Discovery of Novel Approach for Regioselective Synthesis of Thioxotriaza-Spiro Derivatives via Oxalic Acid

Vindya K. Gopinatha; Hassan A. Swarup; Sathees C. Raghavan; Kempegowda Mantelingu; Kanchugarakoppal S. Rangappa

doi:10.1055/s-0039-1690204

Synlett, Table of Contents

Synlett 2019; 30(17): 2004-2009
DOI: 10.1055/s-0039-1690204

letter

Discovery of Novel Approach for Regioselective Synthesis of Thioxotriaza-Spiro Derivatives via Oxalic Acid

Authors

Vindya K. Gopinatha

^aDepartment of Studies in Chemistry, Manasagangotri, University of Mysore, Mysuru-570006, India
Hassan A. Swarup

^aDepartment of Studies in Chemistry, Manasagangotri, University of Mysore, Mysuru-570006, India
Sathees C. Raghavan

^bDepartment of Biochemistry, Indian Institute of Science, Bangalore-560012, India Email: rangappaks@gmail.com Email: kmlingu@gmail.com
Kempegowda Mantelingu∗

^aDepartment of Studies in Chemistry, Manasagangotri, University of Mysore, Mysuru-570006, India
Kanchugarakoppal S. Rangappa∗

^aDepartment of Studies in Chemistry, Manasagangotri, University of Mysore, Mysuru-570006, India

Abstract

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Abstract

A vital approach for the synthesis of a range of novel thioxotriaza-spiro derivatives is described. These new heterocyclic systems are obtained via oxalic acid catalyzed reaction of α,β-unsaturated ketones in the presence of 5,6-diamino-2-mercaptopyrimidine-4-ols; thus, spiro rings are constructed in one step. Notably, this transformation involves condensation of an amino group followed by enamine reaction with alkenes and subsequent reaction promoted by oxalic acid to afford spiro compounds with excellent regioselectivity.

