Synthesis of novel N,3-substituted 3 H -[1,2,3]Triazolo[4,5- d ]pyrimidin-5-amines

Article abstract of DOI:10.1055/s-0029-1218597

Novel N,3-substituted 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amines were prepared by an expedient method starting from 2-chloro-5-nitropyrimidin-4-yl thiocyanate via N,N⁴-substituted 5-nitropyrimidine-2,4-diamines. Georg Thieme Verlag Stuttgart N

Full text of DOI:10.1055/s-0029-1218597

PAPER
689
Synthesis of Novel N,3-Substituted 3H-[1,2,3]Triazolo[4,5-d]pyrimidin-5-
amines
N
, 3-Substitute
i
d
3
H
-[
n
n
o[4,5-
d
]
pyrimidin-
K
5-amines . Hansen, Detlef Geffken*
Institute of Pharmacy, University of Hamburg, Bundesstr. 45, 20146 Hamburg, Germany
Fax +49(40)428386573; E-mail: geffken@chemie.uni-hamburg.de
Received 1 September 2009; revised 29 October 2009
cyclic chemistry. Surprisingly, only few synthetic strate-
gies for N,3-substituted 3H-[1,2,3]triazolo[4,5-
Abstract: Novel N,3-substituted 3H-[1,2,3]triazolo[4,5-d]pyrimi-
din-5-amines were prepared by an expedient method starting from
2-chloro-5-nitropyrimidin-4-yl thiocyanate via N2,N4-substituted 5-
nitropyrimidine-2,4-diamines.
d]pyrimidin-5-amines 5, which suffer from broader
scope, have been published.4a,5 A method developed by
Dille et al.5 gives access only to compounds with identical
N,3-substitution. The procedure described by Love et al.4a
involves a complicated multistep protocol, with a regio-
selective monoaminolysis of 2,4-dichloro-5-nitropyrimi-
dine at ring position 4 as the key step. Due to the high
reactivity of both chlorine atoms this reaction is difficult
to perform and is accompanied by side reactions causing
low yields.6
Key words: triazolopyrimidines, 5-nitropyrimidine-2,4-diamines,
cyclization, hydrogenation, nucleophilic aromatic substitution
3-Substituted 3H-[1,2,3]triazolo[4,5-d]pyrimidines have
attracted considerable attention in medicinal chemistry.
For example, 3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-
amines (8-azaadenines) have been found to display
anticonvulsive1 and adenosine A1 and A3 receptor antago-
nistic activity.2,3 Furthermore, N,3-substituted 3H-
[1,2,3]triazolo[4,5-d]pyrimidin-5-amines are potent in-
hibitors of glycogen synthase kinase-3 (GSK-3)4
(Figure 1).
As part of our research directed to bioactive 1,2,3-triazo-
lo-condensed pyrimidine-amine derivatives, we here de-
scribe a straightforward synthetic method for a series of
novel N,3-substituted 3H-[1,2,3]triazolo[4,5-d]pyrimi-
din-5-amines 5, starting from 2-chloro-5-nitropyrimidin-
4-yl thiocyanate7 (1) as a precursor.
Me
NH
Reaction of 2-chloro-5-nitropyrimidin-4-yl thiocyanate
(1) with two equivalents of primary amines at 0 °C pro-
vided the 2-amino-substituted 5-nitropyrimidin-4-yl thio-
cyanates 2a–d in 91–98% yields (Scheme 1, Table 1),
which were characterized by a sharp SCN absorption band
at 2173–2184 cm–1 in the IR spectra. Without further pu-
rification, the crude starting materials 2 were converted
into the N2,N4-substituted 5-nitropyrimidine-2,4-di-
amines 3a–g by treatment with an excess of primary
amines in DMF. A simple workup procedure, followed by
recrystallization from methanol furnished 3a–g as solid
compounds in 83–93% yields (Scheme 1, Table 2).
