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Copper-Catalyzed Ring Expansion of 2-Aminobenzothiazoles with Alkynyl Carboxylic Acids to 1,4-Benzothiazines Jing-Wen Qiu,a Bo-Lun Hu,a Xing-Guo Zhang,*, a Ri-Yuan Tang,a Ping Zhong a and Jin-Heng Li*, b 5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x A new ring expansion of 2-aminobenzothiazoles with alkynyl carboxylic acids was developed, which allows for one-pot synthesis of 1,4-benzothiazines in moderate to excellent yields. The cascade reaction was achieved through decarboxylative coupling, nucleophilic ring-opening reaction and intramolecular hydroamination process.
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Results and discussion
Introduction 1,4-Benzothiazines are essential structural motifs in numerous natural products and pharmaceuticals with remarkable biological and medicinal properties,[1] such as antibacterial,[2] antidiabetic,[3] antiarrhythmic[4] and antitumor.[5] As a consequence, considerable efforts have devoted to the development of simple and efficient methods for the synthesis of 1,4-benzothiazines and their derivatives.[6,7] Generally, these methods focus on the condensation of 2-aminobenzenethiol derivatives in the presence of strong bases, which suffered from low functional group tolerability and limited efficiency for divergent synthesis of products, such as N-substituted benzothiazines. [7] Therefore, the development of new routes, especially one-pot strategy, for the construction of 1,4-benzothiazine backbone is still highly desirable. Recently, palladium or copper- catalyzed decarboxylative coupling reaction of alkynyl carboxylic acids, has emerged as a powerful protocol for the preparation of internal alkynes, which avoid using the less stable and oxygen sensitive terminal alkynes.[8] Meanwhile, transition-metal-catalyzed intramolecular hydroamination of alkynyl amines has received intensive interest and has come to represent an efficient and convenient strategy for the N-heterocyclic synthesis. [9] During the preparation of this manuscript, Hajra and co-workers reported a copper-catalyzed oxidative coupling between 2-aminobenzothiazole and terminal alkyne using 1,10-phenanthroline as ligand for the formation of benzothiazines. [10] Herein, we report a cascade reaction for onepot synthesis of 1,4-benzothiazines through copper-catalyzed nucleophilic ring-opening reaction of 2-aminobenzothiazole with alkynyl carboxylic acids and subsequent intramolecular hydroamination (Scheme 1). Scheme 1. One-pot synthesis of 1,4-benzothiazines.
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We began our studies by exploring the reaction between 2amino-6-methoxybenzothiazole 1a with 3-phenylpropiolic acid 2a to optimize the reaction conditions (Table 1). Initially, the reaction did not work in presence of 2 equiv of K3PO4 at 100 oC, but 80% yield of target product 3 was obtained when 10 mol % of CuI was used as catalyst (entries 1 and 2). This prompted us to investigate a variety of copper catalysts to improve the reaction, including CuBr, CuCl, Cu2O, CuCl2 and Cu(OAc)2 (entries 3-7). The results showed that CuCl were more effective than others, and provided product 3 in 86% yield (entry 4). The structure of compound 3 was confirmed by X-ray single crystal diffraction analysis. Subsequently, other inorganic bases were tested, but lower yields were observed when Cs2CO3, K2CO3 and K2HPO4 were used (entries 8-10). 1,4-Diazabicyclo[2.2.2]octane (DABCO), an organic base, was also effective for the tandem reaction and provided a 60% yield (entry 11). However, the reaction did not proceed in the absence of base (entry 12), which suggested that basic condition might be essential to the ringopening reaction of 2-aminobenzothiazole.[11] During the examination of solvent, low yields were obtained when DMF, DMSO, THF or toluene was used as solvent (entries 13-16). We found that temperature had an obvious affection on reaction activity, and only 68% yield of product 3 was isolated when the reaction was carried out at 80 oC (entry 17). It is noteworthy that the reaction yield was decreased slightly when the loading of phenylpropiolic acid 2a was reduced to 1.5 equiv or when the reaction proceeded under N2 atmosphere (entries 18 and 19). With the optimal reaction conditions in hand, we investigated the substrate scope of this ring expansion by testing the reaction of a wide variety of 2-aminobenzothiazole with alkynyl carboxylic acids under standard conditions (Table 2). Initially, the substitution effect on the benzothiazole moiety was examined. The results demonstrated that both electron-donating group and electron-withdrawing group were tolerated well, and provided corresponding product in good yields (5-9). For examples, benzo[d]thiazol-2-amine afford product 4 in 80% yield. Methyl substituted benzothiazoles provided 75-87% yields (5, 6 and 7). [journal], [year], [vol], 00–00 | 1
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Table 1. Screening conditions a
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Entry
Catalyst
Base
Solvent
Yield (%)
1
-
K3PO4
CH3CN
0
2
CuI
K3PO4
CH3CN
80
3
CuBr
K3PO4
CH3CN
85
4
CuCl
K3PO4
CH3CN
86
5
Cu2O
K3PO4
CH3CN
trace
6
CuCl2
K3PO4
CH3CN
60
7
Cu(OAc)2
K3PO4
CH3CN
85
8
CuCl
Cs2CO3
CH3CN
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9
CuCl
K2CO3
CH3CN
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10
CuCl
K2HPO4
CH3CN
30
11
CuCl
DABCO
CH3CN
60
12
CuCl
-
CH3CN
0
13
CuCl
K3PO4
DMF
30
14
CuCl
K3PO4
DMSO
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15
CuCl
K3PO4
THF
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16
CuCl
K3PO4
Toluene
trace
17b
CuCl
K3PO4
CH3CN
68
18c
CuCl
K3PO4
CH3CN
80
19d
CuCl
K3PO4
CH3CN
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DOI: 10.1039/C4OB02467B
CH3CN was carried out at 100 oC for 20h in the absence of CuCl and propiolic acid. Consistent with our hypothesis, 2-aminobenzenethiol could not be detected and almost 95% of reactant 1a was recovered (Scheme 2, eq. 1), which suggested that the ringopening reaction could not proceed without CuCl, even in the high temperature and weak basic conditions. However, substrate 1a was decomposed completely when it was reacted with 10 mol % CuCl, 2 equiv of K3PO4 in CH3CN at 100 oC for 2h in the absence of propiolic acid (eq. 2). These results suggested that copper catalyst play a key role in the nucleophilic ring-opening procedure as well as in the decarboxylative coupling reaction and intramolecular hydroamination. Table 2. Scope of the ring expansion a
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (10 mol %), base (2 equiv) and solvent (2 mL) at 100 oC under air atmosphere for 10 h. bat 80 oC. c2a (0.3 mmol). d Under N2 atmosphere.
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Fluoride and chloride benzothiazines (8 and 9) were isolated in 81% and 80% yields, respectively. Subsequently, a number of substituents on the propiolic acid moiety were evaluated, and the results displayed that both aryl group (including heteroaryl) and aliphatic alkyl group were compatible with the optimal conditions. For examples, o-, m-, p-tolyl propiolic acids provided product 1012 in 83%-87% yield, and bulky mesityl propiolic acid gave product 13 in 87% yield, which indicated that steric hindrance have no effect on reaction yield. o-, m-, p-Methoxyphenyl propiolic acids gave benzothiazines in 75-85% yields (14, 15 and 16). Electron-poor 4-chlorophenyl provided product 17 in 66% yield. Gratifyingly, 65% yield was obtained for the naphthalen-1yl group, and a 52% yield for thiophen-2-yl group. Notably, aliphatic alkyl group substituted propiolic acids were also tolerated very well to produce benzothiazines in good yields. 4,4Dimethylpent-2-ynoic acid, for instance, underwent the ring expansion reaction smoothly to give product 20 in 86% yield. Oct-2-ynoic acid and non-2-ynoic acid afforded product 21 and 22 in 80% and 86% yields, respectively. Unblocked propiolic acid was also a suitable substrate for the ring transformation, albeit providing benzothiazine 23 in a 45% yield. To probe the mechanism of this transformation, the reaction of 2-amino-6-methoxybenzothiazole 1a with 2 equiv of K3PO4 in 2 | Journal Name, [year], [vol], 00–00
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), CuCl (10 mol %) and K3PO4 (2 equiv) in 2 mL CH3CN at 100 oC under air atmosphere for 10 h.
