D. Font et al. / Tetrahedron 62 (2006) 1433–1443
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3106, 1578 cmK1; H NMR (CDCl3): d 1.33 (d, 6H, JZ
(m, 1H), 5.30 (sept, 1H, JZ6.2 Hz), 5.81 (s, 1H); 13C NMR
(CDCl3): d 21.9, 23.3 (2q, 3 CH3), 23.9, 29.9, 48.2 (3t, 3
CH2), 61.1 (d, CH), 68.3 (t, CH2), 68.8 (d, CH), 95.7 (d,
CHpyrim), 161.1, 166.5, 169.6 (3s, 3 Cpyrim); MS (EI) m/z:
251 ([M]%C, 3). Anal. Calcd for C13H21N3O2: C, 62.13; H,
8.42; N, 16.72. Found: C, 62.19; H, 8.64; N, 16.44.
6.2 Hz), 1.81 (q, 2H, JZ5.8 Hz), 2.33 (s, 3H), 3.56 (q, 2H,
JZ6.0 Hz), 3.70 (t, 2H, JZ5.6 Hz), 5.30 (sept, 1H, JZ
6.2 Hz), 5.55 (br, 2H), 5.83 (s, 1H); 13C NMR (CDCl3):
d 21.8, 22.6 (2q, 3 CH3), 32.5, 38.7, 59.9 (3t, 3 CH2),
71.4 (d, CH), 98.4 (d, CHpyrim), 158.3, 167.0, 171.3 (3s, 3
Cpyrim); MS (EI) m/z: 225 ([M]%C, 64). Anal. Calcd for
C11H19N3O2: C, 58.64; H, 8.50; N, 18.65. Found: C, 58.87;
H, 8.62; N, 18.84.
4.2.9. [1-(4-Isopropoxypyrimidin-2-yl)piperidin-2-yl]-
methanol (9i). From 875 mg (3.0 mmol) of sulfone 5a
and 618 mg (5.37 mmol) of piperidin-2-yl-methanol 8f,
596 mg (79%) of compound 9i was obtanied as a colorless
oil. Rf 0.40 (n-hexane/ethyl acetate 1:1). IR (neat): 3405,
4.2.5. 2-(4-Isopropoxy-6-methyl-pyrimidin-2-ylamino)-
3-phenyl-propan-1-ol (9e). From 785 mg (2.56 mmol) of
sulfone 5b and 774 mg (5.13 mmol) of phenylalaninol 8c,
612 mg (79%) of compound 9e was obtained as a colorless
oil. Rf 0.12 (chloroform/methanol 6:1). IR (neat): 3400,
1
1587 cmK1; H NMR (CDCl3): d 1.37 (d, 6H, JZ6.2 Hz),
1.65–1.80 (m, 6H), 3.05 (m, 1H), 3.40 (br, 1H), 3.73 (dd,
1H, JZ10.7 Hz, J0Z5, 5 Hz), 3.96 (dd, 1H, JZ10.7 Hz,
J0Z8.8 Hz, CH2N), 4.60 (m, 1H), 4.90 (m, 1H), 5.28 (sept,
1H, JZ6.2 Hz), 5.90 (d, 1H, JZ6.0 Hz), 7.98 (d, 1H, JZ
6.0 Hz); 13C NMR (CDCl3): d 19.8 (t, CH2), 21.8 (q, 2 CH3),
24.9, 25.6, 39.6 (3t, 3 CH2), 52.7 (d, CH), 62.7 (t, CH2), 68.2
(d, CH), 97.1, 157.4 (2d, 2 CHpyrim), 162.6, 169.0 (2s, 2
Cpyrim); MS (EI) m/z: 251 ([M]%C, 6). Anal. Calcd for
C13H21N3O2: C, 62.13; H, 8.42; N, 16.72. Found: C, 62.22;
H, 8.34; N, 16.54.