R1
NH
N
N
N
N
N
F
N
N
N
N
N
R2
anticonvulsive agent
adenosine A1 antagonists
Ar
NH
O
NH
N
NO2
NO2
N
N
N
R1NH2
N
N
N
N
N
N
R1
Ar
N
N
SCN
R1
N
N
N
Cl
N
SCN
H
H
R2
Ar
1
2
adenosine A3 antagonists
GSK-3 inhibitors
NO2
NH2
R2NH2
N
Figure 1 Selected biologically active 3-substituted 3H-[1,2,3]tria-
zolo[4,5-d]pyrimidines
H2, Pd/C
N
R1
R1
N
N
NH
R2
N
N
NH
R2
H
H
3
4
The development of efficient methods for the preparation
of new analogues of bioactive heterocyclic compounds
represents an important challenge in organic and hetero-
NaNO2
HCl
N
N
N
N
R1
N
N
H
R2
5
SYNTHESIS 2010, No. 4, pp 0689–0693
x
x
.
x
x
.2
0
1
0
Advanced online publication: 11.12.2009
DOI: 10.1055/s-0029-1218597; Art ID: T17009SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Synthesis of N,3-substituted 3H-[1,2,3]triazolo[4,5-
d]pyrimidin-5-amines 5a–g

690
F. K. Hansen, D. Geffken
PAPER
Table 1 2-Amino-Substituted 5-Nitropyrimidin-4-yl Thiocyanates
2a–d Prepared
the leaving groups of 1 can smoothly stepwise be replaced
by amines, 2-chloro-5-nitropyrimidin-4-yl thiocyanate (1)
can act as a powerful and efficient precursor for the syn-
thesis of the target compounds 5.
Product
2a
R1
Yield (%)a
4-FC6H4CH2
98
91
94
93
2b
c-Pr
Et
Melting points (uncorrected) were determined on a Mettler FP 62
apparatus. Elemental analyses were carried out with a Heraeus
CHN-O-Rapid instrument. HRFAB-MS analyses were performed
on a VG 70-250S spectrometer. IR spectra were recorded on a Vari-
2c
2d
Ph
1
an 800 FT-IR spectrometer. H NMR (400 MHz) and 13C NMR
a Yield of crude product.
(100 MHz) spectra were recorded on a Bruker AMX 400 spectrom-
eter using TMS as an internal standard and DMSO-d6 or CDCl3 as
solvent. 2-Chloro-5-nitropyrimidin-4-yl thiocyanate7a (1), 2-(ethyl-
amino)-5-nitropyrimidin-4-yl thiocyanate8 (2c), and 5-nitro-2-(phe-
nylamino)pyrimidin-4-yl thiocyanate7b (2d) were prepared
according to literature procedures.
Table 2 N2,N4-Substituted 5-Nitropyrimidine-2,4-diamines 3a–g
Prepared
Product
3a
R1
R2
Yield (%)
2-Amino-Substituted 5-Nitropyrimidin-4-yl Thiocyanates 2a,b;
General Procedure
Et
4-FC6H4CH2
2-FC6H4CH2
PhCH2CH2
c-Pr
85
92
88
83
85
93
89
To a solution of 2-chloro-5-nitropyrimidin-4-yl thiocyanate (1; 2.17
g, 10 mmol) in benzene (20 mL) was added a solution of the appro-
priate primary amine (20 mmol) in EtOH (20 mL) dropwise under
ice cooling. After stirring for 15 min at 0 °C, the solvent was re-
moved under reduced pressure and EtOH (10 mL) was added. The
separated solid was collected, washed with EtOH (2 × 5 mL), and
dried. Products 2 were used for the synthesis of compounds 3 with-
out further purification.
3b
c-Pr
3c
c-Pr
3d
4-FC6H4CH2
4-FC6H4CH2
Ph
3e
Bn
3f
Bn
3g
c-Pr
Ph
2-[(4-Fluorobenzyl)amino]-5-nitropyrimidin-4-yl Thiocyanate
(2a)
Yield: 2.99 g (98%); yellow solid; mp 160 °C.
IR (KBr): 3221, 2173 cm–1.
1H NMR (DMSO-d6): d = 4.64 (d, J = 6.3 Hz, 0.6 H, ArCH2), 4.69
(d, J = 6.3 Hz, 1.4 H, ArCH2), 7.10–7.52 (m, 4 H, ArH), 9.08 (s, 0.7
H, ArH), 9.15 (s, 0.3 H, ArH), 9.73 (t, J = 6.3 Hz, 0.3 H, NH), 9.85
(t, J = 6.4 Hz, 0.7 H, NH); due to existence of rotamers some signals
appear twice.
