Synthesis of α-Benzamide Cyclobutanones

To a solution of substituted benzoic acid (1 eq, 0.249 mmol) and acetal (±)-2 (1.2 eq, 0.298 mmol) in ethyl acetate (1.25 mL), N-methyl morpholine (5.0 eq, 1.24 mmol) was added. Then, propylphosphonic anhydride (2.5 eq, 0.62 mmol) was added to the above mixture as a solution in ethyl acetate (purchased as ≥50 weight % in EA). The reaction mixture was stirred under N₂ at 80 °C for 48 h or until complete consumption of the benzoic acid determined with TLC (EA/hexane = 50/50 and ~3 to 4 drops of glacial acetic). The reaction was quenched by adding water (3 mL); then, the organic product was extracted using ethyl acetate (3 × 3 mL). The combined organic layers were washed successively with water (3 × 3 mL) and 1N HCl (3 mL) and then dried over Na₂SO₄. The solvent was removed via evaporation under reduced pressure providing the corresponding acetal intermediate. Without further purification, crude acetal (1 eq) was subjected to hydrolysis conditions, wherein the crude mixture was dissolved in acetone (1.2 mL), water (0.17 mL, 10% v/v), and 1N HCl (0.34 mL, 30% v/v). Then, the reaction mixture was stirred at 50 °C for 18 h with periodic TLC and HPLC monitoring. Upon completion, the organic product was extracted using ethyl acetate (3 × 3 mL) or methylene chloride for highly water-soluble analogs, and the combined organic layers were dried over Na₂SO₄. The solvent was evaporated under reduced pressure, and the crude mixture was purified via column chromatography to afford the corresponding alpha-benzamide cyclobutanone.
2-Methyl-N-(2-oxocyclobutyl)benzamide (3a). The crude product of 3a was purified via column chromatography using ethyl acetate/hexane (40/60) to afford compound 3a as a white solid (35.7 mg, 71%): mp 100–102 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.40 (dd, J = 7.6, 1.5 Hz, 1H), 7.35 (td, J = 7.5, 1.5 Hz, 1H), 7.30–7.18 (m, 2H), 6.30 (NH, d, J = 7.8 Hz, 1H), 5.21–5.12 (m, 1H), 3.10–2.96 (m, 2H), 2.63–2.52 (m, 1H), 2.47 (s, 3H), 2.16 (dtd, J = 11.0, 9.6, 8.2 Hz, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 205.0, 169.4, 136.6, 134.8, 131.2, 130.4, 126.8, 125.8, 64.5, 42.3, 19.9. HRMS (ESI) calcd for M+Na⁺ C₁₂H₁₃NO₂: 226.0838, found (M+Na⁺) 226.0840.
3-Methyl-N-(2-oxocyclobutyl)benzamide (3b). The crude product of 3b was purified via column chromatography on a Teledyne Isco Rf Flash chromatography unit (Teledyne ISCO, Lincoln, NE, USA) eluting with ethyl acetate/hexane (20/80) to afford compound 3b as a white crystalline solid (25.5 mg, 50%): mp 94–96 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.52 (s, 1H), 7.51–7.43 (m, 1H), 7.32–7.21 (m, 2H), 6.56 (NH, d, J = 7.4 Hz, 1H), 5.14–5.05 (m, 1H), 2.95 (dd, J = 9.5, 7.8 Hz, 2H), 2.53–2.43 (m, 1H), 2.32 (d, J = 0.8 Hz, 3H), 2.07 (dtd, J = 11.0, 9.6, 8.2 Hz, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 204.1, 166.0, 137.5, 132.1, 131.7, 127.6, 127.5, 126.8, 123.0, 76.3, 76.0, 75.7, 63.6, 41.2, 20.3, 18.9. HRMS (ESI) calcd for M+Na⁺ C₁₂H₁₃NO₂: 226.0838, found (M+Na⁺) 226.083.
4-Methyl-N-(2-oxocyclobutyl)benzamide (3c). The crude product of 3c was purified via column chromatography using ethyl acetate/hexane (40/60) to afford compound 3c as a white solid (27.4 mg, 50.6%): mp 149–150 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.68 (d, 2H), 7.23 (d, J = 7.9 Hz, 2H), 6.80 (NH, d, J = 7.6 Hz, 1H), 5.19–5.10 (m, 1H), 3.05–2.96 (m, 2H), 2.59–2.48 (m, 1H), 2.40 (s, 3H), 2.18 (dtd, J = 11.0, 9.6, 8.1 Hz, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 205.6, 166.8, 142.5, 130.3, 129.3, 127.1, 64.6, 42.2, 21.5, 19.8. HRMS (ESI) calcd for M+Na⁺ C₁₂H₁₃NO₂: 226.0838, found (M+Na⁺) 226.0840.
