A novel multicomponent microwave-assisted synthesis of 5-aza-adenines

Article abstract of DOI:10.1039/c3ra41932k

A novel multicomponent strategy for the efficient synthesis of 5-aza-adenines was developed. 5-Aza-adenines were prepared in a one-pot fashion from 5-amino-1,2,4-triazoles, cyanamide and triethyl orthoformate under microwave irradiation. The operational simplicity, efficiency and accessibility of this method make it highly attractive for the generation of bioactive compound libraries.

Full text of DOI:10.1039/c3ra41932k

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DOI: 10.1039/C3RA41932K
The first one-pot multicomponent synthesis of 5-azapurines was developed using microwave-assisted
reaction of 5-amino-1,2,4-triazoles, cyanamide and triethyl orthoformate .

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DOI: 10.1039/C3RA41932K
NH2
N NH
N
N
R
NH2
N
N
R
microwave
N
N
+
HC(OEt)3
N
NH2

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DOI: 10.1039/C3RA41932K
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A novel multicomponent microwave-assisted synthesis of
5-aza-adenines1
Anton V. Dolzhenko,*a,b Svetlana A. Kalinina,c Dmitrii V. Kalininc
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A novel multicomponent strategy for efficient synthesis of 5-aza-adenines was developed. 5-Aza-
adenines were prepared in one-pot fashion from 5-amino-1,2,4-triazoles, cyanamide and triethyl
orthoformate under microwave irradiation. The operational simplicity, efficiency and accessibility of this
method make it highly attractive for generation of bioactive compound libraries.
drawback of this method was the low yields (36-62%) of the
guanylated intermediates 4 prepared from 5-amino-1,2,4-triazoles
(1).
10 Introduction
Purine can be considered as the most ubiquitous and functional
nitrogen-containing heterocyclic core in nature.2 Constantly in
focus of drug discovery programs, the purine skeleton has
become a privilege structure in medicinal chemistry. Modifying
15 the natural purine structure and using purine analogues and
isosters have been proved to be a fruitful approach in medicinal
chemistry resulted in discovery of many benchmarking drug.3
Pharmacology and medicinal chemistry of adenosine receptors
have been remaining one of the hottest topics of for the last
20 decade.4 Particularly remarkable discovery in this area was
development of ZM 241385, which is a current standard5 in A2A
adenosine receptor research with subnanomolar affinity and high
selectivity. This molecule is based on 5-azapurine (1,2,4-
triazolo[1,5-a][1,3,5]triazine) scaffold.6 We have been
25 extensively exploring this heterocyclic ring system and several
effective method for synthesis of 1,2,4-triazolo[1,5-
a][1,3,5]triazines have been developed by our group.1,7 Herein we
report a new effective and convenient method for preparation of
5-aza-adenines (7-amino-1,2,4-triazolo[1,5-a][1,3,5]triazines, 5)
30 using a novel multicomponent microwave-assisted reaction.
To date several methods for preparation of 5-aza-adenines have
been proposed (Scheme 1), but all of them possess various
limitations. The synthesis of 5-aza-adenine (5a) was first reported
by Taylor and Hendess.8 5-Aminotriazole (1a, R = H) was treated
35 with triethyl orthoformate affording amidine 2, which
subsequently underwent triazine ring closure in the reaction with
calcium cyanamide (Method A). Recently, we reported synthesis
of 5-aza-adenines (5) using condensation of 5-aminotriazoles (1)
with N,N-dimethylformamide dimethyl acetal (DMF-DMA)
40 followed by treatment of the resulted amidine 3 with cyanamide
(Method B).1 The method was demonstrated to be rather general,
but yield of 5-aza-adenine (5a) was quite low (32%). Various 8-
substituted 5-aza-adenines (5) were synthesized using reaction of
hydrochloric salts of 5-amino-1-guanyl-1,2,4-triazoles (4) with
45 triethyl orthoformate (Method C).9 However attempts to prepare
unsubstituted 5a using this reaction were unsuccessful.9 Another
50
Scheme 1 Syntheses of 5-aza-adenines via known routs.
Ethyl N-cyanoformimidate (6), a product of cyanamide and
triethyl orthoformate condensation, was used as a triatomic
55 synthon for annelation of a 1,3,5-triazine ring to the 1,2,4-
triazoles (Method D).10 This reagent (6) was also a building block
in an alternative approach utilizing hydrazones (7) instead of
aminotriazoles (1) (Method E).11 However, direction of the
reaction seemed to be highly sensitive to the substitution pattern
60 of the intermediates 8 and sometimes required additional
oxidation step to convert dihydro-derivatives 9 to 5. Other
problems associated with use of 6 include low stability of this
reagent and need of fractional vacuum distillation prior to using.
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Analysis of the above approaches revealed that the known
methods represent all possible stepwise sequential approaches for
the reaction of 5-amino-1,2,4-triazoles, triethyl orthoformate and 40 orthoformate and cyanamide under the same reaction conditions
addition of amines in the guanylation reactions.16 Adding TMSCl
to the reaction of 5-amino-1,2,4-triazole (1a) with triethyl
View Article Online
DOI: 10.1039/C3RA41932K
cyanamide, sometimes using their synthetic equivalents. Since
the reaction outcome does not depend on the sequence of reagent
introduction, we expected that the reaction can be run in a one-
pot multicomponent format. In general, multicomponent reactions
only slightly improved yield of 5a.
