α-Diazoacetamides in Sc(OTf)₃-Catalyzed Tiffeneau–Demjanov Ring Expansion: Application towards the Synthesis of Rare Bicyclic Pyrazoles

Abstract

A novel Sc(OTf)₃-catalyzed Tiffeneau–Demjanov ring expansion of six-membered cyclic ketones has been developed. The resulting seven-membered cyclic β-keto carboxamides were found to be versatile precursors to rare bicyclic pyrazoles obtained in modest to good yields via condensation with aryl hydrazines in the presence of Lawesson’s reagent.

Keywords

α-diazoacetamides - Tiffeneau–Demjanov ring expansion - scandium triflate - β-keto carboxamides - Lawesson’s reagent - bicyclic pyrazoles

• References and Notes

• 1 Current address: Department of Chemistry and Biochemistry, Florida International University, 11200 SW 8th St, Miami, FL 33199, USA.
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• 8 Characterization Data for Selected CompoundsCompound 4a: yield 250 mg (90%), yellow liquid. ¹H NMR (400 MHz, CDCl₃): δ = 4.95 (s, 1 H), 3.26 (br s, 4 H), 1.14 (t, J = 7.2 Hz, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 164.7, 46.3, 41.4, 13.9. HRMS-ESI: m/z calcd for C₆H₁₁N₃ONa [M + Na]: 164.0794; found: 164.0790.Compound 4c: yield 245 mg (87%), yellow liquid. ¹H NMR (400 MHz, CDCl₃): δ = 4.82 (s, 1 H), 3.55 (br s, 2 H), 3.23 (br s, 2 H), 1.93 (br d, J = 26.7 Hz, 4 H). ¹³C NMR (101 MHz, CDCl₃): δ = 163. 9, 46.5, 46.0, 45.8, 25.9, 24.5. HRMS-ESI: m/z calcd for C₆H₉N₃ONa [M + Na]: 162.0638; found: 162.0646.Compound 4e: yield 290 mg (81%), yellow liquid. ¹H NMR (400 MHz, CDCl₃): δ = 5.05 (s, 1 H), 4.11 (br s, 2 H), 3.13 (br s, 2 H), 2.27 (s, 1 H), 2.09–1.90 (m, 1 H), 0.95 (d, J = 6.7 Hz, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ (rotameric mixture) = 166.0, 162.0, 78.8, 72.1, 54.6, 50.9, 47.0, 45.2, 36.4, 27.8, 27.5, 20.0. HRMS-ESI: m/z calcd for C₉H₁₃N₃ONa [M + Na]: 202.0951; found: 202.0956.
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• 12 General Procedure for the Preparation of Compounds 3a–hIn a glass Schlenk tube under inert atmosphere were placed diazoacetamide 4 (0.35 mmol), cyclic ketone (0.7 mmol, 2 equiv.), and dry CH₂Cl₂ (1 mL). The mixture was cooled during 5 min in ice-salt bath, then scandium triflate (86 mg, 0.175 mmol, 0.5 equiv.) was added in one portion. Intensive gas evolution was observed. The mixture was stirred for 30 min under cooling and left in the ice bath to slowly rise to room temperature. After completion of the reaction (controlled by TLC analysis) the solvent was removed in vacuo. The obtained yelow oil was dissolved in 5 mL of ethyl acetate and washed twice with water (5 mL) and brine (5 mL). The organic phase was dried over MgSO₄ and evaporated in vacuo.
• 13 Characterization Data for Representative CompoundsCompound 3f: purified by column chromatography, ethyl acetate–n-hexane (1:2 to 1:1). Yield 77 mg (78%), transparent oil. ¹H NMR (400 MHz, CDCl₃): δ = 4.17 (q, J = 7.1 Hz, 2 H), 4.05–3.74 (m, 3 H), 3.55–3.13 (m, 5 H), 2.98 (ddd, J = 14.1, 9.1, 4.6 Hz, 1 H), 2.59–2.70 (m, 1 H), 2.14–2.25 (m, 1 H), 1.99–2.10 (m, 1 H), 1.28 (t, J = 7.1 Hz, 3 H), 1.18 (t, J = 7.1 Hz, 3 H), 1.14 (t, J = 7.1 Hz, 3 H). ¹³C NMR (125 MHz, DMSO-d ₆, 80 °C): δ = 207.7, 168.7, 155.2, 61.2, 54.9, 46.7, 43.8 (br s), 42.1, 41.7 (br s), 39.8 (br s), 29.4 (s), 14.9, 14.5 (br s), 13.16 (br s). HRMS-ESI: m/z calcd for C₁₄H₂₄N₂O₄Na [M + Na]: 307.1628; found: 307.1617.Compound 3g: purified by column chromatography, ethyl