Synthesis of isomeric isoxazolopyridinones

Article abstract of DOI:10.1007/PL00010140

Reaction of 4-methylamino-5,6-dihydropyridinone with acetyl chloride yielded exclusively the 3-acetyl derivative. When the methylamino group of the latter was removed by alkaline hydrolysis, a mixture of two hydroxy derivatives was formed. Those cyclized upon treatment with hydroxylamine exclusively to the isoxazolo[4,5-c]pyridinone, whereas the 4-methylamino analogue yielded, depending on pH, mainly the isoxazolo[4,3-c]pyridinone or the isoxazolo[4,5-c]pyridinone. The configurations of the latter compounds were established by NMR experiments.

Full text of DOI:10.1007/PL00010140

Monatshefte fuÈr Chemie 129, 1285±1292 (1998)
Synthesis of Isomeric Isoxazolopyridinones
Robert Weis1;Ã, Klaus Schweiger1, and Walter M. F. Fabian2
1
È
Institut fuÈr Pharmazeutische Chemie, Karl-Franzens-Universitat Graz, A-8010 Graz
È
Institut fuÈr Organische Chemie, Karl-Franzens-Universitat Graz, A-8010 Graz
2
Summary. Reaction of 4-methylamino-5,6-dihydropyridinone with acetyl chloride yielded
exclusively the 3-acetyl derivative. When the methylamino group of the latter was removed by
alkaline hydrolysis, a mixture of two hydroxy derivatives was formed. Those cyclized upon
treatment with hydroxylamine exclusively to the isoxazolo[4,5-c]pyridinone, whereas the
4-methylamino analogue yielded, depending on pH, mainly the isoxazolo[4,3-c]pyridinone or the
isoxazolo[4,5-c]pyridinone. The con®gurations of the latter compounds were established by NMR
experiments.
Keywords. 3-Acetyl-4-methylaminopyridin-2-one; Hydrogen bridge bond; 4-Hydroximinopyridin-
2-one; 3-(1-Hydroxyethyliden)-piperidin-2,4-dione; Isoxazolo[4,3-c]pyridinone; Isoxazolo[4,5-c]-
pyridinone.
Synthese isomerer Isoxazolopyridinone
Zusammenfassung. Bei der Umsetzung von 4-Methylamino-5,6-dihydropyridinon mit Acetyl-
chlorid entstand ausschlieûlich das 3-Acetylderivat. Bei der alkalischen Hydrolyse der Methylami-
nogruppe entstand ein Gemisch zweier Hydroxyderivate. Diese reagieren mit Hydroxylamin zum
È
È
Isoxazolo[4,5-c]pyridinon, wahrend das 4-Methylaminoanaloge in Abhangigkeit vom pH-Wert zum
Isoxazolo[4,3-c]pyridinon oder zum Isoxazolo[4,5-c]pyridinon cyclisiert. Die Kon®guration der
letzteren Verbindungen wurde durch NMR-Messungen gesichert.
Introduction
Isoxazolo[4,5-c]pyridin-4-ones (1) are known as hypolipidemic agents [1].
Moreover, they are used as precursors for hypnotics, muscle relaxants, and
tranquilizers [2, 3]. Usually they are prepared from isoxazoles [1±5], but a few
years ago a dihydropyridin-2(1H)-one was reacted with N, ꢀ-diphenylnitrone to
give selectively the respective isoxazolo[4,5-c]pyridin-4-one in excellent yield [6].
Isoxazolo[4,3-c]pyridin-4-ones (2) are relevant synthons for analogues to
herbicides [7±9]. They are available by thermolysis of 3-acetyl-4-azido-2-
pyridinones [7±10].
This paper presents the preparation of the two isomeric isoxazolopyridin-4-
ones and the feasibility of in¯uencing the isomer ratio.
Ã
Corresponding author

