M. Shekouhy, et al.
Bioorganic&MedicinalChemistry28(2020)115540
an eluent, Rf = 0.58), Isolated Yield: 84%, M.P. = 149–152 °C. υmax (KBr)
1080, 1234, 1419, 1515, 1620, 1712, 2630, 2738, 2823, 2845, 2927,
840, 1307, 1508, 1604, 1670, 2233, 2958, 3120, 3294 cm−1
.
1H NMR
3030, 3101, 3427 cm−1
.
1H NMR (250 MHz, DMSO‑d6): δ (ppm)
(250 MHz, DMSO‑d6): δ (ppm) 1.76–1.95 (m, 4H), 3.94 (t, J = 6.3 Hz,
2H), 4.15 (t, J = 6.3 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 7.39 (s, 2H), 7.61
(d, J = 8.4 Hz, 2H), 8.14 (s, 1H), 8.29 (s, 1H). 13C NMR (62.5 MHz,
DMSO‑d6): δ (ppm) 25.7, 25.9, 43.0, 67.1, 103.4, 114.3, 118.0, 118.4,
132.9, 139.6, 148.6, 151.9, 155.0, 159.1. Anal. Calcd for C16H16N6O: C,
62.32; H, 5.23; N, 27.26%. Found: C, 61.99; H, 5.17; N, 27.51%.
2.20–2.30 (m, 2H), 4.03 (t, J = 6.5 Hz, 2H), 4.13 (t, J = 6.5 Hz, 2H),
5.18 (d, J = 6.4 Hz, 1H), 6.85 (d, J = 7.6 Hz, 2H), 7.14 (d, J = 6.4 Hz,
1H), 7.76 (d, J = 7.6 Hz, 2H), 10.50 (s, 1H). 13C NMR (62.5 MHz,
DMSO‑d6): δ (ppm) 28.2, 44.2, 66.1, 101.6, 113.9, 122.0, 127.0, 146.4,
152.0, 154.2, 159.9. 165.1. Anal. Calcd for C14H14N6O3: C, 53.50; H,
4.49; N, 26.74%. Found: C, 53.61; H, 4.33; N, 26.86%. MS (m/z): 314
(M+).
4.1.3.12. 4-(4-(2-Amino-6-oxo-1,6-dihydro-9H-Purine-9-yl)butoxy)
benzonitrile (5 l). White solid, Purified with column chromatography
usinf n-hexane/EtOAc 1:1 as an eluent, Rf = 0.50), Isolated Yield: 69%,
M.P. = 148–149 °C. υmax (KBr) 837, 1103, 1284, 1508, 1612, 2233,
4.1.4.2. 2-(3-(4-(1H-Tetrazol-5-yl)phenoxy)propyl)-1,2,4-triazine-3,5
(2H, 4H)-dione (6b). White solid, M.P. = 212–213 °C. υmax (KBr) 840,
1018, 1265, 1404, 1450, 1651, 2700, 2800, 2854, 2916, 3039, 3155,
3460 cm−1. 1H NMR (250 MHz, DMSO‑d6): δ (ppm) 2.10–2.21 (m, 2H),
3.99 (t, J = 6.7 Hz, 2H), 4.28 (t, J = 6.7 Hz, 2H), 6.79 (d, J = 7.5 Hz,
2H), 7.28 (s, 1H), 7.71 (d, J = 7.5 Hz, 2H), 10.45 (s, 1H). 13C NMR
(62.5 MHz, DMSO‑d6): δ (ppm) 28.3, 43.0, 66.3, 114.2, 122.2, 127.2,
135.9, 147.7, 154.5, 157.0, 160.2. Anal. Calcd for C13H13N7O3: C,
49.52; H, 4.16; N, 31.10%. Found: C, 49.68; H, 4.18; N, 30.98%.
2947, 3078, 3290 cm−1
.
1H NMR (250 MHz, DMSO‑d6): δ (ppm)
1.77–1.93 (m, 4H), 3.94 (t, J = 6.1 Hz, 2H), 4.14 (t, J = 6.1 Hz, 2H),
6.58 (s, 2H), 6.87 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 7.92 (s,
1H), 10.58 (s, 1H). 13C NMR (62.5 MHz, DMSO‑d6): δ (ppm) 25.2, 25.5,
41.2, 66.7, 103.0, 113.8, 115.8, 117.6, 132.4, 136.7, 150.3, 152.3,
155.8, 158.6. Anal. Calcd for C16H16N6O2: C, 59.25; H, 4.97; N,
25.91%. Found: C, 59.42; H, 5.26; N, 25.98%.
