3984
B. Nawrot et al. / Tetrahedron 57 42001) 3979±3985
4. Conclusions
MeOH, 9/1), mp 197±2008C, 3199±2008C,2 200±2028C,4
164±1658C3), 1H NMR 3200 MHz, DMSO-d6, ppm):
11.33 3br s, 1H, NH), 7.55 3q, J1.1 Hz, 1H, H-6), 4.02
3t, J12.6Hz, 2H, CH 2N, 3.69 3t, J12.6Hz, 2H,
CH2Br), 1.75 3d, J1.1 Hz, 3H, CH3), FAB MS 233
[M11]1, 235 [M13]1.
In summary, the outcome of the alkylation of thymine with
1,2-dibromoethane depends strongly on the reaction condi-
tions. Various alkyl derivatives may be produced, including
N-1- or N-3-monosubstituted alkylthymines and products of
their cyclisation, as well higher molecular weight products
resulting from intermolecular substitution of N-1- and N-3-
mono- and N-1,N-3-dialkylthymines. We have identi®ed
two cyclic products 5 and 6 and the dialkylated derivative
7, for which detailed structural analyses have been
performed.
5.1.1. N-1--2-azidoethyl)thymine 8. To a solution of
bromide 3 3520 mg, 2.24 mmol) in anhydrous THF
320 mL), azidotrimethylsilane 30.6mL) and tetrabutyl-
ammonium ¯uoride 34.5 mL) were added. The reaction
mixture was stirred at 658C for 3 h. After removal of the
solvent, the residue was crystallised from ethanol. The
product 8 was obtained as a white solid 3320 mg, 80%).
Mp 152±1558C, Rf0.61 3ethyl acetate), 1H NMR
3200 MHz, CDCl3, ppm): 7.02 3s, 1H, H-6), 3.82 3br q,
2H, CH2), 3.67 3br q, 2H, CH2), 1.94 3s, 3H, CH3), IR
3KBr, cm21): 2122; HR MS for C7H9N5O2: [M1H]1
196.08345 3calc.), 196.08407 3exp.). Synthesis of azide 8
was performed analogously as described above starting
from cyclic compound 5 376mg, 0.5 mmol). The product
was obtained as a white solid 355 mg, 56%).
5. Experimental
5.1. Alkylation of thymine
Procedure A: 1,2-Dibromoethane 335.52 g, 189 mmol) was
added to a suspension of thymine 36g, 47.6mmol) and
anhydrous potassium carbonate 316.32 g, 124 mmol) in
anhydrous DMF 3100 mL). The mixture was kept at room
temperature for 48 h, then the solid was ®ltered off and the
solvent was evaporated under reduced pressure. The reac-
tion products were separated by ¯ash column chromato-
graphy on silica gel 60G in gradient of methanol in
chloroform.
5.1.2. N-3--2-azidoethyl)thymine 9. Synthesis of azide 9
was performed analogously as described above starting
from cyclic compound 6 3340 mg, 2.23 mmol). The product
was obtained as a white solid 3320 mg, 73%). Mp 119±
1208C, Rf0.75 3ethyl acetate), 1H NMR 3200 MHz,
CD3OD, ppm): 7.24 3q, J1.1 Hz, 1H, H-6), 4.15 3t,
J6.2 Hz, 2H, CH2), 3.50 3t, J6.2 Hz, 2H, CH2), 1.88
3d, J1.1 Hz, 3H, CH3); IR 3KBr, cm21): 2110, 2088; HR
MS for C7H9N5O2: [M1H]1 196.08345 3calc.), 196.08269
3exp.).
Compound
5 32,3-dihydro-6-methyl-7H-oxazolo[3,2-a]-
pyrimidin-7-one) 30.09 g, 1.2%): Rf0.14 3CHCl3/MeOH,
9/1), mp 285±2898C,4 1H NMR 3200 MHz, DMSO-d6,
ppm): 7.63 3q, J1.2 Hz, 1H, H-6), 4.64 3t, J8.45 Hz,
2H, CH2O), 4.18 3t, J8.45 Hz, 2H, CH2N), 1.77 3d,
J1.2 Hz, 3H, CH3), FAB MS 153 [M11]1, IR 3KBr,
cm21): 3049, 2922, 1667, 1611, 1550, 1504, 1377, 880.
