Simple Synthesis of Fused Thiazolo[4,5-b]pyridines through Successive S_NAr Processes

Abstract

A convenient process is described for the synthesis of novel thiazolo[4,5-b]pyridines fused with triazole or pyrimidine rings. The base-promoted reactions of 2-chloro-3-nitropyridines with 1,3-(S,N)-binucleophiles (triazole-5-thiols, 4-oxopyrimidine-2-thiones) resulted in nucleophilic substitution of the chlorine atom and subsequent S–N-type Smiles rearrangement followed by nucleophilic substitution of the nitro group. Reactions with pyrimidine-2-thiones were carried out as one-pot processes while, in the case of triazole-5-thiols, isolation of intermediate substitution products was found to be preferable.

Key words

thiazolo[4,5-b]pyridines - nucleophilic aromatic substitution - Smiles rearrangement - pyrimidine-2-thiones - triazole-5-thiols

Publication History

Received: 10 September 2020

Accepted after revision: 01 October 2020

Article published online:
30 October 2020

• References and Notes

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• 19 Compounds 3a–d,f–h, and 4e; General Procedure To a solution of chloropyridine 1 (1 mmol) and triazole 2 (1 mmol) in DMF (10 mL) was added Na₂CO₃ (106 mg, 1 mmol). The mixture was stirred at 20 °C for 24 h, poured into water (50 mL), acidified with concd HCl to pH 3, and the resulting precipitate was filtered off, washed with water, and dried in air to give target compound 3 or 4. 2-[(3-Methyl-1H-1,2,4-triazol-5-yl)thio]-3,5-dinitropyridine (3a) Beige solid; mp 229–230 °C; yield 71%. ¹H NMR (200.13 MHz, DMSO-d ₆): δ = 2.43 (s, 3 H), 9.12 (d, J = 2.2 Hz, 1 H), 9.35 (d, J = 2.2 Hz, 1 H). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 12.3, 129.9, 140.9, 141.8, 148.5, 151.7, 155.8, 162.0. HRMS (ESI): m/z calcd for C₈H₆N₆O₄S [M + H]: 283.0244; found: 283.0234. 2-[(1H-1,2,4-Triazol-5-yl)thio]-3,5-dinitropyridine (3b) Beige solid; mp 183–185 °C; yield 65%. ¹H NMR (200.13 MHz, DMSO-d ₆): δ = 8.81 (br s, 1 H), 9.14 (d, 1 H, J = 1.8 Hz), 9.34 (d, 1 H, J = 1.8 Hz), 14.69 (br s, 1 H). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 129.5, 131.6, 140.5, 141.4, 146.4 (br s), 147.9. HRMS (ESI): m/z calcd for C₇H₄N₆O₄S [M + H]: 269.0087; found: 269.0089. 2-[(3-Cyclohexyl-1H-1,2,4-triazol-5-yl)thio]-3,5-dinitropyridine (3c) White solid; mp 223–245 °C; yield 84%. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 1.22–1.79 (m, 8 H), 1. 99 (d, 2 H, J = 11.0 Hz), 2.81–2.89 (m, 1 H), 9.14 (s, 1 H), 9.33 (s, 1 H), 14.28 (br s, 1 H). ¹³C NMR (125.76 MHz, DMSO-d ₆): δ = 25.6, 25.8, 31.2, 35.8, 129.9, 140.9, 141.8, 148.4, 151.4, 162.0, 163.5. HRMS (ESI): m/z calcd for C₁₃H₁₂N₆O₄S [M + H]: 351.0870; found: 351.0867. 2-{[3-(3,5-Di-tert-butylphenyl)-1H-1,2,4-triazol-5-yl]thio}-3,5-dinitropyridine (3d) White solid; mp 281–282 °C; yield 78%. ¹H NMR (200.13 MHz, DMSO-d ₆: δ = 1.34 (s, 18 H), 7.57 (s, 1 H), 7.89 (s, 2 H), 9.15 (s, 1 H), 9.36 (s, 1 H). