The Diels-Alder reaction of 4,6-dinitrobenzofuroxan with 1-trimethylsilyloxybuta-1,3-diene: a case example of a stepwise cycloaddition.

The reaction of 4,6-dinitrobenzofuroxan (DNBF) with 1-trimethylsilyloxybuta-1,3-diene (8) is shown to afford a mixture of [2+4] diastereomeric cycloadducts (10, 11) through stepwise addition-cyclization pathways. Zwitterionic intermediate sigma-adduct 9, which is involved in the processes, has been successfully characterized by (1)H and (13)C NMR spectroscopy and UV/visible spectrophotometry in acetonitrile. A kinetic study has been carried out in this solvent that revealed that the rate of formation of 9 nicely fits the three-parameter equation log k=s(E+N) developed by Mayr to describe the feasibility of nucleophile-electrophile combinations. This significantly adds to the NMR spectroscopic evidence that the overall cycloadditions take place through a stepwise mechanism. The reaction has also been studied in dichloromethane and toluene. In these less polar solvents, the stability of 9 is not sufficient to allow direct characterization by spectroscopic methods, but a kinetic investigation supports the view that stepwise processes are still operating. An informative comparison of our reaction with previous interactions firmly identified as prototype stepwise cycloadditions is made on the basis of the global electrophilicity index, omega, defined by Parr within the density functional theory, and highlighted by Domingo et al. as a powerful tool for understanding Diels-Alder reactions.

The versatile electrophilic reactivity of 4,6-dinitrobenzo[d]isoxazole-3-carbonitrile.

The interaction of 4,6-dinitrobenzo[d]isoxazole-3-carbonitrile (5a) with methoxide ion has been kinetically investigated in methanol and a 20:80 (v/v) MeOH-Me2SO mixture. In methanol, stopped-flow experiments have revealed that a monomethoxyl sigma-adduct (5a-Me) is first formed, resulting from a fast MeO- addition at the unsubstituted 7-carbon. Rate and equilibrium constants for this sigma-complexation process could be determined, allowing a ranking of 5a within the pKa scale established for Meisenheimer electrophiles in methanol. With a pKa value of 13.50, the electrophilicity of 5a falls in the range of 1,3,6,8-tetranitronaphthalene, 2,4-dinitrothiophene or 4-nitrobenzofuroxan. This corresponds to a two-pKa units increase in electrophilicity from that of TNB, the common reference in sigma-complex chemistry but it is notably below that of so-called superelectrophilic molecules like 4,6-dinitrobenzofuroxan. In addition to its ease of sigma-complexation, 5a is found to undergo a slow but thermodynamically favourable addition of MeO- to the cyano group bonded to the isoxazole ring, leading to a complete conversion of the adduct 5a-Me into a dinitroimidate 6. The reactivity of 6 could be kinetically assessed. Going to 80% Me2SO still afforded initially the adduct 5a-Me but this anionic species undergoes addition of a second molecule of MeO- to the CN group, giving a dianion whose structure is unprecedented in the literature. Combining the above results with synthetic observations showing that 5a can readily contribute to S(N)Ar reactions under appropriate experimental conditions emphasizes the multifaceted electrophilic reactivity of this electron-deficient heterocycle.

Inhibitory effects of a series of 7-substituted-indazoles toward nitric oxide synthases: particular potency of 1H-indazole-7-carbonitrile.

A series of new 7-monosubstituted and 3,7-disubstituted indazoles have been prepared and evaluated as inhibitors of nitric oxide synthases (NOS). 1H-indazole-7-carbonitrile (6) was found equipotent to 7-nitro-1H-indazole (1) and demonstrated preference for constitutive NOS over inducible NOS. By contrast, 1H-indazole-7-carboxamide (8) was slightly less potent but demonstrated a surprising selectivity for the neuronal NOS. Further substitution of 6 by a Br-atom at carbon-3 of the heterocycle enhanced 10-fold the inhibitory effects. Inhibition of NO formation by 6 appeared to be competitive versus both substrate and the cofactor (6R)-5,6,7,8-tetrahydro-l-biopterin (H(4)B). In close analogies with 1, compound 6 strongly inhibited the NADPH oxidase activity of nNOS and induced a spin state transition of the heme-Fe(III). Our results are explained with the help of the X-ray structures that identified key-features for binding of 1 at the active site of NOS.

A New Cycloaddition Process Involving Nitro Group Participation in Polynitroaromatic Chemistry.

The reaction of ethyl vinyl ether (2 equiv) with 4,6-dinitrobenzofuroxan (DNBF, 1 equiv) in dichloromethane affords a mixture of two diastereomeric dihydrooxazine N-oxide adducts, 5a and 5b, in a 4:1 ratio. Further addition of the enol reagent to this mixture results in a second cycloaddition process with formation of a bis(dihydrooxazine N-oxide) product 6, which can also be obtained directly upon treatment of DNBF with excess ethyl vinyl ether. The observed condensations are accounted for in terms of inverse electron demand Diels-Alder cycloaddition processes between the enol ether dienophile and the heterodienyl moieties of DNBF, constituted first, by the 6-NO(2) group conjugated to the 6,7-double bond and then by the 4-NO(2) group and the 4,5-double bond of the carbocyclic ring. The configurations of the cycloadducts 5a and 5b have been determined on the basis of collected (1)H NMR parameters, as well as NOE experiments. It thus appears that the configuration of the major diastereomer corresponds to the endo product while that of the minor one corresponds to the exo product of the first cycloaddition process. The results obtained emphasize a low aromatic character for the DNBF molecule.