4.1.4.3. 2-((3-(4-(1H-Tetrazol-5-yl)phenoxy)propyl)thio)pyrimidin-4
4.1.3.13. 4-(4-(1,3-Dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-Purine-7-
yl)butoxy)benzonitrile (5 m). White solid, Purified with column
chromatography usinf n-hexane/EtOAc 1:1 as an eluent, Rf = 0.67),
Isolated Yield: 89%, M.P. = 131–133 °C. υmax (KBr) 837, 1188, 1284,
(3H)-one (6c). White solid, M.P. = 170–172 °C. υmax (KBr) 833, 1172,
1450, 1519, 1620, 2710, 2835, 2875, 2923, 3047, 3150, 3425 cm−1
.
1H NMR (250 MHz, DMSO‑d6): δ (ppm) 1.73–1.83 (m, 2H), 3.25 (t,
J = 6.5 Hz, 2H), 4.20 (t, J = 6.5 Hz, 2H), 6.10 (d, J = 6.5 Hz, 1H),
6.66 (d, J = 7.5 Hz, 2H), 7.66 (d, J = 7.4 Hz, 2H), 7.84 (d, J = 6.5 Hz,
1H), 10.16 (s, 1H). 13C NMR (62.5 MHz, DMSO‑d6): δ (ppm) 25.5, 29.8,
67.5, 102.5, 111.7, 115.2, 124.8, 146.3, 149.3, 156.4, 157.8, 165.8.
Anal. Calcd for C14H14N6O2S: C, 50.90; H, 4.27; N, 25.44%. Found: C,
50.99; H, 4.41; N, 25.55%. MS (m/z): 330 (M+).
1666, 1716, 2233, 2970, 3089 cm−1
.
1H NMR (250 MHz, DMSO‑d6): δ
(ppm) 1.77–1.91 (m, 4H), 3.19 (s, 3H), 3.40 (s, 3H), 3.93 (t, J = 6.2 Hz,
2H), 4.03 (t, J = 6.2 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 7.59 (d,
J = 8.6 Hz, 2H), 7.99 (s, 1H). 13C NMR (62.5 MHz, DMSO‑d6): δ (ppm)
24.4, 24.6, 26.4, 26.6, 44.0, 65.8, 102.1, 105.0, 113.0, 116.7, 131.6,
139.1, 146.4, 149.4, 152.5, 157.8. Anal. Calcd for C18H19N5O3: C,
61.18; H, 5.42; N, 19.82%. Found: C, 60.62; H, 5.81; N, 20.13%.
4.1.4.4. 9-(3-(4-(1H-Tetrazol-5-yl)phenoxy)propyl)-9H-Purine-6-amine
(6d). White solid, M.P. = 229–231 °C. υmax (KBr) 840, 1249, 1419,
1604, 1666, 2630, 2692, 2720, 2831, 2950, 3041, 3103, 3294,
4.1.3.14. 4-(4-(3,7-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-Purine-1-
yl)butoxy)benzonitrile (5n). White solid, Purified with column
chromatography usinf n-hexane/EtOAc 1:1 as an eluent, Rf = 0.63),
Isolated Yield: 89%, M.P. = 145–147 °C. υmax (KBr) 837, 1222, 1685,
3407 cm−1
.
1H NMR (250 MHz, DMSO‑d6): δ (ppm) 2.18–2.28 (m,
2H), 4.00 (t, J = 6.0 Hz, 2H), 4.26 (t, J = 6.0 Hz, 2H), 6.83 (d,
J = 7.1 Hz, 2H), 7.30 (s, 2H), 7.82 (d, J = 7.1 Hz, 2H), 8.13 (s, 1H),
8.25 (s, 1H). 13C NMR (62.5 MHz, DMSO‑d6): δ (ppm) 27.5, 42.6, 65.6,
113.4, 118.1, 121.5, 126.5, 140.9, 148.2, 151.6, 153.8, 154.6, 156.5.
Anal. Calcd for C15H15N9O: C, 53.41; H, 4.48; N, 37.37%. Found: C,
53.59; H, 4.39; N, 37.52%.
2233, 2823, 3024 cm−1
.
1H NMR (250 MHz, DMSO‑d6): δ (ppm)
1.75–1.96 (m, 4H), 3.31 (s, 3H), 3.81 (s, 3H), 3.95 (t, J = 6.2 Hz, 2H),
4.14 (t, J = 6.2 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 7.61 (d, J = 8.8 Hz,
2H), 7.95 (s, 1H). 13C NMR (62.5 MHz, DMSO‑d6): δ (ppm) 25.73,
25.76, 32.6, 34.0, 40.3, 66.9, 103.2, 106.7, 114.1, 117.8, 132.7, 141.2,
147.8, 150.5, 154.3, 158.8. Anal. Calcd for C18H19N5O3: C, 61.18; H,
5.42; N, 19.82%. Found: C, 60.86; H, 5.65; N, 20.09%.