Key words

spiro rings - regioselective - oxalic acid - enamine - NHEJ

Full Text

References

References and Notes

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11 CCDC 1888913 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
12 Synthesis of 8-Thioxo-1,7,9-trizaospiro[4,5]dec-1-ene-6,10-dione Analogues A mixture of α,β-unsaturated ketone (1 mmol), 5,6-diamino-2-mercaptopyrimidin-4-ol (1 mmol), and oxalic acid (20 mol%) was taken in an Ace Pressure tube, and the reaction mixture was heated at 120 °C for 16 h. After completion of the reaction (monitored by TLC), DMF (1 mL) was added to the gummy reaction mass and was stirred for 10 min at 120 °C to solubilize the reaction mass. The solution was cooled to room temperature and then poured into ice-cold water. The precipitate formed was filtered, dried, and purified by column chromatography using eluent ethyl acetate and hexane. All compounds were obtained as solids.
13 Analytical Data 4-(4-Methoxyphenyl)-2-phenyl-8-thioxo-1,7,9-triazaspiro[4,5]dec-1-ene-6,10-dione (3a) Yield: 88%; off-white solid; mp 240–242 °C. ¹H NMR (DMSO-d ₆, 400 MHz): δ = 12.64 (s, 1 H), 12.14 (s, 1 H), 7.94 (d, J = 8 Hz, 2 H), 7.49–7.58 (m, 3 H), 7.10 (d, J = 8.8 Hz, 2 H), 6.86 (d, J = 9.2 Hz, 2 H), 4.08 (t, J = 9.6 Hz, 1 H), 3.02 (s, 3 H), 3.54–3.59 (m, 2 H). ¹³C NMR (DMSO-d ₆, 400 MHz): δ = 180.3, 169.6, 166.2, 159.3, 133.5, 132.2, 129.2, 129.1, 128.6, 127.3, 114.4, 85.5, 55.5, 55.2, 40.8. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₁₇N₃O₃S: 380.1024; found: 380.1026. 4-(4-Chlorophenyl)-2-phenyl-8-thioxo-1,7,9-triazaspiro[4,5]dec-1-ene-6,10-dione (3b) Yield: 85%; off-white solid; mp 155–157 °C. ¹H NMR (DMSO-d ₆, 400 MHz): δ = 12.67 (s, 1 H), 12.18 (s, 1 H), 7.94 (d, J = 7.2 Hz, 2 H), 7.49–7.59 (m, 3 H), 7.37 (d, J = 8.4 Hz, 2 H), 7.19 (d, J = 8.4 Hz, 2 H), 4.17 (t, J = 9.2 Hz, 1 H), 3.53–3.67 (m, 2 H). ¹³C NMR (DMSO-d ₆, 400 MHz): δ = 180.1, 179.1, 169.3, 166.0, 134.9, 133.1, 132.9, 132.3, 130.0, 129.1, 128.9, 128.6, 85.4, 54.4, 40.8. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₁₄ClN₃O₂S: 384.0495; found: 384.0498. 4-(4-Methoxyphenyl)-2-(thiophen-2-yl)-8-thioxo-1,7,9-triazaspiro[4,5]dec-1-ene-6,10-dione (3c) Yield: 87%; off-white solid; mp 205–207 °C. ¹H NMR (DMSO-d ₆, 400 MHz): δ = 12.74 (s, 1 H), 12.27 (s, 1 H), 7.86 (d, J = 8.8 Hz, 2 H), 7.44 (dd, J = 5, 1.4 Hz, 1 H), 7.03 (d, J = 8.8 Hz, 2 H), 6.96–6.98 (m, 2 H), 4.34 (dd, J = 11.2, 8.8 Hz, 1 H), 3.81 (s, 3 H), 3.73 (dd, J = 16.6, 8.6 Hz, 1 H), 3.47 (dd, J = 16.6, 11 Hz, 1 H). ¹³C NMR (DMSO-d ₆, 400 MHz): δ = 179.1, 169.4, 166.1, 166.0, 162.6, 138.3, 130.5, 127.6, 126.6, 126.0, 125.7, 114.5, 84.7, 55.8, 50.5, 42.4. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₁₅N₃O₃S₂: 386.4600; found: 386.4606. 