PAPER
A Short, Efficient Synthesis of Substituted Uracil
241
1
3
C NMR (D O): δ = 35.45 (C-2′), 44.84 (C-1′), 58.55 (C-3′), 64.08
2
upon column chromatograpy (silica gel, hexane/EtOAc, 1:2) gave 8
(2.59 g, yield 55%) as a white solid.
2
(
CH OH), 102.25 (C-5), 124.19 and 124.99 (C-5′+C-6′), 127.75
and 128.70 (C-4′+C-7′), 141.44 and 145.47 (C-3′a+C-7′a), 142.40
(
Mp: 109−112 ºC.
C-2), 152.77 (C-2), 163.64 (C-4).
IR (KBr): ν = 3366, 2951, 1732, 1653, 1587, 1435, 1339, 1266,
Anal. calcd. for C H N O : C, 65.11; H, 5.46, N, 10.85. Found: C,
6
−1
1
4
14
2
3
1
169, 765 cm .
5.85; H, 5.24, N, 10.76.
1
H NMR (CDCl ): δ = 2.10 (m, 1H, 2-H), 2.40 (br. s., 2H, NH ),
3
2
2
.75 (m, 1H, 2-H), 3.80 (s, 3H, CO CH ), 3.95 (m, 1H, 3-H), 4.30
2 3
Methyl 3-Oxo-1-indanecarboxylate (6)
A solution of phenylsuccinic anhydride (8 g, 45.41 mmoles) in
1
suspension of aluminium trichloride (13.6 g, 102 mmoles) in 65 mL
of the same solvent at 0 °C. The mixture was stirrred for 40 min at
r.t., quenched with H O (100 mL) at 0 °C, and extracted with Et O
(
1
m, 1H, 1-H), 7.20−7.40 (m, 4H, ArH).
3
,2-dichloroethane (50 mL) was added dropwise to a well-stirred
C NMR (CDCl ): δ = 39.68 (C-2), 48.21 (C-1), 52.63 (C-3), 56.45
3
(CH O), 125.07 and 125.56 (C-5+C-6), 128.31 and 128.58 (C-4+C-
3
7), 140.18 and 146.95 (C-3a+C-7a), 174.66 (C(O)O).
2
2
Anal. calcd. for C H NO : C, 69.09; H, 6.85, N, 7.32. Found: C,
1
1
13
2
(
3 × 75 mL). The pooled organic layers were dried (Na SO ), and
2
4
6
8.89; H, 7.02, N, 7.51.
removal of the solvent under vacuum afforded 3-oxo-1-indanecar-
boxylic acid, which was dissolved in MeOH (20 mL) containing
5
was removed under vacuum, and the resulting oil was distilled in a
Kugelrohr distillation apparatus (185 °C, 0.3 mm Hg) affording 6
(
±)-cis-3-Amino-1-indanylmethanol (4)
drops of H SO . This solution was refluxed for 16 h, the solvent
2 4
A solution of LiBH (180 mg, 8.25 mmoles) in dry THF (45 mL)
4
was refluxed with stirring for 1 h, a solution of 8 (790 mg,
4
.15 mmoles) in 45 mL of the same solvent was added, and reflux-
(
5,75 g, yield 67%) as an oil that crystallised spontaneously as white
ing was continued for 18 h. After cooling at r.t., the mixture was
added to Et O containing a small quantity of ice, and H O was add-
needles.
2
2
Mp: 40−42 ºC.
ed until all excess LiBH had decomposed. The organic solvents
4
were removed under reduced pressure in a rotary evaporator, boron
hydroxides were filtered out, and the resulting aqueous filtrate was
extracted with CH Cl (3 × 50 mL). The pooled organic layers were
IR (KBr): ν = 3009, 2954, 1736, 1715, 1654, 1598, 1342, 1209,
−
1
1
170, 1049, 762 cm .
1
2
2
H NMR (CDCl ): δ = 2.83 (dd, 1H, J = 19.10 Hz, Jvec = 8.0 Hz,
3
gem
dried (Na SO ), and evaporation of the solvent afforded an oil that
2
4
2
-H), 3.14 (dd, 1H, J = 19.1 Hz, J = 3.6 Hz, 2-H), 3.77 (s, 3H,
gem vec
upon cooling afforded 4 (626 mg, yield 93%) as a white solid.
CO CH ), 4.29 (dd, 1H, J = 8.0 Hz, J1,2 = 3.5 Hz, 1-H), 7.45 (t,
2
3
1,2
Mp: 73−75 ºC.
1
H, J = 7.3 Hz, 6-H), 7.60−7.70 (m, 2H, 7-H, 5-H), 7.76 (d, 1H,
,5
J4 = 7.6 Hz, 4-H).
IR (KBr): ν = 3333, 2953, 2848, 1583, 1474, 1458, 1379, 1311,
−
1
1
3
1233, 1032, 978, 746 cm .