5
Nowadays, microwave irradiation has become a very useful
synthetic tool opening new horizons in organic chemistry.17
Microwave-assisted synthesis has been successfully employed in
represent very valuable synthetic approach allowing preparation 45 the preparation of variety of biologically active compounds.18
of complex and diverse final products from simple starting
Selectivity and efficiency of reactions can be often improved
under microwave irradiation.19 The microwave irradiation has
been also widely used in various multicomponent reactions.20 We
found that heating of 5-amino-1,2,4-triazole (1a) with triethyl
10 materials in one operational step.12 5-Amino-1,2,4-triazoles (1)
have been demonstrated to be very versatile synthons with great
potential for multicomponent reactions.13 Triethyl orthoformate
has been demonstrated to have great synthetic utility,14 50 orthoformate and cyanamide in methanol using focused
particularly it was used as one-carbon building block in
15 multicomponent heterocyclic synthesis.15 However, potential of
cyanamide as a bifunctional reagent in multicomponent reactions
has not been explored. A multicomponent one-pot approach for
the synthesis of 5-azapurines has also not been reported.
microwave irradiation dramatically changed outcome of the
reaction compare with the conventional heating under reflux
(Table 1). To our satisfaction, we observed formation of 5-aza-
adenine (5a), which can be easily isolated in pure form via simple
55 filtration. The optimization of the reaction parameters revealed
that reasonable yield with high purity of the product can be
obtained using microwave irradiation at 150 °C for 20 min.
Neither further increase of the reaction time and temperature nor
changing triethyl orthoformate to trimethyl orthoformate
60 improved the reaction yield. Contrary to the conventional heating,
addition of TMSCl did not improve yield of 5a for the
microwave-assisted reaction. Changing solvent to ethanol did not
significantly affect the reaction yield, while using toluene, THF
or acetonitrile compromised the product purity. An attempt to
65 substitute triethyl orthoformate with DMF-DMA in the
multicomponent reaction with 5-amino-1,2,4-triazole (1a) and
cyanamide resulted in the formation of complex mixture of
products with only 18% of 5a as determined by HPLC analysis.
The one-pot reaction of 1a with cyanamide and triethyl
70 orthoformate proceeded regioselectively affording 5-aza-adenine
(5a). No isomeric products 10-12 were isolated.
Results and discussion
20 Initial optimization of the reaction conditions was performed
using 5-amino-1,2,4-triazole (1a) (Table 1). Heating 1a with
triethyl orthoformate and cyanamide in methanol gave a complex
mixture of products. HPLC analysis of the mixture identified only
1.7% of targeted 5-aza-adenine (5a) formed in the reaction under
25 these conditions.
Table 1 Optimization of conditions for the model reactiona
NH2
N
NH
N
N
N
N
+
HC(OEt)3
+
N
NH2
NH2
N
N
1a
5a
Entry
Solvent
Time (min)
Temp. (°C)
Yield (%)
1
2d
3
4
5
6
7
8
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
720
720
15
30
20
20
30
20
20
20
20
20
20
20
20
20
20
20
refluxb
refluxb
120e
120e
140e
150e
150e
160e
150e
150e
150e
150e
150e
150e
150e
150e
150e
150e
1.7c
2.5c
35f
42f
56f
65f
58f
Yield of 5a in the reaction was just moderate, but the procedure
was simple, fast, clean and reproducible, it also employed easily
75 available reagents. The best results were achieved when 5-amino-
1,2,4-triazole (1a), cyanamide and triethyl orthoformate were
mixed together prior to applying microwave irradiation. Our
attempts to carry out the reaction in one-pot manner introducing
reagents sequentially resulted in lower yields and purity of 5a
80 regardless order of the reagent addition (Table 1, entries 16-18).
Synthesis of 8-aryl substituted purines has been well recognized
as a very promising direction in the search of potential
therapeutic agents.21 Therefore we became interested in the
synthesis of 8-aryl substituted 5-aza-adenines (5) and explored
85 scope of our new one-pot three-component microwave-assisted
method for preparation of these compounds (Table 2). A series of
5-amino-1,2,4-triazoles with aryl and hetaryl substitution was
prepared using previously reported method22 and these triazoles
(1) were used as substrates in the multicomponent reaction with
90 cyanamide and triethyl orthoformate under microwave
irradiation. The conditions optimized for preparation of 5a were
58f
9g
10d
11
12
13
14
15h
16i
17j
18k
63f
54f
62f
THF
48c
34c
42c
18c
15.2c
14.0c
12.8c
toluene
MeCN
MeOH
MeOH
MeOH
MeOH
a 1.0 equiv. 1a, 1.2 equiv. H2NCN, 1.8 equiv. HC(OEt)3.b Conventional
heating. c Determined by HPLC, based on 1a. d TMSCl 1.0 equiv. was
added to the reaction. e Microwave irradiation. f Isolated yield.
