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Synthesis 2010(4): 689-693  
DOI: 10.1055/s-0029-1218597
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Finn K. 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;

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Publication History

Received 1 September 2009
Publication Date:
11 December 2009 (online)

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Abstract

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 N²,N4-substituted 5-nitropyrimidine-2,4-diamines.

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 anticonvulsive [¹] and adenosine A1 and A3 receptor antagonistic activity. [²] [³] Furthermore, N,3-substituted 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amines are potent inhibitors of glycogen synthase kinase-3 (GSK-3) [4] (Figure  [¹] ).

Figure 1 Selected biologically active 3-substituted 3H-[1,2,3]triazolo[4,5-d]pyrimidines

The development of efficient methods for the preparation of new analogues of bioactive heterocyclic compounds represents an important challenge in organic and heterocyclic chemistry. Surprisingly, only few synthetic strategies for N,3-substituted 3H-[1,2,3]triazolo[4,5-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 regio­selective monoaminolysis of 2,4-dichloro-5-nitropyrimidine 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]

As part of our research directed to bioactive 1,2,3-triazolo-condensed pyrimidine-amine derivatives, we here describe a straightforward synthetic method for a series of novel N,3-substituted 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amines 5, starting from 2-chloro-5-nitropyrimidin-4-yl thiocyanate [7] (1) as a precursor.

Scheme 1 Synthesis of N,3-substituted 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amines 5a-g

Reaction of 2-chloro-5-nitropyrimidin-4-yl thiocyanate (1) with two equivalents of primary amines at 0 ˚C provided the 2-amino-substituted 5-nitropyrimidin-4-yl thiocyanates 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 purification, the crude starting materials 2 were converted into the N²,N4-substituted 5-nitropyrimidine-2,4-diamines 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] ).

Table 1 2-Amino-Substituted 5-Nitropyrimidin-4-yl Thiocyanates 2a-d Prepared
Product R¹ Yield (%)a
2a 4-FC6H4CH2 98
2b c-Pr 91
2c Et 94
2d Ph 93
a Yield of crude product.
Table 2 N²,N4-Substituted 5-Nitropyrimidine-2,4-diamines 3a-g Prepared
Product R¹ R² Yield (%)
3a Et 4-FC6H4CH2 85
3b c-Pr 2-FC6H4CH2 92
3c c-Pr PhCH2CH2 88
3d 4-FC6H4CH2 c-Pr 83
3e 4-FC6H4CH2 Bn 85
3f Ph Bn 93
3g c-Pr Ph 89

The catalytic hydrogenation of 5-nitropyrimidine-2,4-diamines 3a-g on 10% Pd/C in methanol provided the unstable 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 targeted 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] ).

Table 3 N,3-Substituted 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amines 5a-g Prepared
Product R¹ R² Yield (%)
5a Et 4-FC6H4CH2 63
5b c-Pr 2-FC6H4CH2 66
5c c-Pr PhCH2CH2 68
5d 4-FC6H4CH2 c-Pr 55
5e 4-FC6H4CH2 Bn 59
5f Ph Bn 51
5g c-Pr Ph 75

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 described procedure is advantageous compared with literature methods with regard to performance and yields. Since 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 synthesis of the target compounds 5.

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 Varian 800 FT-IR spectrometer. ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were recorded on a Bruker AMX 400 spectrometer using TMS as an internal standard and DMSO-d 6 or CDCl3 as solvent. 2-Chloro-5-nitropyrimidin-4-yl thiocyanate [7a] (1), 2-(ethyl­amino)-5-nitropyrimidin-4-yl thiocyanate [8] (2c), and 5-nitro-2-(phenylamino)pyrimidin-4-yl thiocyanate [7b] (2d) were prepared according to literature procedures.

2-Amino-Substituted 5-Nitropyrimidin-4-yl Thiocyanates 2a,b; General Procedure

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 appropriate primary amine (20 mmol) in EtOH (20 mL) dropwise under ice cooling. After stirring for 15 min at 0 ˚C, the solvent was removed 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 without further purification.