2-Chloro-N-(2-oxocyclobutyl)benzamide (3d). The crude product of 3d was purified via column chromatography on a Teledyne Isco Rf Flash chromatography unit eluting with ethyl acetate/hexane (40/60) to afford cyclobutanone 3d as a white crystalline solid (32.5 mg, 59%): mp 102–103 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.71 (dd, J = 7.6, 1.7 Hz, 1H), 7.45–7.35 (m, 2H), 7.33 (td, J = 7.3, 1.9 Hz, 1H), 6.81 (NH, d, J = 7.2 Hz, 1H), 5.16 (dt, J = 10.3, 7.9 Hz, 1H), 3.03 (dd, J = 9.6, 7.7 Hz, 2H), 2.57 (tt, J = 10.6, 7.2 Hz, 1H), 2.24–2.13 (m, 1H). 1H NMR (500 MHz, CDCl₃) δ 7.76–7.70 (m, 1H), 7.46–7.35 (m, 2H), 7.35 (ddd, J = 7.5, 6.8, 1.8 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 5.23–5.14 (m, 1H), 3.10–3.01 (m, 2H), 2.64–2.53 (m, 1H), 2.20 (dtd, J = 11.0, 9.6, 8.2 Hz, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 204.4, 165.8, 133.5, 131.9, 130.8, 130.6, 130.4, 127.2, 64.5, 42.4, 19.7. HRMS (ESI) calcd for MNa+ C₁₁H₁₀ClNO₂: 246.0291, found (M+Na⁺) 246.0292.
3-Chloro-N-(2-oxocyclobutyl)benzamide (3e). The crude product of 3e was purified via column chromatography using ethyl acetate/hexane (50/50) to afford compound 3e as a white solid (47.6 mg, 79%): mp 64–66 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.77 (t, J = 1.9 Hz, 1H), 7.65 (dt, J = 7.7, 1.4 Hz, 1H), 7.50 (ddd, J = 8.0, 2.1, 1.0 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 6.82 (d, J = 7.1 Hz, 1H), 5.23–5.14 (m, 1H), 3.12–2.97 (m, 2H), 2.62–2.51 (m, 1H), 2.18 (dtd, J = 11.0, 9.6, 8.2 Hz, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 205.12, 165.61, 134.87, 132.04, 129.99, 127.52, 125.19, 64.51, 42.30, 19.74. HRMS (ESI) calcd for MNa+ C₁₁H₁₀ClNO₂: 246.0292, found (M+Na⁺) 246.0280.
4-Bromo-N-(2-oxocyclobutyl)benzamide (3f). The crude product of 3f was purified via column chromatography on a Teledyne Isco Rf Flash chromatography unit eluting with ethyl acetate/hexane (30/70) to afford compound 3f as a white crystalline solid (23.7 mg, 36%): mp 104–105 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.69–7.61 (m, 2H), 7.58 (dd, J = 8.6, 2.0 Hz, 2H), 6.85–6.77 (NH, s, 1H), 5.15 (tdd, J = 9.6, 7.8, 1.4 Hz, 1H), 3.04 (ddd, J = 9.5, 7.8, 1.6 Hz, 2H), 2.55 (dtdd, J = 12.3, 9.7, 6.9, 2.1 Hz, 1H), 2.19 (dtd, J = 11.0, 9.6, 8.1 Hz, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 205.2, 165.9, 131.9, 128.7, 126.8, 64.5, 42.3, 19.7.
3-Chloro-4-methoxy-N-(2-oxocyclobutyl)benzamide (3g). The crude product of 3g was purified via column chromatography on a Teledyne Isco Rf Flash chromatography unit eluting with ethyl acetate/hexane (40/60) to afford compound 3g as a white solid (29.5 mg, 47%): mp 134–136 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.80 (d, J = 2.2 Hz, 1H), 7.70–7.65 (m, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.63 (d, J = 7.4 Hz, 1H), 5.18–5.09 (m, 1H), 3.95 (s, 3H), 3.06–2.99 (m, 2H), 2.54 (tt, J = 10.5, 7.2 Hz, 1H), 2.21–2.10 (m, 1H). ¹H NMR (500 MHz, CDCl₃) δ 7.80 (d, J = 2.3 Hz, 1H), 7.66 (dd, J = 8.6, 2.3 Hz, 1H), 6.97 (d, J = 7.7 Hz, 1H), 6.92 (d, J = 8.6 Hz, 1H), 5.12 (dt, J = 9.8, 7.6 Hz, 1H), 3.94 (s, 3H), 3.01 (dd, J = 9.4, 7.8 Hz, 2H), 2.57–2.46 (m, 1H), 2.20 (dtd, J = 11.0, 9.5, 8.1 Hz, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 206.0, 165.4, 157.8, 129.4, 127.3, 126.1, 122.7, 111.5, 64.5, 56.3, 42.2, 19.6.
