A convenient one-pot synthesis of 5-carboxyisoxazoles: Trichloromethyl group as a carboxyl group precursor

Article abstract of DOI:10.1016/S0040-4039(99)02047-X

The one-pot synthesis of ten 5-carboxyisoxazoles from the cyclocondensation of β-alkoxyvinyl trichloromethyl ketones [CCl₃C(O)C(R²)=C(R¹)OR, where R¹, R²=H, Me and R=Me, Et] and 2- trichloroacetyl cyclohexanone with hydroxylamine is reported. This work shows that the trichloromethyl group attached to β-alkoxyvinyl trichloromethyl ketones (a heterocyclic CCC building block) is an excellent carboxyl group precursor.

Full text of DOI:10.1016/S0040-4039(99)02047-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 293–297
A convenient one-pot synthesis of 5-carboxyisoxazoles:
trichloromethyl group as a carboxyl group precursor
Marcos A. P. Martins,∗ Alex F. C. Flores, Giovani P. Bastos, Adilson Sinhorin,
Helio G. Bonacorso and Nilo Zanatta
Departamento de Química, Universidade Federal de Santa Maria, 97.105-900 Santa Maria, RS, Brazil
Received 24 August 1999; accepted 26 October 1999
Abstract
The one-pot synthesis of ten 5-carboxyisoxazoles from the cyclocondensation of β-alkoxyvinyl trichloromethyl
ketones [CCl3C(O)C(R2)_C(R1)OR, where R1, R2=H, Me and R=Me, Et] and 2-trichloroacetyl cyclohexanone
with hydroxylamine is reported. This work shows that the trichloromethyl group attached to β-alkoxyvinyl
trichloromethyl ketones (a heterocyclic CCC building block) is an excellent carboxyl group precursor. © 2000
Elsevier Science Ltd. All rights reserved.
1. Introduction
The isoxazole derivatives possess very interesting pharmacological properties, especially alkoxy
carbonyl isoxazoles which show marked action as a diuretic.1 Also, alkoxy carbonyl isoxazoles are
important precursors for the synthesis of other compounds such as agrochemicals and microbicides.2
The synthesis of isoxazoles from the cyclization of β-diketones, α-acetylenic ketones or aldehydes (CCC
block) with hydroxylamine (NO block), and from the condensation of nitrile oxides (CNO block) with
triple bond compounds (CC block) has been presented extensively in the literature.3 However, there are
few reports for the synthesis of 5-alkoxycarbonyl isoxazoles. These report the synthesis 5-alkoxycarbonyl
isoxazoles using methods where the building block (CCC) or (CC) already has an alkoxycarbonyl
group1,4 or a precursor group.5 In the case where the building block has a precursor of the alkoxycarbonyl
group, the conversion requires a strong oxidant agent such as potassium permanganate, chromium
trioxide or nitric acid, and leads to low yields.5 Although the transformation of the trichloromethyl group
in carboxyl derivative groups in a sulfuric acid medium was reported in 1975 for the reactions of chloral,6
the first work which shows the transformation of the trichloromethyl group attached to an isoxazole
ring derivative was reported in 1986 by Spiegler and Götz.7 These authors reported the conversion
∗
Corresponding author. Fax: +55 55 2208031; http://www.ufsm.br/nuquimhe; e-mail: mmartins@base.ufsm.br
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02047-X
tetl 15975

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of 5-trichloromethyl-5-hydroxy-4,5-dihydroisoxazoles to 5-carboxyisoxazole, using 96% sulfuric acid
at 100–120°C.7 However, this reaction was an isolated result using only one substrate and did not
demonstrate the real scope of the reaction. As a part of our research program, we developed a general
one-step procedure for preparing a series of analytically pure β-alkoxyvinyl trihalomethyl ketones, from
the acylation of several enol ethers (or acetals), in molar quantities.8 These compounds have been used
as precursors of a variety of substituted five-, six- and seven-membered heterocyclic compounds, e.g.,
isoxazoles,8,9 pyrazoles,10 pyrimidines11 and diazepines.12 The aim of this work is to report a one-pot
synthesis of 5-carboxyisoxazoles from the cyclocondensation of β-alkoxyvinyl trichloromethyl ketones
with hydroxylamine, in a hydrochloric acid or sulfuric acid medium. The trichloromethyl group attached
to β-alkoxyvinyl trichloromethyl ketones (the CCC building block) can react with water or alcohol
to form the carboxylic acid or ester derivative. In addition, we observed the substituent effect of β-
alkoxyvinyl trichloromethyl ketones on the reaction regiochemistry and product yields (Scheme 1).
