Microwave Promoted Synthesis of 4,7-Dihydro-1H-imidazo[4,5-e]-1,2,4-triazepin-8-ones as Ring-expanded Hypoxanthine Analogues

Abstract

An efficient method for the synthesis of 4,7-dihydro-1H-imidazo[4,5-e]-1,2,4-triazepin-8-one derivatives was accomplished by the use of microwave methodology. The regioselective alkylation of these compounds to the 1-substituted derivatives is also reported.

imidazo[4,5-e]-1,2,4-triazepin-8-one - microwave - hypoxanthine - cyclization - alkylation

References

1

Present address: ArQule Inc., 19 Presidential Way, Woburn, MA 01801-5140, USA, E-mail: [e-mail], Phone: [phone], Fax: [phone].

2a Whitley RJ. Alford C. Ann. Rev. Microbiol.  1978,  32:  285 

2b Nielsen FE. Pedersen EB. Tetrahedron  1982,  38:  1435 

3 Scheiner P. Frank L. Giusti I. Arwin S. Pearson SA. Excellent F. Harper AP. J. Heterocycl. Chem.  1984,  21:  1817 

4 Lidström P. Tierney J. Wathey B. Westman J. Tetrahedron  2001,  57:  9225 

5 Caddick S. Tetrahedron  1995,  51:  10403 

6 Loupy A. Petit A. Hamelin J. Texier-Boullet F. Jacquault P. Mathé D. Synthesis  1998,  1213 

7 Scheiner P. Arwin S. Eliacin M. Tu J. J. Heterocycl. Chem.  1985,  22:  1435 

8

Raboisson, P.; Bourguignon, J.-J.; Norberg, B. unpublished results.

9

Typical Procedure: A mixture of 5-amino-1H-imidazole-4-carboxhydrazide 3 (200 mg, 1.42 mmol) and ortho-ester 4 (1.56 mmol) in ethanol (6 mL) was refluxed for 3 h in a multimods NORMATRON 112^® microwave oven (irradiation at 500 W), equipped with a probe that regulate the ebullition in the reaction medium along with a built-in magnetic stirrer. For this purpose, standard glassware flask was used equipped with a reflux condenser. The resulting yellow solution was cooled to 0 °C, filtered, and washed with small amounts of ethanol. Recrystallization from ethanol afforded the desired product 5a-c as yellow, crystalline solids.
5-Methyl-4,7-dihydro-1 H -imidazo[4,5- e ]-1,2,4-triazepin-8-one(5b): Yellow solid (110 mg, 47%). Mp 222-224 °C. IR (KBr): (C=O) 1685 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 1.92 (s, 3 H), 7.58 (s, 1 H), 8.77 (br s, 1 H), 8.87 (br s, 1 H), 12.65 (br s, 1 H). ¹³C NMR (300 MHz, CDCl₃ + DMSO-d ₆): δ = 25.5, 107.1, 137.2, 148.3, 151.4, 162.9. MS: m/z = 188 [M⁺ + Na]. Anal. Calcd for C₆H₇N₅O: C, 43.64; H, 4.27; N, 42.40. Found: C, 43.61; H, 4.38; N, 42.45.
5- n -Propyl-4,7-dihydro-1 H -imidazo[4,5- e ]-1,2,4-triazepin-8-one(5c): Yellow solid (104 mg, 38%). Mp 214 °C. IR (KBr): (C=O) 1684 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 0.99 (t, 3 H, J = 7.3 Hz), 1.61-1.68 (m, 2 H), 2.19 (t, 2 H, J = 7.3 Hz), 7.58 (s, 1 H), 8.79 (br s, 2 H), 12.64 (br s, 1 H). ¹³C NMR (300 MHz, DMSO-d ₆): δ = 13.6, 20.1, 36.2, 107.3, 137.5, 148.5, 152.3, 162.9.

10 Montgomery JA. Thomas HJ. J. Org. Chem.  1963,  28:  2304 

11 Montgomery JA. Hewson K. Clayton SJ. Thomas HJ. J. Org. Chem.  1966,  31:  2202 

12

1-Benzyl-5- n -propyl-4,7-dihydro-1 H -imidazo[4,5- e ]-1,2,4-triazepin-8-one(8): A mixture of 5-n-propyl-4,7-dihydro-1H-imidazo[4,5-e]-1,2,4-triazepin-8-one (5c, 200 mg, 0.103 mmol), K₂CO₃ (15 mg, 0.103 mmol) and BnCl (13 µL, 0.103 mmol) in anhyd DMF (1.5 mL) was stirred at r.t. for 20 h, then evaporated to dryness. After addition of water (10 mL), the product was extracted in EtOAc (3 × 10 mL). The combined organic layers was dried with Na₂SO₄, evaporated, purified by flash chromatography (EtOAc/EtOH/CH₂Cl₂ 4/1/5), then recrystallized from CH₂Cl₂/hexane to give 27 mg (92%) of yellow prisms. Mp 97 °C. IR (KBr): (C=O) 1686 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 0.95 (t, 3 H, J = 7.5 Hz), 1.60-1.65 (m, 2 H), 2.20 (t, 2 H, J = 7.5 Hz), 5.39 (s, 2 H), 6.85 (br s, 1 H), 7.06 (br s, 1 H), 7.21 (s, 1 H), 7.24-7.40 (m, 5 H). Anal. Calcd for C₁₅H₁₇N₅O: C, 63.59; H, 6.05; N, 24.72. Found: C, 63.89; H, 6.01; N, 24.51.