PAPER
Baylis–Hillman Route to Quinolone Intermediates
967
6,7-Difluoro-1-(2,4-difluorophenyl)-4-oxo-1,4-dihydroquino-
line-3-carboxylic Acid (6d)
residue was chromatographed on silica gel eluting with hexane–
EtOAc (6:1) to afford 9 (528 mg, 85%) as a liquid.
Following the procedure described for the preparation of 6a, com-
pound 6d was prepared in 92% yield as a white solid using 5d; mp
239–241 °C (Lit.25 mp 240 °C).
1H NMR (DMSO-d6): d = 7.43–7.47 (m, 2 H), 7.68–7.76 (m, 1 H),
7.87–7.95 (m, 1 H), 8.32–8.39 (dd, J = 10.4, 8.5 Hz, 1 H), 8.96 (s,
1 H), 14.44 (br s, 1 H).
IR (KBr): 1720, 1688, 1628, 1524, 1484, 1362 cm–1.
1H NMR (CDCl3): d = 3.79 (s, 3 H), 7.67–7.69 (m, 1 H), 8.24 (s, 1
H).
Anal. Calcd for C11H5F4IO3: C, 34.05; H, 1.30. Found: C, 33.87; H,
1.19.
Methyl 2-(2,3,4,5-Tetrafluorobenzoyl)-3-(1-hydroxyprop-2-
ylamino)acrylate (10)
1-Cyclopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic Acid
(6e)
To a stirred solution of 9 (349 mg, 0.9 mmol) in anhyd THF (5 mL)
was added 2-aminopropan-1-ol (0.12 mL, 1.5 mmol) and Et3N (0.12
mL, 0.9 mmol) under ice cooling. The mixture was stirred at r.t. for
30 min, and concentrated to dryness under reduced pressure. The re-
sulting residue was purified by column chromatography on silica
gel eluting with CH2Cl2–EtOAc (3:2) to afford 10 (278 mg, 92%) as
a liquid. The product was an approximate 82:18 mixture of Z and E
isomers.
Following the procedure described for the preparation of 6a, com-
pound 6e was prepared in 85% yield as a white solid using 5e; mp
280–282 °C (Lit.10 mp 284 °C).
1H NMR (DMSO-d6): d = 1.17–1.22 (m, 2 H), 1.29–1.36 (m, 2 H),
3.82–3.90 (m, 1 H), 7.68–7.73 (m, 1 H), 8.00–8.06 (m, 1 H), 8.31
(d, J = 8.6 Hz, 1 H), 8.38 (dd, J = 8.1, 1.7 Hz, 1 H), 8.77 (s, 1 H),
15.09 (br s, 1 H).
IR (KBr): 3440, 1696, 1681, 1632, 1567, 1525, 1482 cm–1.
1-Cyclopropyl-6-methoxy-4-oxo-1,4-dihydroquinoline-3-car-
boxylic Acid (6f)
Following the procedure described for the preparation of 6a, com-
pound 6f was prepared from 5f in 90% yield as a white solid; mp
213–214 °C.
1H NMR (CDCl3): d (major isomer) = 1.36 (d, J = 6.1 Hz, 3 H), 2.05
(br s, 1 H), 3.55–3.67 (m, 2 H), 3.60 (s, 3 H), 3.74–3.80 (m, 1 H),
6.93–6.99 (m, 1 H), 8.20 (d, J = 14.3 Hz, 1 H), 10.92 (br s, 1 H).
Anal. Calcd for C14H13F4NO4: C, 50.16; H, 3.91; N, 4.18. Found: C,
50.10; H, 3.87; N, 4.16.
IR (KBr): 3424, 1721, 1613, 1547, 1470, 1447, 1285 cm–1.
1H NMR (DMSO-d6): d = 1.16–1.23 (m, 2 H), 1.25–1.35 (m, 2 H),
3.83–3.90 (m, 1 H), 3.93 (s, 3 H), 7.63 (dd, J = 9.5, 3.1 Hz, 1 H),
7.71 (d, J = 3.1 Hz, 1 H), 8.26 (d, J = 9.5 Hz, 1 H), 8.69 (s, 1 H),
15.26 (s, 1 H).
Methyl 9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyri-
do[1,2,3-de][1,4]benzoxazine-6-carboxylate (11)
To a stirred solution of 10 (268 mg, 0.8 mmol) in anhyd dioxane (3
mL) was slowly added in portions NaH (95%, 50 mg, 2.0 mmol) at
0 °C, and the mixture was stirred at reflux temperature under N2 for
4 h. H2O (3 mL) was added to the mixture and concentrated under
reduced pressure to precipitate a solid, which was collected by fil-
tration and washed with H2O and Et2O–hexane solution (1:1) to af-
ford 11 (180 mg, 76%); mp 258–260 °C.