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On the basis of the above results and previous reports,[12] a possible mechanism for this ring expansion reaction was proposed in Scheme 3. Initially, the decarboxylation reaction of alkynyl carboxylic acids with CuCl generates copper(I) acetylide A. Subsequently, the oxidative coupling with 2-aminobenzothiazoles readily takes place to give intermediate B, which This journal is © The Royal Society of Chemistry [year]
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undergoes deprotonation by K3PO4 and reductive elimination to produce intermediate C. The tautomerization reaction of intermediate C affords cyanamides D, the final copper(I)catalyzed intramolecular hydroamination results in ring expansion products 3-23.
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Scheme 2. Control experiments.
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Scheme 3. Possible mechanism.
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Conclusions
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In conclusion, we have developed a novel one-pot cascade strategy for the synthesis of 4-cyano-1,4-benzothiazines from 2aminobenzothiazole and alkynyl carboxylic acids in moderate to excellent yields. The ring expansion reaction involves coppercatalyzed decarboxylative coupling reaction of propiolic acids, ring-opening reaction of 2-aminobenzothiazole and intramolecular hydroamination process. This ring transformation shows broad substrate scope for both 2-aminobenzothiazoles and alkynyl carboxylic acids with excellent functional group tolerance. Moreover, this method affords a valuable new approach for the self-assembly of 1,4-benzothiazines from stable and readily available starting materials, which will be useful in the synthesis of N-containing heterocyclics.
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Experimental
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Chemicals were either purchased or purified by standard techniques. 1H NMR and 13C NMR spectra were measured on a 500 MHz spectrometer (1H: 500 MHz, 13C: 125 MHz), using CDCl3 as the solvent with tetramethylsilane (TMS) as an internal standard at room temperature. Chemical shifts are given in δ relative to TMS, the coupling constants J are given in Hz. All reactions under N2 atmosphere were conducted using standard Schlenk techniques. Column chromatography was performed using EM Silica gel 60 (300-400 mesh). This journal is © The Royal Society of Chemistry [year]
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General procedure for copper-catalyzed ring expansion of 2aminobenzothiazoles with alkynyl carboxylic acids. Under air atmosphere, benzo[d]thiazol-2-amine 1 (0.2 mmol), CuCl (10 mol %), K3PO4 (2 equiv), acetonitrile (2 mL), and 3phenylpropiolic acid 2 (0.4 mmol) were successively added into a Schlenk reaction tube. The mixture was stirred at 100 °C for 10h or until complete consumption of starting material as monitored by TLC and GC-MS analysis. After the reaction was finished, the mixture was filtered by a crude column with ethyl acetate as eluent, and evaporated in vacuum. The residue was purified by flash column chromatography on a silica gel using EtOAc/petroleum ether (1:10) as eluent to give the product 3-23. 7-methoxy-3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (3): Yellow solid (48.1 mg, 86% yield), mp. 130-131 oC. 1H NMR (500 MHz, CDCl3) δ: 7.43-7.41 (m, 5H), 7.29-7.26 (m, 1H), 6.81-6.78 (m, 1H), 6.65 (s, 1H), 5.77 (s, 1H), 3.79 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 158.5, 137.9, 132.5, 129.9, 129.0, 129.0, 127.2, 127.0, 119.6, 113.3, 112.4, 110.9, 105.8, 55.8. IR (neat, cm-1): 2360, 1716, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 280 (M+, 100), 265 (38), 237 (30). HRMS (EI) Calcd for C16H12N2OS+ (M+) 280.0665, Found: 280.0663. 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (4): Yellow solid (40.2 mg, 80% yield), mp. 128-129 oC. 1H NMR (500 MHz, CDCl3) δ: 7.44-7.42 (m, 5H), 7.37 (d, J = 8.1 Hz, 1H), 7.29-7.25 (m, 1H), 7.18-7.15 (m, 1H), 7.11-7.10 (m, 1H), 5.76 (s, 1H). 13C NMR (125 MHz, CDCl3) δ: 137.6, 136.4, 132.4, 129.9, 129.0, 128.2, 127.3, 127.2, 127.2, 125.5, 118.6, 110.5, 106.3. IR (neat, cm-1): 2361, 1716, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 250 (M+, 40), 249 (48), 223 (25). HRMS (EI) Calcd for C15H10N2S+ (M+) 250.0559, Found: 250.0567. 7-methyl-3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (5): Yellow solid (43.9 mg, 83% yield), mp. 117-118 oC. 1H NMR (500 MHz, CDCl3) δ: 7.41 (s, 5H), 7.24 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.91 (s, 1H), 5.75 (s, 1H), 2.30 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 137.6, 137.3, 133.7, 132.6, 129.9, 128.9, 128.7, 127.6, 127.2, 125.1, 118.4, 110.7, 106.2, 20.7. IR (neat, cm-1): 1715, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 264 (M+, 100), 263 (38), 231 (22). HRMS (EI) Calcd for C16H12N2S+ (M+) 264.0716, Found: 264.0712. 8-methyl-3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (6): Yellow solid (39.4 mg, 75% yield), mp. 144-145 oC. 1H NMR (500 MHz, CDCl3) δ: 7.55 (d, J = 7.5 Hz, 2H), 7.46-7.40 (m, 3H), 7.16 (d, J = 7.0 Hz, 2H), 7.09-7.08 (m, 1H), 6.41 (s, 1H), 2.64 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 139.0, 133.6, 132.2, 132.1, 130.9, 130.7, 129.6, 129.2, 127.7, 126.3, 125.2, 112.2, 111.3, 18.3. IR (neat, cm-1): 1716, 1362, 1222. LRMS (EI, 70 eV) m/z (%): 264 (M+, 100), 263 (35), 231 (23). HRMS (EI) Calcd for C16H12N2S+ (M+) 264.0716, Found: 264.0709. 6,7-dimethyl-3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (7): Yellow solid (48.6 mg, 87% yield), mp. 128-129 oC. 1H NMR (500 MHz, CDCl3) δ: 7.42-7.39 (m, 5H), 7.15 (s, 1H), 6.85 (s, 1H), 5.75 (s, 1H), 2.25 (s, 3H), 2.19 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 137.4, 137.0, 135.9, 133.7, 132.7, 129.8, 128.9, Journal Name, [year], [vol], 00–00 | 3
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127.9, 127.2, 121.5, 119.7, 110.8, 106.5, 19.5, 19.1. IR (neat, cm1 ): 2219, 1716, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 278 (M+, 100), 277 (27), 245 (22), 131 (13). HRMS (EI) Calcd for C17H14N2S+ (M+) 278.0872, Found: 278.0869.