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 31.6, 35.2, 120.9, 123.6, 125.0, 126.4, 130.0, 141.0, 141.9, 148.6, 151.9, 157.8, 162.0. HRMS (ESI): m/z calcd for C₂₁H₂₄N₆O₄S [M + H]: 457.1653; found: 457.1643. Methyl 5-Nitro-6-(1H-1,2,4-triazol-5-ylthio)nicotinate (3f) Beige solid; mp 189–191 °C; yield 20%. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 3.89 (s, 3 H), 8.73 (br s, 1 H), 8.85 (s, 1 H), 8.97 (s, 1 H), 14.83 (br s, 1 H). ¹³C NMR (125.76 MHz, DMSO-d ₆): δ = 53.0, 123.2, 134.4, 138.05, 141.1, 146.4 (br s), 153.2, 159.8 (br s), 163.4. HRMS (ESI): m/z calcd for C₉H₇N₅O₄S [M + H]: 282.0292; found: 282.0293. 3-Nitro-2-(1H-1,2,4-triazol-5-ylthio)-5-(trifluoromethyl)pyridine (3g) White solid; mp 193–194 °C; yield 46%. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 8.73 (br s, 1 H), 8.92 (s, 1 H), 9.03 (s, 1 H). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 122.4 (q, ² J _CF = 337.8 Hz), 122.5 (q, ¹ J _CF = 272.7 Hz), 132.0, 141.0, 146.1, 150.1, 151.9, 159.8. HRMS (ESI): m/z calcd for C₈H₄F₃N₅O₂S [M +H]: 292.0111; found: 292.0113. 3-Nitro-2-(1H-1,2,4-triazol-5-ylthio)pyridine (3h) Light-yellow solid; mp 206–208 °C; yield 67%. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 7.49 (dd, 1 H, J = 8.1, 4.6 Hz), 8.60–8.67 (m, 3 H). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 122.0, 134.9, 136.0, 142.0, 147.9, 154.5, 155.0. HRMS (ESI): m/z calcd for C₇H₅N₅O₂S [M + H]: 224.0237; found: 224.0243. 7-Nitro-2-pyridin-4-yl[1,2,4]triazolo[5′,1′:2,3][1,3]thiazolo[4,5-b]pyridine (4e) Beige solid; mp >300 °C; yield 52%. ¹H NMR (200.13 MHz, DMSO-d ₆): δ = 8.11 (d, J = 5.9 Hz, 2 H), 8.81 (d, J = 5.9 Hz, 2 H), 9.48 (d, J = 2.2 Hz, 1 H), 9.63 (d, J = 2.2 Hz, 1 H). Due to insufficient solubility we were unable to record ¹³C NMR spectrum. HRMS (ESI): m/z calcd for C₁₂H₆N₆O₂S [M + H]: 299.0346; found: 299.0339. Compounds 4a–d,f ,g, and 5; General Procedure To a solution of compound 3 (1 mmol) in DMF (10 mL) was added Na₂CO₃ (106 mg, 1 mmol; or Et₃N (0.14 mL, 1 mmol)). The mixture was stirred at 80 °C for 3–4 h (TLC), poured in water (50 mL), acidified with concd HCl to pH 3, and the resulting precipitate was filtered off, washed with water, and dried in air to give compound 4. 2-Methyl-7-nitro[1,2,4]triazolo[5′,1′:2,3][1,3]thiazolo[4,5-b]pyridine (4a) Beige solid; mp 263–265 °C; yield 57%. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 2.47 (s, 3 H), 9.39 (s, 1 H), 9.54 (s, 1 H). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 14.9, 125.2, 131.2, 141.5, 143.1, 145.1, 167.9. HRMS (ESI): m/z calcd for C₈H₅N₅O₂S [M + H]: 236.0237; found: 236.0230. 7-Nitro[1,2,4]triazolo[5′,1′:2,3][1,3]thiazolo[4,5-b]pyridine (4b) Beige solid; mp 253–254 °C; yield 67%. ¹H NMR (200.13 MHz, DMSO-d ₆): δ = 8.64 (s, 1 H), 9.42 (d, J = 2.1 Hz, 1 H), 9.58 (d, J = 2.1 Hz, 1 H). