PAPER
Novel 5-(N-Alkylaminouracil) Acyclic Nucleosides
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J = 6.6 Hz, 1 H, H-4¢), 10.07 (d, J = 4.2 Hz, 1 H, NH-1), 11.24 (s,
1 H, NH-3).
13C NMR (75.5 MHz, DMSO-d6): d = 35.6, 111.4, 111.8, 114.3,
122.8, 130.0, 142.2, 149.4, 150.9, 160.1, 161.3.
13C NMR (75.5 MHz, DMSO-d6): d = 45.4, 113.2, 123.0, 127.0,
128.1, 130.0, 131.7, 139.1, 149.4, 161.3.
Anal. Calcd for C11H9F2N3O2: C, 52.18; H, 3.58; N, 16.60. Found:
C, 52.34; H, 3.39; N, 16.55.
Anal. Calcd for C11H9Cl2N3O2: C, 46.18; H, 3.17; N, 14.69. Found:
C, 46.13; H, 3.22; N, 14.44.
1-(2¢-Acetoxyethoxymethyl)-5-(benzylamino)uracil (9a); Typi-
cal Procedure
A suspension of 5-benzylaminouracil (8a; 0.11 g, 0.5 mmol),
(NH4)2SO4 (2 mg) and HMDS (0.43 mL, 2.0 mmol) in anhydrous
MeCN (5 mL) was heated at reflux for 12 h. The reaction mixture
was cooled to r.t. and 2-chloromethoxyethyl acetate (2; 0.16 g, 1.0
mmol) in anhydrous MeCN (0.5 mL) was added. The reaction mix-
ture was stirred at r.t. for 24 h then quenched by pouring into 5% aq
NaHCO3 (15 mL) and extracted with EtOAc (4 × 10 mL). The com-
bined organic extracts were dried over Na2SO4 and evaporated to
give an oily residue. The product was isolated by silica gel column
chromatography (MeOH–CHCl3, 3%).
5-(2¢,4¢-Dichlorobenzylamino)uracil (8c)
Prepared as described above with 5-bromouracil (0.20 g, 1.05
mmol) and 2,4-dichlorobenzylamine (6c; 0.70 g, 4.0 mmol).
Yield: 0.18 g (62%); white solid; mp 296–299 °C.
1H NMR (300 MHz, DMSO-d6): d = 4.14 (d, J = 6.3 Hz, 2 H, H-1¢),
5.12 (t, J = 6.3 Hz, 1 H, NH¢), 6.08 (s, 1 H, H-6), 7.32–7.41 (m, 2 H,
PhH), 7.51 (s, 1 H, PhH), 10.05 (br s, 1 H, NH-3), 11.16 (br s, 1 H,
NH-1).
13C NMR (75.5 MHz, DMSO-d6): d = 44.4, 113.2, 122.9, 127.4,
128.6, 129.9, 132.0, 133.0, 135.4, 149.3, 161.2.
Yield: 0.09 g (51%); white solid; mp 107–110 °C.
1H NMR (300 MHz, CDCl3): d = 1.99 (s, 3 H, CH3), 3.60–3.63 (m,
2 H, CH2), 4.06–4.09 (m, 4 H, CH2, H-1¢), 4.40 (br s, 1 H, NH¢¢¢),
5.05 (s, 2 H, H-1¢¢), 6.14 (s, 1 H, H-6), 7.19–7.30 (m, 5 H, PhH),
9.89 (br s, 1 H, NH-3).
13C NMR (75 MHz, CDCl3): d = 20.9, 48.3, 63.1, 67.2, 76.8, 113.9,
125.6, 127.5, 127.8, 128.9, 137.5, 149.6, 160.9, 170.9.
Anal. Calcd for C11H9Cl2N3O2: C, 46.18; H, 3.17; N, 14.69. Found:
C, 45.98; H, 3.06; N, 14.79.
5-(3¢,4¢-Dichlorobenzylamino)uracil (8d)
Prepared as described above with 5-bromouracil (1; 0.2 g, 1.05
mmol) and 3,4-dichlorobenzylamine (6d; 0.70 g, 4.0 mmol).
Yield: 0.23 g (76%); white solid; mp 276–279 °C.
Anal. Calcd for C16H19N3O5: C, 57.65; H, 5.75; N, 14.61. Found: C,
57.28; H, 5.82; N, 14.50.
1H NMR (300 MHz, DMSO-d6): d = 4.10 (d, J = 6.3 Hz, 2 H, H-1¢),
5.21 (t, J = 6.3 Hz, 1 H, NH¢), 6.13 (s, 1 H, H-6), 7.30 (dd, J = 1.8,
8.4 Hz, 1 H, PhH), 7.55–7.57 (m, 2 H, PhH), 10.03 (br s, 1 H, NH-
3), 11.15 (br s, 1 H, NH-1).
13C NMR (75 MHz, DMSO-d6): d = 45.5, 113.2, 122.9, 127.4,
129.1, 129.2, 130.4, 130.9, 141.0, 149.2, 161.2.
1-(2¢-Acetoxyethoxymethyl)-5-(2¢¢,4¢¢-dichlorobenzylami-
no)uracil (9c)
Prepared as described above with 5-(2,4-dichlorobenzylami-
no)uracil (8c; 0.10 g, 0.35 mmol).
Yield: 0.07 g (50%); waxy yellow solid.
Anal. Calcd for C11H9Cl2N3O2: C, 46.18, H, 3.17; N, 14.69. Found:
C, 46.55; H, 3.01; N, 14.54.