1
3028, 1577 cmK1; H NMR (CDCl3): d 1.34 (d, 6H, JZ
6.2 Hz), 2.97 (d, 2H, JZ7.4 Hz), 3.67 (dd, 01H, JZ10.8 Hz,
J0Z5.6 Hz), 3.82 (dd, 1H, JZ10.8 Hz, J Z2.8 Hz), 4.20
(m, 1H), 4.30 (br, 1H), 5.27 (sept, 1H, JZ6.2 Hz), 5.40 (br,
1H), 5.86 (s, 1H), 7.20–7.40 (m, 5H); 13C NMR (CDCl3): d
22.6, 23.8 (2q, 3 CH3), 38.4 (t, CH2), 55.6 (d, CH), 65.4 (t,
CH2), 69.3 (d, CH), 97.5 (d, CHpyrim), 127.1, 129.2, 129.9
(3d, 5 CHarom), 139.0 (s, Carom), 162.2, 167.3, 170.8 (3s, 3
Cpyrim); MS (EI) m/z: 301 ([M]%C, 4). Anal. Calcd for
C17H23N3O2: C, 67.75; H, 7.69; N, 13.94. Found: C, 67.56;
H, 7.52; N, 14.12.
4.2.10. [1-(4-Isopropoxy-6-methylpyrimidin-2-yl)-piper-
idin-2-yl]-methanol (9j). From 900 mg (2.94 mmol) of
sulfone 5b and 672 mg (5.84 mmol) piperidin-2-yl-
methanol 8f, 716 mg (90%) of compound 9j was obtained
as a colorless oil. Rf 0.44 (n-hexane/ethyl acetate 1:1). IR
(neat): 3400, 1573 cmK1; 1H NMR (CDCl3): d 1.31 (d, 6H,
JZ6.2 Hz), 1.50–1.70 (m, 6H), 2.20 (s, 3H), 3.05 (m, 1H),
3.71 (dd, 1H, JZ10.7 Hz, J0Z4.7 Hz, CH2N), 4.00 (dd, 1H,
JZ10.7 Hz, J0Z9.0 Hz), 4.15 (br, 1H), 4.60 (m, 1H), 4.90
(m, 1H), 5.25 (sept, 1H, JZ6.2 Hz), 5.77 (s, 1H); 13C NMR
(CDCl3): d 20.6 (t, CH2), 21.5, 24.4 (2q, 3 CH3), 25.6, 26.5,
40.3 (3t, 3 CH2), 53.6 (d, CH), 64.1 (t, CH2), 68.7 (d, CH),
96.3 (d, CHpyrim), 163.4, 167.9, 170.2 (3s, 3 Cpyrim); MS (EI)
m/z: 265 ([M]%C, 3). Anal. Calcd for C14H23N3O2: C, 63.37;
H, 8.74; N, 15.84. Found: C, 63.09; H, 8.83; N, 15.66.
4.2.6.
2-[(4-Isopropoxy-6-phenyl-pyrimidin-2-yl)-
methyl-amino]-ethanol (9f). From 1.00 g (2.72 mmol) of
sulfone 5c and 0.38 mL (5.4 mmol) of 2-methylamino-
ethanol 8d, 667 mg (85%) of compound 9f was obtained as
a colorless oil. Rf 0.23 (n-hexane/ethyl acetate 1:1). IR
(neat): 3400–3200, 1534 cmK1; H NMR (CDCl3): d 1.42
1
(d, 6H, JZ6.2 Hz), 3.30 (s, 3H), 3.85–4.00 (m, 4H), 5.40
(sept, 1H, JZ6.2 Hz), 6.40 (s, 1H), 7.40, 7.50 (m, 3H),
7.95–8.00 (m, 2H); 13C NMR (CDCl3): d 22.6, 37.3 (2q, 3
CH3), 53.5, 63.7 (2t, 2 CH2), 69.3 (d, CH), 93.7 (d, CHpyrim),
127.5, 129.2, 130.8 (3d, 5 CHarom), 138.4 (s, Carom), 163.6,
165.7, 170.9 (3s, 3 Cpyrim); MS (EI) m/z: 287 ([M]%C, 11).