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7-fluoro-3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (8): Yellow solid (43.2 mg, 81% yield), mp. 121-122 oC. 1H NMR (500 MHz, CDCl3) δ: 7.42 (s, 5H), 7.34-7.31 (m, 1H), 6.99-6.95 (m, 1H), 6.85-6.83 (m, 1H), 5.74 (s, 1H). 13C NMR (125 MHz, CDCl3) δ: 161.0 (d, 1JC-F = 247.5 Hz), 138.0, 132.3, 132.1, 129.0, 128.1, 128.0, 127.3, 119.8, 114.9 (d, 2JC-F = 23.4 Hz), 114.3. (d, 2 JC-F = 25.1 Hz), 110.3, 105.5. IR (neat, cm-1): 2219, 1716, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 268 (M+, 100), 267 (29), 241 (28). HRMS (EI) Calcd for C15H9FN2S+ (M+) 268.0465, Found: 268.0467. 7-chloro-3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (9): Yellow solid (42.7 mg, 80% yield), mp. 126-127 oC.1H NMR (500 MHz, CDCl3) δ: 7.42 (s, 5H), 7.27 (d, J = 8.5 Hz, 1H), 7.257.21 (m, 1H), 7.08 (s, 1H), 5.72 (s, 1H). 13C NMR (125 MHz, CDCl3) δ: 137.9, 135.0, 132.7, 132.1, 130.2, 129.0, 128.0, 127.4, 127.3, 126.8, 119.5, 110.0, 105.5. IR (neat, cm-1): 2360, 1716, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 286 (M+, 40), 284 (100), 249 (35), 222 (32). HRMS (EI) Calcd for C15H9ClN2S+ (M+) 268.0169, Found: 268.0180. 7-methoxy-3-o-tolyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (10): Yellow solid (50.8 mg, 86% yield), mp. 101-102 oC. 1H NMR (500 MHz, CDCl3) δ: 7.35-7.21 (m, 5H), 7.16 (d, J = 9.0 Hz, H), 6.77-6.74 (m, 1H), 6.64 (s, 1H), 5.50 (s, 1H), 3.78 (s, 3H), 2.33 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 156.5, 135.6, 135.0, 130.6, 128.9, 128.8, 128.4, 126.9, 124.5, 123.8, 116.6, 111.3, 110.7, 108.3, 103.0, 53.9, 17.8. IR (neat, cm-1): 2363, 2224, 1716, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 294 (M+, 100), 279 (19), 234 (36). HRMS (EI) Calcd for C17H14N2OS+ (M+) 294.0821, Found: 294.0825. 7-methoxy-3-m-tolyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (11): Yellow solid (51.1 mg, 87% yield), mp. 116-117 oC. 1H NMR (500 MHz, CDCl3) δ: 7.32-7.20 (m, 5H), 6.79-6.77 (m, 1H), 6.63 (s, 1H), 5.73 (s, 1H), 3.78 (s, 3H), 2.38 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 158.5, 138.7, 138.1, 132.4, 130.7, 129.1, 128.8, 127.9, 127.0, 124.3, 119.6, 113.3, 112.4, 111.0, 105.5, 55.8, 21.5. IR (neat, cm-1): 2223, 1716, 1424, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 294 (M+, 100), 279 (38), 251 (23). HRMS (EI) Calcd for C17H14N2OS+ (M+) 294.0821, Found: 294.0831.
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7-methoxy-3-p-tolyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (12): Yellow solid (48.6 mg, 83% yield), mp. 134-135 oC. 1H NMR (500 MHz, CDCl3) δ: 7.32 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 9.0 Hz, 1H), 7.22 (d, J = 8.5 Hz, 2H), 6.79-6.77 (m, 1H), 6.63 (s, 1H), 5.70 (s, 1H), 3.78 (s, 3H), 2.37 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 158.5, 140.1, 138.1, 129.7, 129.6, 129.1, 127.2, 127.1, 119.6, 113.3, 112.4, 111.0, 104.7, 55.8, 21.4. IR (neat, cm-1): 2359, 2219, 1718, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 294 (M+, 100), 279 (40), 251 (35), 115 (35). HRMS (EI) Calcd for C17H14N2OS+ (M+) 294.0821, Found: 294.0816.
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DOI: 10.1039/C4OB02467B
3-mEItyl-7-methoxy-4H-benzo[b][1,4]thiazine-4-carbonitrile (13): Yellow solid (56.0 mg, 87% yield), mp. 158-159 oC. 1H NMR (500 MHz, CDCl3) δ: 7.11 (d, J = 9.0 Hz, 1H), 6.91 (s, 2H), 6.74-6.72 (m, 1H), 6.63 (s 1H), 5.31 (s, 1H), 3.78 (s, 3H), 2.29 (s, 9H). 13C NMR (125 MHz, CDCl3) δ: 158.3, 139.8, 137.9, 135.2, 129.3, 128.8, 128.7, 124.5, 118.1, 113.1, 112.7, 109.9, 103.2, 55.7, 21.2, 19.9. IR (neat, cm-1): 2361, 1716, 1424, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 322 (M+, 100), 262 (26), 129 (19). HRMS (EI) Calcd for C19H18N2OS+ (M+) 322.1134, Found: 322.1131. 7-methoxy-3-(2-methoxyphenyl)-4H-benzo[b][1,4]thiazine-4carbonitrile (14): Yellow solid (47.1 mg, 76% yield), mp. 126127 oC. 1H NMR (500 MHz, CDCl3) δ: 7.40-7.39 (m, 1H), 7.307.28 (m, 1H), 7.20 (d, J = 8.9 Hz, 1H), 6.98-6.94 (m 2H), 6.806.67 (m, 1H), 6.66 (s, 1H), 5.64 (s, 1H), 3.87 (s, 3H), 3.78 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ: 158.2, 157.0, 136.8, 131.7, 131.4, 129.8, 126.2, 121.4, 121.0, 118.5, 113.2, 112.5, 111.2, 110.7, 105.7, 55.8, 55.8. IR (neat, cm-1): 2223, 1716, 1420, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 310 (M+, 100), 295 (19), 131 (18) . HRMS (EI) Calcd for C17H14N2O2S+ (M+) 310.0770, Found: 310.0780. 7-methoxy-3-(3-methoxyphenyl)-4H-benzo[b][1,4]thiazine-4carbonitrile (15): Yellow solid (46.2 mg, 75% yield), mp. 127128 oC. 1H NMR (500 MHz, CDCl3) δ: 7.35-7.32 (m, 1H), 7.287.26 (m, 1H), 7.02 (d, J = 7.5 Hz, 1H), 6.95-6.94 (m, 2H), 6.806.78 (m, 1H), 6.64 (s 1H), 5.78 (s, 1H), 3.84 (s, 3H), 3.79 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ: 159.9, 158.5, 137.7, 133.8, 130.0, 129.0, 126.9, 119.6, 119.5, 115.5, 113.3, 112.9, 112.4, 110.8, 106.0, 55.8, 55.4. IR (neat, cm-1): 2359, 1716, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 310 (M+, 100), 295 (37), 267 (27). HRMS (EI) Calcd for C17H14N2O2S+ (M+) 310.0770, Found: 310.0783. 7-methoxy-3-(4-methoxyphenyl)-4H-benzo[b][1,4]thiazine-4carbonitrile (16): Yellow solid (52.9 mg, 85% yield), mp. 146147 oC. 1H NMR (500 MHz, CDCl3) δ: 7.38-7.36 (m, 2H), 7.277.26 (m, 1H), 6.95-6.93 (m, 2H), 6.79-6.77 (m, 1H), 6.64 (s, 1H), 5.64 (s, 1H), 3.83 (s, 3H), 3.79 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 160.9, 158.5, 138.0, 129.1, 128.8, 127.3, 124.8, 119.5, 114.4, 113.2, 112.4, 111.0, 103.6, 55.8, 55.4. IR (neat, cm-1): 2220, 1716, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 310 (M+, 100), 295 (39), 267 (42). HRMS (EI) Calcd for C17H14N2O2S+ (M+) 310.0770, Found: 310.0764. 3-(4-chlorophenyl)-7-methoxy-4H-benzo[b][1,4]thiazine-4carbonitrile (17): Yellow solid (41.3 mg, 66% yield), mp. 155156 oC. 1H NMR (500 MHz, CDCl3) δ: 7.41-7.36 (m, 4H), 7.277.25 (m, 1H), 6.81-6.78 (m, 1H), 6.64 (s 1H), 5.79 (s, 1H), 3.79 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 158.6, 136.7, 135.9, 130.9, 129.3, 128.7, 128.4, 126.7, 126.4, 119.7, 113.4, 112.4, 106.6, 55.8. IR (neat, cm-1): 2360, 1716, 1559, 1541, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 316 (38), 314 (M+, 100), 299 (38), 271 (20). HRMS (EI) Calcd for C16H11ClN2OS+ (M+) 314.0275, Found: 314.0279.
