Synthesis of 4-hydroxy-3-quinolinecarboxylic acid derivatives by a condensation/cyclization sequence between o-isocyanobenzoates and magnesium enolates

Article abstract of DOI:10.1246/cl.2001.602

Addition of magnesium ester and amide enolates, generated using an excess amount of a magnesium amide (from diisopropylamine and ethylmagnesium bromide), to o-isocyanobenzoates affords 4-hydroxy-3-quinolinecarboxylic esters and amides by a tandem Claisen-type condensation/cyclization sequence.

Full text of DOI:10.1246/cl.2001.602

602
Chemistry Letters 2001
Synthesis of 4-Hydroxy-3-quinolinecarboxylic Acid Derivatives by a Condensation/Cyclization
Sequence between o-Isocyanobenzoates and Magnesium Enolates
Kazuhiro Kobayashi,* Toshio Nakashima, Masaaki Mano, Osamu Morikawa, and Hisatoshi Konishi
Department of Materials Science, Faculty of Engineering, Tottori University, Koyama-minami, Tottori 680-8552
(Received April 4, 2001; CL-010305)
Addition of magnesium ester and amide enolates, generat-
ed using an excess amount of a magnesium amide (from diiso-
propylamine and ethylmagnesium bromide), to o-isocyanoben-
zoates affords 4-hydroxy-3-quinolinecarboxylic esters and
amides by a tandem Claisen-type condensation/cyclization
sequence.
In connection with the program we have designed to
explore the utility of magnesium enolates, generated using mag-
nesium amides,1 in organic synthesis, we investigated reactions
between o-isocyanobenzoate 32 and magnesium ester or amide
enolates toward the synthesis of 4-hydroxy-3-quinolinecar-
boxylic acid derivatives 5. This class of molecules were impor-
tant due to not only their biological activities3 but also their use
for the preparation of other biologically important compounds.4
Although 4-hydroxy-3-quinolinecarboxylates have been pre-
pared by the condensation of anilines with alkoxymethylene-
malonates,5 a few new method for the syntheses of these deriv-
atives have recently been reported.6 Our results, which offer an
efficient new method for the preparation of 4-hydroxy-3-quino-
linecarboxylic acid esters and amides, are described in this
paper.
The starting 2-isocyanobenzoates 3 were prepared in good
yields as shown in Scheme 1. 2-Aminobenzoates 1 were con-
verted into the corresponding 2-(formylamino)benzoates 2 by
the formylation with formic acid, which were then dehydrated
with POCl3/Et3N to give 3. These isocyanides were isolable by
column chromatography on silica gel and was somewhat unsta-
ble at room temperature. However, they were storable for sev-
eral days at refrigerator temperature.7
cyanobenzoates gave keto ester (or amide) intermediates 4.
Cyclization with the second molar of MBDA leading to the for-
mation of 4-hydroxy-3-quinolinecarboxylic acid esters and
amides 5 was achieved by stirring the reaction mixtures for an
additional 2 h (Scheme 2). As shown in Table 1, fair-to-good
yields of desired products 5 were generally obtained.
Exceptional is the reaction of 3a with methyl acetate, which
resulted in the formation of an intractable mixture of products
(Entry 1). This may be attributable to the high self-condensa-
tion ability of methyl acetate. This methyl ester 3a was used in
the condensation with t-butyl acetate to give the corresponding
3-quinolinecarboxylate 5g (Entry 7). We also found that con-
densation of compounds 3a with N,N-dimethylacetamide fol-
lowed by cyclization smoothly took place to give 3-quino-
linecarbamide 5h (Entry 8). The use of lithium diisopropyl-
amide in place of MBDA gave rather poor results. For exam-
ple, in the LDA-mediated reaction of 3d with butyl acetate only
up to ca. 25% yield of the desired product was detected in the
These isocyanobenzoates 3 were subjected to reaction with
magnesium enolates, generated by treating acetates or N,N-
dimethylacetamide with magnesium bis(diisopropylamide)
(MBDA). The Claisen-type condensation of enolates with iso-
1
reaction mixture, as judged by H NMR. The bivalent magne-
sium ion, which probably stabilizes the anionic intermediate,
arising from the attack of the keto enolate on the isocyano car-
Copyright © 2001 The Chemical Society of Japan