Anal. Calcd for C16H21N3O2: C, 66.88; H, 7.37; N, 14.62.
Found: C, 67.15; H, 7.45; N, 14.35.
4.3. General procedure for the hydrolysis of compounds
9 with HCl. Synthesis of pyrimidinones 10
4.2.7.
2-[(4-Isopropoxy-6-methyl-pyrimidin-2-yl)-
methyl-amino]-ethanol (9g). From 1.23 g (4.02 mmol) of
sulfone 5b and 0.48 mL (6.83 mmol) of 2-methylamino-
ethanol 8d, 721 mg (80%) of compound 9g was obtained as
a colorless oil. Rf 0.38 (n-hexane/ethyl acetate 1:1). IR
A suspension of the corresponding 4-isopropoxypyrimidine
9 (1 equiv) in concd HCl (2 mL/mmol) was heated at 90 8C
for 30 min. After cooling, the mixture was neutralized
with aq 5 N NaOH and extracted with CH2Cl2 (3!10 mL/
mmol). The combined organic layers were washed with
brine (1!10 mL/mmol) and the organic layer was dried
over MgSO4, filtered and concentrated under reduced
pressure. The resulting crude product was purified by
flash-chromatography (ethyl acetate/methanol 10:1) to
afford pyrimidinones 10.
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(neat): 3450–3250, 1576 cmK1; H NMR (CDCl3): d 1.34
(d, 6H, JZ6.2 Hz), 2.24 (s, 3H), 3.20 (s, 3H), 3.74 (t, 2H,
JZ4.0 Hz), 3.89 (t, 2H, JZ4.0 Hz), 5.30 (sept, 1H, JZ
6.2 Hz), 5.81 (s, 1H); 13C NMR (CDCl3): d 21.9, 23.5, 36.6
(3q, 4 CH3), 53.2, 63.3 (2t, 2 CH2), 68.2 (d, CH), 95.7 (d,
CHpyrim), 162.6, 167.0, 169.6 (3s, 3 Cpyrim); MS (EI) m/z:
225 ([M]%C, 29). Anal. Calcd for C11H19N3O2: C, 58.64; H,
8.50; N, 18.65. Found: C, 58.66; H, 8.62; N, 18.56.
4.3.1. 2-(2-Hydroxy-ethylamino)-3H-pyrimidin-4-one
(10a). From 336 mg (1.7 mmol) of 4-isopropoxipyrimidine
9a, 226 mg (86%) of compound 10a was obtained as a
colorless solid. Mp: 176–177 8C. Rf 0.17 (dichloromethane/
4.2.8. [1-(4-Isopropoxy-6-methyl-pyrimidin-2-yl)-pyrro-
lidin-2-yl]-methanol (9h). From 1.00 g (3.27 mmol) of
sulfone 5b and 0.58 mL (5.6 mmol) of prolinol 8e, 825 mg
(95%) of compound 9h was obtained as a colorless oil. Rf
0.34 (n-hexane/ethyl acetate 1:1). IR (neat): 3400–3300,
methanol 10:1). IR (neat): 3220–2880, 1681, 1621 cmK1
;
1H NMR (DMSO-d6): d 3.30 (m, 2H), 3.51 (t, 2H, JZ
5.6 Hz), 4.90 (br, 1H), 5.53 (d, 1H, JZ6.6 Hz), 6.55 (br,
1H), 7.57 (d, 1H, JZ6.6 Hz), 10.60 (br, 1H); 13C NMR
(DMSO-d6): d 43.4, 59.2 (2t, 2 CH2), 103.2, 149.2 (2d, 2
1
1574 cmK1; H NMR (CDCl3): d 1.33 (d, 6H, JZ6.2 Hz),
1.70–2.20 (m, 4H), 2.23 (s, 3H), 3.50–3.80 (m, 4H), 4.25