Ruthenium-Catalyzed Direct N-Formylation of Lactams with Paraformaldehyde

Abstract

Catalytic N-formylation of lactams was conducted with paraformaldehyde using Shvo’s catalyst. Various lactams were smoothly converted into N-formylimides without the use of a stoichiometric activating reagent.

Keywords

N-formylation - lactams - ruthenium - paraformaldehyde - N-formylimide - homogeneous catalysis

• References and Notes

• 1 Li X, Danishefsky SJ. J. Am. Chem. Soc. 2008; 130: 5446
• 2 Wu X, Stockdill JL, Wang P, Danishefsky SJ. J. Am. Chem. Soc. 2010; 132: 4098
• 3 Neurath GB. Planta Med. 1972; 22: 267
• 4 Pasqua AE, Crawford JJ, Long D.-L, Marquez R. J. Org. Chem. 2012; 77: 2149
• 5 Vidal JP, Escale R, Girard JP, Rossi JC, Chantraine JM, Aumelas A. J. Org. Chem. 1992; 57: 5857
• 6 Sewell AL, Villa MV. J, Matheson M, Whittingham WG, Marquez R. Org. Lett. 2011; 13: 800
• 7 Yoshifuji S, Arakawa Y, Nitta Y. Chem. Pharm. Bull. 1987; 35: 357
• 8 Mathieson JE, Crawford JJ, Schmidtmann M, Marquez R. Org. Biomol. Chem. 2009; 7: 2170
• 9a Pasqua AE, Thomas LH, Crawford JJ, Marquez R. Tetrahedron 2011; 67: 7611
• 9b Villa MV. J, Targett SM, Barnes JC, Whittingham WG, Marquez R. Org. Lett. 2007; 9: 1631
• 10 Zhang J, Hong SH. Org. Lett. 2012; 14: 4646
• 11 Sebenda J. Pure Appl. Chem. 1976; 48: 329
• 12a Shvo Y, Czarkie D, Rahamim Y, Chodosh DF. J. Am. Chem. Soc. 1986; 108: 7400
• 12b Menashe N, Shvo Y. Organometallics 1991; 10: 3885
• 12c Conley BL, Pennington-Boggio MK, Boz E, Williams TJ. Chem. Rev. 2010; 110: 2294
• 13 Gramain JC, Rémuson R. Synthesis 1982; 264
• 14 General Procedure for N-Formylation of Amides with Paraformaldehyde Lactam (1.25 mmol), paraformaldehyde (6.25 mmol, 5.0 equiv), Shvo’s catalyst (6.78 mg, 0.5 mol%), and toluene (2.0 mL) were placed in an oven-dried sealed reactor inside a glovebox under a nitrogen atmosphere. The sealed reactor was taken out and heated to 150 °C in an oil bath. After 1 h, the reaction mixture was cooled to r.t. All volatiles were removed under vacuum. Unless the crude product was in solution, the desired product could be simply precipitated by washing using hexane and EtOAc. In the case that the crude was in solution, purification was performed with silica gel column chromatography using hexane and EtOAc (or CH₂Cl₂ and MeOH solvent mixture) as eluent to afford the desired product. All of the reported formylation products, N-formylazetidin-2-one (1c),¹⁰ N-formylpyrrolidin-2-one (2c),^9b N-formylpiperidin-2-one (3c),^9b N-formylazepan-2-one (4c),^9b N-formylazocan-2-one (5c),^9b and N-formyl-5-methylpyrrolidin-2-one (6c),¹³ were identified by spectral comparison with literature data or with analogous literature data. N-Formylisoindolin-1-one (7c) White solid, yield 69%, mp 146 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.31 (s, 1 H), 