Synthesis of Novel N-1 (Allyloxymethyl) Analogues
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 26 5725
CH2)C), 5.16 (s, 2H, NCH2O), 7.12 (d, 2H, J ) 7.3 Hz, aryl),
7.26-7.39 (m, 3H, aryl), 11.36 (s, 1H, NH); 13C NMR (CDCl3):
δ 19.45 (CH2dCCH3), 20.39 (CH(CH3)2), 28.30 (CH(CH3)2),
33.46 (CH2Ph), 72.85 (OCH2N), 73.54 (CCH2O), 112.51 (CH2)),
119.80 (C5), 127.23, 129.20, 135.32 (aryl), 141.26, (CH2C)),
148.45 (C6), 151.97 (C2), 162.50 (C4); MS m/z 328 (M+). Anal.
(C19H24N2O3‚0.25H2O) C, H, N.
1-(Allyloxym e t h yl)-6-(3,5-d im e t h ylb e n zyl)-5-e t h yl-
u r a cil (12). Yield 514 mg (55%); mp 115-116 °C; 1H NMR
(DMSO-d6): δ 0.91 (t, 3H, J ) 7.3 Hz, CH2CH3), 2.24 (s, 6H,
2 × CH3), 2.30 (q, 2H, J ) 7.2 Hz, CH2CH3), 4.01 (s, 2H, OCH2-
CH)), 4.03 (s, 2H, CH2Ph), 5.04 (s, 2H, NCH2O), 5.17 (m, 2H,
dCH2), 5.84 (m, 1H, CH)), 6.78-6.88 (m, 3H, aryl), 11.47 (s,
1H, NH); 13C NMR (DMSO-d6): δ 13.46 (CH2CH3), 18.48 (CH2-
CH3), 20.75 (2 × CH3), 32.78 (CH2Ph), 69.26 (OCH2CH)),
72.00 (OCH2N), 115.58 (C5), 116.90 (CH2)), 138.10, 135.98,
134.40, 128.39, 125.04 (aryl, CH)), 148.47 (C2), 151.67 (C6),
163.16 (C4); MS m/z 328 (M+). Anal. (C19H24N2O3‚0.25H2O) C,
H, N.
6-(3,5-Dim eth ylben zyl)-5-eth yl-1-(3-m eth ylbu t-2-en yl-
oxym eth yl)u r a cil (13). Yield 310 mg (29%); mp 136-138 °C;
1H NMR (CDCl3): δ 1.08 (t, 3H, J ) 7.4 Hz, CH2CH3), 1.66,
1.74 (2 × s, 6H, CdC(CH3)2), 2.28 (s, 6H, 2 × CH3), 2.48 (q,
2H, J ) 7.4 Hz, CH2CH3), 4.09 (m, 4H, CH2Ph, OCH2CH)),
5.13 (s, 2H, NCH2O), 5.31 (t, 1H, J ) 7.0 Hz, OCH2CH)), 6.70
(s, 2H, aryl), 6.90 (s, 1H, aryl), 9.68 (s, 1H, NH); 13C NMR
(CDCl3): δ 13.76 (CH2CH3), 19.10 (CH2CH3), 18.02, 25.77 (2
× dCCH3), 21.23 (2 × CH3), 33.19 (CH2Ph), 65.99 (OCH2CH)),
72.54 (OCH2N), 116.74 (C5), 120.03 (OCH2CH)), 124.99,
128.88, (aryl), 134.94, ((CH3)2C)), 138.23, 138.79 (aryl), 149.22
(C2), 151.93 (C6), 163.50 (C4); MS m/z 356 (M+). Anal.
(C21H28N2O3‚0.1H2O) C, H, N.