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-d 6): δ = 4.64 (d, J = 6.3 Hz, 0.6 H, ArCH 2), 4.69 (d, J = 6.3 Hz, 1.4 H, ArCH 2), 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.

¹³C NMR (DMSO-d 6): δ = 43.3, 44.0, 107.9, 108.1, 115.1 (d, ² J C,F = 21.6 Hz), 115.1 (d, ² J C,F = 20.8 Hz), 129.5 (d, ³ J C,F = 8.5 Hz), 129.9 (d, ³ J C,F = 8.5 Hz), 130.8, 130.9, 134.1 (d, 4 J C,F = 3.1 Hz), 134.1 (d, 4 J C,F = 3.1 Hz), 157.1, 157.4, 160.1, 160.2, 160.5, 160.9, 161.3 (d, ¹ J C,F = 242.8 Hz), 161.4 (d, ¹ J C,F = 242.8 Hz); due to existence of rotamers some signals appear twice.

HRMS-FAB: m/z [M + H]+ calcd for C12H8FN5O2S: 306.0461; found: 306.0446.

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-d 6): δ = 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-d 6): δ = 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.

HRMS-FAB: m/z [M + H]+ calcd for C8H7N5O2S: 238.0399; found: 238.0402.

N ² ,N 4 -Substituted 5-Nitropyrimidine-2,4-diamines 3a-g; General Procedure

To a solution of the respective crude thiocyanates 2 (3 mmol) in DMF (10 mL) was added the appropriate primary amine (15 mmol) 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 recrystallized from MeOH.

N ² -Ethyl- N 4 -(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-d 6): δ = 1.02 (t, J = 7.2 Hz, 2.4 H, NHCH2CH 3), 1.12 (t, J = 7.2 Hz, 0.6 H, NHCH2CH 3), 3.21-3.43 (m, 2 H, NHCH 2CH3), 4.64-4.77 (m, 2 H, ArCH 2), 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-d 6): δ = 14.0, 14.8, 35.7, 35.9, 42.4, 42.9, 114.9 (d, ² J C,F = 21.2 Hz), 119.4, 120.4, 129.3 (d, ³ J C,F = 8.8 Hz), 129.6 (d, ³ J C,F = 8.8 Hz), 135.1 (d, 4 J C,F = 2.9 Hz), 135.3 (d, 4 J C,F = 2.9 Hz), 155.0, 155.3, 157.5, 158.0, 161.1 (d, ¹ J C,F = 242.2 Hz), 161.2, 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.

N ² -Cyclopropyl- N 4 -(2-fluorobenzyl)-5-nitropyrimidine-2,4-diamine (3b)

Yield: 837 mg (92%); yellow crystals; mp 182 ˚C.

IR (KBr): 3382, 3211, 1593, 1564 cm-¹.

¹H NMR (DMSO-d 6): δ = 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, ArCH 2), 4.83 (d, J = 6.1 Hz, 1.5 H, ArCH 2), 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-d 6): δ = 5.8, 6.1, 24.1, 24.2, 37.3 (d, ³ J C,F = 3.7 Hz), 37.5 (d, ³ J C,F = 4.4 Hz), 114.9 (d, ² J C,F = 21.2 Hz), 119.8, 120.9, 124.2 (d, 4 J C,F = 3.7 Hz), 124.3, 125.7 (d, ² J C,F = 13.9 Hz), 128.7 (d, ³ J C,F = 8.1 Hz), 128.9, 129.5 (d, ³ J C,F = 4.4 Hz), 155.1, 155.3, 157.2, 158.0, 160.1 (d, ¹ J C,F = 243.7 Hz), 162.6, 162.8; due to existence of rotamers some signals appear twice.

HRMS-FAB: m/z [M + H]+ calcd for C14H14FN5O2: 304.1210; found: 304.1217.

N ² -Cyclopropyl-5-nitro- N 4 -(2-phenylethyl)pyrimidine-2,4-diamine (3c)

Yield: 790 mg (88%); yellow crystals; mp 176 ˚C.

