−136 °C. 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. IR (KBr) vmax (cm−1): 3294, 3139, 2923, 1622, 1523, 1461, 1350, 756, 701. EIMS (70 eV) m/z: [M]+ 177, 135, 108, 103, 91, 77, 51.

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21672072), Guangdong Province Science Foundation (2017B090903003), and the Fundamental Research Funds for the Central Universities (2017ZD062) for financial support.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01292. Copies of 1H and 13C NMR spectra data for all compounds (PDF) X-ray crystallographic data for 3ak (CIF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Authors

*Fax: (+86) 20-8711-2906; E-mail: [email protected]. *Fax: (+86) 20-8711-2906; E-mail: [email protected]. ORCID

Wanqing Wu: 0000-0001-5151-7788 Huanfeng Jiang: 0000-0002-4355-0294 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank the National Key Research and Development Program of China (2016YFA0602900), the National Natural Science Foundation of China (21420102003 and 9341

DOI: 10.1021/acs.joc.8b01292 J. Org. Chem. 2018, 83, 9334−9343

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