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7-methoxy-3-(naphthalen-1-yl)-4H-benzo[b][1,4]thiazine-4carbonitrile (18): Yellow solid (43.0 mg, 65% yield), mp. 123124 oC. 1H NMR (500 MHz, CDCl3) δ: 7.93-7.88 (m, 3H), 7.537.51 (m, 4H), 7.20 (d, J = 9.0 Hz, 1H), 6.80 (d, J = 9.0 Hz, 1H), 6.70 (s 1H), 5.69 (s, 1H), 3.80 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 158.5, 136.3, 133.7, 131.2, 130.9, 130.3, 129.1, 128.9, 128.8, 127.4, 126.5, 125.7, 125.3, 124.1, 118.8, 113.3, 112.8, 111.2, 106.1, 55.8. IR (neat, cm-1): 2360, 2220, 1716, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 330 (M+, 100), 315 (18), 152 (36). HRMS (EI) Calcd for C20H14N2OS+ (M+) 330.0821, Found: 330.0832. 7-methoxy-3-(thiophen-2-yl)-4H-benzo[b][1,4]thiazine-4carbonitrile (19): Yellow solid (29.6 mg, 52% yield), mp. 119120 oC. 1H NMR (500 MHz, CDCl3) δ: 7.34 (d, J = 5.0 Hz, 1H), 7.29 (d, J = 5.0 Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H), 7.06 (s, 1H), 6.78 (d, J = 8.5 Hz, 1H), 6.64 (s, 1H), 5.89 (s, 1H), 3.79 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ: 158.6, 134.1, 131.7, 128.7, 127.7, 127.2, 127.2, 127.0, 120.1, 113.4, 112.4, 110.7, 106.3, 55.8. IR (neat, cm-1): 2360, 1716, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 286 (M+, 100), 271 (31), 243 (30), 108 (25). HRMS (EI) Calcd for C14H10N2OS2+ (M+) 286.0229, Found: 286.0227. 3-tert-butyl-7-methoxy-4H-benzo[b][1,4]thiazine-4carbonitrile (20): Yellow Oil liquid (44.9 mg, 86% yield). 1H NMR (500 MHz, CDCl3) δ: 7.24 (d, J = 9.0 Hz, 1H), 6.80-6.77 (m, 1H), 6.71 (s, 1H), 5.87 (s, 1H), 3.78 (s, 3H), 1.34 (s, 9H). 13C NMR (125 MHz, CDCl3) δ: 158.4, 147.1, 130.8, 130.4, 121.0, 113.5, 113.2, 111.9, 108.0, 55.7, 37.5, 29.0. IR (neat, cm-1): 2216, 1716, 1488, 1364, 1223, 1049, 837. LRMS (EI, 70 eV) m/z (%): 260 (M+, 100), 245 (25), 204 (27), 57 (36). HRMS (EI) Calcd for C14H16N2OS+ (M+) 260.0978, Found: 260.0977. 7-methoxy-3-pentyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (21): Yellow solid (44.0 mg, 80% yield), mp. 42-43 oC. 1H NMR (500 MHz, CDCl3) δ: 7.10 (d, J = 9.0 Hz, 1H), 6.71-6.68 (m, 1H), 6.56 (s, 1H), 5.24 (s, 1H), 3.75 (s, 3H), 2.40-2.37 (m, 2H), 1.561.53 (m, 2H), 1.33-1.30 (m, 4H), 0.89-0.87 (m, 3H). 13C NMR (125 MHz, CDCl3) δ: 158.1, 136.8, 128.4, 125.1, 118.3, 112.9, 112.4, 110.3, 100.5, 55.7, 32.8, 30.9, 26.8, 22.3, 13.9. IR (neat, cm-1): 2360, 1716, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 274 (M+, 100), 218 (23), 217 (28) . HRMS (EI) Calcd for C15H18N2OS+ (M+) 274.1134, Found: 274.1127. 3-hexyl-7-methoxy-4H-benzo[b][1,4]thiazine-4-carbonitrile (22): Yellow Oil liquid (49.5 mg, 86% yield). 1H NMR (500 MHz, CDCl3) δ: 7.03 (d, J = 8.9 Hz, 1H), 6.64-6.62 (m, 1H), 6.50 (s, 1H), 5.18 (s, 1H), 3.69 (s, 3H), 2.33-2.30 (m, 2H), 1.48-1.46 (m, 2H), 1.27-1.18 (m, 6H), 0.81-0.78 (m, 3H). 13C NMR (125 MHz, CDCl3) δ: 158.1, 136.9, 128.4, 125.1, 118.3, 112.9, 112.4, 110.3, 100.5, 55.7, 32.9, 31.4, 28.4, 27.1, 22.5, 14.0. IR (neat, cm1 ): 2160, 1716, 1424, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 288 (M+, 100), 218 (26), 217 (23), 178(18). HRMS (EI) Calcd for C16H20N2OS+ (M+) 288.1291, Found: 288.1289. 7-methoxy-4H-benzo[b][1,4]thiazine-4-carbonitrile (23): Yellow solid (18.2 mg, 45% yield), mp. 108-109 oC. 1H NMR (500 MHz, CDCl3) δ: 7.01 (d, J = 9.0 Hz, 1H), 6.68-6.66 (m, 1H), This journal is © The Royal Society of Chemistry [year]
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6.49 (s, 1H), 6.19 (d, J = 7.0 Hz, 1H), 5.38 (d, J = 7.0 Hz, 1H), 3.75 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 158.2, 126.6, 124.1, 122.8, 122.1, 117.5, 115.0, 113.0, 104.0, 55.7. IR (neat, cm-1): 2360, 2219, 1716, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 204 (M+, 100), 189 (38), 178 (50), 135 (37), 134 (40). HRMS (EI) Calcd for C10H8N2OS+ (M+) 204.0352, Found: 204.0350.
Acknowledgement We thank the National Natural Science Foundation of China (No. 21272177) for financial support.
Notes and references a 65
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College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China. E-mail:[email protected]; b State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China. E-mail: [email protected]; † Electronic Supplementary Information (ESI) available: [Copy of 1H and 13 C NMR spectra of compounds 3 -23]. See DOI: 10.1039/b000000x/ 1
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Copper-Catalyzed Ring Expansion of 2-Aminobenzothiazoles with Alkynyl Carboxylic Acids to 1,4-Benzothiazines Jing-Wen Qiu,a Bo-Lun Hu,a Xing-Guo Zhang,*, a Ri-Yuan Tang,a Ping Zhong a and Jin-Heng Li*, b 5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x A new ring expansion of 2-aminobenzothiazoles with alkynyl carboxylic acids was developed, which allows for one-pot synthesis of 1,4-benzothiazines in moderate to excellent yields. The cascade reaction was achieved through decarboxylative coupling, nucleophilic ring-opening reaction and intramolecular hydroamination process.