Scheme 1.
2. Discussion
The β-alkoxyvinyl trichloromethyl ketones 1a–c and trichloroacetyl cyclohexanone 1d were synthesi-
zed from the reaction of the respective enol ether or acetal with trichloroacetyl chloride.8 Table 1 shows
the reaction media tested for the reaction of compounds 1a–d with hydroxylamine hydrochloride. The
reactions were carried out with hydrochloric acid (in a molar ratio 3–10:1 of acid:1) or 96% sulfuric acid
(in a molar ratio 3–5:1 of acid:1) in water, methanol, ethanol or isopropanol as solvents. The solvent
governs the product of the trichloromethyl group hydrolysis to give carboxylic acid, methyl ester, ethyl
ester or isopropyl ester. The reaction of compounds 1a,b with hydroxylamine hydrochloride in 96%
sulfuric acid (5:1, acid:1) in water, at 100°C, led regiospecifically to 5-carboxylisoxazole derivatives
2a,b. For compounds 1a,b higher temperatures (100–120°C) caused the loss of regiochemistry, and
the mixtures of 5- and 3-carboxylisoxazole derivatives were obtained. However, when the reaction was
carried out in a sulfuric acid/methanol (or ethanol) mixture (at reflux temperature) or a hydrochloric
acid/water mixture (at 40–100°C), 5-trichloromethylisoxazole derivatives were obtained. When methanol
(or ethanol) was used as solvent, the presence of 3-trichloromethylisoxazole derivatives (<20%) was
detected. An increase of sulfuric acid (>5:1, acid:1) resulted in polymerization products (Table 1).
Compounds 1c,d reacted with hydroxylamine hydrochloride in 96% sulfuric acid in water (3:1, acid:1),
at 100°C, leading to regiospecifically 5-carboxylisoxazole derivative 2c,d. For compound 1c, it was
sufficient to use hydrochloric acid in water (3:1, acid:1) to give the compound 2c. The similar reaction

295
conditions (3–10:1 of hydrochloric acid:1 in water) for compound 1d furnished the 5-trichloromethyl
isoxazole derivative (Table 1).
Table 1
Yieldsa and reaction conditionsb used for the synthesis of 5-carboxyisoxazoles 2a–d, 3, 4, 5c,d
The reactions of compounds 1c,d with hydroxylamine hydrochloride in 96% sulfuric acid (3:1, acid:1)
in methanol, ethanol or isopropanol, at the reflux temperature of the solvent, led regiospecifically to 5-
carboxylisoxazole alkyl ester derivatives 3–5c,d. The ester derivatives 3 and 5c were also obtained in
good yields using hydrochloric acid (3:1, acid:1) in the corresponding alcohol as solvent (Table 1).
Our investigation also included the reaction of 1,1,1-trichloro-4-methoxy-4-phenyl-3-buten-2-one
(R1=Ph, R2=H and R=Me) with hydroxyl amine hydrochloride. The reaction carried out in 96% sulfuric
acid (5–10:1, acid:butenone), at 100–120°C, furnished the 5-trichloromethyl isoxazole derivative only.
Finally, all 5-carboxyisoxazoles (2–5a–d) could be obtained from the reaction of 5-
trichloromethylisoxazole with water, methanol, ethanol or isopropanol in 96% sulfuric acid (3:1,
acid: isoxazole), at reflux of solvent.