30 g HC(OMe)3 was used instead of HC(OEt)3. h DMF-DMA was used
instead of HC(OEt)3. i 1a was added after irradiating other reagents for 10
min followed by another 10 min of irradiation. j H2NCN was added after
irradiating other reagents for 10 min followed by another 10 min of
irradiation. k HC(OEt)3 was added after irradiating other reagents for 10
35 min followed by another 10 min of irradiation.
It has been established that trimethylsilyl chloride (TMSCl) can
effectively activate cyano group of cyanamide promoting
2
| Journal Name, [year], [vol], 00–00
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successfully applied for the synthesis of its 8-substituted 35 triazoles (1), cyanamide and triethyl orthoformate. Operational
analogues 5b-o. In most of the cases, yields of 8-substituted 5-
aza-adenines (5b-o) were higher than that of the unsubstituted
one (5a).
simplicity, short reaction time and high product purity make this
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method especially attractive for library generation in drug
DOI: 10.1039/C3RA41932K
discovery process.
5 Table 2 Synthesis of 8-substituted 5-aza-adenines (5b-o)a
Experimental
40 Melting points (uncorrected) were determined on a Gallenkamp
1
melting point apparatus. H and 13C NMR spectra were recorded
on a Bruker Avance III spectrometer (400 MHz), using DMSO-d6
as a solvent and TMS as an internal reference. Dynamic NMR
experiments were performed at 300, 310, 315, 320 and 325 K.
45 Line-shape analysis was carried out using the Bruker TopSpin
software. HPLC analysis was performed on an Apollo C18 (4.6 ×
50 mm, 5 µm) column with a flow rate of 1 mL min-1. Gradients
(5-90%) of MeOH/MeCN (solvent A) and water (solvent B) were
used as a mobile phase. Microwave-assisted reactions were
50 carried out in the closed vessel focused single mode using a CEM
Discover microwave synthesizer. The reaction temperatures were
monitored by an equipped IR sensor.
Product
R
Yield (%)b
Ph
3-FC6H4
4-FC6H4
68
72
88
65
56
73
59
85
64
56
71
76
70
58
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
2-ClC6H4
3-ClC6H4
4-ClC6H4
3-NO2-C6H4
4-MeC6H4
3-MeOC6H4
4-CF3-C6H4
2-furyl
General method for the microwave-assisted synthesis of 5-
aza-adenines (7-amino-1,2,4-triazolo[1,5-a][1,3,5]triazines, 5)
2-thienyl
3-pyridyl
4-pyridyl
55 The mixture of 5-amino-1,2,4-triazole (1, 2.0 mmol), cyanamide
(100 mg, 2.4 mmol) and triethyl orthoformate (0.6 mL, 3.6
mmol) in MeOH (2 mL) were irradiated in a 10ꢀmL seamless
pressure vial using microwave system operating at maximal
microwave power up to 150 W at 150 °C for 20 min. After
60 cooling, the precipitate was filtered, washed with cold MeOH and
recrystallized from water (5a) or DMF (5b-o).
a 1.0 equiv. 1, 1.2 equiv. H2NCN, 1.8 equiv. HC(OEt)3, MeOH,
microwave irradiation 150 °C, 20 min. b Isolated yield.
It was reported9 that conventional heating 13, which could be
considered as one of presumable intermediates in our reaction,
10 with triethyl orthoformate resulted in formation of a complex
mixture of products and acid catalysis was required to promote
the 5-aza-adenine formation. We explored suitability of the
conditions developed for our multicomponent approach for this
reaction. Guanylation of aminotriazole 1b according to the
15 previously described method7a provided 13. Heating 13 with
triethyl orthoformate in methanol under microwave irradiation
furnished formation of 5b with yield comparable to the one
obtained in our multicomponent reaction.
7-Amino-1,2,4-triazolo[1,5-a][1,3,5]triazine (5a)
Yield 65%. M.p. 328-330 ºC (water). TLC (silica gel, AcOEt): Rf
1
0.38. UV: λmax(H2O)/nm 258 (ε/dm3 mol-1 cm-1 8 640). H NMR
65 (400 MHz, DMSO-d6): δ 8.33 (1H, s, H-5), 8.50 (1H, s, H-2),
8.75 (1H, brs, NH), 9.06 (1H, brs, NH). 13C NMR (100 MHz,
DMSO-d6): δ 151.8 (C-7), 154.8 (C-2), 156.9 (C-3a), 159.0 (C-
5). Anal. calcd for C4H4N6: C, 35.30; H, 2.96; N, 61.74; found: C,
35.43; H, 3.04; N, 61.49.
70 7-Amino-2-phenyl-1,2,4-triazolo[1,5-a][1,3,5]triazine (5b)
Yield 68%. M.p. 358-360 ºC (DMF). TLC (silica gel, AcOEt): Rf
1
0.50. H NMR (400 MHz, DMSO-d6): δ 7.53-7.58 (3H, m, H-3′,
20 In molecules of 5-aza-adenines (5), delocalization of the amino
group lone pair over the π-electron 5-azapurine system caused
downfield shift (8.67-9.19 ppm) of the amino group signal in H
H-4′, and H-5′), 8.18-8.24 (2H, m, H-2′ and H-6′), 8.34 (1H, s, H-
5), 8.72 (1H, brs, NH), 9.09 (1H, brs, NH). 13C NMR (100 MHz,
75 DMSO-d6): δ 127.0 (C-2′ and C-6′), 128.9 (C-3′ and C-5′), 130.1
(C-1′), 130.7 (C-4′), 151.6 (C-7), 157.6 (C-3a), 159.2 (C-5),
163.5 (C-2). Anal. calcd for C10H8N6: C, 56.60; H, 3.80; N,
39.60; found: C, 56.51; H, 4.02; N, 39.43.