2-Chloro-4,5-dimethoxy-N-(2-oxocyclobutyl)benzamide (3h). The crude product of 3h was purified via column chromatography eluting with ethyl acetate/hexane (60/40) to afford 3h as a white solid (38.2 mg, 54%): mp 123–125 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.43 (s, 1H), 7.40–7.29 (m, 1H), 7.24 (NH, d, J = 7.5 Hz, 1H), 6.83 (s, 1H), 5.13–5.04 (m, 1H), 3.90 (d, J = 4.6 Hz, 6H), 3.14–2.85 (m, 2H), 2.59–2.42 (m, 1H), 2.24 (dddd, J = 11.0, 10.1, 9.0, 8.0 Hz, 1H). 1H NMR (500 MHz, CDCl₃) δ 7.46 (s, 1H), 7.25 (d, J = 7.6 Hz, 1H), 6.85 (s, 1H), 5.10 (tdd, J = 10.0, 7.1, 2.2 Hz, 1H), 3.92 (d, J = 4.4 Hz, 6H), 3.15–3.05 (m, 1H), 3.08–2.98 (m, 1H), 2.55 (dtd, J = 11.0, 10.1, 5.1 Hz, 1H), 2.26 (dddd, J = 11.1, 10.1, 9.1, 8.1 Hz, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 204.8, 165.0, 151.5, 148.0, 124.2, 122.8, 113.6, 112.8, 64.8, 56.3, 56.2, 42.3, 19.6.
2-Hydroxy-N-(2-oxocyclobutyl)benzamide (3i). The crude mixture of 3i was purified via column chromatography using ethyl acetate/hexane (50/50) to afford cyclobutanone 3i as a white crystalline solid (49.0 mg, 88%): mp 149–151 °C. ¹H NMR (500 MHz, CDCl₃) δ 11.76 (OH, s, 1H), 7.40–7.28 (m, 1H), 7.28 (dd, J = 8.0, 1.6 Hz, 1H), 6.91 (dd, J = 8.4, 1.2 Hz, 1H), 6.88–6.73 (m, 2H), 5.10–5.01 (m, 1H), 3.05–2.92 (m, 2H), 2.55–2.43 (m, 1H), 2.12 (dtd, J = 11.1, 9.6, 8.2 Hz, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 203.5, 168.6, 160.7, 133.8, 124.6, 117.8, 117.7, 112.3, 62.9, 41.4, 18.7. HRMS (ESI) calcd for M+Na⁺ C₁₁H₁₂NO₃: 228.0631, found (M+Na⁺) 228.0600.
2-Hydroxy-4-methoxy-N-(2-oxocyclobutyl)benzamide (3j). The crude product of 3j was purified via column chromatography using ethyl acetate/hexane (50/50) to afford cyclobutanone 3j as a white crystalline solid (38.4 mg, 88%): mp 131–133 °C. ¹H NMR (500 MHz, CDCl₃) δ 12.20 (s, 1H), 7.30–7.25 (m, 1H), 6.96 (NH, d, J = 7.7 Hz, 1H), 6.41 (d, J = 2.6 Hz, 1H), 6.37 (dd, J = 8.8, 2.6 Hz, 1H), 5.09 (dt, J = 9.9, 7.7 Hz, 1H), 3.79 (s, 3H), 3.01 (dd, J = 9.4, 7.8 Hz, 2H), 2.55–2.44 (m, 1H), 2.26–2.14 (m, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 205.0, 169.5, 164.8, 164.0, 126.9, 107.3, 106.3, 101.6, 64.0, 55.5, 42.3, 19.8. HRMS (ESI) calcd for MNa+ C₁₂H₁₃NO₄: 258.0737, found (M+Na⁺) 258.0730.
3,4,5-Trimethoxy-N-(2-oxocyclobutyl)benzamide (3k). Acetal (±)-2 (30 mg, 0.18 mmol) was suspended in methylene chloride (0.9 mL) and cooled to 0 °C. Triethylamine (49.9 µL, 0.36 mmol) was then added to the solution, followed by dropwise addition of 3,4,5-trimethoxybenzoyl chloride (41.5 mg, 0.18 mmol). The reaction was allowed to stir for 5 h at room temperature with periodic TLC (hexane/diethyl ether = 50/50) and HPLC monitoring. Upon completion, the reaction mixture was successively washed with 1 M HCl (3 mL) and water (3 mL). Then, this methylene chloride layer containing the acetal intermediate was subjected to hydrolysis by vigorously stirring with 1 M HCl (1 mL) overnight. After the hydrolysis was determined to be complete via TLC and HPLC, the organic layer was successively washed with water (3 mL) and brine (3 mL) and dried over Na₂SO₄. Then the solvent was removed under reduced pressure, and the resultant crude product was purified via column chromatography using ethyl acetate/hexane (50/50) to afford compound 3k as a white solid (25 mg, 21%): mp 144–146 °C. ¹H NMR (500 MHz, CDCl₃) δ 6.99 (s, 2H), 6.90 (NH, d, J = 7.6 Hz, 1H), 5.11–5.02 (m, 1H), 3.87 (d, J = 1.9 Hz, 9H), 3.10–3.01 (m, 1H), 3.04–2.94 (m, 1H), 2.51 (dtd, J = 11.0, 9.7, 5.6 Hz, 1H), 2.22 (dddd, J = 11.1, 10.0, 9.1, 8.1 Hz, 1H). ¹³C NMR (126 MHz, CDCl₃) δ 206.1, 166.6, 153.1, 141.3, 128.3, 104.5, 77.3, 77.1, 76.8, 64.7, 60.9, 56.3, 42.2, 19.6. HRMS (ESI) calcd for M+Na⁺ C14H17NO5: 302.0999, found (M+Na⁺) 302.0990.