194
Papers
SYNTHESIS
5,8-Dimethoxycarbostyrils; General Procedures:
(7) Benetti, S.; Romagnoli, R.; De Risi, C,; Spalluto, G. Chem. Rev.
1995, 95, 1065.
(8) Wang, W.-B.; Roskamp, E. J. J. Org. Chem. 1992, 57, 6101.
(9) CIemens, R. J. Chem. Rev. 1986, 86, 241.
Method A: Cyclization with H2SO4: A solution of N-(2,5-dimethoxy-
phenyl)-3-oxobutanamide 18, 19, 20 or 23 (0.30–0.15 g, 1.20–0.54
mmol) in 96% H2SO4 (2–3 mL) was stirred at r.t. for 50 min–3 h, and
was then quenched with ice, made basic with 25% aq NH4OH and ex- (10) Clemens, R. J.; Hyatt, J. A. J. Org. Chem. 1985, 50, 2431.
tracted with CHCl3 (3 ´ 25–50 mL). The combined organic layers (11) Ley, S. V.; Woodward, P. R. Tetrahedron Lett. 1987, 32, 2431.
were washed with brine (25–50 mL), dried (Na2SO4) and concentrat- (12) Booth, P. M.; Fox, C. M. J.; Ley, S. V. J. Chem. Soc., Perkin
ed under reduced pressure to give an off-white solid. Chromatogra-
phy (50% Et2O/EtOAc to EtOAc) afforded the corresponding 4-mono
or 3,4-disubstituted 5,8-dimethoxyquinolin-2(1H)-ones as white sol-
ids (compounds 27, 30 and 31).
Trans. 1 1987, 121.
Ley, S. V.; Trudell, M.; Wadsworth, D. J. Tetrahedron 1991,
47, 8285.
Booth, P. M.; Broughton, H. B.; Ford, M. J.; Fox, C. M. J.; Ley,
S. V.; Slawin, A. M. Z.; Williams, D. J.; Woodward, P. R.
Tetrahedron 1991, 47, 2005.
Method B: Cyclization with HCl: A suspension of amide 21 or 24
(0.30 g; 0.92 mmol) in 35% HCl (25 mL) was vigorously stirred at r.t.
for 4–7 d. The product was isolated following Method A and the chro-
matography was performed using Et2O as the mobile phase (com-
pounds 28 and 33).
(13) Compounds 2 and 4 had been previously obtained using this
methodology in 46% and 65% yields, respectively: Booth, P.
M.; Fox, C. M. J.; Ley, S. V. Tetrahedron Lett. 1983, 24, 5143.
(14) Bell, H. C.; Pinhey, J. T.; Sternhell, S. Aust. J. Chem. 1979, 32,
1521.
Method C: Cyclization with TsOH: Compound 22 or 25 (70–90 mg;
0.25–0.33 mmol) was cyclized by heating in refluxing xylene at 185 °C
for 3–4 h in the presence of a catalytic amount of TsOH (50–60 mg,
1.0 equiv). The mixture was washed with H2O (2 ´ 30–50 mL), dried
(Na2SO4), and concentrated under reduced pressure to give a dark oil,
and chromatographed (EtOAc) (compounds 29 and 34).
(15) Pinhey, J. T. Aust. J. Chem. 1991, 44, 1353.
(16) Aryllead triacetates give 2,2-disubstituted derivatives by treat-
ment with the anions derived from several types of b- dicarbo-
nyl compounds. See, for example:
Rowe, B. A.; Pinhey, J. T. Aust. J. Chem. 1979, 32, 1561.
May, G. L.; Pinhey, J. T. Aust. J. Chem. 1982, 35, 1859.
(17) Dialkylation through this mechanism is a common problem in
the reaction of enolate anions and alkyl halides. See:
Jackman, L. M. Tetrahedron 1977, 33, 2737.
Caine, D. In Comprehensive Organic Synthesis; Trost, B. M.;
Fleming, I., Eds.; Pergamon: Oxford 1991; Vol. 3, p 1.
(18) Umemoto, T.; Tomita, K.; Kawada, K. Org. Synth. 1991, 69,
129.
Quinoline-2,5,8(1H)-triones from 5,8-Dimethoxycarbostyrils;
General Procedure:
Method A: To a solution of 5,8-dimethoxyquinolin-2(1H)-one 27, 28,
30, 31, 33 or 34 (20–184 mg, 0.07–0.70 mmol) in a mixture of
CH3CN and H2O (2:1), cerium ammonium nitrate (CAN) (0.106–
1.159 g, 0. 19–0.21 mmol; 3 equiv) was added. The solution was
stirred at r.t. for 30 min–5 h, and was then diluted with H2O (10–20
mL) and extracted with CHCl3 (3 ´ 20–50 mL). The CHCl3 layer was
washed with H2O (2 ´ 25–50 mL), dried (Na2SO4) and concentrated
under reduced pressure to give an orange-red solid. Quick chromatog-
raphy (Et2O) or sublimation (compounds 35–40) was used to purify
the quinones, which were isolated as dark-orange or red solids.
Umemoto, T.; Kawada, K.; Tomita, K. Tetrahedron Lett. 1986,
27, 4465.
(19) Rogers, M. T.; Burdett, J. L. Can. J. Chem. 1965, 43, 1516.
Allen, G.; Dwek, R. A. J. Chem. Soc. (B) 1966, 161.
(20) Compound 18 had been previously prepared from 2,5-di-
methoxyaniline and 2,2,6-trimethyl-l,3-dioxin-4-one. See ref 4a.
(21) Kettrup, A. Monatsch. Chem. 1975, 106, 55.