5.1.3. N-1--2-aminoethyl)thymine 1. 10% Pd/C 320 mg)
was added to the solution of azide 8 3300 mg, 1.54 mmol)
in methanol 310 mL) and hydrogen was bubbled through the
reaction mixture for 2.5 h 3TLC control). The reaction
mixture was ®ltered and the solvent removed under reduced
pressure. The crude product was puri®ed by ¯ash column
chromatography in gradient of methanol in chloroform.
Amine 1 was obtained as a white solid 3230 mg, 90%).
Mp 180±1858C; Rf0.08 32£CHCl3/MeOH, 8/2); 1H
NMR 3200 MHz, CD3OD): 7.40 3q, J1.2 Hz, 1H, H-6),
3.763t, J6.28 Hz, 2H, CH2), 2.89 3t, J6.28 Hz, 2H,
CH2), 1.87 3d, J1.2 Hz, 3H, CH3); FAB MS 170
[M11]1, 168 [M-1]2; IR 3KBr, cm21): 3342, 3289, 3054,
2960, 1705, 1660, 1481, 1358, 1046, 760.
Compound
6 32,3-dihydro-6-methyl-5H-oxazolo[2,3-a]-
pyrimidin-5-one) 30.70 g, 10.0%): Rf0.53 3CHCl3/
MeOH, 9/1), Rf0.15 3ethyl acetate), mp.3908C, 1H
NMR 3200 MHz, DMSO-d6, ppm): 7.57 3q, J1.1 Hz,
1H, H-6), 4.67 3t, J8.45 Hz, 2H, CH2O), 4.29 3t,
J8.45 Hz, 2H, CH2N), 1.863d, J1.1 Hz, 3H, CH3); HR
MS for C7H8O2N2: [M]1 152.05858 3calc.), 152.05731
3exp.); IR 3KBr, cm21): 2922, 1663, 1611, 1561, 1437,
1358, 1256, 1000, 766.
Compound 7 30.118 g, 0.9%): Rf0.53 3CHCl3/MeOH, 9/
1
1), Rf0.52 3ethyl acetate), H NMR 3200 MHz, CDCl3,
ppm): 7.05 3q, J1.2 Hz, 1H, H-6), 4.03 3t, J6.0 Hz, 2H,
CH2), 3.58 3t, J6.0 Hz, 2H, CH2), 1.84 3d, J1.2 Hz, 3H,
CH3); HR MS for C9H13O2N2Br2379): 338.93437 3calc.)
338.93372 3exp.), for C9H13O2N2Br379)Br381): 340.93233
3calc.), 340.931263exp.).
5.1.4. N-3--2-aminoethyl)thymine 2. Synthesis of amine 2
was performed analogously as described above starting
from azide 9 3340 mg, 2.23 mmol). The product was
obtained as a white foam 3320 mg, 73%). Rf0.16
32£CHCl3/MeOH, 8/2), 1H NMR 3200 MHz, CD3OD,
ppm): 7.23 3q, J1.2 Hz, 1H, H-6), 4.05 3t, J6.4 Hz, 2H,
CH2), 2.93 3t, J6.4 Hz, 2H, CH2), 1.88 3d, J1.2 Hz, 3H,
CH3); HR MS for C7H11N3O2: [M1H]1 170.09295 3calc.),
170.09392 3exp.); IR 3KBr, cm21): 3343, 3281, 3058, 2895,
1703, 1637, 1343, 1000, 770.
Procedure B: A solution of 2,4-bis3trimethylsilyloxyl)-5-
methylpyrimidine16 39.0 g, 33.3 mmol) in 1,2-dibromo-
ethane 3115 mL) was stirred for 10 days at room tempera-
ture. Then water 3300 mL) was added to the reaction
mixture and the products were extracted with chloroform
33£300 mL). After removal of solvents, the residue was
poured onto the silica gel column. The product was eluted
with gradient of methanol in chloroform. Bromide 3 30.78 g,
10%) was obtained as a white solid. Rf0.59 3CHCl3/
5.1.5. N-3--2-hydroxyethyl)thymine 10 and N-3--2-
aminoethyl)thymine 2. Cyclic derivative 6 3390 mg,
2.56mmol) was treated with aqueous ammonium hydroxide