One-Pot Regioselective Synthesis of 2,6,9-Trisubstituted Adenines

Abstract

A series of 2,6,9-substituted adenines were obtained from the easily accessible 5-amino-4-cyanoformimidoyl imidazoles, acetic and benzoic anhydrides, and primary alkyl amines in a three-step sequence. Acylation of 5-amino-4-cyanoformimidoyl imidazoles followed by addition of the amine led to the intermediates 5-amino-4-(N-acyl)formamidino imidazoles under mild conditions. Cyclization of 5-amino-4-(N-acyl)formamidino imidazoles under reflux in ethanol led to the desired substituted adenine. A preliminary stepwise study led to the development of three general and efficient one-pot methods for the synthesis of adenine derivatives. The one-pot, three-step reaction in the presence of DMAP was the most convenient synthetic approach.

Key words

heterocycles - cyclization - ring closure - ring opening - imidazole - purine

References and Notes

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• General Procedure for the Synthesis of 6a
• 16a

  Method A
  A white suspension of 4a (1.75 mmol) in EtOH (2 mL) was heated at reflux for 5 min. The solution was evaporated in vacuum and after cooling, a white solid precipitated out of solution. The bright white solid was filtered and washed with EtOH and Et₂O to give compound 6a (92%).
  

• 16b

  A suspension of imidazole 8a in EtOH (2 mL) was heated under reflux for 5 min. After that, the solution was evaporated in vacuum and, after cooling, a solid precipitated out of solution. The bright white solid was filtered and washed with EtOH and Et₂O to give compound 6a (87% yield). The structure of the product obtained was confirmed by elemental analysis, ^¹H NMR and ^¹³C NMR spectroscopy.
  Method D
  Acetic anhydride (1.2 equiv) and DMAP (1.5 equiv) were added to a beige suspension of 1 (1.80 mmol) in MeCN (1 mL) at 0 ˚C. The mixture immediately turned in an orange solution and 3 min later, a white solid precipitated out of solution. The solid was filtered and benzylamine (1.2 equiv) and EtOH (2 mL) were added, and the mixture was heated under reflux for 1 h. After cooling, a white solid precipitated out of solution and it was filtered and washed with EtOH and Et₂O to give compound 6a (76% yield).
  
  
  Characterization of N -Benzyl-2-methyl-9-phenyl-9 H -purin-6-amine (6a)
  Mp 175.6-176.7 ˚C. ^¹H NMR (300 MHz, DMSO-d ₆):
  δ = 8.48 (s, 1 H), 8.30 (br s, 1 H), 7.85 (d, J = 7.8 Hz, 2 H), 7.57 (t, J = 7.8 Hz, 2 H), 7.43 (t, J = 7.8 Hz, 1 H), 7.38 (d, J = 6.9 Hz, 2 H), 7.30 (t, J = 6.9 Hz, 2 H), 7.20 (t, J = 6.9 Hz, 1 H), 4.80 (br s, 2 H)), 2.42 (s, 3 H). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 161.84, 154.32, 149.39, 140.21, 139.11, 135.15, 129.46, 128.19, 127.61, 127.60, 126.19, 123.15, 117.95, 42.60, 26.11. Anal. Calcd for C₁₉H₁₇N₅: C, 72.36; H, 5.43; N, 22.21. Found: C, 72.21; H, 5.28; N, 22.06. IR (mull): 3270, 3223, 3063, 1617, 1598, 1581, 1530 cm^-¹.

