A. Gambacorta et al. / Tetrahedron 62 (2006) 6848–6854
6853
J 5.5 Hz, C5-H), 4.40 (2H, q, J 7.0 Hz, O2-CH2), 3.97 (3H, s,
O4-CH3), 1.32 (3H, t, J 7.0 Hz, CH3); dC 171.1 (C4), 169.5
(C2), 161.1 (C6), 101.0 (C5), 62.9 (O2-C), 54.9 (O4-C),
14.1 (Me); m/z (%) 154 (28), 139 (41), 126 (34), 110
(100), 96 (42), 68 (60); nmax 1580, 1460, 1380, 1268,
1085 cmꢀ1; HRMS found, 154.0744. C7H10N2O2 requires
154.0742.
HPLC among the other products and recognised by GC–MS
coupling; m/z (%) 182 (M+, 27), 167 (18), 154 (100), 138
(20), 126 (64), 110 (54), 96 (50).
4.2.5. Products from uracil 5.
4.2.5.1. Methylation. 1,3-Dimethyl-2,4-pyrimidindione
10c (0.15 g, 12%); 3-methyl-2,4(1H)-pyrimidindione
12c (56 mg, 5%);16 1-methyl-2,4(3H)-pyrimidindione 9c
(0.33 g, 30%).24
4-Ethoxy-1-ethyl-2(1H)-pyrimidinone 11d (3 mg, 0.2%);9a
1,3-diethyl-2,4-pyrimidindione 10d (46 mg, 3.5%);23 1-ethyl-
4-methoxy-2(1H)-pyrimidinone 6d (0.63 g, 52%);9a 1-ethyl-
2,4(3H)-pyrimidindione 9d (33 mg, 3%). Traces of 6c were
also found by GC–MS.
4.2.5.2. Ethylation.
4.2.5.2.1. 2-Ethoxy-3-ethyl-2(3H)-pyrimidinone (13d).
m/z (%) 168 (M+, 57), 140 (56), 112 (53), 96 (40), 82
(100), 69 (30), 68 (31) in 1:6 mixture (0.22 g, 15%) via
HPLC with 10d;23 the mixture 13d+10d (50 mg) was
dissolved in 2 M HCl (2.5 ml), warmed at 60 ꢁC for 2 h,
evaporated, redissolved in MeOH and analysed via HPLC
to give a 1:6 mixture of 12d and 10d.
4.2.3. Products from 4-acetylamino-2(1H)-pyrimidinone 3.
4.2.3.1. Methylation. 4-Acetylamino-2-methoxypyrimi-
dine 7e (54 mg, 5%);20 4-acetylamino-1-methyl-2(1H)-pyri-
midinone 6e (0.52 g, 48%).19
4.2.3.2. Ethylation.
4-Ethoxy-1-ethyl-2(1H)-pyrimidinone 11d (45 mg, 3%);9a
3-ethyl-2,4(1H)-pyrimidindione 12d (62 mg, 5%);16 1-ethyl-
2,4(3H)-pyrimidindione 9d (0.52 g, 42%).
4.2.3.2.1. 4-Acetylamino-2-ethoxypyrimidine (7f). White
solid (106 mg, 9%); dH 8.22 (1H, d, J 5.5 Hz, C6H), 7.62
(1H, d, J 5.5 Hz, C5H), 4.26 (2H, q, J 7.0 Hz, O2-CH2),
2.07 (3H, s, N4-COCH3), 1.27 (3H, t, J 7.0 Hz, CH3); dC
172.85 (C2), 165.99 (C]O), 161.26 (C4), 161.14 (C6),
104.63 (C3), 64.42 (O2-C), 24.29 (C(O)-CH3), 14.78
(CH3); m/z (%) 181 (M+, 20), 166 (47), 137 (47), 111 (47),
95 (100), 68 (28), 43 (83); nmax 3230, 1675, 1390,
1265 cmꢀ1; HRMS found, 181.0849. C8H11N3O2 requires
181.0851.
When KH was used in place of LiH (see run 18 in Table 2)
2,4-diethoxy-pyrimidine 14d (4%)9a was detected by HPLC
among the other products and recognised by GC–MS
coupling; m/z (%) 168 (M+, 29), 140 (53), 124 (17), 112
(68), 96 (100), 82 (25), 70 (51).