Chemistry Letters 2001
603
Haemers, B. D. Vanden, S. R. Pattyn,W. Bollaert, and I.
Levshin, J. Heterocycl. Chem., 28, 685 (1991); P. Guerry, S.
Jolidon, R. Masciadri, H. Staider, and R. Them, PCT Int.
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bon, to promote the cyclization step, might be responsible for
the success of the present reaction sequence.
A typical procedure is illustrated by the preparation of
ethyl 4-hydroxy-3-quinolinecarboxylate (5b). To a stirred tur-
bid solution of a magnesium amide (0 °C), generated by treat-
ing ethylmagnesium bromide (11 mmol) with diisopropylamine
(11 mmol, 1.1 g) in refluxing ether (15 mL), was added ethyl
acetate (3.6 mmol, 0.32 g) dropwise. After 5 min, a solution of
ethyl 2-isocyanobenzoate (2b) (1.8 mmol, 0.31g) in diethyl
ether (5 mL) was added, and stirring was continued for an addi-
tional 2 h. The resulting mixture was treated with saturated
aqueous ammonium chloride and extracted with
dichloromethane three times. The combined extracts were
washed with brine, dried over anhydrous sodium sulfate, and
evaporated. The residual solid was triturated with
hexane–diethyl ether to give the crude 5b (0.35 g), which was
recrystallized from chloroform to give pure 5b (0.31 g, 79%).8
In summary, a novel and convenient synthesis of 4-
hydroxy-3-quinolinecarboxylic acid derivatives has been
achieved. The present method may find some value in organic
synthesis, because the reaction procedure is simple and the
starting materials are readily available.
5
6
K. Uneyama, O. Morimoto, and F. Yamashita, Tetrahedron
Lett., 30, 4821 (1989); E. J. Latham, S. M. Murphy, and S. P.
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nent references in ref 3.
7
3a:2 Rf 0.41 (1:4 AcOEt–hexane); IR (neat) 2127, 1732 cm–1;
1H NMR (270 MHz, CDCl3) δ 3.98 (3H, s), 7.4–7.6 (3H, m),
8.01 (1H, dd, J = 8.0, 1.6 Hz); MS m/z 161 (M+, 37), 146
(53), 130 (92), 102 (100). 3b: Rf 0.56 (1:4 AcOEt–hexane);
1
IR (neat) 2125, 1730 cm–1; H NMR (270 MHz, CDCl3) δ
1.44 (3H, t, J = 7.3 Hz), 4.45 (2H, q, J = 7.3 Hz), 7.4–7.6
(3H, m), and 8.00 (1H, dd, J = 8.1, 1.7 Hz); MS m/z 175 (M+,
29), 130 (100). 3c: Rf 0.54 (1:4 AcOEt–hexane); IR (neat)
1
2125, 1731 cm–1; H NMR (270 MHz, CDCl3) δ 1.06 (3H, t,
J = 7.3 Hz), 1.75–1.9 (2H, m), 4.35 (2H, t, J = 6.6 Hz),
7.4–7.6 (3H, m), 8.01 (1H, dd, J = 7.3, 2.3 Hz); MS m/z 189
(M+, 4.1), 188 (4.5), 174 (43), 130 (100). 3d: Rf 0.54 (1:4
1
AcOEt–hexane); IR (neat) 2125, 1731 cm–1; H NMR (270
MHz, CDCl3) δ 0.98 (3H, t, J = 7.3 Hz), 1.45–1.6 (2H, m),
1.7–1.85 (2H, m), 4.39 (2H, t, J = 6.6 Hz), 7.4–7.6 (3H, m),
8.00 (1H, dd, J = 7.6, 1.7 Hz); MS m/z 203 (M+, 0.42), 188
(9.3), 174 (38), 130 (83), 102 (100). 3e: mp 58–60 °C (hexa-