acetate–n-hexane (1:1). Yield 61 mg (76%), transparent oil. ¹H NMR (400 MHz, CDCl₃): δ = 3.81 (dd, J = 9.5, 4.7 Hz, 1 H), 3.44 (dq, J = 14.1, 7.1 Hz, 1 H), 3.38–3.28 (m, 2 H), 3.27–3.10 (m, 2 H), 3.02–2.84 (m, 3 H), 2.84–2.62 (m, 2 H), 2.46–2.27 (m, 2 H), 1.17 (t, J = 7.1 Hz, 3 H), 1.12 (t, J = 7.1 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 207.04, 168.07, 55.92, 45.77, 41.82, 40.40, 31.34, 31.21, 26.51, 14.30, 12.79. HRMS-ESI: m/z calcd for C₁₁H₁₉NO₂SNa [M + Na]: 252.1034; found: 252.1025.Compound 3h: purified by column chromatography, ethyl acetate–n-hexane (1:1). Yield 40 mg (54%), transparent oil. ¹H MR (400 MHz, CDCl₃): δ = 4.17 (ddd, J = 12.9, 5.8, 2.5 Hz, 1 H), 4.03 (ddd, J = 12.5, 5.6, 3.9 Hz, 1 H), 3.78 (dd, J = 9.8, 4.7 Hz, 1 H), 3.71–3.53 (m, 2 H), 3.51–3.49 (m, 2 H), 3.34 (dt, J = 13.6, 7.0 Hz, 1 H), 3.25 (dq, J = 14.5, 7.2 Hz, 1 H), 3.14 (ddd, J = 14.0, 9.7, 4.0 Hz, 1 H), 2.64 (ddd, J = 14.3, 5.6, 2.8 Hz, 1 H), 2.45–2.35 (m, 1 H), 2.07–1.97 (m, 1 H), 1.21 (t, J = 7.1 Hz, 3 H), 1.15 (t, J = 7.1 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 207.6, 168.6, 70.6, 66.2, 55.2, 46.5, 42.2, 40.5, 29.7, 14.6, 12.9. HRMS-ESI: m/z calcd for C₁₁H₁₉NO₃Na [M + Na]: 236.1263; found: 236.1274.
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• 26 General Procedure for the Preparation of Pyrazoles 6a–hTo a mixture of cyclic β-ketoamide 3 (0.23 mmol), the corresponding arylhydrazine (0.26 mmol, 1.1 equiv.), and Lawesson’s reagent (143 mg, 0.35 mmol, 1.5 equiv.) in a 10 mL dry vial was added 2 mL of dry THF. The reaction mixture was stirred at room temperature for 15 min, and the vial was transferred to a preheated oil bath. The mixture was heated at 55 °C for 24 h. After evaporation of volatiles the resulting oil was purified by flash chromatography on SiO₂ eluting with diethyl ether–n-heptane (1:1).
• 27 Characterization Data for Selected CompoundsCompound 6a: yield 44 mg (68%), pale yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.71–7.62 (m, 2 H), 7.42–7.35 (m, 2 H), 7.30–7.21 (m, 1 H), 3.02 (q, J = 7.2 Hz, 4 H), 2.81–2.74 (m, 2 H), 2.62–2.54 (m, 2 H), 1.91–1.81 (m, 2 H), 1.77–1.61 (m, 4 H), 0.99 (t, J = 7.2 Hz, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 154.3, 144.9, 140.4, 128.3, 125.9, 124.0, 116.7, 77.3, 77.0, 76.7, 47.4, 32.6, 30.5, 29.2, 27.9, 24.7, 13.3. HRMS-ESI: m/z calcd for C₁₈H₂₆N₃ [M + H]: 284.2121; found: 284.2136.Compound 6g: yield 22 mg (32%), pale yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.60 (dd, J = 7.7, 1.6 Hz, 2 H), 7.41 (t, J = 7.8 Hz, 2 H), 7.33–7.18 (m, 1 H), 3.68 (dd, J = 5.7, 3.5 Hz, 4 H), 3.09 (dd, J = 5.7, 3.5 Hz, 4 H), 2.83–2.72 (m, 2 H), 2.73–2.64 (m, 2 H), 1.94–1.81 (m, 2 H), 1.74–1.68 (m, 4 H). ¹³C NMR (101 MHz, CDCl₃): δ = 154.7, 145.4, 139.8, 128.5, 126.4, 124.2, 115.4, 67.3, 51.1, 32.5, 30.3, 29.2, 27.7, 24.6. HRMS-ESI: m/z calcd for C₁₈H₂₆N₃O [M + H]: 298.1914; found: 298.1928.Compound 6h: yield 27 mg (31%), pale yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.60 (d, J = 7.9 Hz, 2 H), 7.40 (t, J = 7.8 Hz, 2 H), 7.33–7.23 (m, 1 H), 4.22 (q, J = 7.1 Hz, 2 H), 3.71–3.54 (m, 4 H), 3.04–2.88 (m, 6 H), 2.78–2.64 (m, 2 H), 1.31 (t, J = 7.1 Hz, 3 H), 0.98 (t, J = 7.2 Hz, 6 H). ¹³C NMR (101 MHz, DMSO-d ₆, 80 °C): δ = 155.4, 150.9, 145.8, 140.5, 128.9, 126.6, 124.0, 114.5, 61.1, 48.3, 47.3, 47.1, 30.7, 25.0, 15.0, 13.6. HRMS-ESI: m/z calcd for C₂₀H₂₈N₄O₂Na [M + Na]: 379.2104; found: 379.2110.