The catalytic hydrogenation of 5-nitropyrimidine-2,4-di-
amines 3a–g on 10% Pd/C in methanol provided the un-
stable pyrimidine-2,4,5-triamines 4, which upon
successive nitrosation with sodium nitrite in a mixture of
hydrochloric acid and ethanol at 0 °C afforded the target-
ed N,3-substituted 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-
amines 5a–g in satisfactory yields of 51–75% (Scheme 1,
Table 3).
13C NMR (DMSO-d6): d = 43.3, 44.0, 107.9, 108.1, 115.1 (d,
2JC,F = 21.6 Hz), 115.1 (d, 2JC,F = 20.8 Hz), 129.5 (d, 3JC,F = 8.5 Hz),
3
4
129.9 (d, JC,F = 8.5 Hz), 130.8, 130.9, 134.1 (d, JC,F = 3.1 Hz),
134.1 (d, 4JC,F = 3.1 Hz), 157.1, 157.4, 160.1, 160.2, 160.5, 160.9,
161.3 (d, 1JC,F = 242.8 Hz), 161.4 (d, 1JC,F = 242.8 Hz); due to exist-
ence of rotamers some signals appear twice.
Table 3 N,3-Substituted 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-
amines 5a–g Prepared
Product
5a
R1
R2
Yield (%)
HRMS-FAB: m/z [M + H]+ calcd for C12H8FN5O2S: 306.0461;
found: 306.0446.
Et
4-FC6H4CH2
2-FC6H4CH2
PhCH2CH2
c-Pr
63
66
68
55
59
51
75
5b
c-Pr
2-(Cyclopropylamino)-5-nitropyrimidin-4-yl Thiocyanate (2b)
Yield: 2.16 g (91%); yellow solid; mp 196 °C (CH2Cl2–n-hexane).
IR (KBr): 3283, 2184 cm–1.
1H NMR (DMSO-d6): d = 0.61–0.92 (m, 4 H, CH2), 2.98–3.12 (m,
1 H, CH), 9.05 (s, 0.7 H, ArH), 9.18 (s, 0.3 H, ArH), 9.31 (d, J = 4.3
Hz, 0.3 H, NH), 9.46 (d, J = 3.8 Hz, 0.7 H, NH); due to existence of
rotamers some signals appear twice.
13C NMR (DMSO-d6): d = 6.0, 6.1, 24.7, 24.9, 107.7, 107.9, 130.7,
130.7, 156.5, 157.3, 159.6, 160.8, 161.4, 161.6; due to existence of
rotamers some signals appear twice.
5c
c-Pr
5d
4-FC6H4CH2
4-FC6H4CH2
Ph
5e
Bn
5f
Bn
5g
c-Pr
Ph
HRMS-FAB: m/z [M + H]+ calcd for C8H7N5O2S: 238.0399; found:
238.0402.
In summary, we have developed an expedient four step
preparation of N,3-substituted 3H-[1,2,3]triazolo[4,5-
d]pyrimidin-5-amines 5a–g starting from easily available
2-chloro-5-nitropyrimidin-4-yl thiocyanate (1). The de-
scribed procedure is advantageous compared with litera-
ture methods with regard to performance and yields. Since
N2,N4-Substituted 5-Nitropyrimidine-2,4-diamines 3a–g; Gen-
eral Procedure
To a solution of the respective crude thiocyanates 2 (3 mmol) in
DMF (10 mL) was added the appropriate primary amine (15 mmol)
Synthesis 2010, No. 4, 689–693 © Thieme Stuttgart · New York

PAPER
Synthesis of Novel N,3-Substituted 3H-[1,2,3]Triazolo[4,5-d]pyrimidin-5-amines
691
and the mixture was stirred at r.t. for 1.5 h. The reaction was
quenched with H2O (40 mL), the resulting precipitate filtered, and
washed with H2O (2 × 5 mL). The crude products were recrystal-
lized from MeOH.
N4-Cyclopropyl-N2-(4-fluorobenzyl)-5-nitropyrimidine-2,4-di-
amine (3d)
Yield: 756 mg (83%); yellow solid; mp 195 °C.
IR (KBr): 3345, 3248, 1591, 1565 cm–1.