(22) Similar oxygen additions to other enols and enolates are describ-
ed: Jones, A. B. In Comprehensive Organic Synthesis; Trost, B.
M.; Fleming, I., Eds.; Pergamon: Oxford 1991; Vol. 7, p 151.
(23) We have observed a similar oxidative degradation in the ab-
sence of metals for 3-aryl-b- oxo anilides, which exist predomi-
nantly as enol tautomers. López-Alvarado, P.; Avendano, C.;
Menéndez, J. C. J. Org. Chem. 1996, 61, 5865.
Method B: To a solution of 5,8-dimethoxyquinolin-2(1H)-one 28 or
33 (20–155 mg, 0.065–0.501 mmol) in MeCN (2–10 mL), a solution
of cerium ammonium nitrate (CAN) (0.071–0.549 g, 0.13–
1.00 mmol; 2 equiv) in H2O (1–5 mL) was added. If necessary, slight
heating can be applied to dissolve completely the starting material,
but the addition of the oxidant should be carried out at r.t. Compounds
36 and 39 were isolated following Method A. In the case of the oxi-
dation of compounds 29 and 32, the quinones could not be isolated
from the aqueous phase.
(24) López-Alvarado, P.; Avendaño, C.; Menéndez, J. C. Synth.
Commum. 1992, 22, 2329.
(1) Gesto, C.; de la Cuesta, E.; Avendano, C. Tetrahedron 1989, 45,
4477.
(25) S-tert-Butyl 2-acetyl-2-allylpent-4-enethioate: Anal. calcd. for
C14H22SO2, M = 254: C, 66.10 H, 8.71. Found: C, 66.23; H,
8.51. IR (NaCl): n = 1721 (C=O), 1672 (t-BuS-C=O) cm–1, 1H
NMR (CDCl3, 300 MHz): d = 5.60–5.46 (ddt, 2H, J = 17.0; 9.5
and 7.5 Hz, C2¢-H), 5.04 (d, 2H, J = 17.5 Hz, C3¢-Htrans), 5.03 (d,
2H, J = 9.5 Hz, C3¢-Hcis), 2.58 (m, 4H, C1¢-H), 2.13 (s, 3H, C4-
H), 1.46 (s, 9H, t-Bu).13C NMR (CDCl3, 75 MHz): d = 203.71
(C3), 199.47 (C1), 131.70 (C2¢), 119.36 (C3¢), 70.82 (C2), 48.86
[C(CH3)3], 35.42 (C2-CH2), 29.66 [C(CH3)3], 26.68 (C4).
(26) Dialkylation is favored by the use of more concentrated solu-
tions. For example, starting from S-tert-butyl acetothioacetate
(1) (1.50 g, 8.62 mmol), MeI (1.281 g, 9.05 mmol) and NaH
(379 mg of a 60% dispersion in mineral oil, 9.48 mmol) in DME
(13 mL) a yield of 1.118 g (69%) of 2 and 278 mg (16%) of S-
tert-butyl 2,2-dimethyl-3-oxobutanethioate was obtained. IR
Pérez, J. M.; Vidal, L.; Grande, M. T.; Menéndez, J. C.; Aven-
dano, C. Tetrahedron 1994, 50, 7923.
Villacampa, M.; Pérez, J. M.; Avendano, C.; Menéndez, J. C.
Tetrahedron 1994, 50, 10047.
Pérez, J. M.; Avendano, C.; Menéndez, J. C. Tetrahedron 1995,
51, 6573.
Blanco, M. M;. Alonso, M. A.; Avendano, C.; Menéndez, J. C.
Tetrahedron 1996, 52, 5933.
(2) Omura, S.; Iwai, Y.; Hinotozawa, K.; Tanaka, H.; Takahashi,
Y.; Nakagawa, A. J. Antibiot. 1982, 35, 1425.
(3) Friedländer reaction: Blanco, M. M.; Avendano, C.; Cabezas,
N.; Menéndez, J. C. Heterocycles 1993, 36, 1387.
Vilsmeier–Haack reaction: Alonso, M. A.; Blanco, M. M.;
Avendano, C.; Menéndez, J. C. Heterocycles 1993, 36, 2315.
lntramolecular Wittig reaction: Ferrer, P.; Avendano, C.; Söll-
huber, M. Liebigs Ann. Chem. 1995, 1895.
(4) a)Avendano, C.; de la Cuesta, E.; Gesto, C. Synthesis 1991, 727.
b) Martín, O.; de la Cuesta, E.; Avendano, C. Tetrahedron 1995,
51, 7547.
(5) Jones, G. Adv. Heterocycl. Chem. 1977, 32, 137.
Manske, R. H. Chem. Rev. 1942, 30, 121.
1
(NaCl): n = 1724 (C=O), 1671 (t-BuS-C=O) cm–1. H NMR
(CDCl3, 250 MHz): d = 2.16 (s, 3H, C4-H); 1.47 (s, 9H, t-Bu);
1.37 [s, 6H, (CH3)2-C2].13C NMR (CDCl3, 63 MHz): d = 205.78
(C3), 201.79 (C1), 64.06 (C2), 48.30 [C(CH3)3], 29.61
[C(CH3)3], 25.83 (C4), 22.07 [( CH3)2-C2].
(27) Janssen, D. E.; Wilson, C. V. Org. Synth. 1956, 36, 47.
(28) The reaction was complete after 1.5 h in most cases. However,
if the mixture is quenched in this moment, the yield obtained is
lower because silver species in solution interfere during the pu-
rification process.
(6) For an example see: Kelly, T. R.; Field, J. A.; Li, Q. Tetrahe-
hedron Lett. 1988, 29, 3545.