Third International Electronic Conference on Synthetic Organic Chemistry (ECSOC-3), www.mdpi.org/ecsoc-3.htm, September 1-30, 1999

[A00012]

Robert Weis^a, Klaus Schweiger^a and Walter M. F. Fabian^b

aInstitute of Pharmaceutical Chemistry, Schubertstr. 1
^bInstitute of Organic Chemistry, Heinrichstr. 28
Karl-Franzens University Graz, A-8010 Graz, Austria
E-mail: [email protected], [email protected], [email protected]

Received: 24 July 1999 / Uploaded: 6 August 1999

Abstract

Depending on the substituent at C-4 (OH or MeNH) 3-acyl-5,6-dihydropyridinones 1 and 2 react with hydroxylamine to give either isoxazolo[5,4-c]pyridinone 3 and isoxazolo[4,3-c]pyridinone 4, respectively. The tautomeric equilibria of 1 and 2 are investigated by means of NMR spectroscopy and density functional calculations. The mechanisms of formation of 3  and 4 are interpreted with the aid of semiempirical molecular orbital calculations.

Introduction

Isoxazolo[4,5-c]pyridinones, e.g. 3, show a wide variety of biological activity. They can act as  hypolipidemic agents and are important precursors for hypnotics, muscle relaxants as well as tranquillizers[1]. The isomeric isoxazolo[4,3-c]pyridinones, e.g. 4, are relevant synthons for analogues of herbicides[2]. In the following, the synthesis of the two isomeric compounds 3 and 4, the feasibility to  influence the isomer ratio as well as their tautomeric equilibria as evidenced by NMR spectroscopy and densitiy functional calculations, will be described. 

Synthesis[3]

Acylation of 4-methylamino-5,6-dihydropyridin-2(1H)-one under Friedel-Crafts conditions selectively yields the 3-acetyl derivative 2. Alkaline hydrolysis of 2 is used to synthesize the 4-hydroxy derivative 1. In contrast to 3-acetyl-4-hydroxy-2(1H)-quinolinones, which on reaction with hydroxylamine, yield the oximes [4], both 1  as well as 2  cyclize to isoxazolopyridinones. Interestingly, there is a strong dependence of the outcome of these cyclizations on the substituent at C-4: In case of the 4-hydroxy derivative 1 exclusively the isoxazolo[4,5-c]pyridinone 3 is formed. In contrast, reaction of the 4-methylamino derivative 2 with hydroxylamine results in a mixture of 3 and the isomeric isoxazolo-[4,3-c]pyridione 4. The composition of this mixture can be regulated by the reaction conditions, namely the acidity of the solution: 

Tautomeric Equilibria of 1 and 2

4-Methylaminopyridin-2(1H)-one 2 exists according to NMR spectroscopy in one single tautomeric form with an intramolecular hydrogen bond between the 4-MeN-H and the 3-acetyl group:

In contrast, for 1 both a tautomeric as well as configurational equilibrium was established by NMR spectroscopy:

Structure 1C appears to be negligible, 1A and (E)-1B are in a rapid equilibrium (approx. 20%) and (Z)-1B is the dominant species. 
Hybrid Hartree-Fock/densitiy functional calculations (Table 1) corroborate these experimental results.

Molecular Orbital Calculations[5]

In order to rationalize this unexpected behavior and to establish the mechanisms of these reactions, semiempirical molecular orbital calculations (PM3) including solvent effects (SCRF approximation) were performed. For 1, both tautomeric forms - 1A and (Z)-1B - were taken into account; for 2 only the amino tautomer was treated. For each structure four different pathways were considered:

The detailed mechanisms for these four pathways turned out to be quite complicated [5]; thus, in Table 2 only the relative energies of the rate determining transition states are collected.
The main conclusions from these calculations are:

• The highest activation energies are found for reaction of the nucleophile with the vinylic (C-4 or exocyclic) carbon atom of compounds 1 and 2. Thus, depending on the respective mechanism either addition of the nucleophile to form the intermediates (Scheme 3) or their cyclization, will be rate determining.
• Proton transfer steps are characterized by the highest activation energies; solvent assistance should lower these barriers.
• Reaction of hydroxylamine via its oxygen atom as nucleophile is far less feasible than reaction via the nitrogen atom.
• Tautomer (Z)-1B is not only more stable than 1A but also more reactive.
• For the hydroxy derivative 1 the preferred reaction is calculated to be formation of 3  via path B.
• The preferred reaction of the 4-methylamino derivative 2 is formation of 4  via path A.

References

[1]    J. Nadelson (Sandoz), US 4 049 813 (1977); (1978); CA 88, 68 62w; J. Nadelson(Sandoz), Ger Offen 2 609 127 (1976); (1976); CA 85, 192582r; J. Nadelson (Sandoz), US 4 131 679 (1978); (1979); CA 90, 186802z.
[2]    P. Roschger and W. Stadlbauer, Liebigs Ann. Chem. 821 (1990); W. Steinschifter, W. Fiala and W. Stadlbauer, J. Heterocycl. Chem. 31, 1647 (1994); T. Kappe and B. Schnell, J. Heterocycl. Chem. 33, 663 (1996).
[3]     R. Weis, K. Schweiger and W. M. F. Fabian, Monatsh. Chem. 129, 1285 (1998).
[4]     T. Kappe, R. Aigner, M. Jobstl, P. Hohengassner and W. Stadlbauer, Heterocycl. Commun. 1, 341 (1995).
[5]    W. M. F. Fabian, K. Schweiger and R. Weis, J. Phys. Org. Chem., in the press.

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