IR (KBr): 3380, 1619, 1589, 1561 cm-¹.

¹H NMR (DMSO-d 6): δ = 0.55-0.79 (m, 4 H, CH2), 2.84-3.00 (m, 3 H, CH and NHCH2CH 2Ph), 3.66-3.85 (m, 2 H, NHCH 2CH2Ph), 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-d 6): δ = 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.

HRMS-FAB: m/z [M + H]+ calcd for C15H17N5O2: 300.1461; found: 300.1462.

N 4 -Cyclopropyl- N ² -(4-fluorobenzyl)-5-nitropyrimidine-2,4-diamine (3d)

Yield: 756 mg (83%); yellow solid; mp 195 ˚C.

IR (KBr): 3345, 3248, 1591, 1565 cm-¹.

¹H NMR (DMSO-d 6): δ = 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, ArCH 2), 4.57 (d, J = 6.3 Hz, 0.4 H, ArCH 2), 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.

¹³C NMR (DMSO-d 6): δ = 6.4, 6.5, 23.9, 23.9, 43.5, 43.9, 114.9 (d, ² J C,F = 20.8 Hz), 114.9 (d, ² J C,F = 21.6 Hz), 119.8, 120.8, 129.2 (d, ³ J C,F = 7.7 Hz), 129.6 (d, ³ J C,F = 8.5 Hz), 135.3 (d, 4 J C,F = 3.1 Hz), 135.5 (d, 4 J C,F = 3.1 Hz), 156.5, 156.7, 157.4, 157.7, 161.2 (d, ¹ J C,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.

N 4 -Benzyl- N ² -(4-fluorobenzyl)-5-nitropyrimidine-2,4-diamine (3e)

Yield: 899 mg (85%); yellow solid; mp 166 ˚C.

IR (KBr): 3361, 1591, 1561 cm-¹.

¹H NMR (DMSO-d 6): δ = 4.38-4.77 (m, 4 H, ArCH 2), 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.

¹³C NMR (DMSO-d 6): δ = 42.8, 43.2, 43.4, 43.7, 114.9 (d, ² J C,F = 21.2 Hz), 114.9 (d, ² J C,F = 21.2 Hz), 119.8, 120.7, 126.7, 126.8, 127.1, 127.5, 128.2, 128.2, 129.0 (d, ³ J C,F = 8.1 Hz), 129.2 (d, ³ J C,F = 8.1 Hz), 135.1 (d, 4 J C,F = 2.9 Hz), 135.5 (d, 4 J C,F = 2.9 Hz), 138.8, 138.9, 155.1, 155.3, 157.7, 158.0, 161.1 (d, ¹ J C,F = 242.2 Hz), 161.2 (d, ¹ J C,F = 242.2 Hz), 161.4, 161.7; due to existence of rotamers some signals appear twice.

HRMS-FAB: m/z [M + H]+ calcd for C18H16FN5O2: 354.1366; found: 354.1351.

N 4 -Benzyl-5-nitro- N ² -phenylpyrimidine-2,4-diamine (3f)

Yield: 897 mg (93%); yellow crystals; mp 193 ˚C.

IR (KBr): 3376, 1592, 1552 cm-¹.

¹H NMR (DMSO-d 6): δ = 4.79 (d, J = 6.1 Hz, 2 H, ArCH 2), 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-d 6): δ = 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 C17H15N5O2: 322.1304; found: 322.1295.

N ² -Cyclopropyl-5-nitro- N 4 -phenylpyrimidine-2,4-diamine (3g)

Yield: 727 mg (89%); yellow crystals; mp 228 ˚C.

IR (KBr): 3224, 1585, 1551 cm-¹.

¹H NMR (DMSO-d 6): δ = 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 appear twice.

¹³C NMR (DMSO-d 6): δ = 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.

HRMS-FAB: m/z [M + H]+ calcd for C13H13N5O2: 272.1148, found: 272.1145.