1H NMR (DMSO-d6): d = 0.60–0.85 (m, 4 H, CH2), 2.95–3.11 (m,
1 H, CH), 4.54 (d, J = 6.3 Hz, 1.6 H, ArCH2), 4.57 (d, J = 6.3 Hz,
0.4 H, ArCH2), 7.00–7.48 (m, 4 H, ArH), 8.31 (d, J = 4.5 Hz, 0.2 H,
NH), 8.44 (d, J = 4.0 Hz, 0.8 H, NH), 8.68 (t, J = 6.4 Hz, 0.2 H,
NH), 8.81–8.89 (m, 1.6 H, NH and ArH), 8.91 (s, 0.2 H, ArH); due
to existence of rotamers some signals appear twice.
N2-Ethyl-N4-(4-fluorobenzyl)-5-nitropyrimidine-2,4-diamine
(3a)
Yield: 743 mg (85%); yellow crystals; mp 177 °C.
IR (KBr): 3367, 3256, 2975, 1596 cm–1.
1H NMR (DMSO-d6): d = 1.02 (t, J = 7.2 Hz, 2.4 H, NHCH2CH3),
1.12 (t, J = 7.2 Hz, 0.6 H, NHCH2CH3), 3.21–3.43 (m, 2 H,
NHCH2CH3), 4.64–4.77 (m, 2 H, ArCH2), 7.09–7.49 (m, 4 H, ArH),
8.09 (t, J = 5.6 Hz, 0.2 H, NH), 8.28 (t, J = 5.4 Hz, 0.8 H, NH), 8.85
(s, 0.8 H, ArH), 8.94 (s, 0.2 H, ArH), 9.03 (t, J = 5.8 Hz, 0.2 H, NH),
9.29 (t, J = 5.8 Hz, 0.8 H, NH); due to existence of rotamers some
signals appear twice.
13C NMR (DMSO-d6): d = 6.4, 6.5, 23.9, 23.9, 43.5, 43.9, 114.9 (d,
2JC,F = 20.8 Hz), 114.9 (d, 2JC,F = 21.6 Hz), 119.8, 120.8, 129.2 (d,
3
4
3JC,F = 7.7 Hz), 129.6 (d, JC,F = 8.5 Hz), 135.3 (d, JC,F = 3.1 Hz),
4
135.5 (d, JC,F = 3.1 Hz), 156.5, 156.7, 157.4, 157.7, 161.2 (d,
1JC,F = 242.0 Hz), 161.4, 161.7; due to existence of rotamers some
signals appear twice.
HRMS-FAB: m/z [M + H]+ calcd for C14H14FN5O2: 304.1210;
found: 304.1216.
13C NMR (DMSO-d6): d = 14.0, 14.8, 35.7, 35.9, 42.4, 42.9, 114.9
(d, 2JC,F = 21.2 Hz), 119.4, 120.4, 129.3 (d, 3JC,F = 8.8 Hz), 129.6 (d,
4
3JC,F = 8.8 Hz), 135.1 (d, JC,F = 2.9 Hz), 135.3 (d, 4JC,F = 2.9 Hz),
1
155.0, 155.3, 157.5, 158.0, 161.1 (d, JC,F = 242.2 Hz), 161.2,
N4-Benzyl-N2-(4-fluorobenzyl)-5-nitropyrimidine-2,4-diamine
(3e)
Yield: 899 mg (85%); yellow solid; mp 166 °C.
161.5; due to existence of rotamers some signals appear twice.
HRMS-FAB: m/z [M + H]+ calcd for C13H14FN5O2: 292.1210;
found: 292.1213.
IR (KBr): 3361, 1591, 1561 cm–1.
1H NMR (DMSO-d6): d = 4.38–4.77 (m, 4 H, ArCH2), 6.98–7.41
(m, 9 H, ArH), 8.58 (t, J = 6.3 Hz, 0.2 H, NH), 8.78 (t, J = 6.3 Hz,
0.8 H, NH), 8.82–8.95 (m, 1 H, ArH), 9.04 (t, J = 6.0 Hz, 0.2 H,
NH), 9.25 (t, J = 6.2 Hz, 0.8 H, NH); due to existence of rotamers
some signals appear twice.
N2-Cyclopropyl-N4-(2-fluorobenzyl)-5-nitropyrimidine-2,4-di-
amine (3b)
Yield: 837 mg (92%); yellow crystals; mp 182 °C.
IR (KBr): 3382, 3211, 1593, 1564 cm–1.