1
NMR spectra and signal splitting due to increased rotational
barrier. This hindered rotation resulted in two separate signals
25 attributable to the amino group protons. Activation parameters for
the rotation around the C-NH2 bond were estimated for 5-aza-
adenine (5a) using dynamic NMR spectroscopy. The line-shape
7-Amino-2-(3-fluorophenyl)-1,2,4-triazolo[1,5-
80 a][1,3,5]triazine (5c)
1
analysis of H NMR spectra of 1a revealed the following values
for activation of the amino group rotation: ΔH‡ = 47.2 kJ mol-1
30 and ΔS‡ = –59.0 J K-1 mol-1.
Yield 72%. M.p. 359-361 ºC (DMF). TLC (silica gel, AcOEt): Rf
1
3
0.77. H NMR (400 MHz, DMSO-d6): δ 7.41 (1H, ddd, J = 8.6
Hz, 3JHF = 8.6 Hz, 4J = 2.7 Hz, H-4′), 7.64 (1H, dt, 4JHF = 6.0 Hz,
3J = 8.0 Hz, H-5′), 7.92 (1H, ddd, 3JHF = 10.0 Hz, 4J = 2.6 Hz, 4J
85 = 1.4 Hz, H-2′), 8.06 (1H, dt, 3J = 7.7 Hz, 4J = 1.1 Hz, H-6′), 8.37
(1H, s, H-5), 8.78 (1H, brs, NH), 9.15 (1H, brs, NH). 13C NMR
Conclusions
In summary, the first multicomponent microwave-assisted
synthesis of 5-azapurines was developed. 5-Aza-adenines (5)
were prepared from easily available reagents viz. 5-amino-1,2,4-
2
(100 MHz, DMSO-d6): δ 113.4 (d, JCF = 23.3 Hz, C-2′), 117.5
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

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(d, 2JCF = 21.1 Hz, C-4′), 123.1 (d, 4JCF = 2.7 Hz, C-6′), 131.2 (d,
8.90 (1H, brs, NH), 8.97 (1H, t, 4J = 1.8 Hz, H-2′), 9.19 (1H, brs,
3JCF = 8.3 Hz, C-5′), 132.5 (d, JCF = 8.4 Hz, C-1′), 151.6 (C-7),
NH). 13C NMR (100 MHz, DMSO-d6): δ 121.2 (C-2′), 125.6 (C-
4′), 130.8 (C-5′), 131.7 (C-1′), 133.0 (C-6′)D,O1I:4180.2.10(3VC9ie-/w3C′)A3,Rrt1Aic5l4e11O.96n3li2nKe
(C-7), 157.8 (C-3a), 159.5 (C-5), 161.5 (C-2). Anal. calcd for
60 C10H7N7O2: C, 46.70; H, 2.74; N, 38.12; found: C, 46.62; H,
2.80; N, 38.02.
3
157.7 (C-3a), 159.3 (C-5), 162.3 (d, 4JCF = 3.1 Hz, C-2), 162.3 (d,
1JCF = 243.9 Hz, C-3′). Anal. calcd for C10H7FN6: C, 52.17; H,
3.07; N, 36.51; found: C, 52.08; H, 3.14; N, 36.38.
5
7-Amino-2-(4-fluorophenyl)-1,2,4-triazolo[1,5-
a][1,3,5]triazine (5d)
7-Amino-2-(4-methylphenyl)-1,2,4-triazolo[1,5-
a][1,3,5]triazine (5i)
Yield 88%. M.p. 378-380 ºC (DMF). TLC (silica gel, AcOEt): Rf
0.75. H NMR (400 MHz, DMSO-d6): δ 7.41 (2H, dd, J = 8.7
1
3
Yield 85%. M.p. 383-385 ºC (DMF). TLC (silica gel, AcOEt): Rf
1
10 Hz, 3JHF = 9.0 Hz, H-3′ and H-5′), 8.25 (2H, dd, 3J = 8.7 Hz, 4JHF 65 0.76. H NMR (400 MHz, DMSO-d6): δ 2.40 (3H, s, Me), 7.37
= 5.6 Hz, H-2′ and H-6′), 8.35 (1H, s, H-5), 8.74 (1H, brs, NH),
9.11 (1H, brs, NH). 13C NMR (100 MHz, DMSO-d6): δ 116.0 (d,
(2H, d, 3J = 8.1 Hz, H-3′ and H-5′), 8.10 (2H, d, 3J = 8.1 Hz, H-2′
and H-6′), 8.32 (1H, s, H-5), 8.67 (1H, brs, NH), 9.06 (1H, brs,
NH). 13C NMR (100 MHz, DMSO-d6): δ 21.1 (Me), 127.0 (C-2′
and C-6′), 127.4 (C-1′), 129.5 (C-3′ and C-5′), 140.5 (C-4′), 151.6
4
2JCF = 22.0 Hz, C-3′ and C-5′), 126.7 (d, JCF = 2.9 Hz, C-1′),
129.3 (d, 3JCF = 8.8 Hz, C-2′ and C-6′), 151.6 (C-7), 157.7 (C-3a),
1
15 159.2 (C-5), 162.6 (C-2), 163.6 (d, JCF = 247.9 Hz, C-4′). Anal. 70 (C-7), 157.6 (C-3a), 159.1 (C-5), 163.5 (C-2). Anal. calcd for
calcd for C10H7FN6: C, 52.17; H, 3.07; N, 36.51; found: C, 52.05;
H, 3.12; N, 36.38.