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Results and discussion
Introduction 1,4-Benzothiazines are essential structural motifs in numerous natural products and pharmaceuticals with remarkable biological and medicinal properties,[1] such as antibacterial,[2] antidiabetic,[3] antiarrhythmic[4] and antitumor.[5] As a consequence, considerable efforts have devoted to the development of simple and efficient methods for the synthesis of 1,4-benzothiazines and their derivatives.[6,7] Generally, these methods focus on the condensation of 2-aminobenzenethiol derivatives in the presence of strong bases, which suffered from low functional group tolerability and limited efficiency for divergent synthesis of products, such as N-substituted benzothiazines. [7] Therefore, the development of new routes, especially one-pot strategy, for the construction of 1,4-benzothiazine backbone is still highly desirable. Recently, palladium or copper- catalyzed decarboxylative coupling reaction of alkynyl carboxylic acids, has emerged as a powerful protocol for the preparation of internal alkynes, which avoid using the less stable and oxygen sensitive terminal alkynes.[8] Meanwhile, transition-metal-catalyzed intramolecular hydroamination of alkynyl amines has received intensive interest and has come to represent an efficient and convenient strategy for the N-heterocyclic synthesis. [9] During the preparation of this manuscript, Hajra and co-workers reported a copper-catalyzed oxidative coupling between 2-aminobenzothiazole and terminal alkyne using 1,10-phenanthroline as ligand for the formation of benzothiazines. [10] Herein, we report a cascade reaction for onepot synthesis of 1,4-benzothiazines through copper-catalyzed nucleophilic ring-opening reaction of 2-aminobenzothiazole with alkynyl carboxylic acids and subsequent intramolecular hydroamination (Scheme 1). Scheme 1. One-pot synthesis of 1,4-benzothiazines.
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We began our studies by exploring the reaction between 2amino-6-methoxybenzothiazole 1a with 3-phenylpropiolic acid 2a to optimize the reaction conditions (Table 1). Initially, the reaction did not work in presence of 2 equiv of K3PO4 at 100 oC, but 80% yield of target product 3 was obtained when 10 mol % of CuI was used as catalyst (entries 1 and 2). This prompted us to investigate a variety of copper catalysts to improve the reaction, including CuBr, CuCl, Cu2O, CuCl2 and Cu(OAc)2 (entries 3-7). The results showed that CuCl were more effective than others, and provided product 3 in 86% yield (entry 4). The structure of compound 3 was confirmed by X-ray single crystal diffraction analysis. Subsequently, other inorganic bases were tested, but lower yields were observed when Cs2CO3, K2CO3 and K2HPO4 were used (entries 8-10). 1,4-Diazabicyclo[2.2.2]octane (DABCO), an organic base, was also effective for the tandem reaction and provided a 60% yield (entry 11). However, the reaction did not proceed in the absence of base (entry 12), which suggested that basic condition might be essential to the ringopening reaction of 2-aminobenzothiazole.[11] During the examination of solvent, low yields were obtained when DMF, DMSO, THF or toluene was used as solvent (entries 13-16). We found that temperature had an obvious affection on reaction activity, and only 68% yield of product 3 was isolated when the reaction was carried out at 80 oC (entry 17). It is noteworthy that the reaction yield was decreased slightly when the loading of phenylpropiolic acid 2a was reduced to 1.5 equiv or when the reaction proceeded under N2 atmosphere (entries 18 and 19). With the optimal reaction conditions in hand, we investigated the substrate scope of this ring expansion by testing the reaction of a wide variety of 2-aminobenzothiazole with alkynyl carboxylic acids under standard conditions (Table 2). Initially, the substitution effect on the benzothiazole moiety was examined. The results demonstrated that both electron-donating group and electron-withdrawing group were tolerated well, and provided corresponding product in good yields (5-9). For examples, benzo[d]thiazol-2-amine afford product 4 in 80% yield. Methyl substituted benzothiazoles provided 75-87% yields (5, 6 and 7). [journal], [year], [vol], 00–00 | 1
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Table 1. Screening conditions a
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Entry
Catalyst
Base
Solvent
Yield (%)
1
-
K3PO4
CH3CN
0
2
CuI
K3PO4
CH3CN
80
3
CuBr
K3PO4
CH3CN
85
4
CuCl
K3PO4
CH3CN
86
5
Cu2O
K3PO4
CH3CN
trace
6
CuCl2
K3PO4
CH3CN
60
7
Cu(OAc)2
K3PO4
CH3CN
85
8
CuCl
Cs2CO3
CH3CN
65
9
CuCl
K2CO3
CH3CN
76
10
CuCl
K2HPO4
CH3CN
30
11
CuCl
DABCO
CH3CN
60
12
CuCl
-
CH3CN
0
13
CuCl
K3PO4
DMF
30
14
CuCl
K3PO4
DMSO
25
15
CuCl
K3PO4
THF
35
16
CuCl
K3PO4
Toluene
trace
17b
CuCl
K3PO4
CH3CN
68
18c
CuCl
K3PO4
CH3CN
80
19d
CuCl
K3PO4
CH3CN
82
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DOI: 10.1039/C4OB02467B
CH3CN was carried out at 100 oC for 20h in the absence of CuCl and propiolic acid. Consistent with our hypothesis, 2-aminobenzenethiol could not be detected and almost 95% of reactant 1a was recovered (Scheme 2, eq. 1), which suggested that the ringopening reaction could not proceed without CuCl, even in the high temperature and weak basic conditions. However, substrate 1a was decomposed completely when it was reacted with 10 mol % CuCl, 2 equiv of K3PO4 in CH3CN at 100 oC for 2h in the absence of propiolic acid (eq. 2). These results suggested that copper catalyst play a key role in the nucleophilic ring-opening procedure as well as in the decarboxylative coupling reaction and intramolecular hydroamination. Table 2. Scope of the ring expansion a
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Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (10 mol %), base (2 equiv) and solvent (2 mL) at 100 oC under air atmosphere for 10 h. bat 80 oC. c2a (0.3 mmol). d Under N2 atmosphere.
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Fluoride and chloride benzothiazines (8 and 9) were isolated in 81% and 80% yields, respectively. Subsequently, a number of substituents on the propiolic acid moiety were evaluated, and the results displayed that both aryl group (including heteroaryl) and aliphatic alkyl group were compatible with the optimal conditions. For examples, o-, m-, p-tolyl propiolic acids provided product 1012 in 83%-87% yield, and bulky mesityl propiolic acid gave product 13 in 87% yield, which indicated that steric hindrance have no effect on reaction yield. o-, m-, p-Methoxyphenyl propiolic acids gave benzothiazines in 75-85% yields (14, 15 and 16). Electron-poor 4-chlorophenyl provided product 17 in 66% yield. Gratifyingly, 65% yield was obtained for the naphthalen-1yl group, and a 52% yield for thiophen-2-yl group. Notably, aliphatic alkyl group substituted propiolic acids were also tolerated very well to produce benzothiazines in good yields. 4,4Dimethylpent-2-ynoic acid, for instance, underwent the ring expansion reaction smoothly to give product 20 in 86% yield. Oct-2-ynoic acid and non-2-ynoic acid afforded product 21 and 22 in 80% and 86% yields, respectively. Unblocked propiolic acid was also a suitable substrate for the ring transformation, albeit providing benzothiazine 23 in a 45% yield. To probe the mechanism of this transformation, the reaction of 2-amino-6-methoxybenzothiazole 1a with 2 equiv of K3PO4 in 2 | Journal Name, [year], [vol], 00–00
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Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), CuCl (10 mol %) and K3PO4 (2 equiv) in 2 mL CH3CN at 100 oC under air atmosphere for 10 h.
