A selective synthesis of 3,6-dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7- ones

Article abstract of DOI:10.1246/cl.2005.1022

The carbodiimides 2, obtained from aza-Wittig reactions of iminophosphorane 1 with aromatic isocyanates, reacted with primary amine RNH₂ (R ≠ H, Me) to produce isolable guanidine intermediates 3, which were further treated with sodium ethoxide

Full text of DOI:10.1246/cl.2005.1022

1022
Chemistry Letters Vol.34, No.7 (2005)
A Selective Synthesis of 3,6-Dihydro-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones
Jun-Feng Zhao, Chang Xie, Ming-Wu Ding,ꢀ and Hong-Wu Heꢀ
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry,
Central China Normal University, Wuhan, 430079, P. R. China
(Received April 8, 2005; CL-050474)
The carbodiimides 2, obtained from aza-Wittig reactions of
iminophosphorane 1 with aromatic isocyanates, reacted with pri-
mary amine RNH2 (R ¼ H, Me) to produce isolable guanidine
intermediates 3, which were further treated with sodium ethox-
ide in a mixed solvent to give selectivly one of the regioisomer
4 via a base catalytic cyclization mechanism. However, another
regioisomers 5 were obtained directly as RNH2 (R ¼ H, Me)
were used in the absence of sodium ethoxide, via a direct cycli-
zation mechanism.
3.41–3.46 ppm as multiplet, which strongly suggest the exis-
tence of NHCH2CH2CH2CH3 group in 4c. When the primary
amine used is from ethylamine to bulky t-butylamine, the cycli-
zation was achieved all in good yields with similar selectivity.
The results are listed in Table 1. The solitary formation of 4
can be rationalized in terms of a base catalytic cyclization of
the guanidine intermediate 3 to give 4 across the arylamino
group rather than the alkylamino one. This may probably be
due to the preferential generation of –NꢁAr from more acidic
–NHAr under the catalysis of EtONa.
7H-1,2,3-Triazolo[4,5-d]pyrimidin-7-ones (azaguanines)
are of great importances because of their remarkable biological
properties such as antitumor, antiviral, anti-HIV, and antifungal
activities.1–7 The methods described for the preparation of this
ring system either involves the reaction of properly substituted
diaminopyrimidines with sodium nitrate and acetic acid, or the
reaction of aminotriazolecarbonamides with orthoformate, or
the cyclization of 5-acetamido-4-ethoxycarbonyl-1,2,3-triazoles
with amine in the presence of phosphorus pentoxide.7–13 Howev-
er, these methods often require relatively harsh acid, dehydrating
conditions or the heating at high temperature, and there is no
report of a generally useful synthesis of 5-amino substituted
7H-1,2,3-triazolo[4,5-d] pyrimidin-7-ones starting from easily
accessible 5-amino-4-ethoxycarbonyl-1,2,3-triazoles.
COOEt
N=C=NAr
N
COOEt
N=PPh
N
N
N
2
Ar NCO
2
N
3
N
1
1
Ar
Ar
2
1
O
2
Ar
COOEt
N
N
2
N
NHAr
NHR
N
N
EtONa
NHR
N
N
N
N
1
1
Ar
Ar
3
4
(R = Et, Pr, Bu, etc.)
Recently we have been interested in the synthesis of quina-
zolinones, thienopyrimidinones and imidazolinones via the aza-
Wittig reaction of ꢀ or ꢁ-ethoxycarbonyl iminophosphorane
with aromatic isocyanate and the subsequent reaction with vari-
ous nucleophile under mild conditions.14 Here we wish to report
a new selective approach to the synthesis of 7H-1,2,3-triazolo-
[4,5-d]pyrimidin-7-ones 4 and 5.
Scheme 1.
On the other hand, the reaction of carbodiimides 2 with a
small amine, such as ammonia or methylamine (R ¼ H, Me),
generated the reversed selectivity. In this case, 5-arylamino-
7H-1,2,3-triazolo[4,5-d]pyrimidin-7-one 5, another of the possi-
ble regioisomers, was directly precipitated from the reaction
mixture when the small amine was added to the solution of
Iminophosphorane 115,16 reacted with aromatic isocyanates
to give carbodiimides 2, which were allowed to react with pri-
mary amines to provide isolable guanidine intermediates 3 as
R ¼ H, Me. When treated with sodium ethoxide in EtOH at room
temperature, the guanidines 3 were recovered unchanged proba-
bly because of the low solubility of 3 in EtOH. In refluxing EtOH
in presence of EtONa, a complex mixture was obtained probably
owning to unstability of the product at refluxing temperature un-
der strong basic conditions. However, when a mixed solvent
(CH2Cl2/EtOH) was used in the presence of EtONa, 3 cyclized
easily at room temperature to provide only 5-alkylamino-7H-
1,2,3-triazolo[4,5-d] pyrimidin-7-ones 4, one of the possible re-
gioisomers (Scheme 1). This may be due to the good solubility of
3 in the mixed solvent. Different from the early result in similar
cases,17 we obtained only 4 from the reaction mixture after re-
crystallization; the other isomer was not found by 1H NMR anal-
ysis of the reaction mixture. The structure of 4 is deduced from
its 1H NMR data. For example, the 1H NMR spectrum in 4c
shows the signals of NH at 4.48 ppm as triplet and NCH2 at
COOEt
COOEt
N
2
RNH
N
2
NHAr
N
2
N=C=NAr
N
N
N
N
1
Ar
1
NHR
Ar
2
3
O
R
N
N
N
2
NHAr
N
N
1
Ar
5
(R = H, Me)
Scheme 2.
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.7 (2005)
1023
Table 1. Preparation of compounds 4 or 5
2
3
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Ar1
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4c
4d
4e
4f
4g
4h
4i
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
n-Pr
n-Bu
PhCH2
i-Pr
85
88
76
84
80
78
83
81
74
81
90
82
87
76
83
4
cyclohexyl
i-Pr
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6
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4-ClC6H4
4-ClC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
t-Bu
i-Pr
cyclohexyl
H
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H
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4k
5a
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7
8
9
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ated but cyclizes quickly and the catalysis by sodium ethoxide
is not needed (Scheme 2). The reversed-selective formation of
5 can be rationalized in terms of a direct cyclization of the
guanidine intermediate 3 to give 5 across the little steric and
strong nucleophilic amino or methylamino group rather than
the arylamino one.
It is worth noting that the selectivity of the reaction between
ꢀ- or ꢁ-ethoxycarbonyl carbodiimide and amine seems to be
controversial. Sometimes the alkylamino substituted heterocycle
was isolated as the major or sole product,17,18 whereas the aryla-
mino substituted heterocycle was produced as the sole product
in other cases.19 The results we report here reveal firstly that
the different selectivity is probably due to the different reaction
condition (in the presence or absence of a base catalyst) and then
different reaction mechanism (base catalytic cyclization mecha-
nism or direct cyclization mechanism).
In conclusion, we have developed an efficient and selective
synthesis of 7H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones via the
aza-Wittig reaction. Owing to the mild reaction conditions, good
yields, easily accessible starting materials and straightforward
product isolation, we think that the versatile synthetic approach
discussed here in many cases compares favorably with other
existing methods.
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We gratefully acknowledge financial support of this work by
the National Basic Research Program of China (2003CB114400)
and the National Natural Science Foundation of China (Project
Nos. 20372023 and 20102001).
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Published on the web (Advance View) June 18, 2005; DOI 10.1246/cl.2005.1022