N,3-Substituted 3 H -[1,2,3]Triazolo[4,5- d ]pyrimidin-5-amines; 5a-g; General Procedure

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, Germany) 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 precipitate was filtered and recrystallized from MeOH to afford compounds 5a-g as solid products.

N -Ethyl-3-(4-fluorobenzyl)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-5-amine (5a)

Yield: 343 mg (63%); colorless solid; mp 131 ˚C.

IR (KBr): 3256, 2966, 1618 cm-¹.

¹H NMR (CDCl3): δ = 1.29 (t, J = 7.3 Hz, 3 H, NHCH2CH 3), 3.48-3.59 (m, 2 H, NHCH 2CH3), 5.61 (s, 2 H, ArCH 2), 5.73 (s, 1 H, NH), 6.97-7.50 (m, 4 H, ArH), 9.00 (s, 1 H, ArH).

¹³C NMR (CDCl3): δ = 14.4, 36.6, 48.9, 115.7 (d, ² J C,F = 21.4 Hz), 130.4 (d, ³ J C,F = 8.4 Hz), 130.9 (d, 4 J C,F = 3.1 Hz), 131.2, 150.9, 152.6, 161.3, 162.6 (d, ¹ J C,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)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-5-amine (5b)

Yield: 376 mg (66%); colorless solid; mp 132 ˚C.

IR (KBr): 3236, 1614 cm-¹.

¹H NMR (CDCl3): δ = 0.55-0.92 (m, 4 H, CH2), 2.81-2.89 (m, 1 H, CH), 5.76 (s, 2 H, ArCH 2), 5.89 (s, 1 H, NH), 7.05-7.43 (m, 4 H, ArH), 9.05 (s, 1 H, ArH).

¹³C NMR (CDCl3): δ = 7.3, 24.3, 43.1 (d, ³ J C,F = 5.4 Hz), 115.6 (d, ² J C,F = 20.8 Hz), 122.2 (d, ² J C,F = 14.6 Hz), 124.3 (d, 4 J C,F = 3.9 Hz), 130.3 (d, ³ J C,F = 8.5 Hz), 130.6, 131.4, 151.2, 152.5, 160.6 (d, ¹ J C,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.

N -Cyclopropyl-3-(2-phenylethyl)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-5-amine (5c)

Yield: 382 mg (68%); colorless solid; mp 112 ˚C.

IR (KBr): 3236, 1610 cm-¹.

¹H NMR (CDCl3): δ = 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, NHCH2CH 2Ph), 4.70-4.80 (m, 2 H, NHCH 2CH2Ph), 5.88 (s, 1 H, NH), 7.16-7.32 (m, 5 H, ArH), 9.03 (s, 1 H, ArH).

¹³C NMR (CDCl3): δ = 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)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-5-amine (5d)

Yield: 313 mg (55%); colorless solid; mp 130 ˚C.

IR (KBr): 3249, 1612 cm-¹.

¹H NMR (CDCl3): δ = 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, ArCH 2), 6.19 (s, 1 H, NH), 6.94-7.42 (m, 4 H, ArH), 8.96 (s, 1 H, ArH).

¹³C NMR (CDCl3): δ = 6.5, 28.4, 45.6, 115.9 (d, ² J C,F = 21.4 Hz), 129.8 (d, ³ J C,F = 7.6 Hz), 134.6, 152.3, 153.2, 161.7, 162.6 (d, ¹ J C,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)-3 H -[1,2,3]triazolo[4,5- d ]pyrimidin-5-amine (5e)

Yield: 448 mg (59%); colorless solid; mp 192 ˚C.

IR (KBr): 3246, 1614 cm-¹.

¹H NMR (CDCl3): δ = 4.66 (d, J = 5.6 Hz, 2 H, ArCH2), 5.63 (s, 2 H, ArCH 2), 6.05 (s, 1 H, NH), 6.96-7.41 (m, 9 H, ArH), 9.01 (s, 1 H, ArH).

