Novel Synthesis of N-Phenyl-2-aminopyrimidine Derivatives under Solvent-Free Conditions

Abstract

An efficient method for the solvent-free synthesis of N-phenyl-2-aminopyrimidines has been developed through cyclocondensation of N-phenylguanidine with enaminone in the presence of DBU. The procedure is experimentally simple with very short reaction times and good yields. According to this procedure a variety of N-phenyl-2-aminopyrimidines were synthesized.

Key words

cyclization - DBU - pyrimidines - solid-phase extraction - solvent-free conditions

References

• 1a Zimmermann J. Buchdunger E. Mett H. Meyer T. Lydon NB. Traxler P. Bioorg. Med. Chem. Lett.  1996,  6:  1221 
• 1b Paul R. Hallett WA. Hanifin JW. Riech MF. Johnson BD. Lenhard RH. Dusza JP. Kerwar SS. Lin Y. Pickett WC. Seifert CM. Torley LW. Tarrant ME. Wrenn S. J. Med. Chem.  1993,  36:  2716 
• 1c Bennett GB. Mason RB. Alden LJ. Roach JB. J. Med. Chem.  1978,  21:  623 
• 1d Moffat D. Davis P. Hutchings M. Davis J. Berg D. Batchelor M. Johnson J. O’Connell J. Martin R. Crabbe T. Delgado J. Perry M. Bioorg. Med. Chem. Lett.  1998,  9:  3351 
• 1e Bingham AH. Davenport RJ. Gowers L. Knight RL. Lowe C. Owen DA. Parry DM. Pitt WR. Bioorg. Med. Chem. Lett.  2004,  14:  409 
• 2 Brown DJ. Evans RF. Cowden WB. Fenn MD. The Pyrimidines, In The Chemistry of Heterocyclic Compounds   Vol. 52:  John Wiley & Sons; New York: 1994. 
• 3a Dawood KM. Kandeel ZE. Farag AM. Heteroat. Chem.  1999,  10:  417 
• 3b Sansebastiano L. Mosti L. Menozzi G. Schenone P. Muratore O. Petta A. Debbia E. Schito AP. Scito GC. Il Farmaco  1993,  48:  335 
• 3c Porcheddu A. Giacomelli G. De Luca L. Ruda AM. J. Comb. Chem.  2004,  6:  105 
• 3d Davis PD, Hutchings MC, and Moffat DFC. inventors; PCT Int. Appl. WO  9841512 A1.  ; Chem. Abstr. 1998, 129, 275921
• 3e Davis PD, Moffat DFC, Davis JM, and Hutchings MC. inventors; PCT Int. Appl. WO  9719065 A1.  ; Chem. Abstr. 1997, 127, 81461
• 4a Abdula RF. Fuhr KH. J. Org. Chem.  1978,  43:  4248 
• 4b SanMartín R. de Marigorta EM. Domínguez E. Tetrahedron  1994,  50:  2255 
• 4c Pleier AK. Glas H. Grosche M. Sirch P. Thiel WR. Synthesis  2001,  55 
• 5a Hughes JL. Liu RC. Enkoji T. Smith CM. Bastian JW. Luna PD. J. Med. Chem.  1975,  18:  1077 
• 5b Pazdera P. Potacek M. Chem. Pap. - Chem. Zvesti  1988,  42:  527 
• 7a Berrueta LA. Gallo B. Vicente F. Chromatographia  1995,  40:  474 
• 7b Nilsson KJ. J. Chromatogr., A  2000,  885:  305 

6

Guanidine 3a and enaminone 2a were dissolved in MeOH and K₂CO₃ was added. The solvent was removed in vacuo and the solid was heated at 145 °C for 2 h (solvent-free reaction conditions).

8

General Procedure for the Preparation of 4-Substituted N -Phenyl-2-aminopyrimidines.
Guanidines 3a-f (0.12 mmol) and enaminones 2a-h (0.1 mmol) were placed in 2 mL vials and DBU was added (60 µL, 0.4 mmol). The mixture was heated and vigorously stirred for 1 h at 120 °C. After cooling to r.t., CH₂Cl₂ (2 mL) was added and solution was loaded onto silica SPE column (1 g). The desired product was collected by eluting the silica column with n-hexane-EtOAc (1:1, 2 × 5 mL). After removal of the solvent, the final product was obtained as a yellow solid. All new compounds were fully characterized.
Selected Analytical Data.
Compound 1a: MS (ESI): m/z = 356.2 [M + H⁺]. ¹H NMR (300 MHz, CDCl₃): δ = 3.85 (s, 3 H), 3.89 (s, 6 H), 7.03 (s, 2 H), 7.11 (d, J = 5.3 Hz, 1 H), 7.17 (t, J = 7.0 Hz, 2 H), 7.59 (s, 1 H), 8.11-8.07 (m, 2 H), 8.45 (d, J = 5.3 Hz, 1 H).
Compound 1n: MS (ESI): m/z = 336.2 [M + H⁺]. ¹H NMR (300 MHz, CDCl₃): δ = 1.73-1.83 (m, 6 H), 1.99 (m, 6 H), 2.11 (m, 3 H), 3.85 (s, 3 H), 6.58 (ddd, J = 8.2 Hz, J = 2.4 Hz, J = 0.8 Hz, 1 H), 6.69 (d, J = 5.3 Hz, 1 H), 7.04 (ddd, J = 8.1 Hz, J = 2.0 Hz, J = 0.8 Hz, 1 H), 7.21 (dd, J = 8.2 Hz, J = 8.1 Hz, 1 H), 7.46 (br s, 1 H), 7.65 (dd, J = 2.4 Hz, J = 2.2 Hz, 1 H), 8.32 (d, J = 5.1 Hz, 1 H).