C NMR (CDCl ): δ = 39.90, 44.01, 53.08, 124.35, 126.91, 129.21,
3
1
35.40, 136.75, 151.47, 172.63, 204.49.
1
H NMR (DMSO): δ = 1.352 (dt, 1H, J = 12.46 Hz, J = 7.94 Hz,
d
t
2
(
J
β-H), 2.449 (dt, 1H, J = 12.46 Hz, J = 7.36 Hz, 2α-H), 3.068
Anal. calcd. for C H O : C, 69.46; H, 5.30. Found: C, 69.65; H,
d
t
11
10
3
quint, 1H, J = 6.69 Hz, 1β-H), 3.535 (part A of an ABM system,
5
.13.
= 10.32 Hz, J = 6.22 Hz, 1-CHHOH), 3.727 (part B of an
AB
AM
ABM system, JBA = 10.32 Hz, JBM = 5.47 Hz, 1-CHHOH), 4.137
Methyl 3-Hydroxyimino-1-indanecarboxylate (7)
Compound 6 (5 g, 26.28 mmoles) was added to a solution of hy-
droxylamine hydrochloride (2.25 g, 31.58 mmoles) and sodium ac-
(
1
s.n.r., 1H, ω1/2 = 18 Hz, 3β-H), 7.118-7.330 (m, 4H, ArH).
3
C NMR (DMSO): δ = 41.23 (C-2), 45.12 (C-1), 55.57 (C-3), 65.04
etate (7.15 g, 52.5 mmoles) in H O (20 mL), and enough EtOH was
(1-CH OH), 123.88 and 124.04 (C-5+C-6), 126.78 and 127.01 (C-
2
2
added to achieve solution. The mixture was refluxed for 1 h, cooled
4+C-7), 144.38 (C-3a+C-7a).
to r.t., and extracted with Et O (3 × 100 mL). The pooled organic
2
Anal. calcd. for C H NO: C, 73.59; H, 8.03, N, 8.58. Found: C,
1
0
13
layers were then dried (Na SO ) and concentrated under reduced
2
4
7
3.39; H, 8.16, N, 8.43.
pressure, affording a mixture of the oximes syn-7 and anti-7 (4.9 g,
yield 91%) as a white solid.
9
Acknowledgement
Mp: 128−131 ºC (Lit: mp: 132−133 ºC).
IR (KBr): ν = 3259, 2934, 1739, 1596, 1462, 1325, 1208, 946, 934,
The authors thank the Spanish Ministry of Education and Science
and the Xunta de Galicia for financial support of this work under
projects PB94-0617 and XUGA 20309B98 respectively.
−
1
7
57 cm .
1
H NMR (CDCl ): δ = 3.16−3.25 (dd, 1H, J = 19.10 Hz,
3
gem
J
= 8.84 Hz, 2-H), 3.38−3.46 (dd, 1H, J = 19.1 Hz, Jvec = 4.12
vec
gem
Hz, 2-H), 3.77 (s, 3H, CO CH ), 4.20−4.24 (q, 1H, 1-H), 7.32−7.42
(
2
3
References
m, 2H, 5-H, 6-H), 7.54 (d, 1H, J = 7.61 Hz, 7-H), 7.69 (d, 1H,
4,5
J4,5 = 7.61 Hz, 4-H).
(1) For recent reviews on CANs: a) Marquez, V. E. Adv. Antiviral
Drug Des. 1997, 10, 674.
1
3
C NMR (CDCl ): δ = 30.16, 46.59, 52.93, 122.16, 126.20, 128.97,
3
b) De Clercq, E. J. Med. Chem. 1995, 38, 2491.
c) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.;
Chaland, S. R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50,
1
31.19, 136.10, 145.09, 161.91, 173.15.
Anal. calcd. for C H NO : C, 64.38; H, 5.40, N, 6.83. Found: C,
11
11
3
6
4.64; H, 5.57, N, 6.61.
1
0611.
d) Borthwick, A. D.; Briggadike, K. Tetrahedron 1992, 48,
71.
Methyl (±)-cis-3-Amino-1-indanecarboxylate (8)
A solution of the oxime mixture 7 (4.85 g, 23.63 mmoles) in MeOH
5
(2) Vince, R.; Hua, M. J. Med. Chem. 1990, 33, 17.
(
(
50 mL) was hydrogenated over 100 mg of 10% Pd/C for 20 h
PH2 = 50 psi). The catalyst was filtered out, and concentration of the
(
3) Daluge, S. M.; Good, S. S.; Faleto, M. B.; Martin, M. T.;
Miller, W. H.; Averett, D. R.; St. Clair, M. H.; Boone, L. R.;
Tisdale, M.; Reardon, J. E. Antiviral Res. 1995, 26, A229.
filtrate under reduced pressure afforded a 60:40 mixture of methyl
±)-cis- and (±)-trans-3-amino-1-indanecarboxylates as a solid that
(
Synthesis 2001, No. 2, 239–242 ISSN 0039-7881 © Thieme Stuttgart · New York