4.3. HPLC distribution of products
4.2.3.2.2. 4-Acetylamino-1-ethyl-2(1H)-pyrimidinone
(6f). White solid (0.75 g, 63%); dH 7.91 (1H, d, J 7.0 Hz,
C6H), 7.28 (1H, d, J 7.0 Hz, C5H), 3.84 (2H, q, J 7.0 Hz, N1-
CH2), 2.07 (3H, s, N4-COCH3), 1.23 (3H, t, J 7.0 Hz, CH3);
dC 73.04 (C]O), 164.20 (C4), 158.68 (C]O), 150.70 (C6),
98.25 (C5), 41.12 (N1-C), 24.53 (C(O)-CH3), 14.50 (CH3);
m/z (%) 81 (M+, 70), 166 (100), 139 (41), 138 (64), 111 (62),
One equivalent of the appropriate metal hydride (LiH or KH)
was added under stirring to 5.0 ml of a 0.07 M solution of
the substrates 1–5 in dioxane or DMF, and the mixture was
stirred for 30 min at 60 ꢁC under a dry Ar atmosphere.
Subsequently, 1.3 equiv of the appropriate alkylating agent
(DMS, DES, MeI or EtI) were added and stirring at 60 ꢁC
was continued for the time reported in Tables 1 and 2.
After this time, 1 equiv of solid NH4Cl was added and
the resulting suspension was filtered. DMF solutions were
analysed directly by HPLC, while reactions in dioxane
were evaporated under reduced pressure and redissolved in
MeOH. Reaction mixtures from 2 and 5 were analysed
through a gradient elution from 100% H2O (1 min) to
100% MeCN in 15 min (flow¼0.7 ml/min), while a gradient
elution from H2O/MeCN¼90:10 to 100% MeCN in 20 min
(flow¼1 ml/min) was used for mixtures from 1, 3 and 4.
Results are reported in Tables 1 and 2 as average of two
independent runs.
81 (49), 43 (97); nmax 3240, 1700, 1674, 1645, 1495 cmꢀ1
;
HRMS found, 181.0853. C8H11N3O2 requires 181.0851.
4.2.4. Products from thymine 4.
4.2.4.1. Methylation. 1,3,5-Trimethyl-2,4-pyrimidindione
10a (86 mg, 7%);24 3,5-dimethyl-2,4(1H)-pyrimidindione
12a (56 mg, 5%);16 1,5-dimethyl-2,4(3H)-pyrimidindione 9a
(0.22 g, 20%).
4.2.4.2. Ethylation.
4.2.4.2.1. 2-Ethoxy-3-ethyl-5-methyl-2(3H)-pyrimidi-
none (13b). m/z (%) 182 (M+, 40), 154 (55), 126 (100),
110 (83), 83 (55), 82 (58) in 1:5 mixture (0.13 g, 12%) via
HPLC with 10b;22 the mixture 13b+10b (50 mg) was
dissolved in 2 M HCl (2.5 ml), warmed at 60 ꢁC for 2 h,
evaporated, redissolved in MeOH and analysed via HPLC
to give a 1:5 mixture of 12b and 10b.
References and notes
1. (a) Amblard, F.; Nolan, S. P.; Schinazi, R. F.; Agrofoglio, L. A.
Tetrahedron 2005, 61, 537–554; (b) Bronson, J. J.; Ghazzouli,
I.; Hitchcock, M. J. M.; Webb, R. R.; Martin, J. C. J. Med.
Chem. 1989, 32, 1457–1463; (c) Bhat, S. Collect. Czech.
Chem. Commun. 1993, 58, 683–690.
4-Ethoxy-1-ethyl-5-methyl-2(1H)-pyrimidinone 11b (43 mg,
3%);24 3-ethyl-5-methyl-2,4(1H)-pyrimidindione12b (50 mg,
4%);16 1-ethyl-5-methyl-2,4(3H)-pyrimidindione 9b (0.42 g,
34%).
2. Senda, S.; Hirota, K.; Banno, K. J. Med. Chem. 1972, 15,
471–476.
When KH was used in place of LiH (see run 9 in Table 2) 2,4-
diethoxy-5-methylpyrimidine 14b (3.2%)24 was detected by
3. (a) Faul, M. M.; Huff, B. E.; Kaldor, S. W.; Werner, J. A.
Tetrahedron 1997, 53, 8085–8104; (b) Danel, K.; Larsen, E.;