1286
R. Weis et al.
Scheme 1
Results and Discussion
Our method is based on the reaction of 4-substituted 3-acetyldihydropyridin-2-ones
with hydroxylamine affording isoxazolo[4,3-c]pyridinones or isoxazolo[4,5-c]-
pyridinones. The con®guration of these isomers is directed both by the reaction
conditions and the substitution at C-4. 4-Methylamino-5,6-dihydropyridin-2(1H)-
one 3 [11] serves as starting material. Under Friedel-Crafts reaction conditions, the
methylamino group of 3 is not attacked, and with acetyl chloride the 3-acetyl
derivative 4 is obtained selectively. In its 1H NMR spectrum the hydrogen bond of
4 is characterized by a 6 ppm down®eld shift of the signal for the methylamino
proton as compared to 3. The corresponding tautomer 5 is ruled out by a 5.5 Hz
coupling between the NH and the methyl proton.
The 4-aminopyridin-2-one 4 is hydrolyzed by potash lye yielding a mixture of
two tautomeric hydroxy compounds (6 and 7) in a ratio of 4:1. Hydrogen bonds in
both structures were indicated by the extreme down®eld shift (>17 ppm) of the
resonances of the OH groups in their NMR spectra. The signals in the 13C NMR
spectra were assigned by means of heteronuclear shift correlation experiments
which were optimized for long-range couplings. Crosspeaks in those spectra from
OH to ring carbon atom 2 and C-1 of the ethylidene group established the main
component to exist in an equilibrium between structures 6a and 6b, predominantly
favouring 6a, as indicated by a much smaller cross peak to C-2 in analogy to the
cross peak from the OH proton to the carbonyl carbon in salicylaldehyde.
Furthermore, we observed a coupling of the C-1 of the ethylidene group which
disappeared upon treatment with deuterium oxide. The value of 3J(COH) ˆ 4.6 Hz
coincides exactly with the corresponding coupling in salicylaldehyde [12].
For the by-product, no such correlations were visible in coupled spectra, and
the respective cross peaks were missing in the above mentioned long range
experiment. Increasing the number of scans did not lead to improved quality of the
spectra due to folding of the large cross peaks of the methyl and methylene groups;
Scheme 2

Synthesis of Isoxazolopyridinones
1287
Scheme 3
its interpretation was not possible beyond all doubt. The problem was solved by a
further experiment which was run using real-time digital signal processing to
supress peaks coming from outside the region of interest in the 1H domain (digital
®ltering). For the OH group of the by-product, we obtained two cross peaks with
approximately equal intensity to C-4 and the exocyclic carbon, respectively,
establishing the equilibrium 7a, 7b.
Hydroxylamine has been reported to attack ꢀ,ꢁ-unsaturated 3-aminoketones at
the carbon atom bearing the amino group rather than the carbonyl group [13±15].
However, the 4-methylamino compound 4 gave, depending on reaction conditions,
differently composed mixtures of the two possible isoxazolopyridinones 8 and 9. In
faintly acid environment, approximately equal amounts of the isomers 8 and 9 were
obtained. The base-catalized reaction yielded the isoxazolo[4,3-c]pyridinone 8,
whereas under strongly acidic conditions the isoxazolo[4,5-c]pyridinone 9 was
formed, most probably due to protonation of the amino group. The hydroxy
Scheme 4

1288
R. Weis et al.
compounds 6 resp. 7 gave exclusively the isoxazolo[4,5-c]pyridinone 9 in neutral
and faintly acid environment.
Some authors revealed confusion of previously published fused isoxazoles with
the corresponding oxazoles or reported about remaining uncertainties concerning
that isomer problem when structure elucidation was based solely on spectroscopic
methods [8, 16]. Evidence of structure was furnished by alternative syntheses,
respectively [8, 16]. We investigated 8 and 9 by means of NMR measurements and
®nally compared the chemical shifts in 13C NMR spectra to those of 2-methyl-
oxazolo- and 3-methyl-isoxazoloquinolones with already con®rmed structures [8].
For compounds 8 and 9 we assigned the signals in the 13C NMR spectra with the
aid of ge-HMQC spectra which were optimized for 10 Hz. If 8 and 9 were
oxazolopyridinones, the ring-atoms bearing the single methyl group should have
similar 13C NMR shifts. Actually, it differs by about 13 ppm. The signals for the
3-methyl groups in both compounds appear roughly at 11 ppm, which is also
typical for fused 3-methyl-isoxazoles [17±22] and not for 2-methyl-oxazoles
resonating usually at 14 ppm [16, 23, 24]. Moreover, an oxazolopyridinone
structure is de®nitely ruled out by comparison with the corresponding shifts for the
above-mentioned reference compounds in the 13C NMR spectra, suggesting good
correlations only between 8, 9 and 3-methyl-isoxazoloquinolones.
The oxygen bearing C-3 in 9 is expected to resonate more than 10 ppm [25, 26]
down®eld from the nitrogen bearing C-3 in 8. The same effect should be
observable for the shifts of C-7a in both compounds. In fact, shift differences of
approximately 13 ppm made the distinction between both compounds feasible.
The deacetylated compounds 10a, b and 11a, b were isolated as by-products
and in some cases even as major products (see Table). The tautomers 10a, b had
already been prepared from the 4-methylaminopyridin-2-one 3 [27]. When
1
measured in DMSO-d6, the oximes 11a, b appear in a ratio of 4.3:1 in the H
NMR spectrum. The C=NOH fragments were easily identi®ed by their typical
chemical shifts [28], exhibiting resonances at 10.6 ppm in the 1H NMR spectra and
at 151 ppm in the 13C NMR spectra. Alternatively, they were synthesized from 10a,
b. Their resonances in the NMR spectra were assigned by means of ge-HMQC
spectra optimized for 10 Hz couplings. The distinction of syn- and anti-isomers
succeeded by means of NOE experiments. Upon irradiation of H-3 in 11A resp.
H-5 in 11B, we observed NOEs at the NOH groups. Typical up®eld shifts [29] in
the 13C NMR spectra for C-3 resp. C-5 in syn position to the OH group established
the assignments.
Dihydropyridin-2(1H)-ones are valuable synthons for the preparation of
isoxazolopyridin-4-ones. The isomer ratio of the products may be controlled by
Scheme 5