7.91 (d, J = 8.0 Hz, 1 H), 7.67 (d, J = 7.6 Hz, 1 H), 7.54 (t, J = 8.0 Hz, 2 H), 4.74 (s, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 168.7, 160.1, 142.1, 134.7, 130.1, 128.9, 125.3, 123.8, 45.5. ESI-HRMS: m/z [M + Na]⁺ calcd for C₉H₇NO₂: 184.0374; found: 184.0365. N-Formyl-5-methylisoindolin-1-one (8c) White solid, yield 99%, mp 110 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.21 (s, 1 H), 7.75 (d, J = 7.6 Hz, 1 H), 7.26 (d, J = 8.4 Hz, 2 H), 4.61 (s, 2 H), 2.43 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 168.6, 160.1, 146.1, 142.5, 130.0, 127.4, 125.0, 124.1, 45.3, 22.1. ESI-HRMS: m/z [M + Na]⁺ calcd for C₁₀H₉NO₂: 198.0531; found: 198.0524. N-Formyl-5-hydroxyisoindolin-1-one (9c) Ivory solid, yield 81%, mp 298 °C. ¹H NMR (500 MHz, DMSO): δ = 10.18 (s, 1 H), 7.54 (d, J = 5.5 Hz, 1 H), 6.91 (s, 1 H), 6.88 (d, 1 H), 5.21 (s, 1 H), 4.38 (s, 2 H). ¹³C NMR (101 MHz, DMSO): δ = 180.34, 173.2, 166.2, 148.7, 129.7, 127.5, 120.8, 114.0, 53.9. HRMS (CI): m/z [M + H]⁺ calcd for C₉H₇NO₃: 178.0504; found: 178.0505. N-Formyl-5-fluoroisoindolin-1-one (10c) White solid, yield 97%, mp 143 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.27 (s, 1 H), 7.94 (d, J = 5.2 Hz, 1 H), 7.21 (d, J = 7.6 Hz, 2 H), 4.73 (s, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 166.89 (d, J = 257.8 Hz), 167.5, 159.9, 144.8 (d, J = 11.4 Hz), 127.8 (d, J = 15.2 Hz), 126.3, 177.3 (d, J = 30.4 Hz), 111.3, (d, J = 26.6 Hz), 45.4 (d, J = 2.8 Hz). ¹⁹F NMR (282 MHz, CDCl₃): δ = –103.1 (q, J = 8.4 Hz). HRMS (CI): m/z [M + H]⁺ calcd for C₉H₆FNO₂: 184.0461; found: 180.0461. N-Formyl-5-chloroisoindolin-1-one (11c) White solid, yield 68%, mp 168 °C. ¹H NMR (500 MHz, CDCl₃): δ = 9.31 (s, 1 H), 7.91 (d, J = 8.0 Hz, 1 H), 7.57 (s, 1 H), 7.54 (d, J = 8.0 Hz, 1 H), 4.76 (s, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 167.5, 160.0, 143.5, 141.3, 129.7, 128.6, 126.5, 124.3, 45.2. ESI-HRMS: m/z [M + Na]⁺ calcd for C₉H₆ClNO₂: 217.9985; found: 217.9981. N-Formyl-5-bromoisoindolin-1-one (12c) Yellow solid, yield 44%, mp 173 °C. ¹H NMR (400 MHz, CDCl₃): δ = 9.30 (s, 1 H), 7.82 (d, J = 7.6 Hz, 1 H), 7.79 (s, 1 H), 7.68 (d, J = 8.0 Hz, 1 H), 4.73 (s, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 168.1, 160.6, 145.6, 132.4, 129.6, 128.9, 128.2, 126.7, 45.8. ESI-HRMS: m/z [M + Na]⁺ calcd for C₉H₆BrNO₂: 261.9480; found: 261.9471. N-Formyl-3,4-dihydroisoquinolin-1(2H)-one (13c) Ivory solid, yield 51%, mp 76 °C. ¹H NMR (500 MHz, CDCl₃): δ = 9.63 (s, 1 H), 8.15 (d, J = 2.0 Hz, 1 H), 7.57 (t, J = 1.5 Hz, 1 H), 7.43 (t, J = 6.5 Hz, 1 H), 7.30 (d, J = 6.5 Hz, 1 H), 4.01 (t, J = 6.3 Hz, 2 H), 3.05 (t, J = 6.3 Hz, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 165.6, 162.4, 139.9, 134.1, 129.3, 127.8, 127.7, 127.6, 38.7, 27.4. ESI-HRMS: m/z [M + Na]⁺ calcd for C₁₀H₉NO₂: 198.0531; found: 198.0523.