13

General Procedure for the Synthesis of 4a-d Benzylamine (1.1 equiv for 4a,b), methylamine (for 4c), or isopropylamine (for 4d) was added to a suspension of the acylated imidazole 2 (0.59-2.82 mmol) in MeCN (0.5 mL), and the mixture turned immediately into a beige solution. The mixture was stirred at 0 ˚C (20 min for 4a, 10 min for 4b, and 5 min for 4c) or at r.t. (10 min for 4d). Bright white solids precipitated and were filtered and washed with MeCN and Et₂O to give compounds 4a-d (44-63%). The structure of the products was confirmed by elemental analysis, ^¹H NMR, and ^¹³C NMR spectroscopy.
Characterization of N -[(5-Amino-1-phenyl-1 H -imidazol-4-yl)benzylaminomethylene]acetamide (4a)
Mp 159.1-160.2 ˚C. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 11.69 (br s, 1 H), 7.58 (m, 2 H), 7.52-7.47 (m, 3 H), 7.49 (s, 1 H), 7.40-7.30 (m, 5 H), 7.30 (br s, 2 H), 5.32 (br s, 2 H), 1.98 (s, 3 H). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 182.93, 161.94, 147.19, 139.09, 131.30, 129.91, 129.05, 128.51, 128.28, 127.23, 126.19, 124.97, 111.32, 47.41, 28.19. Anal. Calcd for C₁₉H₁₉N₅O: C, 68.45; H, 5.74; N, 21.01. Found: C, 68.51; H, 5.61; N, 21.41. IR (mull): 3374, 3256, 1620, 1549, 1455 cm^-¹.

14

General Procedure for the Synthesis of 7c
Method B
A beige suspension of the imidazole 3 (0.82 mmol) in MeCN (2 mL) stirred at r.t. was combined with benzylamine (1.2 equiv). After 2 h, the mixture turned to an orange solution and was heated under reflux for 7 h. After cooling, the product precipitated out of solution, and the solid was filtered and washed with MeCN and Et₂O to give compound 7c (50% yield).
Method C
Benzoic anhydride (2 equiv) was added to a beige suspension of imidazole 1 in MeCN (4 mL), and the mixture was stirred at r.t. for 5 h, when the mixture turned into an orange suspension. Benzylamine (1.2 equiv) and EtOH (4 mL) were added, and the mixture was heated under reflux for 5 h. After cooling, a solid precipitated out of solution and was filtered and washed with MeCN, EtOH, and Et₂O to give compound 7c (63%).
Characterization of N -Benzyl-2-phenyl-9-( p -tolyl)-9 H -purin-6-amine (7c)
Mp 199.8-200.7 ˚C. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 8.57 (s, 1 H), 8.56 (br s, 1 H), 8.34 (d, J = 7.2 Hz, 2 H), 7.93 (d, J = 8.4 Hz, 2 H), 7.83 (d, J = 8.4 Hz, 2 H), 7.47-7.41 (m, 3 H), 7.38 (d, J = 7.6 Hz, 2 H), 7.30 (t, J = 7.6 Hz, 2 H), 7.20 (t, J = 7.6 Hz, 1 H), 4.85 (br s, 2 H), 2.39 (s, 3 H). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 158.00, 154.29, 149.49, 140.35, 139.96, 138.38, 136.85, 132.73, 129.66, 129.14, 128.19, 128.12, 127.64, 127.39, 126.62, 122.84, 118.73, 43.17, 20.57. Anal. Calcd for C₂₅H₂₁N₅: C, 76.70; H, 5.41; N, 17.89. Found: C, 76.70; H, 5.24; N, 17.64. IR (mull): 3270, 3084, 1623, 1571, 1529, 1519, 1496 cm^-¹.

15

General Procedure for the Synthesis of 8a
A yellow suspension of imidazole 2 (1.82 mmol) in EtOH (50 mL) was stirred at r.t. for 50 min. Benzylamine (1.1 equiv) was added to this solution and 10 min later, the mixture was evaporated in vacuum (30 ˚C). The residual oil was cooled and a solid precipitated by addition of acetone. The solid was filtered and washed with EtOH and Et₂O to give compound 8a (91%).
Characterization of N -{4-[(benzylamino)(imino)methyl]-1-phenyl-1 H -imidazol-5-yl}acetamide (8a)
Mp 160.6-161.5 ˚C. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 7.81 (s, 1 H), 7.46-7.43 (m, 5 H), 7.43-7.34 (m, 5 H), 4.50 (s, 2 H), 1.72 (s, 3 H). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 171.83, 155.80, 148.66, 138.73, 136.01, 134.17, 129.08, 128.32, 127.44, 126.92, 124.09, 115.21, 45.52, 24.78. Anal. Calcd for C₁₉H₁₉N₅O: C, 68.45; H, 5.74; N, 21.01. Found: C, 68.41; H, 5.75; N, 20.86. IR (mull) 3370, 3251, 1631, 1551 cm^-¹.