C11H10N6: C, 58.40; H, 4.46; N, 37.15; found: C, 58.28; H, 4.52;
N, 37.10.
7-Amino-2-(2-chlorophenyl)-1,2,4-triazolo[1,5-
7-Amino-2-(3-methoxyphenyl)-1,2,4-triazolo[1,5-
a][1,3,5]triazine (5e)
a][1,3,5]triazine (5j)
20 Yield 65%. M.p. 309-310 ºC (DMF). TLC (silica gel, AcOEt): Rf 75 Yield 64%. M.p. 295-297 ºC (DMF). TLC (silica gel, AcOEt): Rf
1
0.85. 1H NMR (400 MHz, DMSO-d6): δ 7.52 (1H, td, 3J = 7.4 Hz,
0.70. H NMR (400 MHz, DMSO-d6): δ 3.86 (3H, s, OMe), 7.12
3
4
3
4
4
4J = 1.5 Hz, H-5′), 7.57 (1H, td, J = 7.6 Hz, J = 1.9 Hz, H-4′),
(1H, ddd, J = 8.4 Hz, J = 2.7 Hz, J = 1.0 Hz, H-4′), 7.48 (1H,
dd, 3J = 7.7 Hz, 3J = 8.4 Hz, H-5′), 7.74 (1H, dd, 4J = 2.6 Hz, 4J =
3
4
3
7.66 (1H, dd, J = 7.9 Hz, J = 1.4 Hz, H-3′), 7.93 (1H, dd, J =
7.5 Hz, 4J = 1.9 Hz, H-6′), 8.39 (1H, s, H-5), 8.78 (1H, brs, NH),
3
4
4
1.5 Hz, H-2′), 7.81 (1H, ddd, J = 7.7 Hz, J = 1.4 Hz, J = 1.0
25 9.16 (1H, brs, NH). 13C NMR (100 MHz, DMSO-d6): δ 127.2 (C- 80 Hz, H-6′), 8.34 (1H, s, H-5), 8.74 (1H, brs, NH), 9.09 (1H, brs,
5′), 129.6 (C-6′), 130.5 (C-3′), 131.6 (C-1′), 132.0 (C-4′), 132.2
(C-2′), 151.6 (C-7), 157.0 (C-3a), 159.3 (C-5), 162.6 (C-2). Anal.
calcd for C10H7ClN6: C, 48.69; H, 2.86; N, 34.07; found: C,
48.60; H, 2.92; N, 33.88.
NH). 13C NMR (100 MHz, DMSO-d6): δ 55.3 (OMe), 111.9 (C-
2′), 116.6 (C-4′), 119.3 (C-6′), 130.1 (C-5′), 131.5 (C-1′), 151.6
(C-7), 157.6 (C-3a), 159.2 (C-5), 159.5 (C-2), 163.3 (C-3′). Anal.
calcd for C11H10N7O: C, 54.54; H, 4.16; N, 34.69; found: C,
85 54.48; H, 4.22; N, 34.62.
30 7-Amino-2-(3-chlorophenyl)-1,2,4-triazolo[1,5-
a][1,3,5]triazine (5f)
7-Amino-2-(4-trifluoromethylphenyl)-1,2,4-triazolo[1,5-
a][1,3,5]triazine (5k)
Yield 56%. M.p. 317-319 ºC (DMF). TLC (silica gel, AcOEt): Rf
0.86. H NMR (400 MHz, DMSO-d6): δ 7.59-7.65 (2H, m, H-4′
and H-5′), 8.14-8.18 (1H, m, H-6′), 8.19-8.22 (1H, m, H-2′), 8.37
1
Yield 56%. mp 385-387 ºC (DMF). TLC (silica gel, AcOEt): Rf
0.94. 1H NMR (400 MHz, DMSO-d6): δ 7.96 (2H, d, 3J = 8.2 Hz,
35 (1H, s, H-5), 8.79 (1H, brs, NH), 9.16 (1H, brs, NH). 13C NMR 90 H-3′ and H-5′), 8.38 (1H, s, H-5), 8.41 (2H, d, J = 8.2 Hz, H-2′
3
(100 MHz, DMSO-d6): δ 125.5 (C-6′), 126.4 (C-2′), 130.5 (C-5′),
131.0 (C-4′), 132.2 (C-1′), 133.6 (C-3′), 151.6 (C-7), 157.7 (C-
3a), 159.3 (C-5), 162.1 (C-2). Anal. calcd for C10H7ClN6: C,
48.69; H, 2.86; N, 34.07; found: C, 48.60; H, 2.94; N, 33.96.