2-(4-Methoxyphenyl)-4-(thiophen-2-yl)-8-thioxo-1,7,9-triazaspiro[4,5]dec-1-ene-6,10-dione (3d) Yield: 86%; off-white solid; mp 230–232 °C. ¹H NMR (DMSO-d ₆, 400 MHz): δ = 12.61 (s, 1 H), 12.12 (s, 1 H), 7.84–7.85 (m, 1 H), 7.70 (d, J = 2.8 Hz, 1 H), 7.22 (dd, J = 5, 3.8 Hz, 1 H), 7.06 (d, J = 8.8 Hz, 2 H), 6.84 (d, J = 8.4 Hz, 2 H), 4.06 (t, J = 9.6 Hz, 1 H), 3.69 (s, 3 H), 3.51–3.55 (m, 2 H). ¹³C NMR (DMSO-d ₆, 400 MHz): δ = 178.5, 174.1, 169.0, 165.8, 158.8, 137.1, 132.7, 131.9, 128.7, 128.1, 126.6, 114.4, 84.6, 55.1, 40.8. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₁₅N₃O₃S₂: 386.4600; found: 386.4606. 2,4-Diphenyl-8-thioxo-1,7,9-triazaspiro[4,5]dec-1-ene-6,10-dione(3e) Yield: 89%; off-white solid; mp 230–232 °C. ¹H NMR (DMSO-d ₆, 400 MHz): δ = 12.69 (s, 1 H), 12.16 (s, 1 H), 7.96 (d, J = 5.6 Hz, 2 H), 7.51–7.61 (m, 3 H), 7.27–7.33 (m, 3 H), 7.18 (d, J = 5.2 Hz, 2 H), 4.17 (t, J = 8 Hz, 1 H), 3.58–3.67 (m, 2 H). ¹³C NMR (DMSO-d ₆, 400 MHz): δ = 180.4, 179.1, 169.7, 166.2, 133.7, 132.4, 129.2, 129.1, 128.7, 128.4, 128.2, 85.5, 55.6, 39.9. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₁₅N₃O₂S: 350.4063; found: 350.4067. 4-(4-Chlorophenyl)-2-(4-methoxyphenyl)-8-thioxo-1,7,9-triazaspiro[4,5]dec-1-ene-6,10-dione (3f) Yield: 84%; off-white solid; mp 225–227 °C; ¹H NMR (DMSO-d ₆, 400 MHz): δ = 12.67 (s, 1 H), 12.17 (s, 1 H), 7.88 (d, J = 8.8 Hz, 2 H), 7.36 (d, J = 8.4 Hz, 2 H), 7.17 (d, J = 8.4 Hz, 2 H), 7.04 (d, J = 8.4 Hz, 2 H), 4.13 (t, J = 9.4 Hz, 1 H), 3.80 (s, 3 H), 3.48–3.62 (m, 2 H). ¹³C NMR (DMSO-d ₆, 400 MHz): δ = 179.3, 179.2, 169.6, 166.4, 162.6, 132.9, 130.6, 130.1, 129.0, 125.9, 114.5, 85.5, 54.4. 54.1, 40.7. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₀H₁₆ClN₃O₃S: 414.8773; found: 414.8778. 4-(4-Chlorophenyl)-2-(thiophen-2-yl)-8-thioxo-1,7,9-triazaspiro[4,5]dec-1-ene-6,10-dione (3g) Yield: 86%; off-white solid; mp 210–212 °C. ¹H NMR (DMSO-d ₆, 400 MHz): δ = 12.65 (s, 1 H), 12.17 (s, 1 H), 7.85 (d, J = 4.4 Hz, 1 H), 7.70 (d, J = 2.8 Hz, 1 H), 7.36 (d, J = 8.4 Hz, 2 H), 7.22 (dd, J = 4.8, 4 Hz, 1 H), 7.17 (d, J = 8.4 Hz, 2 H), 4.16 (t, J = 9.4 Hz, 1 H), 3.51–3.64 (m, 2 H). ¹³C NMR (DMSO-d ₆, 400 MHz): δ = 179.1, 174.5, 169.2, 166.2, 137.4, 134.8, 133.4, 133.0, 132.6, 130.1, 129.1, 128.8, 85.5, 54.8, 41.3. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₁₂ClN₃O₂S₂: 390.0059; found: 390.0063. 4-(4-Fluorophenyl)-2-phenyl-8-thioxo-1,7,9-triazaspiro[4,5]dec-1-ene-6,10-dione (3h) Yield: 88%; off-white solid; mp 208–210 °C. ¹H NMR (DMSO-d ₆, 400 MHz): δ = 12.69 (s, 1 H), 12.19 (s, 1 H), 7.96 (d, J = 7.2 Hz, 2 H), 7.51–7.59 (m, 3 H), 7.14–7.24 (m, 4 H), 4.17 (t, J = 9.4 Hz, 1 H), 3.54–3.68 (m, 2 H). ¹³C NMR (DMSO-d ₆, 400 MHz): δ = 180.2, 179.1, 169.3, 166.1, 133.2, 132.3, 130.2, 130.1, 129.1, 128.6, 115.9, 115.7, 85.5, 54.7, 40.9. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₁₄FN₃O₂S: 368.0791; found: 368.0795. 