6-(3,5-Dim eth ylben zyl)-5-eth yl-1-(2-m eth yla llyloxym e-
th yl)u r a cil (14). Yield 120 mg (13%); mp 142-144 °C; 1H
NMR (CDCl3): δ 1.08 (t, 3H, J ) 7.4 Hz, CH2CH3), 1.73 (s,
3H, CH2dCCH3), 2.29 (s, 6H, 2 × CH3), 2.51 (q, 2H, J ) 7.4
Hz, CH2CH3), 4.03, 4.10 (2 × s, 4H, CH2Ph, OCH2C), 4.90, 4.98
(2 × s, 2H, CH2)C), 5.16 (s, 2H, NCH2O), 6.71 (s, 2H, aryl),
6.91 (s, 1H, aryl), 9.58 (s, 1H, NH); 13C NMR (CDCl3): δ 13.74
(CH2CH3), 19.12 (CH2CH3), 19.45 (CH2dCCH3), 21.25 (2 ×
CH3), 33.22 (CH2Ph), 72.74 (OCH2N), 73.56 (OCH2CH)),
112.47 (CH2)C), 116.81 (C5), 124.99, 128.94, (aryl), 134.89,
138.87 (aryl), 141.29 (CH2C)), 149.34, (C2), 151.96 (C6),
164.91 (C4); MS m/z 342 (M+). Anal. (C20H26N2O3‚0.1H2O) C,
H, N.
7.4 Hz, CH2CH3), 4.07 (s, 2H, CH2Ph), 4.28 (d, 2H, J ) 2.4
Hz, OCH2Ct), 5.20 (s, 2H, OCH2N), 6.71 (s, 2H, aryl), 6.90 (s,
1H, aryl), 9.49 (s, 1H, NH); 13C NMR (CDCl3): δ 13.78
(CH2CH3), 19.14 (CH2CH3), 21.25 (2 × CH3), 33.25 (CH2Ph),
57.22 (OCH2Ct), 72.56 (OCH2N), 74.64 (HCtC), 79.11 (HCt
C), 116.97 (C5), 125.01, 129.00, 134.74, 138.89 (aryl), 149.16
(C6), 152.01 (C2), 163.32 (C4). HRMS-MALDI (M + Na+), calcd
for C19H22N2O3Na, 349.1523; found, 349.1521.
1-Allyloxym et h yl-5-et h yl-6-(n a p h t h a len -1-ylm et h yl)-
u r a cil (16). Yield 253 mg (72%); mp 119-123 °C; 1H NMR
(DMSO-d6): δ 0.90 (t, 3H, J ) 7.4 Hz, CH2CH3), 2.27 (q, 2H,
J ) 7.4 Hz, CH2CH3), 3.97 (dd, 2H, J ) 4.3, 1.4 Hz, OCH2-
CH)), 4.52 (s, 2H, CH2Naph), 4.96 (s, 2H, NCH2O), 5.12 (m,
2H, dCH2), 5.76 (m, 1H, CH)), 7.11-8.21 (m, 7H, Naph),
11.54 (s, 1H, NH); 13C NMR (DMSO-d6): δ 13.49 (CH2CH3),
18.50 (CH2CH3), 30.19 (CH2Naph), 69.24 (OCH2CH)), 72.21
(OCH2N), 116.13 (C5), 116.96 (CH2)), 123.12, 123.68, 125.84,
126,26, 126.71, 127.49, 128.79, 130.96, 131.95, 133.44, 134.27
(Naph, CH)), 148.50 (C2), 151.72 (C6), 163.11 (C4); MS m/z
350 (M+). Anal. (C21H22N2O3‚0.5 H2O) C, H, N.