1H NMR (DMSO-d6): d = 0.41–0.72 (m, 4 H, CH2), 2.70–2.97 (m,
1 H, CH), 4.78 (d, J = 6.1 Hz, 0. 5 H, ArCH2), 4.83 (d, J = 6.1 Hz,
1.5 H, ArCH2), 7.10–7.47 (m, 4 H, ArH), 8.15 (d, J = 4.0 Hz, 0.25
H, NH), 8.40 (d, J = 3.8 Hz, 0.75 H, NH), 8.84 (s, 0.75 H, ArH),
8.94 (t, J = 5.7 Hz, 0.25 H, NH), 9.00 (s, 0.25 H, ArH), 9.22 (t,
J = 5.8 Hz, 0.75 H, NH); due to existence of rotamers some signals
appear twice.
13C NMR (DMSO-d6): d = 42.8, 43.2, 43.4, 43.7, 114.9 (d,
2
2JC,F = 21.2 Hz), 114.9 (d, JC,F = 21.2 Hz), 119.8, 120.7, 126.7,
3
126.8, 127.1, 127.5, 128.2, 128.2, 129.0 (d, JC,F = 8.1 Hz), 129.2
3
4
4
(d, JC,F = 8.1 Hz), 135.1 (d, JC,F = 2.9 Hz), 135.5 (d, JC,F = 2.9
Hz), 138.8, 138.9, 155.1, 155.3, 157.7, 158.0, 161.1 (d,
1JC,F = 242.2 Hz), 161.2 (d, 1JC,F = 242.2 Hz), 161.4, 161.7; due to
existence of rotamers some signals appear twice.
13C NMR (DMSO-d6): d = 5.8, 6.1, 24.1, 24.2, 37.3 (d, 3JC,F = 3.7
HRMS-FAB: m/z [M + H]+ calcd for C18H16FN5O2: 354.1366;
found: 354.1351.
3
2
Hz), 37.5 (d, JC,F = 4.4 Hz), 114.9 (d, JC,F = 21.2 Hz), 119.8,
4
2
120.9, 124.2 (d, JC,F = 3.7 Hz), 124.3, 125.7 (d, JC,F = 13.9 Hz),
3
3
128.7 (d, JC,F = 8.1 Hz), 128.9, 129.5 (d, JC,F = 4.4 Hz), 155.1,
155.3, 157.2, 158.0, 160.1 (d, 1JC,F = 243.7 Hz), 162.6, 162.8; due
to existence of rotamers some signals appear twice.
N4-Benzyl-5-nitro-N2-phenylpyrimidine-2,4-diamine (3f)
Yield: 897 mg (93%); yellow crystals; mp 193 °C.
IR (KBr): 3376, 1592, 1552 cm–1.
1H NMR (DMSO-d6): d = 4.79 (d, J = 6.1 Hz, 2 H, ArCH2), 6.99–
7.62 (m, 10 H, ArH), 9.02 (s, 1 H, ArH), 9.44 (s, 1 H, NH), 10.34
(s, 1 H, NH).
13C NMR (DMSO-d6): d = 43.9, 120.1, 123.2, 126.7, 128.2, 128.4,
138.6, 138.7, 155.4, 157.3, 159.4.
HRMS-FAB: m/z [M + H]+ calcd for C14H14FN5O2: 304.1210;
found: 304.1217.
N2-Cyclopropyl-5-nitro-N4-(2-phenylethyl)pyrimidine-2,4-di-
amine (3c)
Yield: 790 mg (88%); yellow crystals; mp 176 °C.
IR (KBr): 3380, 1619, 1589, 1561 cm–1.
HRMS-FAB: m/z [M + H]+ calcd for C17H15N5O2: 322.1304; found:
1H NMR (DMSO-d6): d = 0.55–0.79 (m, 4 H, CH2), 2.84–3.00 (m,
3 H, CH and NHCH2CH2Ph), 3.66–3.85 (m, 2 H, NHCH2CH2Ph),
7.17–7.35 (m, 5 H, ArH), 8.18 (d, J = 4.3 Hz, 0.25 H, NH), 8.43 (d,
J = 4.0 Hz, 0.75 H, NH), 8.56 (t, J = 5.4 Hz, 0.25 H, NH), 8.75–8.89
(m, 1.5 H, NH and ArH), 8.96 (s, 0.25 H, ArH); due to existence of
rotamers some signals appear twice.