2-Phenyl-4-(thiophen-2-yl)-8-thioxo-1,7,9-triazaspiro[4,5]dec-1-ene-6,10-dione (3i) Yield: 89%; off-white solid; mp 166–168 °C. ¹H NMR (DMSO-d ₆, 400 MHz): δ = 12.78 (s, 1 H), 12.31 (s, 1 H), 7.92 (d, J = 7.2 Hz, 2 H), 7.56 (t, J = 7.4 Hz, 1 H), 7.49 (t, J = 7.4 Hz, 2 H), 7.44 (t, J = 3 Hz, 1 H), 6.97 (d, J = 2.4 Hz, 2 H), 4.36 (t, J = 9.4 Hz, 1 H), 3.76 (dd, J = 16.6, 8.6 Hz, 1 H), 3.51 (dd, J = 16.4, 10.8 Hz, 1 H). ¹³C NMR (DMSO-d₆, 400 MHz): δ = 180.0, 179.2, 169.3, 165.8, 138.1, 133.0, 132.4, 129.1, 128.6, 127.7, 126.7, 126.1, 84.8, 50.6, 42.4. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₁₃N₃O₂S₂: 356.4340; found: 356.4344. 2,4-Bis(4-methoxyphenyl)-8-thioxo-1,7,9-triazaspiro[4,5]dec-1-ene-6,10-dione (3j) Yield: 88%; off-white solid; mp 224–226 °C. ¹H NMR (DMSO-d ₆, 400 MHz): δ = 12.62 (s, 1 H), 12.12 (s, 1 H), 7.88 (d, J = 8.8 Hz, 2 H), 7.07 (d, J = 8.8 Hz, 2 H), 7.03 (d, J = 8.8 Hz, 2 H), 6.84 (d, J = 8.4 Hz, 2 H), 4.04 (t, J = 9.4 Hz, 1 H), 3.81 (s, 3 H), 3.69 (s, 3 H), 3.46–3.55 (m, 2 H). ¹³C NMR (DMSO-d ₆, 400 MHz): δ = 179.3, 179.1, 169.9, 166.5, 162.4, 159.2, 130.4, 129.2, 127.4, 126.0, 114.4, 114.3, 85.3, 55.8, 55.5, 55.2, 40.7. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₁₉N₃O₄S: 410.4583; found: 410.4587. 4-(Naphthalen-1-yl)-2-phenyl-8-thioxo-1,7,9-triazaspiro[4,5]dec-1-ene-6,10-dione (3k) Yield: 89%; off-white solid; mp 130–132 °C. ¹H NMR (DMSO-d ₆, 400 MHz): δ = 12.50 (s, 1 H), 12.95 (s, 1 H), 7.98–8.00 (m, 2 H), 7.84–7.92 (m, 3 H), 7.44–7.61 (m, 7 H), 5.05 (t, J = 9.2 Hz, 1 H), 3.74–3.79 (m, 2 H). ¹³C NMR (DMSO-d ₆, 400 MHz): δ = 180.3, 178.6, 169.9, 166.2, 133.8, 133.3, 132.3, 132.1, 131.4, 129.3, 129.2, 128.9, 128.7, 127.0, 126.1, 125.8, 125.7, 122.7, 85.2, 50.2, 42.3. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₁₇N₃O₂S: 400.4650; found: 400.4656. 2,4-Bis(4-chlorophenyl)-8-thioxo-1,7,9-triazaspiro[4,5]dec-1-ene-6,10-dione (3l) Yield: 84%; off-white solid; mp 223–225 °C. ¹H NMR (DMSO-d ₆, 400 MHz): δ = 12.71 (s, 1 H), 12.21 (s, 1 H), 7.98 (d, J = 8 Hz, 2 H), 7.61 (d, J = 4 Hz, 2 H), 7.40 (d, J = 8 Hz, 2 H), 7.21 (d, J = 4 Hz, 2 H), 4.19 (t, J = 8 Hz, 1 H), 3.60–3.64 (m, 2 H). ¹³C NMR (DMSO-d ₆, 400 MHz): δ = 179.3, 179.2, 169.3, 166.0, 137.0, 134.9, 133.0, 132.0, 130.5, 130.1, 129.4, 129.1, 85.6, 54.7, 40.8. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₁₃Cl₂N₃O₂S: 418.2964; found: 418.2968. 2-(4-Chlorophenyl)-4-(4-fluorophenyl)-8-thioxo-1,7,9-triazaspiro[4,5]dec-1-ene-6,10-dione (3m) Yield: 84%; off-white solid; mp 184–186 °C. ¹H NMR (DMSO-d ₆, 400 MHz): δ = 12.67 (s, 1 H), 12.16 (s, 1 H), 7.94 (d, J = 8 Hz, 2 H), 7.58 (d, J = 8 Hz, 2 H), 7.12–7.20 (m, 4 H), 4.14 (t, J = 9.2 Hz, 1 H), 3.55–3.60 (m, 2 H). ¹³C NMR (DMSO-d ₆, 400 MHz): δ = 179.3, 179.0, 169.2, 166.0, 137.1, 132.0, 131.7, 130.4, 130.2, 130.1, 129.3, 115.9, 85.5, 54.8, 40.8. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₁₃ClFN₃O₂S: 402.0401; found: 402.0406. 