5-Eth yl-1-(3-m eth ylbu t-2-en yloxym eth yl)-6-(n a p h th a -
len -1-ylm eth yl)u r a cil (17). Yield 276 mg (73%); mp 179-
181 °C; 1H NMR (CDCl3): δ 1.03 (t, 3H, J ) 7.3 Hz, CH2CH3),
1.62, 1.65 (2 × s, 6H, CdC(CH3)2), 2.39 (q, 2H, J ) 7.3 Hz,
CH2CH3), 4.06 (d, 2H, J ) 6.9 Hz, OCH2CH), 4.55 (s, 2H, CH2-
Naph), 5.04 (s, 2H, NCH2O), 5.23 (t, 1H, J ) 7.0 Hz,
OCH2CH)), 7.02-8.08 (m, 7H, Naph), 9.84 (s, 1H, NH); 13C
NMR (CDCl3): δ 13.73 (CH2CH3), 18.00 (CH3), 19.10 (CH2CH3),
25.64 (CH3), 30.41 (CH2Naph), 66.07 (OCH2CH)), 72.70
(OCH2N), 117.36 (C5), 119.96 (OCH2CH)), 122.57, 123.42,
125.53, 126.19, 126.70, 127.98, 128.96, 131.03, 131.21, 133.80
(Naph), 138.13, ((CH3)2C)), 149.29 (C6), 151.92 (C2), 163.33
(C4); MS m/z 378 (M+). Anal. (C23H26N2O3‚0.75 H2O) C, H, N.
5-E t h yl-1-(2-m et h yla llyloxym et h yl)-6-(n a p h t h a len -1-
ylm eth yl)u r a cil (18). Yield 258 mg (71%); mp121-123 °C;
1H NMR (CDCl3): δ 1.04 (t, 3H, J ) 7.3 Hz, CH2CH3), 1.70 (s,
3H, CH2dCCH3), 2.40 (q, 2H, J ) 7.3 Hz, CH2CH3), 4.01 (s,
2H, OCH2C), 4.57 (s, 2H, CH2Naph), 4.86, 4.94 (2 × s, 2H,
CH2)C), 5.07 (s, 2H, NCH2O), 7.03-8.08 (m, 7H, Naph), 9.84
(s, 1H, NH); 13C NMR (CDCl3): δ 13.73 (CH2CH3), 19.13 (CH2-
CH3), 19.41 (CH2dCCH3), 30.31 (CH2Naph), 72.94 (OCH2N),
73.54 (OCH2CH)), 112.43 (CH2dC), 117.46 (C5), 122.49,
123.49, 125.56, 126.23, 126.74, 128.06, 129.01, 130.92, 131.22,
133.84 (Naph), 141.18 (CH2C)), 149.25, (C6), 152.00 (C2),
163.37 (C4); MS m/z 364 (M+). Anal. (C22H24N2O3‚0.25 H2O)
C, H, N.
1-(Allyloxym eth yl)-6-(3,5-d im eth ylben zyl)-5-isop r op yl-
u r a cil (19). Yield 245 mg (72%); mp 104-105 °C; 1H NMR
(CDCl3): δ 1.29 (d, 6H, J ) 6.7 Hz, CH(CH3)2), 2.29 (s, 6H, 2
× CH3), 2.82 (sep, 1H, J ) 6.7 Hz, CH(CH3)2), 4.11-4.14 (m,
4H, OCH2CH, CH2Ph), 5.16 (s, 2H, NCH2O), 5.21-5.33 (m,
2H, dCH2) 5.81-5.92 (m, 1H, CH)) 6.71 (s, 2H, aryl), 6.90 (s,
1H, aryl), 9.47 (s, 1H, NH); 13C NMR (CDCl3): δ 20.41 (CH-
(CH3)2), 21.26 (2 × CH3), 28.34 (CH(CH3)2), 33.35 (CH2Ph),
70.52 (OCH2CH)), 72.72 (OCH2N), 117.66 (CH2)), 119.68
(C5), 125.01, 128.84, 133.69, 138.83 (aryl), 135.01 (CH)),
148.72 (C6), 152.04 (C2), 162.53 (C4); MS m/z 342 (M+). Anal.
(C20H26N2O3) C, H, N.