Synthesis of Isoxazolopyridinones
1289
Table 1. Yields of reaction products (given for isolated products unless stated otherwise)
Starting
material
Method A
Method B
Method C
Method D
(basic)
(neutral)
(faintly acidic)
(acidic)
4
8 (14.5%)
11a, b (55.0%)
8 (16.7%)
11a, b (65.7%)
8a (23.7%)
9a (26.6%)
11a, b (3.7%)
9 (62.7%)
9 (31.9%)
10a, b (13.3%)
11a, b (23.9%)
9 (2.2%)
6, 7
10a, b (58.0%)
11a, b (17.1%)
9 (51.8%)
11a, b (31.1%)
10a, b (36.8%)
11a, b (41.4%)
a
1
Compounds not isolated; yields determined by H NMR integration after separation of 11a, b
the substitution of C-4 as well as by the reaction conditions. The formation of both
isomers is a helpful support for unequivocal structure elucidation.
Experimental
All melting points (BuÈchi 510) are uncorrected; IR: Perkin Elmer 2000 FT-IR; NMR: Varian INOVA
(400 MHz), internal standard: TMS; microanalyses: Microanalytical Laboratory at the Institute of
Physical Chemistry, University of Vienna; their values were in satisfactory agreement with the
calculated ones; ¯ash chromatography: column diameter 30 mm, layer thickness 40mm, Merck silicagel
60, 0.040±0.063 mm (230±400 mesh), rate of ¯ow: 30 ml/min, eluent: CH2Cl2:CH3OH ˆ 19:1
3-Acetyl-4-methylamino-6,6-dimethyl-5,6-dihydropyridin-2(1H)-one (4; C10H16N2O2)
Aluminum chloride (0.012 mol) was dissolved in 30 ml of nitrobenzene. Then, 0.011 mol acetyl
chloride were added dropwise to the ice-cooled solution. Finally, 0.01 mol of compound 3 were
added, and the mixture was stirred at room temperature for 16 h. The solution was diluted with
100 ml CHCl3 and poured on ice. The aqueous layer was neutralized and extracted once with 30 ml
CHCl3. The combined organic layers were carefully washed with H2O, NaHCO3 solution, H2O, and
brine. After drying over Na2SO4, the solvents were removed in vacuo. The crystalline residue was
triturated with 2-propanol, ®ltered with suction, and recrystallized from 2-propanol.
Yield: 1.46 g (74.4%); m.p: 227 ꢀC; IR (KBr): ꢀv ˆ 3250(w), 3160(w), 1755(s), 1693(s), 1607(s),
1576(m), 1306(s), 1188(s) cmꢁ1; 1H NMR (CDCl3, ꢂ, 400 MHz): 1.26 (s, 6H, (CH3)2), 2.50 (s, 2H,
5-H), 2.51 (s, 3H, COCH3), 2.98 (d, J ˆ 5.5 Hz, 3H, NCH3), 5.41 (s, 1H, NH), 12.32 (br, 1H,
NHCH3) ppm; 13C NMR (CDCl3, ꢂ, 100 MHz): 28.67 (CH3)2, 29.86 (NCH3), 31.33 (COCH3), 38.39
(C-5) 48.56 (C-6), 99.58 (C-3), 167.41 (C-2), 168.08 (C-4), 199.44 (COCH3) ppm.
3-(1-Hydroxyethyliden)-6,6-dimethylpiperidine-2,4-dione and its tautomers (6, 7; C6H13NO3)
Compound 4 (0.01 mol) was added to an aqueous ethanolic solution of 0.03 mol KOH, and the
mixture was re¯uxed for 8 h. After cooling, the mixture was concentrated to a small volume in
vacuo. The residue was acidi®ed with HCl and extracted three times with CHCl3. The organic layer
was washed with H2O and brine and dried over Na2SO4. The solvent was removed and the residue
recrystallized from H2O. Yield: 1.20 g (65.5%) 6 and 0.30 g 7 (16.4%); m.p.: 109 ꢀC; IR (KBr):
ꢀv ˆ 3255(w), 2976(w), 1755(s), 1645(s), 1635(s), 1570(m) cmꢁ1
.
1
6 (main product): H NMR (CDCl3, ꢂ, 400 MHz): 1.33 (s, 6H, (CH3)2), 2.52 (s, 2H, 5-H), 2.56
(s, 3H, CH3), 5.72 (br, s, 1H, NH), 17.65 (s, 1H, OH) ppm; 13C NMR (CDCl3, ꢂ, 100 MHz): 24.56