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On the basis of the above results and previous reports,[12] a possible mechanism for this ring expansion reaction was proposed in Scheme 3. Initially, the decarboxylation reaction of alkynyl carboxylic acids with CuCl generates copper(I) acetylide A. Subsequently, the oxidative coupling with 2-aminobenzothiazoles readily takes place to give intermediate B, which This journal is © The Royal Society of Chemistry [year]
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undergoes deprotonation by K3PO4 and reductive elimination to produce intermediate C. The tautomerization reaction of intermediate C affords cyanamides D, the final copper(I)catalyzed intramolecular hydroamination results in ring expansion products 3-23.
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Scheme 2. Control experiments.
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Scheme 3. Possible mechanism.
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In conclusion, we have developed a novel one-pot cascade strategy for the synthesis of 4-cyano-1,4-benzothiazines from 2aminobenzothiazole and alkynyl carboxylic acids in moderate to excellent yields. The ring expansion reaction involves coppercatalyzed decarboxylative coupling reaction of propiolic acids, ring-opening reaction of 2-aminobenzothiazole and intramolecular hydroamination process. This ring transformation shows broad substrate scope for both 2-aminobenzothiazoles and alkynyl carboxylic acids with excellent functional group tolerance. Moreover, this method affords a valuable new approach for the self-assembly of 1,4-benzothiazines from stable and readily available starting materials, which will be useful in the synthesis of N-containing heterocyclics.
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Experimental
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Chemicals were either purchased or purified by standard techniques. 1H NMR and 13C NMR spectra were measured on a 500 MHz spectrometer (1H: 500 MHz, 13C: 125 MHz), using CDCl3 as the solvent with tetramethylsilane (TMS) as an internal standard at room temperature. Chemical shifts are given in δ relative to TMS, the coupling constants J are given in Hz. All reactions under N2 atmosphere were conducted using standard Schlenk techniques. Column chromatography was performed using EM Silica gel 60 (300-400 mesh). This journal is © The Royal Society of Chemistry [year]
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DOI: 10.1039/C4OB02467B
General procedure for copper-catalyzed ring expansion of 2aminobenzothiazoles with alkynyl carboxylic acids. Under air atmosphere, benzo[d]thiazol-2-amine 1 (0.2 mmol), CuCl (10 mol %), K3PO4 (2 equiv), acetonitrile (2 mL), and 3phenylpropiolic acid 2 (0.4 mmol) were successively added into a Schlenk reaction tube. The mixture was stirred at 100 °C for 10h or until complete consumption of starting material as monitored by TLC and GC-MS analysis. After the reaction was finished, the mixture was filtered by a crude column with ethyl acetate as eluent, and evaporated in vacuum. The residue was purified by flash column chromatography on a silica gel using EtOAc/petroleum ether (1:10) as eluent to give the product 3-23. 7-methoxy-3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (3): Yellow solid (48.1 mg, 86% yield), mp. 130-131 oC. 1H NMR (500 MHz, CDCl3) δ: 7.43-7.41 (m, 5H), 7.29-7.26 (m, 1H), 6.81-6.78 (m, 1H), 6.65 (s, 1H), 5.77 (s, 1H), 3.79 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 158.5, 137.9, 132.5, 129.9, 129.0, 129.0, 127.2, 127.0, 119.6, 113.3, 112.4, 110.9, 105.8, 55.8. IR (neat, cm-1): 2360, 1716, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 280 (M+, 100), 265 (38), 237 (30). HRMS (EI) Calcd for C16H12N2OS+ (M+) 280.0665, Found: 280.0663. 3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (4): Yellow solid (40.2 mg, 80% yield), mp. 128-129 oC. 1H NMR (500 MHz, CDCl3) δ: 7.44-7.42 (m, 5H), 7.37 (d, J = 8.1 Hz, 1H), 7.29-7.25 (m, 1H), 7.18-7.15 (m, 1H), 7.11-7.10 (m, 1H), 5.76 (s, 1H). 13C NMR (125 MHz, CDCl3) δ: 137.6, 136.4, 132.4, 129.9, 129.0, 128.2, 127.3, 127.2, 127.2, 125.5, 118.6, 110.5, 106.3. IR (neat, cm-1): 2361, 1716, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 250 (M+, 40), 249 (48), 223 (25). HRMS (EI) Calcd for C15H10N2S+ (M+) 250.0559, Found: 250.0567. 7-methyl-3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (5): Yellow solid (43.9 mg, 83% yield), mp. 117-118 oC. 1H NMR (500 MHz, CDCl3) δ: 7.41 (s, 5H), 7.24 (d, J = 8.0 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.91 (s, 1H), 5.75 (s, 1H), 2.30 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 137.6, 137.3, 133.7, 132.6, 129.9, 128.9, 128.7, 127.6, 127.2, 125.1, 118.4, 110.7, 106.2, 20.7. IR (neat, cm-1): 1715, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 264 (M+, 100), 263 (38), 231 (22). HRMS (EI) Calcd for C16H12N2S+ (M+) 264.0716, Found: 264.0712. 8-methyl-3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (6): Yellow solid (39.4 mg, 75% yield), mp. 144-145 oC. 1H NMR (500 MHz, CDCl3) δ: 7.55 (d, J = 7.5 Hz, 2H), 7.46-7.40 (m, 3H), 7.16 (d, J = 7.0 Hz, 2H), 7.09-7.08 (m, 1H), 6.41 (s, 1H), 2.64 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 139.0, 133.6, 132.2, 132.1, 130.9, 130.7, 129.6, 129.2, 127.7, 126.3, 125.2, 112.2, 111.3, 18.3. IR (neat, cm-1): 1716, 1362, 1222. LRMS (EI, 70 eV) m/z (%): 264 (M+, 100), 263 (35), 231 (23). HRMS (EI) Calcd for C16H12N2S+ (M+) 264.0716, Found: 264.0709. 6,7-dimethyl-3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (7): Yellow solid (48.6 mg, 87% yield), mp. 128-129 oC. 1H NMR (500 MHz, CDCl3) δ: 7.42-7.39 (m, 5H), 7.15 (s, 1H), 6.85 (s, 1H), 5.75 (s, 1H), 2.25 (s, 3H), 2.19 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 137.4, 137.0, 135.9, 133.7, 132.7, 129.8, 128.9, Journal Name, [year], [vol], 00–00 | 3
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127.9, 127.2, 121.5, 119.7, 110.8, 106.5, 19.5, 19.1. IR (neat, cm1 ): 2219, 1716, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 278 (M+, 100), 277 (27), 245 (22), 131 (13). HRMS (EI) Calcd for C17H14N2S+ (M+) 278.0872, Found: 278.0869.