and H-6′), 8.85 (1H, brs, NH), 9.18 (1H, brs, NH). 13C NMR (100
1
MHz, DMSO-d6): δ 124.1 (q, JCF = 272.3 Hz, CF3), 125.9 (q,
3JCF = 3.8 Hz, C-3′ and C-5′), 127.6 (C-2′ and C-6′), 130.5 (q,
2JCF = 32.0 Hz, C-4′), 134.0 (q, 5JCF = 1.4 Hz, C-1′), 151.7 (C-7),
95 157.8 (C-3a), 159.4 (C-5), 162.1 (C-2). Anal. calcd for
C11H7F3N6: C, 47.15; H, 2.52; N, 29.99; found: C, 47.08; H, 2.60;
N, 29.87.
40 7-Amino-2-(4-chlorophenyl)-1,2,4-triazolo[1,5-
a][1,3,5]triazine (5g)
Yield 73%. M.p. 380-382 ºC (DMF). TLC (silica gel, AcOEt): Rf
0.86. 1H NMR (400 MHz, DMSO-d6): δ 7.64 (2H, d, 3J = 8.7 Hz,
H-3′ and H-5′), 8.19 (2H, d, J = 8.7 Hz, H-2′ and H-6′), 8.34
7-Amino-2-(2-furyl)-1,2,4-triazolo[1,5-a][1,3,5]triazine (5l)
3
Yield 71 %. M.p. 325-327 ºC (DMF). TLC (silica gel, AcOEt): Rf
45 (1H, s, H-5), 8.75 (1H, brs, NH), 9.11 (1H, brs, NH). 13C NMR
(100 MHz, DMSO-d6): δ 128.7 (C-2′ and C-6′), 129.0 (C-1′),
129.1 (C-3′ and C-5′), 135.4 (C-4′), 151.6 (C-7), 157.7 (C-3a),
159.3 (C-5), 162.5 (C-2). Anal. calcd for C10H7ClN6: C, 48.69; H,
2.86; N, 34.07; found: C, 48.55; H, 2.94; N, 33.93.
1
3
100 0.45. H NMR (400 MHz, DMSO-d6): δ 6.74 (1H, dd, J = 3.4
Hz, 3J = 1.8 Hz, H-4′), 7.23 (1H, dd, 3J = 3.4 Hz, 4J = 0.8 Hz, H-
3′), 7.95 (1H, dd, 3J = 1.8 Hz, 4J = 0.8 Hz, H-5′), 8.33 (1H, s, H-
5), 8.84 (1H, brs, NH), 9.09 (1H, brs, NH). 13C NMR (100 MHz,
DMSO-d6): δ 112.2 (C-3′), 112.8 (C-4′), 145.4 (C-5′), 145.5 (C-
105 2′), 151.7 (C-7), 156.4 (C-3a), 157.4 (C-5), 159.4 (C-2). Anal.
calcd for C8H6N6O: C, 47.53; H, 2.99; N, 41.57; found: C, 47.44;
H, 3.03; N, 41.49.
50 7-Amino-2-(3-nitrophenyl)-1,2,4-triazolo[1,5-a][1,3,5]triazine
(5h)
Yield 59%. M.p. 295-297 ºC (DMF). TLC (silica gel, AcOEt): Rf
0.83. 1H NMR (400 MHz, DMSO-d6): δ 7.89 (1H, t, 3J = 8.0 Hz,
7-Amino-2-(2-thienyl)-1,2,4-triazolo[1,5-a][1,3,5]triazine (5m)
Yield 76%. M.p. 351-353 ºC (DMF). TLC (silica gel, AcOEt): Rf
4
H-5′), 8.38 (1H, s, H-5), 8.40 (1H, ddd, 3J = 8.3 Hz, J = 2.3 Hz,
3
4
55 4J = 0.9 Hz, H-6′), 8.59 (1H, dt, J = 7.8 Hz, J = 1.3 Hz, H-4′),
4
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]

Page 7 of 8
RSC Advances
1
3
1
Part 23 in the series “Fused heterocyclic systems with s-triazine
ring”, for part 22 see: D. V. Kalinin, S. A. Kalinina and A. V.
Dolzhenko, Heterocycles, 2013, 87, 147.
0.75. H NMR (400 MHz, DMSO-d6): δ 7.25 (1H, dd, J = 5.0
Hz, 3J = 3.6 Hz, H-4′), 7.80 (1H, dd, 3J = 5.0 Hz, 4J = 1.2 Hz, H-
5′), 7.85 (1H, dd, 3J = 3.6 Hz, 4J = 1.2 Hz, H-3′), 8.32 (1H, s, H-
5), 8.72 (1H, brs, NH), 9.07 (1H, brs, NH). 13C NMR (100 MHz,
DMSO-d6): δ 128.3 (C-5′), 128.6 (C-3′), 129.6 (C-4′), 132.3 (C-
2′), 151.5 (C-7), 157.3 (C-3a), 159.3 (C-5), 159.7 (C-2). Anal.
calcd for C8H6N6S: C, 44.03; H, 2.77; N, 38.51; found: C, 43.96;
H, 2.83; N, 38.44.