1290
R. Weis et al.
(CH3), 28.71 (CH3)2, 50.31 (C-6), 51.09 (C-5), 100.89 (C-3), 173.02 (C-2), 191.50 (C-4), 192.45
(COH) ppm.
1
7 (by-product): H NMR (CDCl3, ꢂ, 400 MHz): 1.32 (s, 6H, (CH3)2), 2.61 (s, 2H, 5-H), 2.63
(s, 3H, CH3), 5.50 (br, s, 1H, NH), 17.65 (s, 1H, OH) ppm; 13C NMR (CDCl3, ꢂ, 100 MHz): 25.71
(CH3), 28.97 (CH3)2, 46.68 (C-5), 49.30 (C-6), 105.05 (C-3), 165.60 (C-2), 196.07 (C-4), 197.65
(COH) ppm.
Reaction of 4 resp. 6, 7 with hydroxylamine
Method A: NH2OH Á HCl (3 mmol) was added to a solution of 6 mmol Na in 50 ml abs. alcohol. The
mixture was re¯uxed for 1 h. The 5, 6-dihydropyridinone (1 mmol) was added, and re¯uxing was
continued for 4 h. The mixture was cooled, diluted with 30 ml ethanol, and neutralized with HCl. The
solution was evaporated to dryness. The residue was treated with warm ethanol and ®ltered to
remove the inorganic salt. The solvent was removed in vacuo, and the residue was treated with
chloroform/ethyl acetate (1:3). The insoluble compounds 10a, b resp. 11a, b were removed by
®ltration. The ®ltrate was evaporated and the residue recrystallized. Compounds 10a, b and 11a, b
were ± if necessary ± separated by ¯ash chromatography.
Method B: NH2OH Á HCl (3 mmol) was added to a solution of 3 mmol Na in 30 ml abs. alcohol.
The mixture was re¯uxed for 1 h. The 5, 6-dihydropyridinone (1 mmol) was added, and re¯uxing was
continued for 18 h. The mixture was cooled, diluted with 30 ml ethanol, and the inorganic salt was
removed by ®ltration. Further workup was performed according to method A.
Method C: NH2OH Á HCl (3 mmol) was added to a solution of 1.5 mmol Na in 30 ml abs. alcohol.
The mixture was re¯uxed for 1 h. The 5, 6-dihydropyridinone (1 mmol) was added, and re¯uxing was
continued for 12 h. The mixture was cooled and diluted with 30 ml ethanol, and the inorganic salt
was removed by ®ltration. Further workup was performed according to method A.
Method D: The 5, 6-dihydropyridinone (1 mmol) was mixed with 3 mmol NH2OH Á HCl and
0.1 ml concentrated HCl in 30 ml absolute alcohol. The mixture was re¯uxed for 12 h, diluted with
30 ml ethanol, neutralized, and evaporated to dryness. The residue was treated with warm ethanol
and ®ltered. Further workup was performed according to method A.
3,6,6-Trimethyl-6,7-dihydro-isoxazolo[4,3-c]pyridin-4(5H)-one (8; C9H12N2O2)
Yield: see Table; m.p.: 189ꢀC (2-propanol); IR (KBr): ꢀv ˆ 3203(m), 1678(s), 1431(m), 1371(m),
1
1255(m), 1152(m), 797(m) cmꢁ1; H NMR (DMSO-d6, ꢂ, 400 MHz): 1.24 (s, 6H, (CH3)2), 2.60
(s, 3H, CH3), 2.85 (s, 2H, 7-H), 7.85 (s, 1H, NH) ppm; 13C NMR (DMSO-d6, ꢂ, 100 MHz): 11.78
(CH3), 28.59 (CH3)2, 33.29 (C-7), 53.55 (C-6), 106.95 (C-3a), 160.66 (C-7a), 161.01 (C-4), 170.73
(C-3) ppm.
3,6,6-Trimethyl-6,7-dihydro-isoxazolo[4,5-c]pyridin-4(5H)-one (9; C9H12N2O2)
Yield: see Table, m.p.: 173ꢀC (ethanol/water); IR (KBr): ꢀv ˆ 3207(m), 1691(s), 1640(m), 1494(s),
1365(m), 1243(m), 1162(m), 781(m) cmꢁ1; 1H NMR (DMSO-d6, ꢂ, 400 MHz): 1.25 (s, 6H, (CH3)2),
2.34 (s, 3H, CH3), 3.00 (s, 2H, 7-H), 7.60 (s, 1H, NH) ppm; 13C NMR (DMSO-d6, ꢂ, 100 MHz):
10.18 (CH3), 28.79 (CH3)2, 34.76 (C-7), 53.97 (C-6), 108.07 (C-3a), 157.39 (C-3), 161.93 (C-4),
175.07 (C-7a) ppm.
4-Hydroxy-6,6-dimethyl-5,6-dihydropyridin-2(1H)-one (10a) resp.
6,6-Dimethylpiperidin-2,4-dione 10b
Yield: see Table; m.p. and NMR data agree with those of a sample prepared according to Ref. [27].