13C NMR (DMSO-d6): d = 6.0, 6.2, 24.2, 34.5, 34.7, 41.4, 41.8,
119.6, 120.6, 126.1, 128.3, 128.6, 128.6, 139.2, 154.8, 155.3, 157.2,
157.9, 162.7; due to existence of rotamers some signals appear
twice.
322.1295.
N2-Cyclopropyl-5-nitro-N4-phenylpyrimidine-2,4-diamine (3g)
Yield: 727 mg (89%); yellow crystals; mp 228 °C.
IR (KBr): 3224, 1585, 1551 cm–1.
1H NMR (DMSO-d6): d = 0.56–0.80 (m, 4 H, CH2), 2.72–2.80 (m,
0.75 H, CH), 2.92–3.00 (m, 0.25 H, CH), 7.12–7.95 (m, 5 H, ArH),
8.39 (d, J = 4.3 Hz, 0.25 H, NH), 8.72 (d, J = 3.5 Hz, 0.75 H, NH),
8.97 (s, 0.75 H, ArH), 9.09 (s, 0.25 H, ArH), 10.18 (s, 0.25 H, NH),
10.40 (s, 0.75 H, NH); due to existence of rotamers some signals ap-
pear twice.
HRMS-FAB: m/z [M + H]+ calcd for C15H17N5O2: 300.1461; found:
13C NMR (DMSO-d6): d = 6.1, 6.1, 24.3, 24.4, 119.8, 122.2, 122.7,
124.4, 124.5, 128.5, 128.6, 137.4, 153.5, 157.7, 158.4, 162.8; due to
existence of rotamers some signals appear twice.
300.1462.
Synthesis 2010, No. 4, 689–693 © Thieme Stuttgart · New York

692
F. K. Hansen, D. Geffken
PAPER
HRMS-FAB: m/z [M + H]+ calcd for C13H13N5O2: 272.1148, found:
272.1145.
1H NMR (CDCl3): d = 1.15–1.49 (m, 4 H, CH2), 3.72–3.84 (m, 1 H,
CH), 4.68 (d, J = 5.6 Hz, 2 H, ArCH2), 6.19 (s, 1 H, NH), 6.94–7.42
(m, 4 H, ArH), 8.96 (s, 1 H, ArH).
N,3-Substituted 3H-[1,2,3]Triazolo[4,5-d]pyrimidin-5-amines;
5a–g; General Procedure
2
13C NMR (CDCl3): d = 6.5, 28.4, 45.6, 115.9 (d, JC,F = 21.4 Hz),
3
129.8 (d, JC,F = 7.6 Hz), 134.6, 152.3, 153.2, 161.7, 162.6 (d,
A suspension of the respective diamine 3 (2 mmol) in MeOH (20
mL) was hydrogenated using a catalytic amount of 10% Pd/C (2 h/
2 bar). Afterwards, the suspension was filtered through an SPE tube
RP-18 purchased from Supelco (Sigma-Aldrich, Munich, Germa-
ny) in order to remove the catalyst. The filtrate was evaporated to
dryness and the residue dissolved in a mixture of EtOH (20 mL) and
aq 1 M HCl (20 mL). To this mixture, was added a solution of
NaNO2 (2 mmol) in H2O (3 mL) dropwise at 0 °C and stirred at r.t.
for 1 h. Next, 20–30 mL of the solvent was removed under reduced
pressure and the suspension was stored at 5–8 °C for 5 h. The pre-
cipitate was filtered and recrystallized from MeOH to afford com-
pounds 5a–g as solid products.
1JC,F = 246.4 Hz).
Anal. Calcd for C14H13FN6: C, 59.15; H, 4.61; N, 29.56. Found: C,
59.21; H, 4.91; N, 29.30.
3-Benzyl-N-(4-fluorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimi-
din-5-amine (5e)
Yield: 448 mg (59%); colorless solid; mp 192 °C.
IR (KBr): 3246, 1614 cm–1.
1H NMR (CDCl3): d = 4.66 (d, J = 5.6 Hz, 2 H, ArCH2), 5.63 (s, 2
H, ArCH2), 6.05 (s, 1 H, NH), 6.96–7.41 (m, 9 H, ArH), 9.01 (s, 1
H, ArH).