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7-fluoro-3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (8): Yellow solid (43.2 mg, 81% yield), mp. 121-122 oC. 1H NMR (500 MHz, CDCl3) δ: 7.42 (s, 5H), 7.34-7.31 (m, 1H), 6.99-6.95 (m, 1H), 6.85-6.83 (m, 1H), 5.74 (s, 1H). 13C NMR (125 MHz, CDCl3) δ: 161.0 (d, 1JC-F = 247.5 Hz), 138.0, 132.3, 132.1, 129.0, 128.1, 128.0, 127.3, 119.8, 114.9 (d, 2JC-F = 23.4 Hz), 114.3. (d, 2 JC-F = 25.1 Hz), 110.3, 105.5. IR (neat, cm-1): 2219, 1716, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 268 (M+, 100), 267 (29), 241 (28). HRMS (EI) Calcd for C15H9FN2S+ (M+) 268.0465, Found: 268.0467. 7-chloro-3-phenyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (9): Yellow solid (42.7 mg, 80% yield), mp. 126-127 oC.1H NMR (500 MHz, CDCl3) δ: 7.42 (s, 5H), 7.27 (d, J = 8.5 Hz, 1H), 7.257.21 (m, 1H), 7.08 (s, 1H), 5.72 (s, 1H). 13C NMR (125 MHz, CDCl3) δ: 137.9, 135.0, 132.7, 132.1, 130.2, 129.0, 128.0, 127.4, 127.3, 126.8, 119.5, 110.0, 105.5. IR (neat, cm-1): 2360, 1716, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 286 (M+, 40), 284 (100), 249 (35), 222 (32). HRMS (EI) Calcd for C15H9ClN2S+ (M+) 268.0169, Found: 268.0180. 7-methoxy-3-o-tolyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (10): Yellow solid (50.8 mg, 86% yield), mp. 101-102 oC. 1H NMR (500 MHz, CDCl3) δ: 7.35-7.21 (m, 5H), 7.16 (d, J = 9.0 Hz, H), 6.77-6.74 (m, 1H), 6.64 (s, 1H), 5.50 (s, 1H), 3.78 (s, 3H), 2.33 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 156.5, 135.6, 135.0, 130.6, 128.9, 128.8, 128.4, 126.9, 124.5, 123.8, 116.6, 111.3, 110.7, 108.3, 103.0, 53.9, 17.8. IR (neat, cm-1): 2363, 2224, 1716, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 294 (M+, 100), 279 (19), 234 (36). HRMS (EI) Calcd for C17H14N2OS+ (M+) 294.0821, Found: 294.0825. 7-methoxy-3-m-tolyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (11): Yellow solid (51.1 mg, 87% yield), mp. 116-117 oC. 1H NMR (500 MHz, CDCl3) δ: 7.32-7.20 (m, 5H), 6.79-6.77 (m, 1H), 6.63 (s, 1H), 5.73 (s, 1H), 3.78 (s, 3H), 2.38 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 158.5, 138.7, 138.1, 132.4, 130.7, 129.1, 128.8, 127.9, 127.0, 124.3, 119.6, 113.3, 112.4, 111.0, 105.5, 55.8, 21.5. IR (neat, cm-1): 2223, 1716, 1424, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 294 (M+, 100), 279 (38), 251 (23). HRMS (EI) Calcd for C17H14N2OS+ (M+) 294.0821, Found: 294.0831.
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7-methoxy-3-p-tolyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (12): Yellow solid (48.6 mg, 83% yield), mp. 134-135 oC. 1H NMR (500 MHz, CDCl3) δ: 7.32 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 9.0 Hz, 1H), 7.22 (d, J = 8.5 Hz, 2H), 6.79-6.77 (m, 1H), 6.63 (s, 1H), 5.70 (s, 1H), 3.78 (s, 3H), 2.37 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 158.5, 140.1, 138.1, 129.7, 129.6, 129.1, 127.2, 127.1, 119.6, 113.3, 112.4, 111.0, 104.7, 55.8, 21.4. IR (neat, cm-1): 2359, 2219, 1718, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 294 (M+, 100), 279 (40), 251 (35), 115 (35). HRMS (EI) Calcd for C17H14N2OS+ (M+) 294.0821, Found: 294.0816.
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DOI: 10.1039/C4OB02467B
3-mEItyl-7-methoxy-4H-benzo[b][1,4]thiazine-4-carbonitrile (13): Yellow solid (56.0 mg, 87% yield), mp. 158-159 oC. 1H NMR (500 MHz, CDCl3) δ: 7.11 (d, J = 9.0 Hz, 1H), 6.91 (s, 2H), 6.74-6.72 (m, 1H), 6.63 (s 1H), 5.31 (s, 1H), 3.78 (s, 3H), 2.29 (s, 9H). 13C NMR (125 MHz, CDCl3) δ: 158.3, 139.8, 137.9, 135.2, 129.3, 128.8, 128.7, 124.5, 118.1, 113.1, 112.7, 109.9, 103.2, 55.7, 21.2, 19.9. IR (neat, cm-1): 2361, 1716, 1424, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 322 (M+, 100), 262 (26), 129 (19). HRMS (EI) Calcd for C19H18N2OS+ (M+) 322.1134, Found: 322.1131. 7-methoxy-3-(2-methoxyphenyl)-4H-benzo[b][1,4]thiazine-4carbonitrile (14): Yellow solid (47.1 mg, 76% yield), mp. 126127 oC. 1H NMR (500 MHz, CDCl3) δ: 7.40-7.39 (m, 1H), 7.307.28 (m, 1H), 7.20 (d, J = 8.9 Hz, 1H), 6.98-6.94 (m 2H), 6.806.67 (m, 1H), 6.66 (s, 1H), 5.64 (s, 1H), 3.87 (s, 3H), 3.78 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ: 158.2, 157.0, 136.8, 131.7, 131.4, 129.8, 126.2, 121.4, 121.0, 118.5, 113.2, 112.5, 111.2, 110.7, 105.7, 55.8, 55.8. IR (neat, cm-1): 2223, 1716, 1420, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 310 (M+, 100), 295 (19), 131 (18) . HRMS (EI) Calcd for C17H14N2O2S+ (M+) 310.0770, Found: 310.0780. 7-methoxy-3-(3-methoxyphenyl)-4H-benzo[b][1,4]thiazine-4carbonitrile (15): Yellow solid (46.2 mg, 75% yield), mp. 127128 oC. 1H NMR (500 MHz, CDCl3) δ: 7.35-7.32 (m, 1H), 7.287.26 (m, 1H), 7.02 (d, J = 7.5 Hz, 1H), 6.95-6.94 (m, 2H), 6.806.78 (m, 1H), 6.64 (s 1H), 5.78 (s, 1H), 3.84 (s, 3H), 3.79 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ: 159.9, 158.5, 137.7, 133.8, 130.0, 129.0, 126.9, 119.6, 119.5, 115.5, 113.3, 112.9, 112.4, 110.8, 106.0, 55.8, 55.4. IR (neat, cm-1): 2359, 1716, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 310 (M+, 100), 295 (37), 267 (27). HRMS (EI) Calcd for C17H14N2O2S+ (M+) 310.0770, Found: 310.0783. 7-methoxy-3-(4-methoxyphenyl)-4H-benzo[b][1,4]thiazine-4carbonitrile (16): Yellow solid (52.9 mg, 85% yield), mp. 146147 oC. 1H NMR (500 MHz, CDCl3) δ: 7.38-7.36 (m, 2H), 7.277.26 (m, 1H), 6.95-6.93 (m, 2H), 6.79-6.77 (m, 1H), 6.64 (s, 1H), 5.64 (s, 1H), 3.83 (s, 3H), 3.79 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 160.9, 158.5, 138.0, 129.1, 128.8, 127.3, 124.8, 119.5, 114.4, 113.2, 112.4, 111.0, 103.6, 55.8, 55.4. IR (neat, cm-1): 2220, 1716, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 310 (M+, 100), 295 (39), 267 (42). HRMS (EI) Calcd for C17H14N2O2S+ (M+) 310.0770, Found: 310.0764. 3-(4-chlorophenyl)-7-methoxy-4H-benzo[b][1,4]thiazine-4carbonitrile (17): Yellow solid (41.3 mg, 66% yield), mp. 155156 oC. 1H NMR (500 MHz, CDCl3) δ: 7.41-7.36 (m, 4H), 7.277.25 (m, 1H), 6.81-6.78 (m, 1H), 6.64 (s 1H), 5.79 (s, 1H), 3.79 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 158.6, 136.7, 135.9, 130.9, 129.3, 128.7, 128.4, 126.7, 126.4, 119.7, 113.4, 112.4, 106.6, 55.8. IR (neat, cm-1): 2360, 1716, 1559, 1541, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 316 (38), 314 (M+, 100), 299 (38), 271 (20). HRMS (EI) Calcd for C16H11ClN2OS+ (M+) 314.0275, Found: 314.0279.
