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Communication | Special issue | Vol. 77, No. 2, 2009, pp. 849-854
Received, 8th September, 2008, Accepted, 15th October, 2008, Published online, 16th October, 2008.
DOI: 10.3987/COM-08-S(F)111
The Facile Synthesis of 6-Azapurines by Transformation of Toxoflavins (7-Azapteridines)

Tomohisa Nagamatsu,* Jun Ma, and Fumio Yoneda

Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Okayama 700-8530, Japan

This paper describes a reliable and facile synthesis of 6-azapurines (1,5-dimethyl-1H-imidazo[4,5-e][1,2,4]triazin-6(5H)-ones) by treatment of toxoflavins (7-azapteridines) with 10% aqueous sodium hydroxide at 5–25 °C along with a benzilic acid type rearrangement, followed by decarboxylation and oxidation by air. Furthermore, heating the 6-azapurines in 10% ethanolic sodium hydroxides afforded the corresponding 1,2,4-triazine-5,6(1H,4H)-diones to be caused by ring fission of the imidazole of 6-azapurines.

As the 7-azapteridine (pyrimido[5,4-e][1,2,4]triazines) antibiotics isolated from natural sources, toxoflavin (1), fervenulin (2) and reumycin (3) are known.1 We have developed several convenient synthetic procedures for the preparation of toxoflavin (1) and its 3- and/or 6-substituted derivatives,27 and evaluated their potential anti-viral7 and antitumor activities8 and their ability as herbicides.9 However, we encountered difficulties when attempting to prepare the derivatives possessing a substituent of some kind at the 1-position of the toxoflavin skeleton (1). Because, we have previously reported that toxoflavin and its 3-substituted derivatives (1) readily undergo demethylation at the 1-position upon heating with some nucleophiles, e.g. DMF and dimethylacetamide, to give the corresponding 1-demethyltoxoflavin (reumycins 3) derivatives, while the nucleophiles themselves were methylated by the methyl group eliminated, and during the reactions novel radical species were observed (Scheme 1).10,11 On the other hand, the methylation of reumycin and its 3-substituted derivatives (3) under alkaline conditions with dimethyl sulfate or methyl iodide in DMF provided not toxoflavins (1) but fervenulins (2), whose methyl

at the 8-position was stable.1215 Heating 2 with alcoholic sodium hydroxide afforded the corresponding 6-azapurines (5,7-dimethyl-5H-imidazo[4,5-e][1,2,4]triazin-6(7H)-ones) (4) along with the benzilic acid type rearrangement.16 We have been thinking that it is impossible to produce such 6-azapurines from toxoflavins (1) by the rearrangement up-to-date due to tendency to eliminate the methyl or alkyl by acid, nucleophilic solvent or heating. However, we found now that the methyl group at the 1-position of toxoflavins (1) is appreciably stable in alkali solution, not in acid solution, and the toxoflavins (1) transformed gradually to the 6-azapurines (1,5-dimethyl-1H-imidazo[4,5-e][1,2,4]triazin-6(5H)-ones) without demethylation. Recent years have seen dramatic development in the synthesis of modified purine derivatives and azapurines as therapeutic agents1721 and antiviral agents.2225 Herein, we wish to report a further unique synthetic approach to be 6-azapurines (5) by the transformation of toxoflavins (7-azapteridines) (1) along with a benzilic acid type rearrangement (Scheme 2).
The desired 3-substituted toxoflavins (1a–l) were prepared by nitrosative cyclization of the appropriate 6-(2-alkylidene- or 2-benzylidene-1-methylhydrazino)-3-methyluracils according to our previous reports.
1-6,15 Treatment of the 3-substituted toxoflavins (1a–l) (2.5 mmol) with 10% aqueous sodium hydroxide (10 mL) under the conditions described in Table 1, followed by neutralization with 10% aqueous hydrochloric acid, and the solution was concentrated to dryness in vacuo. The solid thus obtained was recrystallized from a mixture of ethanol and water to afford the corresponding 6-azapurines (1,5-dimethyl-1H-imidazo[4,5-e][1,2,4]triazin-6(5H)-ones) (5a–l) as colorless needles in 40–90% yields. Furthermore, treatment of the 6-azapurines (5e, i, j, and k) (1.2 mmol) with 10% ethanolic sodium hydroxide (10 mL) under reflux for 6 h, followed by neutralization with glacial acetic acid to deposit the

products as solid, which were recrystallized from DMF to afford the corresponding 3-substituted 1-methyl-1,2,4-triazine-5,6(1H,4H)-diones (6a–d) as colorless powdery crystals in 80–90% yields. The structures of compounds (5 and 6) were confirmed on the basis of elemental analysis, ir and 1H-NMR26 spectra.

We suggest that these 6-azapurines (5) are formed from toxoflavins (7-azapteridines) (1) by a benzilic acid type rearrangement in alkali solution, followed by decarboxylation and oxidation by air, as depicted in the following Scheme 3. Moreover, heating the 6-azapurines (5) in alkali solution gave 1,2,4-triazines (6) and methylurea to be caused by ring fission of the imidazole of 5.