55
View Article Online
DOI: 10.1039/C3RA41932K
2. (a) T. A. J. Haystead, Curr. Top. Med. Chem., 2006, 6, 1117; (b) J.
M. Murray and D. E. Bussiere, Methods Mol. Biol., 2009, 575, 47; (c)
C. Volonté and N. D'Ambrosi, FEBS J., 2009, 276, 318.
60 3. (a) R. Jorda, K. Paruch and V. Krystof, Curr. Pharm. Des., 2012, 18,
2974; (b) N. A. Meanwell, J. Med. Chem., 2011, 54, 2529.
4. (a) B.B. Fredholm, A.P. Ijzerman, K.A. Jacobson, J. Linden and C.
E. Müller, Pharmacol. Rev., 2011, 63, 1; (b) P. G. Baraldi, D. Preti,
P. A. Borea and K. Varani, J. Med. Chem., 2012, 55, 5676; (c) P.
Fishman, S. Bar-Yehuda, B. T. Liang and K. A. Jacobson, Drug
Discov. Today, 2012, 17, 359; (d) N. P. Riksen and G. A. Rongen,
Expert Rev. Clin. Pharmacol., 2012, 5, 199; (e) J. F. Chen, H. K.
Eltzschig and B. B. Fredholm, Nat. Rev. Drug Discov., 2013, 12, 265.
5. S. P. H. Alexander; A. Mathie and J. A. Peters, Br. J. Pharmacol.,
2008, 153, S11.
5
7-Amino-2-(3-pyridyl)-1,2,4-triazolo[1,5-a][1,3,5]triazine (5n)
65
70
75
10 Yield 70%. M.p. 334-336 ºC (DMF). TLC (silica gel, AcOEt): Rf
1
3
0.51. H NMR (400 MHz, DMSO-d6): δ 7.62 (1H, ddd, J = 7.9
3
4
Hz, J = 4.8 Hz, J = 0.8 Hz, H-5′), 8.37 (1H, s, H-5), 8.50 (1H,
dt, 3J = 7.9 Hz, 4J = 2.0 Hz, H-4′), 8.75 (1H, dd, 3J = 4.8 Hz, 4J =
1.7 Hz, H-6′), 8.85 (1H, brs, NH), 9.13 (1H, brs, NH), 9.36 (1H,
15 dd, 4J = 2.2 Hz, 4J = 0.8 Hz, H-2′). 13C NMR (100 MHz, DMSO-
d6): δ 124.1 (C-5′), 126.1 (C-3′), 134.4 (C-4′), 147.9 (C-2′), 151.4
(C-6′), 151.7 (C-7), 157.7 (C-3a), 159.4 (C-5), 161.4 (C-2). Anal.
calcd for C9H7N7: C, 50.70; H, 3.31; N, 45.99; found: C, 50.66;
H, 3.34; N, 45.92.
6. A. V. Dolzhenko, A. V. Dolzhenko and W.-K. Chui, Heterocycles,
2006, 68, 1723.
7. (a) A. V. Dolzhenko, A. V. Dolzhenko and W.-K. Chui, Tetrahedron,
2007, 63, 12888; (b) A. V. Dolzhenko, A. V. Dolzhenko and W.-K.
Chui, Heterocycles, 2007, 71, 429; (c) A. V. Dolzhenko, G. Pastorin,
A. V. Dolzhenko and W. K. Chui, Tetrahedron Lett., 2008, 49, 7180;
(d) D. V. Kalinin, S. A. Kalinina and A. V. Dolzhenko, Heterocycles,
2012, 85, 2515.
20 7-Amino-2-(4-pyridyl)-1,2,4-triazolo[1,5-a][1,3,5]triazine (5o)
8. E. C. Taylor and R. W. Hendess, J. Am. Chem. Soc., 1965, 87, 1980.
80 9. R. Bokaldere and V. Grinsteins, Khim. Geterotsikl. Soedin., 1970,
563.
10. I. Lalezari and S. Nabahi, J. Heterocycl. Chem., 1980, 17, 1121.
11. (a) Y. Miyamoto, H. Kohno, W. Pfleiderer, P. Boeger and K.
Wakabayashi, Nippon Noyaku Gakkaishi, 1995, 20, 119; (b) Y.
Yield 58%. M.p. 347-349 ºC (DMF). TLC (silica gel, AcOEt): Rf
1
3
0.49. H NMR (400 MHz, DMSO-d6): δ 8.10 (2H, dd, J = 4.4
4
Hz, J = 1.6 Hz, H-3′ and H-5′), 8.39 (1H, s, H-5), 8.80 (2H, dd,
3J = 4.4 Hz, 4J = 1.6 Hz, H-2′ and H-6′), 9.04 (2H, brs, NH2). 13
C
85
90
Miyamoto, C. Yamazaki and M. Matzui, J. Heterocycl. Chem., 1990,
27, 1553.
12. (a) P. Slobbe, E. Ruijter and R. V. A. Orru, Med. Chem. Commun.,
2012, 3, 1189; (b) A. Domling, W. Wang and K. Wang, Chem. Rev.,
2012, 112, 3083; (c) E. Ruijter, R. Scheffelaar and R. V. A. Orru,
Angew. Chem., Int. Ed., 2011, 50, 6234.