Anal. Calcd for C14H13NO4: C, 64.86; H, 5.05; N, 5.40. Found: C,
64.62; H, 4.82; N, 5.28.
Methyl 2-[(2,3,4,5-Tetrafluorophenyl)(hydroxy)methyl]-3-io-
doprop-2-enoate (8)
To a mixture of 2,3,4,5-tetrafluorobenzaldehyde (7; 1.78 g, 10
mmol), methyl propiolate (0.98 mL, 11 mmol) and Bu4NI (4.06 g,
11 mmol) in anhyd CH2Cl2 (40 mL) was added ZrCl4 (2.80 g, 12
mmol) at 0 °C. The mixture was stirred at 0 °C under N2 for 8 h.
Then, H2O (40 mL) was added and the mixture was extracted with
CH2Cl2 (3 × 40 mL). The combined organic layers were dried
(MgSO4) and the solvent was evaporated in vacuo. The resulting
mixture was chromatographed on silica gel eluting with hexane–
EtOAc (8:1) to afford 8 (3.31 g, 85%) as a white solid, which was
recrystallized from Et2O–hexane. The product was an approximate
90:10 mixture of the Z and E isomers; mp 63–65 °C.
IR (KBr): 1724, 1624, 1569, 1530, 1487, 1448 cm–1.
1H NMR (DMSO-d6): d = 1.43 (d, J = 6.7 Hz, 3 H), 3.76 (s, 3 H),
4.45 (dd, J = 11.3, 2.4 Hz, 1 H), 4.60 (dd, J = 11.3, 2.4 Hz, 1 H),
4.81 (m, 1 H), 7.60 (dd, J = 11.0, 7.9 Hz, 1 H), 8.72 (s, 1 H).
Anal. Calcd for C14H11F2NO4: C, 56.95; H, 3.76; N, 4.74. Found: C,
56.72; H, 3.59; N, 4.60.
9,10-Difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-
de][1,4]benzoxazine-6-carboxylic Acid (12)
A suspension of 11 (89 mg, 0.3 mmol) in a mixture of 10% HCl (2
mL) and MeOH (2 mL) was stirred at reflux temperature for 8 h. Af-
ter addition of H2O (2 mL), the resulting precipitate was collected
by filtration and washed with cold H2O to give 6a (67 mg, 80%),
which was recrystallized from a mixture of CHCl3 and EtOH (1:1);
mp 309–311 °C (Lit.6a >300).
IR (KBr): 3491, 1713, 1600, 1524, 1487, 1296 cm–1.
(Z)-8
1H NMR (CDCl3): d = 3.25 (d, J = 5.8 Hz, 1 H), 3.80 (s, 3 H), 5.80
(d, J = 5.8 Hz, 1 H), 7.06–7.15 (m, 1 H), 7.45 (s, 1 H).
(E)-8
1H NMR (DMSO-d6): d = 1.48 (d, J = 6.7 Hz, 1 H), 4.50 (dd,
J = 11.3, 2.4 Hz, 1 H), 4.70 (dd, J = 11.3, 2.4 Hz, 1 H), 5.02 (m, 1
H), 7.83 (dd, J = 10.4, 7.6 Hz, 1 H), 9.01 (s, 1 H), 14.81 (br s, 1 H).
1H NMR (CDCl3): d = 3.77 (s, 3 H), 4.20 (d, J = 10.4 Hz, 1 H), 5.94
(d, J = 10.4 Hz, 1 H), 7.06–7.15 (m, 1 H), 8.20 (s, 1 H).
Anal. Calcd for C11H7F4IO3: C, 33.87; H, 1.81. Found: C, 33.78; H,
1.76.
References
Methyl 3-(2,3,4,5-Tetrafluorophenyl)-2-(iodomethylene)-3-oxo-
propanoate (9)
To a mixture of 8 (624 mg, 1.6 mmol) in anhyd CH2Cl2 (75 mL) was
added Dess–Martin periodinane (850 mg, 2 mmol). The mixture
was stirred at r.t. for 1 h. After evaporation of CH2Cl2, Et2O (100
mL) was added. Precipitated periodinane by-products were re-
moved by filtration and the filtrate was concentrated to dryness. The
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(2) Koga, H.; Itoh, A.; Murayama, S.; Suzue, S.; Irikura, T. J.
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Synthesis 2006, No. 6, 963–968 © Thieme Stuttgart · New York