6-(3,5-Dim et h ylb en zyl)-5-isop r op yl-1-(3-m et h ylb u t -2-
en yloxym eth yl)u r a cil (20). Yield 240 mg (65%); mp 133-
134 °C; 1H NMR (CDCl3): δ 1.29 (d, 6H, J ) 6.9 Hz, CH(CH3)2),
1.66, 1.74 (2 × s, 6H, CdC(CH3)2), 2.28 (s, 6H, 2 × CH3), 2.84
(sep, 1H, J ) 6.9 Hz, CH(CH3)2), 4.09-4.10 (m, 4H, OCH2CH,
CH2Ph), 5.14 (br.s, 2H, NCH2O), 5.31 (t, 1H, J ) 6.4 Hz,
OCH2CH)), 6.70 (s, 2H, aryl), 6.89 (s, 1H, aryl), 9.47 (s, 1H,
NH). 13C NMR (CDCl3); δ 18.03, 25.80 (CdC(CH3)2) 20.41 (CH-
(CH3)2), 21.25 (2 × CH3), 28.30 (CH(CH3)2), 33.27 (CH2Ph),
65.99 (OCH2CH)), 72.67 (OCH2N), 119.57 (C5), 120.06
(OCH2CH)), 125.00, 128.78, 135.08, 138.75 (aryl), 138.23
((CH3)2C)), 148.80 (C6), 151.94 (C2), 162.51 (C4); MS m/z 370
(M+). Anal. (C22H30N2O3‚0.5 H2O) C, H, N.
Acyclic Ur a cil Der iva tives 11, 15-21. Gen er a l P r oce-
d u r e. The appropriate uracil 7 (1 mmol) was stirred in dry
CH3CN (15 mL) under N2, and N,O-bis(trimethylsilyl)aceta-
mide (BSA) (0.87 mL, 3.5 mmol) was added. The mixture
became clear after stirring at room temperature for 10 min.
The reaction mixture was cooled to -50 °C and TMS triflate
(0.18 mL, 1 mmol) was added followed by dropwise addition
of the appropriate acetal (2 mmol). The reaction mixture was
stirred at room temperature for 3 h, quenched with ice-cold
saturated solution of NaHCO3 (5 mL), and evaporated under
reduced pressure. The residue was extracted with Et2O (3 ×
50 mL), and the combined organic fractions were dried
(MgSO4), evaporated under reduced pressure, and chromato-
graphed on silica gel with CHCl3 to afford the product.
6-Ben zyl-5-isop r op yl-1-(p r op -2-yn yloxym eth yl)u r a cil
1
(11). Yield 180 mg (58%); mp 103-104 °C; H NMR (CDCl3):
δ 1.29 (d, 6H, J ) 6.9 Hz, CH(CH3)2), 2.44 (t, 1H, J ) 2.3 Hz,
tCH), 2.85 (sep, 1H, J ) 6.9 Hz, CH(CH3)2), 4.18 (s, 2H, CH2-
Ph), 4.29 (d, 2H, J ) 2.3 Hz, OCH2Ct), 5.21 (s, 2H, NCH2O),
7.11-7.37 (m, 5H, aryl), 9.34 (s, 1H, NH); 13C NMR (CDCl3):
δ 20.40 (CH(CH3)2), 28.32 (CH(CH3)2), 33.48 (CH2Ph), 57.18
(OCH2Ct), 72.64 (OCH2N), 74.72 (HCtC), 79.05 (HCtC),-
119.98 (C5), 127.25, 127.29, 129.21, 135.15 (aryl), 148.25 (C6),
151.97 (C2), 162.31 (C4); HRMS-MALDI (M + H+) calcd for
C
18H21N2O3, 313.1547; found, 313.1552.
6-(3,5-Dim et h ylb en zyl)-5-et h yl-1-(p r op -2-yn yloxym e-
th yl)u r a cil (15). Yield 195 mg (60%); mp 154-156 °C; 1H
NMR (CDCl3): δ 1.06 (t, 3H, J ) 7.4 Hz, CH2CH3), 2.28 (s,
6H, 2 × CH3), 2.44 (t, 1H, J ) 2.5 Hz, dCH), 2.45 (q, 2H, J )
6-(3,5-Dim et h ylb en zyl)-5-isop r op yl-1-(2-m et h yla llyl-
oxym eth yl)u r a cil (21). Yield 356 mg (67%); mp 137-139 °C;
1H NMR (CDCl3): δ 1.29 (d, 6H, J ) 6.9 Hz, CH(CH3)2), 1.73