25 NMR (100 MHz, DMSO-d6): δ 120.9 (C-3′ and C-5′), 137.4 (C-
4′), 150.6 (C-2′ and C-6′), 151.8 (C-7), 157.8 (C-3a), 159.5 (C-5),
161.4 (C-2). Anal. calcd for C9H7N7: C, 50.70; H, 3.31; N, 45.99;
found: C, 50.48; H, 3.45; N, 45.64.
Synthesis
of
7-amino-2-phenyl-1,2,4-triazolo[1,5-
13. (a) V. A. Chebanov, K. A. Gura and S. M. Desenko, Top. Heterocycl.
Chem., 2010, 23, 41; (b) Yu. V. Sedash, N. Yu. Gorobets, V. A.
Chebanov, I. S. Konovalova, O. V. Shishkin and S. M. Desenko, RCS
Adv., 2012, 2, 6719.
95 14. V. V. Mezheritskii, E. P. Olekhnovich and G. N. Dorofeenko, Usp.
Khim., 1973, 42, 896.
15. (a) A. K. Yadav, G. R. Sharma, P. Dhakad and T. Yadav,
Tetrahedron Lett., 2012, 53, 859; (b) Y. Y. Pedgaonkar, M. S.
Degani and P. P. Iyer, Mol. Divers., 2011, 15, 263; (c) M. R.
30 a][1,3,5]triazines, 5b) from 13
The mixture of 5-amino-1-guanyl-3-phenyl-1,2,4-triazole (13, 2.0
mmol) and triethyl orthoformate (0.7 mL, 4.2 mmol) in MeOH (2
mL) were irradiated in a 10ꢀmL seamless pressure vial using
microwave system operating at maximal microwave power up to
35 150 W at 150 °C for 20 min. After cooling, the precipitate was
filtered, washed with cold MeOH and recrystallized from DMF to
give a product identical to 5b obtained using the multicomponent
approach. Yield 70%.
100
Shaaban, T. S. Saleh, A. S. Mayhoub and A. M. Farag, Eur. J. Med.
Chem., 2011, 46, 3690; (d) F. Yu, S. Yan, R. Huang, Y. Tang and J.
Lin, RCS Adv., 2011, 1, 596.
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Chem., 2012, 10, 4586; (b) R. E. Looper, T. J. Haussener and J. B. C.
Mack, J. Org. Chem., 2011, 76, 6967.
Acknowledgements
105
110
115
120
17. C. O. Kappe, Chem. Sov. Rev., 2008, 37, 1127.
40 Authors acknowledge financial support of Russian Ministry of Education
and Science. We also thank Michael Boddy (Curtin University) for his
help with HPLC analysis.
18. (a) J. Gising, L. R. Odell and M. Larhed, Org. Biomol. Chem., 2012,
10, 2713; (b) R. Osborne, RSC Drug Discov. Ser., 2012, 11, 63; (c)
A. Sharma, P. Appukkuttan and E. Van der Eycken, Chem.
Commun., 2012, 48, 1623; (d) V. Polshettiwar and R. S. Vivek, RSC
Green Chem. Ser., 2010, 7, 91; (e) V. Polshettiwar and R. S. Vivek,
Pure Appl. Chem., 2008, 80, 777.
19. (a) J. D. Moseley and C. O. Kappe, Green Chem., 2011, 13, 794; (b)
A. de la Hoz, A. Díaz-Ortiz and A. Moreno, in Microwaves in
Organic Synthesis, ed. A. Loupy, Wiley-VCH Verlag GmbH,
Weinheim, Germany, 2nd edn., 2008, ch. 5, pp. 219-277.
20. (a) J. B. Bariwal, J. C. Trivedi, and E. V. Van der Eycken, Top.
Heterocycl. Chem., 2010, 25, 169; (b) T. de Boer, A. Amore and R.
V. A. Orru, in Microwaves in Organic Synthesis, ed. A. Loupy,
Wiley-VCH Verlag GmbH, Weinheim, Germany, 2nd edn., 2008, ch.
17, pp. 788-819.
Notes and references
a School of Pharmacy, Monash University Sunway Campus, Jalan Lagoon
45 Selatan, Bandar Sunway, Selangor 46150, Malaysia. Fax: +603
551406207; Tel: +603 55145867; E-mail: anton.dolzhenko@monash.edu
b School of Pharmacy, Curtin Health Innovation Research Institute,
Curtin University, GPO Box U1987 Perth, Western Australia 6845,
Australia. E-mail: anton.dolzhenko@curtin.edu.au
50 c Perm State Pharmaceutical Academy, 2 Polevaya Street, Perm 614990,
Russian Federation
† Electronic Supplementary Information (ESI) available: NMR spectra of
synthesized compounds. See DOI: 10.1039/b000000x/
21. N. M. Thomsen, V. Vongsutilers, P. M. Gannett, Crit. Rev. Eukaryot.
Gene Expr., 2011, 21, 155.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 5

RSC Advances
Page 8 of 8
22. A. V. Dolzhenko, G. Pastorin, A. V. Dolzhenko and W. K. Chui,
Tetrahedron Lett., 2009, 50, 2124.
View Article Online
DOI: 10.1039/C3RA41932K
6
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]