Synthesis of Isoxazolopyridinones
1291
4-Hydroximino-6,6-dimethylpiperidin-2-one (11a, b; C7H12N2O2)
A mixture of 10a, b (0.01 mol), 0.035 mol NH2OH Á HCl, and 0.03 mol CH3COONa in 100 ml
ethanol/H2O (19:1) was re¯uxed for 9 h, neutralized, and evaporated. The residue was triturated with
warm ethanol, ®ltered, and the ®ltrate was evaporated. Compounds 11a, b were puri®ed by ¯ash
chromatography.
Yield: 1.27 g (81.3%), m.p.: 225±227 ꢀC (ethanol/water); Rf ˆ 0.38 (dichloromethane/
methanol ˆ 9:1); IR (KBr): ꢀv ˆ 3171(m), 2980(w), 1637(s), 1446(m), 1430(m), 1259(m), 960(m)
cmꢁ1
;
11a (main component): 1H NMR (DMSO-d6, ꢂ, 400MHz): 1.14 (s, 6H, (CH3)2), 2.32 (s, 2H, 5-H),
3.09 (s, 2H, 3-H), 7.89 (s, 1H, NH), 10.63 (s, 1H, NOH) ppm; 13C NMR (DMSO-d6, ꢂ, 100 MHz):
28.88 (CH3)2, 30.99 (C-3), 41.20 (C-5), 50.64 (C-6), 150.96 (C-4), 167.33 (C-2) ppm.
11b (minor constituent): 1H NMR (DMSO-d6, ꢂ, 400MHz): 1.15 (s, 6H, (CH3)2), 2.54 (s, 2H, 5-H),
2.96 (s, 2H, 3-H), 7.82 (s, 1H, NH), 10.60 (s, 1H, NOH) ppm; 13C NMR (DMSO-d6, ꢂ, 100 MHz):
29.48 (CH3)2, 35.40 (C-5), 36.22 (C-3), 50.64 (C-6), 150.86 (C-4), 168.02 (C-2) ppm.
Acknowledgements
We are grateful to Prof. Dr. E. Haslinger for illuminating discussions concerning the equilibria of
compounds 6 and 7. Many thanks go to Prof. Dr. W. Stadlbauer for samples of isoxazolo- and
oxazoloquinolones.
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