¹³C NMR (CDCl3): δ = 45.2, 49.8, 115.5 (d, ² J C,F = 21.1 Hz), 128.4, 128.4, 128.8, 129.3 (d, ³ J C,F = 8.3 Hz), 135.0, 152.9.

Anal. Calcd for C18H15FN6: C, 64.66; H, 4.52; N, 25.13. Found: C, 64.49; H, 4.80; N, 25.04.

3-Benzyl- N -phenyl-3 H -[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): δ = 5.72 (s, 2 H, ArCH 2), 7.10-7.69 (m, 10 H, ArH), 7.72 (s, 1 H, NH), 9.14 (s, 1 H, ArH).

¹³C NMR (CDCl3): δ = 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.

Anal. Calcd for C17H14N6: C, 67.54; H, 4.67; N, 27.80. Found: C, 67.15; H, 4.74; N, 27.60.

N -Cyclopropyl-3-phenyl-3 H -[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): δ = 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): δ = 7.3, 24.4, 120.5, 127.7, 129.4, 132.4, 136.6, 150.6, 152.9, 162.6.

Anal. Calcd for C13H12N6: C, 61.89; H, 4.79; N, 33.31. Found: C, 61.87; H, 4.88; N, 33.14.

    References

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    References

  • 1 Kelley JL. Davis RG. McLean EW. Glen RC. Soroko FE. Cooper BR. J. Med. Chem.  1995,  38:  3884 
    CrossrefSearch in Google Scholar
  • 2 Betti L. Biagi G. Giannaccini G. Giorgi I. Livi O. Lucacchini A. Manera C. Scartoni V. J. Med. Chem.  1998,  41:  668 
    CrossrefSearch in Google Scholar
  • 3 Biagi G. Bianucci AM. Coi A. Costa B. Fabbrini L. Giorgi I. Livi O. Micco I. Pacchini F. Santini E. Leonardi M. Nofal FA. Salerni OL. Scartoni V. Bioorg. Med. Chem.  2005,  13:  4679 
    CrossrefSearch in Google Scholar
  • 4a Love CJ, Cooymans LP, and Vandermaesen N. inventors; (Janssen Pharmaceutica N.V., Belgium) Patent WO  2006075023.  ; Chem. Abstr. 2006, 145, 167273
  • 4b Lum C. Kahl J. Kessler L. Kucharski J. Lundstrom J. Miller S. Nakanishi H. Pei Y. Pryor K. Roberts E. Sebo L. Sullivan R. Urban J. Wang Z. Bioorg. Med. Chem. Lett.  2008,  18:  3578 
    Search in Google Scholar
  • 5 Dille KL. Sutherland ML. Christensen BE. J. Org. Chem.  1955,  20:  171 
    CrossrefSearch in Google Scholar
  • 6a Brown DJ. J. Appl. Chem.  1954,  4:  72 
    Search in Google Scholar
  • 6b Brown DJ. J. Appl. Chem.  1957,  7:  109 
    Search in Google Scholar
  • 6c Wiley RH. Lanet J. Hussung KH. J. Heterocycl. Chem.  1964,  1:  175 
    Search in Google Scholar
  • 6d Bacon RGR. Hamilton SD. J. Chem. Soc., Perkin Trans. 1  1974,  1970 
  • 6e Barlin GB. J. Chem. Soc. B  1967,  954 
  • For nucleophilic displacement of the SCN group, see:
  • 7a Takahashi T. Naito T. Inoue S. Chem. Pharm. Bull.  1958,  6:  334 
    Search in Google Scholar
  • 7b Naito T. Inoue S. Chem. Pharm. Bull.  1958,  6:  338 
    Search in Google Scholar
  • 8 Sugiura S. Suzuki E. Naito T. Inoue S. Chem. Pharm. Bull.  1968,  16:  745 
    CrossrefSearch in Google Scholar
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Figure 1 Selected biologically active 3-substituted 3H-[1,2,3]triazolo[4,5-d]pyrimidines

Scheme 1 Synthesis of N,3-substituted 3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amines 5a-g