4.1.4.5. 9-(3-(4-(1H-Tetrazol-5-yl)phenoxy)propyl)-2-amino-1,9-dihydro-
6H-Purine-6-one (6e). White solid, M.P. = 221–223 °C. υmax (KBr) 840,
1080, 1249, 1411, 1512, 1612, 2630, 2707, 2854, 2931, 3024, 3130,
4.1.4. General procedure for the synthesis of nucleobase-contained hybrids
of tetrazoles (6a-n)
3305, 3425 cm−1
.
1H NMR (250 MHz, DMSO‑d6): δ (ppm) 2.25–2.35
(m, 2H), 4.10 (t, J = 6.2 Hz, 2H), 4.28 (t, J = 6.2 Hz, 2H), 6.66 (s, 2H),
6.79 (d, J = 7.4 Hz, 2H), 7.70 (d, J = 7.4 Hz, 2H), 8.29 (s, 1H), 10.61
(s, 1H). 13C NMR (62.5 MHz, DMSO‑d6): δ (ppm) 28.0, 42.9, 65.9,
113.7, 116.3, 121.8, 126.8, 137.8, 150.2, 152.8, 154.0, 156.3, 159.7.
Anal. Calcd for C15H15N9O2: C, 50.99; H, 4.28; N, 35.68%. Found: C,
50.74; H, 4.12; N, 35.82%.
To a 250 mL round-bottomed flask was added the nucleobase-con-
tained nitrile (5a-n) (20 mmol), sodium azide (30 mmol, 1.95 g), zinc
bromide (4.50 g, 20 mmol), and 40 mL of water. The reaction mixture was
refluxed for 24 h. (Vigorous stirring is essential). HCl (3 N, 30 mL) and
ethyl acetate (100 mL) were added, and vigorous stirring was continued
until no solid was present and the aqueous layer had a pH of 1. If ne-
cessary, additional ethyl acetate was added. The organic layer was isolated
and the aqueous layer extracted with 2 × 100 mL of ethyl acetate. The
combined organic layers were evaporated, 200 mL of 0.25 N NaOH was
added, and the mixture was stirred for 30 min, until the original pre-
cipitate was dissolved and a suspension of zinc hydroxide was formed. The
suspension was filtered, and the solid washed with 20 mL of 1 N NaOH. To
the filtrate was added 40 mL of 3 N HCl with vigorous stirring causing the
tetrazole to precipitate. The tetrazole was filtered and washed with
2 × 20 mL of HCl (3 N) and dried in a drying oven to furnish the nu-
cleobase-contained hybrids of tetrazole (6a-n) as white solids.
4.1.4.6. 7-(3-(4-(1H-Tetrazol-5-yl)phenoxy)propyl)-1,3-dimethyl-3,7-
dihydro-1H-Purinee-2,6-dione (6f). White solid, M.P. = 238–241 °C.
υmax (KBr) 840, 1188, 1442, 1566, 1666, 2607, 2715, 2854, 2923,
3062, 3124, 3409 cm−1
.
1H NMR (250 MHz, DMSO‑d6): δ (ppm)
2.18–2.28 (m, 2H), 3.13 (s, 3H), 3.31 (s, 3H), 4.01 (t, J = 6.2 Hz, 2H),
4.31 (t, J = 6.2 Hz, 2H), 6.84 (d, J = 7.7 Hz, 2H), 7.79 (d, J = 7.7 Hz,
2H), 8.00 (s, 1H). 13C NMR (62.5 MHz, DMSO‑d6): δ (ppm) 27.8, 28.0,
28.1, 23.7, 66.0, 106.4, 113.9, 121.9, 126.9, 140.5, 147.8, 150.8,
153.9, 154.2, 159.9. Anal. Calcd for C17H18N8O3: C, 53.40; H, 4.74; N,
29.30%. Found: C, 53.69; H, 4.71; N, 29.29%.
4.1.4.1. 1-(3-(4-(1H-Tetrazol-5-yl)phenoxy)propyl)pyrimidine-2,4 (1H,
4.1.4.7. 1-(3-(4-(1H-Tetrazol-5-yl)phenoxy)propyl)-3,7-dimethyl-3,7-
3H)-dione (6a). White solid, M.P. = 189–191 °C. υmax (KBr) 840,
dihydro-1H-Purinee-2,6-dione (6 g). White solid, M.P. = 219–222 °C.
7