The facile synthesis of 6-azapurines by transformation of toxoflavins (7-azapteridines)

Article abstract of DOI:10.3987/COM-08-S(F)111

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 rearr

Full text of DOI:10.3987/COM-08-S(F)111

HETEROCYCLES, Vol. 77, No. 2, 2009
849
HETEROCYCLES, Vol. 77, No. 2, 2009, pp. 849 - 854. © The Japan Institute of Heterocyclic Chemistry
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,a,* Jun Ma,a and Fumio Yonedab
aDepartment of Drug Discovery and Development, Division of Pharmaceutical
Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,
b
Okayama University, Tsushima-naka, Okayama 700-8530, Japan and Fujimoto
Pharmaceutical Co., Ltd, Matsubara, Osaka 580-0011, Japan; E-mail:
nagamatsu@pheasant.pharm.okayama-u.ac.jp
Abstract – 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,2–7
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
This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

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HETEROCYCLES, Vol. 77, No. 2, 2009
O
O
4
5
6
MeN
7
3
N
N
R
N
R
i
MeN
O
2
N
N
N
Me
O
N
8
N
Me
1
ii
i
fervenulins (2)
toxoflavins (1)
iii
O
Me
N
N
R
N
N
R
MeN
O
N
N
N
N
O
N
H
Me
6-azapurines (4)
reumycins (3)
Scheme 1. Reagents and conditions: i, MeI, K2CO3, DMF, reflux; ii, DMF, reflux;
iii, 10% NaOH in EtOH, 60 °C or reflux.
at the 8-position was stable.12–15 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 agents17–21 and antiviral agents.22–25 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

HETEROCYCLES, Vol. 77, No. 2, 2009
851
O
N
Me
NH
H
N
Me
N
N
R
N
N
R
O
O
R
ii
i
N
MeN
O
+
O
O
N
N
N
NH2
N
N
Me
Me
Me
6-azapurines (5a–l)
toxoflavins (1a–l)
1,2,4-triazines (6a–d)
a: R = Ph
g: R = 4-Cl-C6H4
a: R = H
b: R = 4-Me-C6H4
c: R = 4-MeO-C6H4
h: R = 4-HO-C6H4
i: R = 4-Me-C6H4
b: R = Me
c: R = Et
d: R = 3,4,5-(MeO)3-C6H2
j: R = 4-MeO-C6H4
k: R = 3,4,5-(MeO)3-C6H2
l: R = 4-Me2N-C6H4
d: R = Pr
e: R = Ph
f: R = 4-F-C6H4
Scheme 2. Reagents and conditions: i, 10% aq NaOH, 5–25 °C, 1–3 d for R = H and alkyl,
60–70 °C, 10–45 min for R = aryl; ii, 10% NaOH in EtOH, reflux, 6 h.
Table 1. Formation of 6-azapurines (5a–l) and 1,2,4-triazines (6a–d) by reaction of toxoflavins
(7-azapteridines) (1a–l) with 10% NaOH aqueous solution or ethanolic solution.
Mp (°C)b
Yield (%)
Reaction conditionsa
Starting
material
R
Product
1a
1b
1c
1d
1e
1f
H
5–10 °C, 3 d
5a
5b
5c
5d
5e
5f
89
68
42
46
80
63
40
50
61
76
82
47
84
87
83
89
192–194
211–213
215–217
218–220
211–213
253–255
262–264
> 300
Me
Et
Pr
5–10 °C, 3 d
5–10 °C, 3 d
20–25 °C, 1 d
60–70 °C, 15 min
60–70 °C, 10 min
60–70 °C, 15 min
60–70 °C, 20 min
60–70 °C, 20 min
60–70 °C, 15 min
60–70 °C, 25 min
60–70 °C, 45 min
reflux, 6 h
Ph
4-F-C6H4
1g
1h
1i
4-Cl-C6H4
5g
5h
5i
4-HO-C6H4
4-Me-C6H4
4-MeO-C6H4
3,4,5-(MeO)3-C6H2
4-Me2N-C6H4
Ph
233–235
235-237
202–204
193–195
243–245
246–248
256–258
279–281
1j
5j
1k
1l
5k
5l
5e
5i
6a
6b
6c
6d
4-Me-C6H4
4-MeO-C6H4
3,4,5-(MeO)3-C6H2
reflux, 6 h
5j
reflux, 6 h
5k
reflux, 6 h
a) All reactions were carried out in the atmosphere.
b) Products (5a–l) were recrystallized from aqueous EtOH and 6a–d were recrystallized from DMF.
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

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HETEROCYCLES, Vol. 77, No. 2, 2009
1
structures of compounds (5 and 6) were confirmed on the basis of elemental analysis, ir and H-NMR26
pectra.
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.
O H
O
MeN
O
O
N
O
MeN
O
OH
H
N
C
N
N
N
R
R
R
N
R
R
R
H
OH
MeN
O
N
N
N
– CO2
N
N
Me
N
Me
Me
toxoflavins (1a–l)
H
Me
Me
N
Me
N
N
N
N
N
R
R
OH
H
O
O
O
N
N
N
N
N
– H2
N
N
N
Me
N
Me
H
Me
HO
6-azapurines (5a–l)
H
O
Me
Me
Me
N
N
N
N
N
R
N
H
OH
N
O
O
O
N
N
N
N
N
N
Me
O
O
H2N
H2N
H
Me
O
Me
H
H
N
Me
NH
O
R
+
O
N
NH2
O
N
Me
1,2,4-triazines (6a–d)
Scheme 3. Plausible mechanism for formation of 1,2,4-triazines via 6-azapurines produced by
transformation of toxoflavins (7-azapteridines).
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.

HETEROCYCLES, Vol. 77, No. 2, 2009
853
ACKNOWLEDGEMENTS
The authors are grateful to the SC-NMR Laboratory of Okayama University, Japan for the NMR
experiments.
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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).