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 126.0, 131.3, 141.7, 143.0, 145.2, 158.2, 159.0. HRMS (ESI): m/z calcd for C₇H₃N₅O₂S [M + H]: 222.0080; found: 222.0082. 2-Cyclohexyl-7-nitro[1,2,4]triazolo[5′,1′:2,3][1,3]thiazolo[4,5-b]pyridine (4c) Beige solid; mp 163–165 °C; yield 36%. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 1.21–1.82 (m, 8 H), 2.06 (d, J = 11.6 Hz, 2 H), 2.86–2.93 (m, 1 H), 9.39 (d, J = 1.8 Hz), 9.55 (d, J = 1.8 Hz). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 25.7, 26.0, 31.5, 38.3, 125.8, 131.6, 141.9, 143.5, 145.7, 159.4, 175.6. HRMS (ESI): m/z calcd for C₁₃H₁₃N₅O₂S [M + H]: 304.0863; found: 304.0851. 2-(3,5-Di-tert-butylphenyl)-7-nitro[1,2,4]triazolo[5′,1′:2,3][1,3]thiazolo[4,5-b]pyridine (4d) White solid; mp 340–342 °C; yield 16%. ¹H NMR (600.13 MHz, DMSO-d ₆): δ = 1.39 (s, 18 H), 7.61 (s, 1 H), 8.06 (d, J = 1.2 Hz, 2 H), 9.42 (d, J = 2.2 Hz, 1 H), 9.56 (d, J = 2.2 Hz, 1 H). ¹³C NMR (150.90 MHz, DMSO-d ₆): δ = 30.8, 34.3, 120.5, 124.2, 125.2, 128.9, 130.7, 141.4, 142.7, 144.9, 150.9, 159.3, 168.3. HRMS (ESI): m/z calcd for C₂₁H₂₃N₅O₂S [M + H]: 410.1645; found: 410.1636. 7-(Trifluoromethyl)[1,2,4]triazolo[5′,1′:2,3][1,3]thiazolo[4,5-b]pyridine (4g) Beige solid; mp 204–205 °C; yield 60%. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 8.62 (s, 1 H), 9.04 (s, 1 H), 9.18 (s, 1 H). Due to insufficient solubility we were unable to record ¹³C NMR spectrum. HRMS (ESI): m/z calcd for C₈H₃F₃N₄S [M + H]: 245.0103; found: 245.0111. Methyl [1,2,4]Triazolo[5′,1′:2,3][1,3]thiazolo[4,5-b]pyridine-7-carboxylate (4f) and Methyl [1,2,4]Triazolo[3′,4′:2,3][1,3]thiazolo[4,5-b]pyridine-7-carboxylate (5) Beige solid; yield 86%. ¹H NMR (300.13 MHz, DMSO-d ₆): δ (major isomer) = 3.97 (s, 3 H), 8.31 (s, 1 H), 9.07 (d, J = 1.6 Hz, 1 H), 9.31 (d, J = 1.7 Hz, 1 H); δ (minor isomer) = 3.96 (s, 3 H), 8.62 (s, 1 H), 9.12 (d, J = 1.9 Hz, 1 H), 9.27 (d, J = 1.9 Hz, 1 H). HRMS (ESI): m/z calcd for C₉H₆N₄O₂S [M + H]: 235.0284; found: 235.0283. Compounds 7a–f, and 8c – General Procedure To a solution of compound 1 (1 mmol) and thione 6 (1 mmol) in DMF (10 mL) was added Na₂CO₃ (106 mg, 1 mmol). The mixture was stirred at 80 °C until TLC showed no starting materials (3–6 h), poured into water (50 mL), acidified with concd HCl to pH 3, and the resulting precipitate was filtered off, washed with water, and dried in air to give compound 7 or 8. 3-Nitro-9H-pyrido[2′,3′:4,5][1,3]thiazolo[3,2-a]pyrimidin-9-one (7a) Yellow solid; mp 242 °C (dec.); yield 54%. ¹H NMR (600.13 MHz, DMSO-d ₆): δ = 6.45 (d, J = 6.7 Hz, 1 H), 7.99 (d, J = 6.7 Hz, 1 H), 9.40 (s, 2 H). ¹³C NMR (150.90 MHz, DMSO-d ₆): δ = 110.4, 121.1, 127.9, 141.9, 142.0, 151.4, 151.5, 157.8, 162.4. ¹⁵N NMR (60.83 MHz, DMSO-d ₆): δ = –84.33, –145.51, –177.19. HRMS (ESI): m/z calcd for C₉H₄N₄NaO₃S [M + Na]: 270.9896; found: 270.9892. 