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.

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 

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).

7a Berrueta LA. Gallo B. Vicente F. Chromatographia  1995,  40:  474 

7b Nilsson KJ. J. Chromatogr., A  2000,  885:  305 

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).