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Organic & Biomolecular Chemistry
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7-methoxy-3-(naphthalen-1-yl)-4H-benzo[b][1,4]thiazine-4carbonitrile (18): Yellow solid (43.0 mg, 65% yield), mp. 123124 oC. 1H NMR (500 MHz, CDCl3) δ: 7.93-7.88 (m, 3H), 7.537.51 (m, 4H), 7.20 (d, J = 9.0 Hz, 1H), 6.80 (d, J = 9.0 Hz, 1H), 6.70 (s 1H), 5.69 (s, 1H), 3.80 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 158.5, 136.3, 133.7, 131.2, 130.9, 130.3, 129.1, 128.9, 128.8, 127.4, 126.5, 125.7, 125.3, 124.1, 118.8, 113.3, 112.8, 111.2, 106.1, 55.8. IR (neat, cm-1): 2360, 2220, 1716, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 330 (M+, 100), 315 (18), 152 (36). HRMS (EI) Calcd for C20H14N2OS+ (M+) 330.0821, Found: 330.0832. 7-methoxy-3-(thiophen-2-yl)-4H-benzo[b][1,4]thiazine-4carbonitrile (19): Yellow solid (29.6 mg, 52% yield), mp. 119120 oC. 1H NMR (500 MHz, CDCl3) δ: 7.34 (d, J = 5.0 Hz, 1H), 7.29 (d, J = 5.0 Hz, 1H), 7.26 (d, J = 8.5 Hz, 1H), 7.06 (s, 1H), 6.78 (d, J = 8.5 Hz, 1H), 6.64 (s, 1H), 5.89 (s, 1H), 3.79 (s, 3H). 13 C NMR (125 MHz, CDCl3) δ: 158.6, 134.1, 131.7, 128.7, 127.7, 127.2, 127.2, 127.0, 120.1, 113.4, 112.4, 110.7, 106.3, 55.8. IR (neat, cm-1): 2360, 1716, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 286 (M+, 100), 271 (31), 243 (30), 108 (25). HRMS (EI) Calcd for C14H10N2OS2+ (M+) 286.0229, Found: 286.0227. 3-tert-butyl-7-methoxy-4H-benzo[b][1,4]thiazine-4carbonitrile (20): Yellow Oil liquid (44.9 mg, 86% yield). 1H NMR (500 MHz, CDCl3) δ: 7.24 (d, J = 9.0 Hz, 1H), 6.80-6.77 (m, 1H), 6.71 (s, 1H), 5.87 (s, 1H), 3.78 (s, 3H), 1.34 (s, 9H). 13C NMR (125 MHz, CDCl3) δ: 158.4, 147.1, 130.8, 130.4, 121.0, 113.5, 113.2, 111.9, 108.0, 55.7, 37.5, 29.0. IR (neat, cm-1): 2216, 1716, 1488, 1364, 1223, 1049, 837. LRMS (EI, 70 eV) m/z (%): 260 (M+, 100), 245 (25), 204 (27), 57 (36). HRMS (EI) Calcd for C14H16N2OS+ (M+) 260.0978, Found: 260.0977. 7-methoxy-3-pentyl-4H-benzo[b][1,4]thiazine-4-carbonitrile (21): Yellow solid (44.0 mg, 80% yield), mp. 42-43 oC. 1H NMR (500 MHz, CDCl3) δ: 7.10 (d, J = 9.0 Hz, 1H), 6.71-6.68 (m, 1H), 6.56 (s, 1H), 5.24 (s, 1H), 3.75 (s, 3H), 2.40-2.37 (m, 2H), 1.561.53 (m, 2H), 1.33-1.30 (m, 4H), 0.89-0.87 (m, 3H). 13C NMR (125 MHz, CDCl3) δ: 158.1, 136.8, 128.4, 125.1, 118.3, 112.9, 112.4, 110.3, 100.5, 55.7, 32.8, 30.9, 26.8, 22.3, 13.9. IR (neat, cm-1): 2360, 1716, 1419, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 274 (M+, 100), 218 (23), 217 (28) . HRMS (EI) Calcd for C15H18N2OS+ (M+) 274.1134, Found: 274.1127. 3-hexyl-7-methoxy-4H-benzo[b][1,4]thiazine-4-carbonitrile (22): Yellow Oil liquid (49.5 mg, 86% yield). 1H NMR (500 MHz, CDCl3) δ: 7.03 (d, J = 8.9 Hz, 1H), 6.64-6.62 (m, 1H), 6.50 (s, 1H), 5.18 (s, 1H), 3.69 (s, 3H), 2.33-2.30 (m, 2H), 1.48-1.46 (m, 2H), 1.27-1.18 (m, 6H), 0.81-0.78 (m, 3H). 13C NMR (125 MHz, CDCl3) δ: 158.1, 136.9, 128.4, 125.1, 118.3, 112.9, 112.4, 110.3, 100.5, 55.7, 32.9, 31.4, 28.4, 27.1, 22.5, 14.0. IR (neat, cm1 ): 2160, 1716, 1424, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 288 (M+, 100), 218 (26), 217 (23), 178(18). HRMS (EI) Calcd for C16H20N2OS+ (M+) 288.1291, Found: 288.1289. 7-methoxy-4H-benzo[b][1,4]thiazine-4-carbonitrile (23): Yellow solid (18.2 mg, 45% yield), mp. 108-109 oC. 1H NMR (500 MHz, CDCl3) δ: 7.01 (d, J = 9.0 Hz, 1H), 6.68-6.66 (m, 1H), This journal is © The Royal Society of Chemistry [year]
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6.49 (s, 1H), 6.19 (d, J = 7.0 Hz, 1H), 5.38 (d, J = 7.0 Hz, 1H), 3.75 (s, 3H). 13C NMR (125 MHz, CDCl3) δ: 158.2, 126.6, 124.1, 122.8, 122.1, 117.5, 115.0, 113.0, 104.0, 55.7. IR (neat, cm-1): 2360, 2219, 1716, 1363, 1222. LRMS (EI, 70 eV) m/z (%): 204 (M+, 100), 189 (38), 178 (50), 135 (37), 134 (40). HRMS (EI) Calcd for C10H8N2OS+ (M+) 204.0352, Found: 204.0350.
Acknowledgement We thank the National Natural Science Foundation of China (No. 21272177) for financial support.
Notes and references a 65
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College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China. E-mail:[email protected]; b State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China. E-mail: [email protected]; † Electronic Supplementary Information (ESI) available: [Copy of 1H and 13 C NMR spectra of compounds 3 -23]. See DOI: 10.1039/b000000x/ 1
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