7-Methyl-3-nitro-9H-pyrido[2′,3′:4,5][1,3]thiazolo[3,2-a]pyrimidin-9-one (7b) Brown solid; mp 294 °C; yield 41%. ¹H NMR (200.13 MHz, DMSO-d ₆): δ = 2.30 (s, 3 H), 6.30 (s, 1 H), 9.36 (s, 2 H). ¹³C NMR (75.47 MHz, DMSO-d ₆): δ = 23.0, 107.6, 120.9, 127.9, 141.9, 142.0, 151.5, 157.8, 161.4, 162.2. HRMS (ESI): m/z calcd for C₁₀H₆N₄O₃S [M + Na]: 263.0233; found: 263.0231. 3-Nitro-7-propyl-9H-pyrido[2′,3′:4,5][1,3]thiazolo[3,2-a]pyrimidin-9-one (7c) Beige solid; mp 245–246 °C (CHCl₃); yield 81%. ¹H NMR (300.13 MHz, CDCl₃): δ = 1.01 (t, J = 7.4 Hz, 3 H), 1.76 (sext, J = 7.3 Hz, 2 H), 2.60 (t, J = 7.4 Hz, 2 H), 6.33 (s, 1 H), 8.88 (d, J = 2.3 Hz, 1 H), 9.49 (d, J = 2.4 Hz, 1 H). ¹³C NMR (75.47 MHz, CDCl₃): δ = 13.7, 21.0, 39.2, 108.4, 120.9, 126.3, 142.0, 143.0, 151.7, 158.8, 159.6, 166.6. ¹⁵N NMR (60.83 MHz, CDCl₃): δ = –84.57, –139.07, –181.49 HRMS (ESI): m/z calcd for C₁₂H₁₀N₄O₃S [M + H]: 291.0546; found: 291.0542. 3-Nitro-7-phenyl-9H-pyrido[2′,3′:4,5][1,3]thiazolo[3,2-a]pyrimidin-9-one (7d) Light yellow solid; mp >300 °C; yield 70%. Due to insufficient solubility we were unable to record ¹H NMR and ¹³C NMR spectra. HRMS (ESI): m/z calcd for C₁₅H₈N₄O₃S [M + H]: 325.0390; found: 325.0393. Anal. Calcd for C₁₅H₈N₄O₃S (%): C, 55.55; H, 2.49; N, 17.28; S, 9.89. Found (%): C, 55.71; H, 2.69; N, 16.77; S, 10.33. Methyl 7-Methyl-9-oxo-9H-pyrido[2′,3′:4,5][1,3]thiazolo[3,2-a]pyrimidine-3-carboxylate (7e) White solid; mp >300 °C; yield 18%. Due to insufficient solubility we were unable to record the ¹³C NMR spectrum, while all signals in the ¹H NMR spectrum appeared as broad singlets. ¹H NMR (300.13 MHz, CDCl₃): δ = 2.40 (br s, 3 H), 4.03 (br s, 3 H), 6.35 (br s, 1 H), 8.68 (br s, 1 H), 9.30 (br s, 1 H). HRMS (ESI): m/z calcd for C₁₂H₉N₃O₃S [M + H]: 276.0476; found: 276.0472. 7-Methyl-3-(trifluoromethyl)-9H-pyrido[2′,3′:4,5][1,3]thiazolo[3,2-a]pyrimidin-9-one (7f) Beige solid; mp >300 °C (dec.); yield 30%. ¹H NMR (300.13 MHz, DMSO-d ₆): δ = 2.30 (s, 3 H), 6.28 (s, 1 H), 8.96 (s, 2 H). ¹³C NMR (150.90 MHz, DMSO-d ₆): δ = 23.1, 107.7, 120.7, 123.2 (q, ² J _CF = 33.1 Hz), 124.3, 129.7 (d, ³ J _CF = 3.4 Hz), 143.2 (d, ³ J _CF = 3.5 Hz), 151.1, 158.1, 161.1, 162.2. HRMS (ESI): m/z calcd for C₁₁H₆F₃N₃OS [M + H]: 286.0266; found: 286.0265. 2-[(3,5-Dinitropyridin-2-yl)thio]-6-propylpyrimidin-4(3H)-one (8с) Beige solid; mp 169–170 °C (CHCl₃); yield 41%. ¹H NMR (300.13 MHz, CDCl₃): δ = 0.98 (t, J = 7.4 Hz, 3 H), 1.69 (sext, J = 7.3 Hz, 2 H), 2.54 (t, J = 7.4 Hz, 2 H), 6.18 (s, 1 H), 9.35 (d, J = 2.1 Hz, 1 H), 9.49 (d, J = 2.1 Hz, 1 H), 12.93 (br s, 1 H). ¹³C NMR (75.47 MHz, CDCl₃): δ = 13.6, 21.2, 39.4, 112.5, 129.5, 140.8, 141.6, 147.6, 153.1, 161.2, 163.7, 169.9. HRMS (ESI): m/z calcd for C₁₂H₁₁N₅O₅S [M + H]: 338.0554; found: 338.0554.