Appreciation is expressed to Mrs. Miyuki Tanmatsu of this
Department, for determining the mass spectra.
1
ne); IR (KBr disk) 2131, 1732 cm–1; H NMR (270 MHz,
CDCl3) δ 1.06 (3H, t, J = 7.3 Hz), 1.75–1.95 (2H, m), 4.36
(2H, t, J = 6.5 Hz), 7.42 (1H, d, J = 8.6 Hz), 7.53 (1H, dd, J =
8.6, 2.3 Hz), 7.98 (1H, d, J = 2.3 Hz); MS m/z 223 (M+, 5.3),
208 (22), 181 (47), 164 (100). 3f: mp 100–102 °C
References and Notes
1
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1
(hexane–Et2O); IR (KBr disk) 2130, 1703 cm–1; H NMR
(270 MHz, CDCl3) δ 1.06 (3H, t, J = 7.3 Hz), 1.75–1.95 (2H,
m), 3.94 (6H, s), 4.34 (2H, t, J = 6.6 Hz), 6.90 (1H, s), 7.47
(1H, s); MS m/z 249 (M+, 12), 207 (100).
8
5b: mp 267–270 °C (Et2O) (lit.9 270 °C); 5c: mp 67–69 °C
(Et2O); IR (KBr disk) 3400–2700, 1716, 1645, 1611 cm–1; 1H
NMR (270 MHz, CDCl3) δ 0.99 (3H, t, J = 7.3 Hz), 1.6–1.8
(2H, m), 4.13 (2H, t, J = 7.1 Hz), 5.75 (1H, s), 7.3–7.4 (2H,
m), 7.45–7.6 (2H, m, including s at 7.54), 7.62 (1H, d, J = 7.9
Hz); MS m/z 231 (M+, 5.8), 189 (9.6), 172 (37), 145 (100).
5d: mp 220–225 °C (Et2O); IR (KBr disk) 3400–2700, 1702,
1616 cm–1; 1H NMR (270 MHz, DMSO-d6) δ 0.92 (3H, t, J =
7.3 Hz), 1.3–1.5 (2H, m), 1.55–1.7 (2H, m), 4.16 (2H, t, J =
6.6 Hz), 7.40 (1H, t, J = 8.2 Hz), 7.60 (1H, d, J = 8.2 Hz),
7.68 (1H, t, J = 8.2 Hz), 8.15 (1H, d, J = 8.2 Hz), 8.51 (1H,
s), 11.23 (1H, br s); MS m/z 245 (M+, 17), 171 (100). 5e: mp
128–132 °C (Et2O–CHCl3); IR (KBr disk) 3400–2700, 1729,
2
3
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1
1651, 1609 cm–1; H NMR (270 MHz, CDCl3) δ 0.99 (3H, t,
J = 7.3 Hz), 1.6–1.8 (2H, m), 4.12 (2H, t, J = 6.9 Hz), 5.70
(1H, s), 7.31 (1H, d, J = 8.6 Hz), 7.47 (1H, dd, J = 8.6, 2.3
Hz), 7.51 (1H, s), 7.58 (1H, d, J = 2.3 Hz); MS m/z 265 (M+,
14), 223 (17), 206 (37), 179 (100). 5f: mp 163–165 °C
(Et2O); IR (KBr disk) 3400–2700, 1699, 1642, 1612 cm–1; 1H
NMR (270 MHz, CDCl3) δ 1.00 (3H, t, J = 7.3 Hz), 1.6–1.8
(2H, m), 3.94 (6H, s), 4.13 (2H, t, J = 6.9 Hz), 5.54 (1H, s),
6.86 (1H, s), 6.94 (1H, s), 7.54 (1H, s); MS m/z 291 (M+, 17),
205 (100). 5g: mp 175–180 °C (CHCl3); IR (KBr disk)
3400–2700, 1697, 1630 cm–1; 1H NMR (270 MHz, CDCl3) δ
1.52 (9H, s), 5.67 (1H, s), 7.3–7.4 (2H, m), 7.50 (1H, t, J =
7.0 Hz), 7.52 (1H, s), 7.58 (1H, d, J = 7.9 Hz); MS m/z 245
(M+, 14), 189 (100). 5h: mp 76–79 °C (CHCl3); IR (KBr
4
D. Humbert, J. C. Gasc, and P. F. Hunt, Eur. Patent, 168309
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1
disk) 3400–2700, 1631 cm–1; H NMR (270 MHz, CDCl3) δ
3.08 (6H, s), 5.97 (1H, s), 7.4–7.5 (4H, m), 7.79 (1H, dd, J =
7.9, 2.0 Hz); MS m/z 217 (11), 216 (M+, 10), 172 (79), 116
(100).
9
G. F. Duffin and J. D. Kendall, J. Chem. Soc., 1948, 893.