Thus, the reliable and facile synthetic method for 6-azapurines is noteworthy owing to expectation of biological activities. Further synthetic and mechanistic investigations and biological activities for 6-azapurine nucleosides produced by the benzilic acid type rearrangement from 7-azapteridine nucleosides are in progress, and will be reported in detail shortly.

The authors are grateful to the SC-NMR Laboratory of Okayama University, Japan for the NMR experiments.

This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.


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26. 1H-NMR spectral data in (DMSO-d6). For 5a: δ 3.23 (3H, s, 5-Me), 3.91 (3H, s, 1-Me), 8.33 (1H, s, 3-H). For 5b: δ 2.45 (3H, s, 3-Me), 3.25 (3H, s, 5-Me), 3.87 (3H, s, 1-Me). For 5c: δ 1.16 (3H, t, J = 6.9 Hz, 3-CH2Me), 2.90 (2H, q, J = 6.9 Hz, 3-CH2Me), 3.30 (3H, s, 5-Me), 3.99 (3H, s, 1-Me). For 5d: δ 0.90 (3H, t, J = 6.9 Hz, 3-CH2CH2Me), 1.77 (2H, m, 3-CH2CH2Me), 2.94 (2H, t, J = 6.9 Hz, 3-CH2CH2Me), 3.33 (3H, s, 5-Me), 4.00 (3H, s, 1-Me). For 5e: δ 3.25 (3H, s, 5-Me), 4.00 (3H, s, 1-Me), 7.52-7.58 (3H, m, Ph-m,pH), 8.19-8.28 (2H, m, Ph-oH). For 5f: δ 3.35 (3H, s, 5-Me), 3.99 (3H, s, 1-Me), 7.39 (2H, dd, JH,H = 8.4, JH,F = 8.7 Hz, Ar-mH), 8.27 (2H, dd, JH,H = 8.4, JH,F = 5.8 Hz, Ar-oH). For 5g: δ 3.39 (3H, s, 5-Me), 3.98 (3H, s, 1-Me), 7.86 (2H, d, J = 8.7 Hz, Ar-mH), 8.22 (2H, d, J = 8.7 Hz, Ar-oH). For 5h: δ 3.33 (3H, s, 5-Me), 3.96 (3H, s, 1-Me), 6.90 (2H, d, J = 8.7 Hz, Ar-mH), 8.07 (2H, d, J = 8.7 Hz, Ar-oH), 10.02 (1H, s, exchangeable with D2O, Ar-OH). For 5i: δ 2.38 (3H, s, Ar-Me), 3.36 (3H, s, 5-Me), 4.19 (3H, s, 1-Me), 7.32 (2H, d, J = 8.1 Hz, Ar-mH), 7.96 (2H, d, J = 8.1 Hz, Ar-oH). For 5j: δ 3.33 (3H, s, 5-Me), 3.83 (3H, s, Ar-OMe), 3.96 (3H, s, 1-Me), 7.08 (2H, d, J = 8.7 Hz, Ar-mH), 8.16 (2H, d, J = 8.7 Hz, Ar-oH). For 5k: δ 3.33 (3H, s, 5-Me), 3.76 (3H, s, 4’-OMe), 3.89 (6H, s, 3’- and 5’-OMe), 4.00 (3H, s, 1-Me), 7.54 (2H, s, 2’- and 6’-H). For 5l: δ 3.01 (6H, s, Ar-NMe2), 3.32 (3H, s, 5-Me), 3.94 (3H, s, 1-Me), 6.79 (2H, d, J = 9.0 Hz, Ar-mH), 8.04 (2H, d, J = 9.0 Hz, Ar-oH). For 6a: δ 3.48 (3H, s, 1-Me), 7.44-7.50 (3H, m, Ph-m, pH), 7.79-7.85 (2H, m, Ph-oH), 12.56 (1H, br s, exchangeable with D2O, 4-NH). For 6b: δ 2.33 (3H, s, Ar-Me), 3.47 (3H, s, 1-Me), 7.27 (2H, d, J = 8.4 Hz, Ar-mH), 7.71 (2H, d, J = 8.4 Hz, Ph-oH), 12.42 (1H, br s, exchangeable with D2O, 4-NH). For 6c: δ 3.47 (3H, s, 1-Me), 3.79 (3H, s, Ar-OMe), 7.01 (2H, d, J = 8.7 Hz, Ar-mH), 7.77 (2H, d, J = 8.7 Hz, Ar-oH), 12.47 (1H, br s, exchangeable with D2O, 4-NH). For 6d: δ 3.53 (3H, s, 1-Me), 3.72 (3H, s, 4’-OMe), 3.86 (6H, s, 3’-OMe and 5’-OMe 7.19 (2H, s, 2’- and 6’-H), 12.61 (1H, br s, exchangeable with D2O, 4-NH).

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