13C NMR (CDCl3): d = 45.2, 49.8, 115.5 (d, 2JC,F = 21.1 Hz), 128.4,
N-Ethyl-3-(4-fluorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-
5-amine (5a)
128.4, 128.8, 129.3 (d, 3JC,F = 8.3 Hz), 135.0, 152.9.
Yield: 343 mg (63%); colorless solid; mp 131 °C.
IR (KBr): 3256, 2966, 1618 cm–1.
Anal. Calcd for C18H15FN6: C, 64.66; H, 4.52; N, 25.13. Found: C,
64.49; H, 4.80; N, 25.04.
1H NMR (CDCl3): d = 1.29 (t, J = 7.3 Hz, 3 H, NHCH2CH3), 3.48–
3.59 (m, 2 H, NHCH2CH3), 5.61 (s, 2 H, ArCH2), 5.73 (s, 1 H, NH),
6.97–7.50 (m, 4 H, ArH), 9.00 (s, 1 H, ArH).
3-Benzyl-N-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine
(5f)
Yield: 309 mg (51%); colorless solid; mp 194 °C.
IR (KBr): 3248, 1618, 1547 cm–1.
1H NMR (CDCl3): d = 5.72 (s, 2 H, ArCH2), 7.10–7.69 (m, 10 H,
ArH), 7.72 (s, 1 H, NH), 9.14 (s, 1 H, ArH).
13C NMR (CDCl3): d = 50.3, 119.6, 123.5, 128.5, 128.5, 128.9,
129.0, 132.0, 134.8, 138.7, 150.4, 152.7, 158.6.
13C NMR (CDCl3): d = 14.4, 36.6, 48.9, 115.7 (d, 2JC,F = 21.4 Hz),
3
4
130.4 (d, JC,F = 8.4 Hz), 130.9 (d, JC,F = 3.1 Hz), 131.2, 150.9,
152.6, 161.3, 162.6 (d, 1JC,F = 247.2 Hz).
Anal. Calcd for C13H13FN6: C, 57.35; H, 4.81; N, 30.86. Found: C,
57.17; H, 5.15; N, 30.72.
N-Cyclopropyl-3-(2-fluorobenzyl)-3H-[1,2,3]triazolo[4,5-d]py-
rimidin-5-amine (5b)
Yield: 376 mg (66%); colorless solid; mp 132 °C.
Anal. Calcd for C17H14N6: C, 67.54; H, 4.67; N, 27.80. Found: C,
67.15; H, 4.74; N, 27.60.
IR (KBr): 3236, 1614 cm–1.
N-Cyclopropyl-3-phenyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-
amine (5g)
Yield: 379 mg (75%); colorless solid; mp 184 °C.
IR (KBr): 3229, 1617, 1560 cm–1.
1H NMR (CDCl3): d = 0.55–0.92 (m, 4 H, CH2), 2.81–2.89 (m, 1 H,
CH), 5.76 (s, 2 H, ArCH2), 5.89 (s, 1 H, NH), 7.05–7.43 (m, 4 H,
ArH), 9.05 (s, 1 H, ArH).
1H NMR (CDCl3): d = 0.61–0.96 (m, 4 H, CH2), 2.86–2.95 (m, 1 H,
CH), 6.00 (s, 1 H, NH), 7.39–7.61 (m, 3 H, ArH), 8.32 (s, 2 H, ArH),
9.13 (s, 1 H, ArH).
13C NMR (CDCl3): d = 7.3, 24.4, 120.5, 127.7, 129.4, 132.4, 136.6,
150.6, 152.9, 162.6.
13C NMR (CDCl3): d = 7.3, 24.3, 43.1 (d, 3JC,F = 5.4 Hz), 115.6 (d,
2JC,F = 20.8 Hz), 122.2 (d, 2JC,F = 14.6 Hz), 124.3 (d, 4JC,F = 3.9 Hz),
3
130.3 (d, JC,F = 8.5 Hz), 130.6, 131.4, 151.2, 152.5, 160.6 (d,
1JC,F = 248.9 Hz), 162.4.
Anal. Calcd for C14H13FN6: C, 59.15; H, 4.61; N, 29.56. Found: C,
59.11; H, 4.89; N, 29.64.