Unless otherwise indicated, all common reagents and solvents were used as obtained from commercial
suppliers without further purification. Yields listed in Table 1 are of isolated compound. Selected physical
and spectral data are presented in Ref. 13. Elemental analysis was carried out on a Vario EL elemental
analysing system. 1H and 13C NMR: spectra were recorded on a Bruker AC-80 spectrometer (1H at 80
MHz and 13C at 20 MHz), 298 K, digital resolution of ±0.01 ppm, 0.5 M in chloroform-d1/TMS. The
17O NMR: spectra were recorded on a Bruker DPX 400 at 54.25 MHz, at 313±1 K and the general
reproducibility of chemical shift data is estimated to be better than ±1.0 ppm, the half-height widths
were in the range 220–600 Hz. All spectra were acquired in a 10 mm tube, at natural abundance,
2.0 M in acetonitrile-d3 (referenced to external H2O, in a capillary coaxial tube). For synthesis of 5-
trichloromethyl isoxazole derivatives see Refs. 8 and 9.
2.1. Synthesis of 5-carboxyisoxazoles acid 2a–d: general procedure
To a stirred solution of β-alkoxyvinyl trichloromethyl ketones 1 (10 mmol) in water (10 mL), at room
temperature, hydroxylamine hydrochloride (0.84 g, 12 mmol) in 96% sulfuric acid (2.94–4.90 g, 30–50
mmol) was added. The mixture was stirred for 2–4 h, then heated at 90–95°C for 8 h. The product 2
was obtained in high purity by filtration from the cold reactional mixture, and washed with water. The
product was recrystalized in hexane (Table 1 and Ref. 13).

296
2.2. Synthesis of 5-carboxyisoxazoles acid esters 3–5c,d: general procedure
To a stirred solution of β-alkoxyvinyl trichloromethyl ketone 1 (10 mmol) in 10 mL of alcohol
(methanol, ethanol or isopropanol, for obtention of 3, 4, or 5, respectively), at room temperature, was
added hydroxylamine hydrochloride (0.84 g, 12 mmol) in 96% sulfuric acid (2.94 g, 30 mmol). The
mixture was stirred for 2–4 h, then heated to the reflux point of the solvent for 4–8 h. After evaporation of
the excess of alcohol in the reaction mixture containing 3 and 4c, the residue was dissolved in chloroform
and washed (3×10 mL) with water and with a 5% solution of potassium carbonate (1×10 mL). After
evaporation of the solvent, the product was obtained by distillation; the products 5c,d were purified by
column chromatography with silica gel 60, 70–230 mesh using the mixture dichloromethane:hexane (1:1)
as eluent; and the products 3 and 4d were recrystallized from hexane (Table 1 and Ref. 13).
2.3. Synthesis of 5-carboxyisoxazoles acid derivatives from 5-trichloromethylisoxazoles: general pro-
cedure
To a stirred solution of 5-trichloromethylisoxazole derivative (5 mmol) a solution (1:1, v/v) of 96%
sulfuric acid (1.47 g, 15 mmol) and water, methanol, ethanol or isopropanol, at room temperature was
added. The mixture was then heated to reflux for 4–8 h. The products were isolated and purified as
described above.
Acknowledgements
The authors thank the Conselho Nacional de Desenvolvimento Científico e Tecnológico
(CNPq/PADCT III, Contract No. 62.0228/97-0-QEQ), Fundação de Amparo à Pesquisa do Estado
do Rio Grande do Sul (FAPERGS) for financial support and fellowships.
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Bonacorso, H. G.; Zanatta, N.; Siqueira, G. M.; Flores, A. F. C. Tetrahedron Lett. 1999, 40, 4309.