2-(3-Bromophenyl)-4-(4-fluorophenyl)-8-thioxo-1,7,9-triazaspiro[4,5]dec-1-ene-6,10-dione (3n) Yield: 82%; off-white solid; mp 222–224 °C. ¹H NMR (DMSO-d ₆, 400 MHz): δ = 12.68 (s, 1 H), 12.17 (s, 1 H), 8.10 (s, 1 H), 7.93 (d, J = 7.6 Hz, 1 H), 7.78 (d, J = 8 Hz, 1 H), 7.49 (t, J = 8 Hz, 1 H), 7.21 (t, J = 7 Hz, 2 H), 7.14 (t, J = 8.6 Hz, 2 H), 4.14 (t, J = 9.4 Hz, 1 H), 3.58–3.61 (m, 2 H). ¹³C NMR (DMSO-d ₆, 400 MHz): δ = 179.2, 179.0, 169.1, 165.8, 135.3, 134.9, 131.7, 131.4, 131.0, 130.2, 130.1, 127.6, 122.4, 115.9, 85.5, 54.8, 40.8. HRMS (ESI): m/z [M + 2H]⁺ calcd for C₁₉H₁₃BrFN₃O₂S: 446.2928; found: 446.2933. 2-(3-Bromophenyl)-4-(4-chlorophenyl)-8-thioxo-1,7,9-triazaspiro[4,5]dec-1-ene-6,10-dione (3o) Yield: 83%; off-white solid; mp 212–214 °C. ¹H NMR (DMSO-d ₆, 400 MHz): δ = 12.70 (s, 1 H), 12.20 (s, 1 H), 8.09 (s, 1 H), 7.92 (d, J = 7.6 Hz, 1 H), 7.77 (d, J = 8 Hz, 1 H), 7.46–7.50 (m, 1 H), 7.37 (d, J = 8 Hz, 2 H), 7.19 (d, J = 8.8 Hz, 2 H), 4.15 (t, J = 9.2 Hz, 1 H), 3.59–3.61 (m, 2 H). ¹³C NMR (DMSO-d ₆, 400 MHz): δ = 179.2, 179.0, 169.0, 165.8, 135.3, 134.9, 134.7, 133.0, 131.4, 131.0, 130.0, 129.0, 127.7, 122.5, 85.5, 54.6, 40.7. HRMS (ESI): m/z [M + 2H]⁺ calcd for C₁₉H₁₃BrClN₃O₂S: 462.7474; found: 462.7478. 2,4-Bis(4-fluorophenyl)-8-thioxo-1,7,9-triazaspiro[4,5]dec-1-ene-6,10-dione (3p) Yield: 86%; off-white solid; mp 184–186 °C. ¹H NMR (DMSO-d ₆, 400 MHz): δ = 12.66 (s, 1 H), 12.16 (s, 1 H), 8.01 (dd, J = 8.4, 5.6 Hz, 2 H), 7.35 (t, J = 8.8 Hz, 2 H), 7.12–7.23 (m, 4 H), 4.14 (t, J = 9.4 Hz, 1 H), 3.56–3.61 (m, 2 H). ¹³C NMR (DMSO-d ₆, 400 MHz): δ = 179.0, 169.3, 166.1, 165.9, 131.2, 131.1, 130.2, 130.1, 116.3, 116.1, 115.9, 115.7, 85.5, 54.8, 40.9. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₁₃F₂N₃O₂S: 386.0697; found: 386.0699. 4-(4-Chlorophenyl)-2-(4-fluorophenyl)-8-thioxo-1,7,9-triazaspiro[4,5]dec-1-ene-6,10-dione (3q) Yield: 85%; off-white solid; mp 224–226 °C. ¹H NMR (DMSO-d ₆, 400 MHz): δ = 12.71 (s, 1 H), 12.22 (s, 1 H), 8.01–8.04 (m, 2 H), 7.35–7.41 (m, 4 H), 7.21 (d, J = 8.4 Hz, 2 H), 4.18 (t, J = 9.4 Hz, 1 H), 3.59–3.64 (m, 2 H). ¹³C NMR (DMSO-d ₆, 400 MHz): δ = 179.0, 169.2, 166.0, 163.4, 134.8, 132.9, 131.3, 131.2, 130.0, 129.8, 128.9, 116.3, 85.4, 54.5, 40.8. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₁₃ClFN₃O₂S: 402.0401; found: 402.0406. 4-(4-Fluorophenyl)-2-(thiophen-2-yl)-8-thioxo-1,7,9-triazaspiro[4,5]dec-1-ene-6,10-dione (3r) Yield: 86%; off-white solid; mp 194–196 °C. ¹H NMR (DMSO-d ₆, 400 MHz): δ = 12.63 (s, 1 H), 12.14 (s, 1 H), 7.85 (d, J = 4.8 Hz, 1 H), 7.70 (d, J = 2.8 Hz, 1 H), 7.11–7.23 (m, 5 H), 4.14 (t, J = 9.4 Hz, 1 H), 3.49–3.63 (m, 2 H). ¹³C NMR (DMSO-d ₆, 400 MHz): δ = 179.0, 174.5, 169.2, 166.2, 137.4, 133.3, 132.5, 131.6, 130.2, 130.1, 128.6, 115.9, 85.2, 55.0, 41.3. HRMS (ESI): m/z [M + H]⁺ calcd for C₁₇H₁₂FN₃O₂S₂: 374.0355; found: 374.0358.

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