Anal. Calcd for C13H12N6: C, 61.89; H, 4.79; N, 33.31. Found: C,
61.87; H, 4.88; N, 33.14.
N-Cyclopropyl-3-(2-phenylethyl)-3H-[1,2,3]triazolo[4,5-d]pyri-
midin-5-amine (5c)
Yield: 382 mg (68%); colorless solid; mp 112 °C.
IR (KBr): 3236, 1610 cm–1.
References
(1) Kelley, J. L.; Davis, R. G.; McLean, E. W.; Glen, R. C.;
Soroko, F. E.; Cooper, B. R. J. Med. Chem. 1995, 38, 3884.
(2) Betti, L.; Biagi, G.; Giannaccini, G.; Giorgi, I.; Livi, O.;
Lucacchini, A.; Manera, C.; Scartoni, V. J. Med. Chem.
1998, 41, 668.
1H NMR (CDCl3): d = 0.55–0.92 (m, 4 H, CH2), 2.79–2.88 (m, 1 H,
CH), 3.34 (t, J = 7.7 Hz, 2 H, NHCH2CH2Ph), 4.70–4.80 (m, 2 H,
NHCH2CH2Ph), 5.88 (s, 1 H, NH), 7.16–7.32 (m, 5 H, ArH), 9.03
(s, 1 H, ArH).
(3) Biagi, G.; Bianucci, A. M.; Coi, A.; Costa, B.; Fabbrini, L.;
Giorgi, I.; Livi, O.; Micco, I.; Pacchini, F.; Santini, E.;
Leonardi, M.; Nofal, F. A.; Salerni, O. L.; Scartoni, V.
Bioorg. Med. Chem. 2005, 13, 4679.
(4) (a) Love, C. J.; Cooymans, L. P.; Vandermaesen, N. (Janssen
Pharmaceutica N.V., Belgium) Patent WO 2006075023,
2006; Chem. Abstr. 2006, 145, 167273. (b) Lum, C.; Kahl,
J.; Kessler, L.; Kucharski, J.; Lundstrom, J.; Miller, S.;
Nakanishi, H.; Pei, Y.; Pryor, K.; Roberts, E.; Sebo, L.;
13C NMR (CDCl3): d = 7.3, 24.3, 35.4, 47.3, 126.9, 128.7, 128.7,
131.5, 137.4, 151.2, 152.4, 162.2.
Anal. Calcd for C15H16N6: C, 64.27; H, 5.75; N, 29.98. Found: C,
64.31; H, 5.75; N, 30.18.
3-Cyclopropyl-N-(4-fluorobenzyl)-3H-[1,2,3]triazolo[4,5-d]py-
rimidin-5-amine (5d)
Yield: 313 mg (55%); colorless solid; mp 130 °C.
IR (KBr): 3249, 1612 cm–1.
Synthesis 2010, No. 4, 689–693 © Thieme Stuttgart · New York

PAPER
Synthesis of Novel N,3-Substituted 3H-[1,2,3]Triazolo[4,5-d]pyrimidin-5-amines
693
Sullivan, R.; Urban, J.; Wang, Z. Bioorg. Med. Chem. Lett.
2008, 18, 3578.
(5) Dille, K. L.; Sutherland, M. L.; Christensen, B. E. J. Org.
Chem. 1955, 20, 171.
(7) For nucleophilic displacement of the SCN group, see:
(a) Takahashi, T.; Naito, T.; Inoue, S. Chem. Pharm. Bull.
1958, 6, 334. (b) Naito, T.; Inoue, S. Chem. Pharm. Bull.
1958, 6, 338.
(6) (a) Brown, D. J. J. Appl. Chem. 1954, 4, 72. (b) Brown, D.
J. J. Appl. Chem. 1957, 7, 109. (c) Wiley, R. H.; Lanet, J.;
Hussung, K. H. J. Heterocycl. Chem. 1964, 1, 175.
(d) Bacon, R. G. R.; Hamilton, S. D. J. Chem. Soc., Perkin
Trans. 1 1974, 1970. (e) Barlin, G. B. J. Chem. Soc. B 1967,
954.
(8) Sugiura, S.; Suzuki, E.; Naito, T.; Inoue, S. Chem. Pharm.
Bull. 1968, 16, 745.
Synthesis 2010, No. 4, 689–693 © Thieme Stuttgart · New York