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217. Martins, M. A. P.; Freitag, R. A.; Flores, A. F. C.; Zanatta, N. Synthesis 1995, 1491. Bonacorso, H. G.; Oliveira, M. R.;
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13. All compounds 2–5 were fully characterized by spectroscopic methods. Data for 2a: C4H3NO3, m.p. 142–143°C (lit. 7:
144°C; lit. 13, 144–149°C); 1H NMR: δ 8.8 (H3, 1.9), 7.16 (H4, 1.9); 13C NMR: δ 157.8 (COOH), 109.0 (C4), 151.9 (C3),
160.7 (C5); 17O NMR: δ 352 (O1), 258 (C_O, OH); anal. calcd: C, 42.47; H, 2.68; N, 12.39; found: C, 42.30; H, 2.70;
N, 12.50; 2b: C5H5NO3, mp 208–210°C; 1H NMR: δ 2.3 (3H, CH3), 6.98 (H4); 13C NMR: δ 158.7 (COOH), 110.3 (C4),
161.6 (C3), 161.4 (C5); 17O NMR: δ 347 (O1), 262 (C_O, OH); anal. calcd: C, 42.23; H, 3.97; N, 11.02; found: C, 42.32;
H, 4.02; N, 11.00; 2c: C5H5NO3, mp 159–160°C; 1H NMR: δ 8.33 (H3), 2.25 (3H, CH3); 13C NMR: δ 154.0 (C3), 121.9
(C4), 155.3 (C5), 158.4 (COOH); 17O NMR: δ 347 (O1), 258 (C_O, OH); anal. calcd: C, 42.23; H, 3.97; N, 11.02; found:
1
C, 42.32; H, 4.02; N, 11.09; 2d: C8H9NO3, mp 128–130°C; H NMR: δ 2.75–2.82 (8H, -(CH2)4-); 13C NMR: δ 160.8
(COOH), 123.2 (C4), 152.9 (C3), 162.1 (C5); 17O NMR: δ 347 (O1) 259 (C_O, OH); anal. calcd: C, 57.46; H, 5.43; N,
1
8.39; found: C, 57.61; H, 5.44; N, 8.51; 3c: C6H7NO3, oil; H NMR: δ 8.21 (H3), 2.32 (3H, CH3); 13C NMR: δ 152.9
(C3), 121.0 (C4), 154.6 (C5), 157.8 (COOR); 17O NMR: δ 354 (O1, C_O)144 (OMe); anal. calcd: C, 51.05; H, 5.00; N,
9.93; found: C, 49.87; H, 4.97; N, 9.84; 3d: C9H11NO3, mp 73–75°C; 1H NMR: δ 2.70–2.89 (8H, -(CH2)4-); 13C NMR: δ
157.5 (C3), 121.4 (C4), 152.9 (C5), 161.4 (COOR); 17O NMR: δ 342 (O1), 354 (C_O), 143 (OMe); anal. calcd: C, 59.64;
1
H, 6.12; N, 7.73; found: C, 59.49; H, 6.04; N, 7.65; 4c: C7H9NO3, bp 69–71°C/20 mBar; H NMR: δ (J, Hz) 8.21 (H3,
0.35), 2.32 (CH3, 0.35); 13C NMR: δ 152.9 (C3), 120.8 (C4), 154.7 (C5), 157.3 (COOR); 17O NMR: δ 354 (O1, C_O), 174
(OEt); anal. calcd C, 54.16; H, 5.85; N, 9.03; found: C, 54.15; H, 5.87; N, 8.95; 4d: C10H15NO3, mp 66–67°C; 1H NMR: δ
2.71–2.86 (8H, -(CH2)4-); 13C NMR: δ 157.5 (C3), 121.6 (C4), 153.5 (C5), 161.7 (COOR); Anal. calcd C, 61.51; H, 6.72;
N, 7.18; found: C, 61.61; H, 6.67; N, 7.06; 5c: C8H11NO3, oil; 1H NMR: δ (J, Hz) 8.3 (H3, 1.1), 2.27 (CH3, 1.1); 13C NMR:
δ 153.0 (C3), 120.5 (C4), 155.0 (C5), 157.0 (COOR); anal. calcd: C, 56.78; H, 6.56; N, 8.28; found: C, 56.70; H, 6.60; N,
8.21; 5d: C11H15NO3, mp 43–45°C; 1H NMR: δ 2.70–2.86 (8H, -(CH2)4-); 13C NMR: δ 157.0 (C3), 121.2 (C4), 153.6 (C5),
161.6 (COOR); 17O NMR: δ 343 (O1), 352 (C_O, 198 (O–iPr); anal. calcd C, 63.13; H, 7.23; N, 6.70; found: C, 63.10; H,
7.30; N, 6.74.