1H NMR (300 MHz, CDCl3): d = 2.06 (s, 3 H, CH3), 3.71–3.74 (m,
2 H, CH2), 4.16–4.24 (m, 4 H, CH2, H-1¢), 4.60 (br s, 1 H, NH¢¢),
5.13 (s, 2 H, H-1¢¢), 6.20 (s, 1 H, H-6), 7.23 (dd, J = 2.4, 8.4 Hz, 1 H,
PhH), 7.30 (d, J = 8.4 Hz, 1 H, PhH), 7.41 (d, J = 2.4 Hz, 1 H, PhH),
10.11 (br s, 1 H, NH-3).
13C NMR (75 MHz, CDCl3): d = 20.9, 45.3, 63.1, 67.3, 76.8, 114.3,
125.2, 127.5, 129.6, 129.7, 133.6, 134.0, 134.1, 149.6, 160.8, 170.9.
5-(2¢,4¢-Difluorobenzyloamino)uracil (8e)
Prepared as described above with 5-bromouracil (1; 0.22 g, 1.15
mmol) and 2,4-difluorobenzylamine (6e; 0.60 g, 4.2 mmol).
Yield: 0.23 g (93%); grey solid; mp 304–305 °C.
1H NMR (300 MHz, DMSO-d6): d = 4.11 (d, J = 6.0 Hz, 2 H, H-1¢),
4.91 (t, J = 6.0 Hz, 1 H, NH¢), 6.21 (d, J = 2.7 Hz, 1 H, H-6), 7.01–
7.07 (m, 1 H, PhH), 7.14–7.22 (m, 1 H, PhH), 7.34–7.43 (m, 1 H,
PhH), 10.09 (br s, 1 H, NH-3), 11.16 (br s, 1 H, NH-1).
13C NMR (75 MHz, DMSO-d6): d = 40.2, 103.6 (t, JC–F = 25.9 Hz),
111.3 (dd, JC–F = 3.6, 21.0 Hz), 113.2, 122.2 (dd, JC–F = 3.6,
15.0 Hz), 122.9, 130.4 (dd, JC–F = 6.3, 9.7 Hz), 149.3, 160.1 (dd,
JC–F = 12.3, 246 Hz), 161.2, 161.3 (dd, JC–F = 12.2, 245.2 Hz).
MS (EI, 70 eV): m/z (%) = 403 (14) [M]+, 401 (21) [M]+, 87 (100).
1-(2¢-Acetoxyethoxymethyl)-5-(2¢¢,4¢¢-difluorobenzylami-
no)uracil (9e)
Prepared as described above with 5-(2,4-dichlorobenzylami-
no)uracil (8e; 0.10 g, 0.40 mmol).
Yield: 0.05 g (33%); waxy yellow solid.
1H NMR (300 MHz, CDCl3): d = 2.06 (s, 3 H, CH3), 3.70–3.74 (m,
2 H, CH2), 4.15–4.18 (m, 4 H, CH2, H-1¢), 4.47 (br s, 1 H, NH¢¢),
5.13 (s, 2 H, H-1¢¢), 6.30 (s, 1 H, H-6), 6.80–6.90 (m, 2 H, PhH),
7.29 (m, 1 H, PhH), 10.86 (br s, 1 H, NH-3).
MS (EI, 60 eV): m/z (%) = 253 (16) [M]+, 127 (100).
Anal. Calcd for C11H9F2N3O2: C, 52.18; H, 3.58; N, 16.60. Found:
C, 51.56; H, 3.47; N, 16.27.
13C NMR (75 MHz, CDCl3): d = 20.6, 40.9 (d, JC–F = 3.6 Hz), 62.8,
66.8, 76.4, 103.7 (t, JC–F = 25.5 Hz), 111.2 (dd, JC–F = 3.7, 21.1 Hz),
114.0, 120.5 (dd, J = 3.8 Hz, JC–F = 14.9 Hz), 124.8, 130.4 (dd,
JC–F = 5.9, 9.6 Hz), 149.4, 160.5 (dd, JC–F = 11.9, 248.7 Hz), 160.7,
162.1 (dd, JC–F = 11.9, 248.5 Hz).
5-(2¢,6¢-Difluorobenzylamino)uracil (8f)
5-Bromouracil (1; 1.16 mmol, 0.22 g), 2,6-difluorobenzylamine
(6f; 3.5 mmol, 0.50 g) and n-butanol (5 mL) were mixed and heated
to reflux. After 6 h, the reaction mixture was cooled and dried under
vacuum. The residue was recrystallised form glacial AcOH (8 mL)
containing a few drops of H2O.
MS (EI, 70 eV): m/z (%) = 369 (34) [M]+, 127 (100).
Yield: 0.06 g (20%); white crystalline powder; mp 276–278 °C.
1-(2¢-Acetoxyethoxymethyl)-5-bromouracil (4)
1H NMR (300 MHz, DMSO-d6): d = 4.13 (d, J = 5.4 Hz, 2 H, CH2),
4.41 (d, J = 6.0 Hz, 1 H, NH), 6.50 (d, J = 5.7 Hz, 1 H, H-6), 7.10
(t, J = 8.1 Hz, 2 H, H-3¢,5¢), 7.40 (quint, J = 8.4 Hz, 1 H, H-4¢),
10.23 (d, J = 4.5 Hz, NH-1), 11.53 (s, 1 H, NH-3).
The product was obtained through a modified method described in
the literature.21 To a suspension of 5-bromouracil (1; 1.91 g, 10
mmol) in anhydrous MeCN (30 mL), BSA (3 mL, 12 mmol) was
added. The reaction mixture was stirred for 12 h until the suspension
Synthesis 2011, No. 4, 603–610 © Thieme Stuttgart · New York