Américo Lemos

Addition and Cycloaddition Reactions of Phosphinyl- and Phosphonyl-2H-Azirines, Nitrosoalkenes and Azoalkenes

An overview of the use of 2H-azirines, conjugated nitrosoalkenes and conjugated azoalkenes bearing phosphorus substituents in addition and cycloaddition reactions is presented, focused on strategies for the synthesis of aminophosphonate and aminophosphine oxide derivatives.

Reactions of azoalkenes derived from hydrazones of ethyl bromopyruvate with electron rich alkenes and heterocycles

Abstract Three hydrazones of ethyl bromopyruvate, the dinitrophenylhydrazone 2a, the toluene-4-sulphonylhydrazone 2b and the t-butoxycarbonylhydrazone 2c, have been reacted with a series of nucleophilic alkenes and heterocycles in the presence of sodium carbonate. Azoalkenes 3 are presumed as intermediates and adducts have been isolated. The azoalkenes derived from hydrazones 2a and 2c are found to be useful electrophiles and electrophilic dienes.

Reactions of Nitrosoalkenes with Dipyrromethanes and Pyrroles: Insight into the Mechanistic Pathway

The reactivity of nitrosoalkenes toward dipyrromethanes, pyrrole, and 2,5-dimethylpyrrole is described. 1-(p-Bromophenyl)nitrosoethylene shows a different chemical behavior with these heterocycles than the previously reported reactions of ethyl nitrosoacrylate, which proceeds via a Diels-Alder reaction. 1-(p-Bromophenyl)nitrosoethylene reacts with dipyrromethanes and pyrrole to afford two isomeric oximes via conjugate addition followed by rearomatization of the pyrrole unit. On the other hand, this nitrosoalkene reacts with 2,5-dimethylpyrrole through an initial conjugate addition followed by intramolecular O- and N-nucleophilic addition with the formation of the corresponding bicyclic oxazine and five-membered cyclic nitrone, respectively. Quantum chemical calculations, at the DFT level of theory, indicate that the barriers associated with the Diels-Alder reactions of ethyl nitrosoacrylate are over 30 kJ/mol lower than those that would be required for the cycloadditions of 1-(p-bromophenyl)nitrosoethylene. Thus, calculations predict that the Diels-Alder reaction is privileged in the case of ethyl nitrosoacrylate and point to a different reaction pathway for 1-(p-bromophenyl)nitrosoethylene, corroborating the experimental findings.

Reactions of Nitrosovinylphosphonates with Electron-Rich Alkenes and Heterocycles

In the presence of a base, chlorohydroxyiminophosphonates are converted in situ into the corresponding transient nitrosovinylphosphonates, which react as heterodienes with electron-rich alkenes and heterocycles producing oxazines and open-chain oximes in moderate yields and good selectivity. This approach may be regarded as a new strategy for the synthesis of precursors of α-amino phosphonic acids.

Novel approach to bis(indolyl)methanes: de novo synthesis of 1-hydroxyiminomethyl derivatives with anti-cancer properties.

A versatile and broad range approach to previously unknown bis(indolyl)methane oximes based on two consecutive hetero Diels-Alder cycloaddition reactions of electrophilic conjugated nitrosoalkenes with indoles is disclosed. The cytotoxic properties and selectivity of some adducts against several human cancer cell lines pointing to a promising role in the development of anti-tumoural drugs, in particular for leukaemia and lymphoma.

The Neber Approach to 2-(Tetrazol-5-yl)-2H-Azirines

The synthesis of 2-(tetrazol-5-yl)-2H-azirines is reported for the first time. Using the Neber approach, β-ketoxime-1H-tetrazoles were converted into the target 2H-azirines bearing phenyl, furan-2-yl, thiophen-2-yl, or pyrrol-2-yl substituents at C-3. It was demonstrated that the alkaloid-mediated Neber reaction allows the asymmetric synthesis of 2-(tetrazol-5-yl)-2H-azirines.

Synthesis of 2-acylamino-1,2-dihydropyrrolizin-3-ones from pyrrole

Abstract The pyrrolizidin-3-ones 5, 7 and 10 have been prepared from pyrrole by making use of its reaction with ethyl bromopyruvate oxime in the presence of sodium carbonate to introduce the side chain. The 5-substituents were introduced into the pyrrole ester 2 before hydrolysis and dehydrative cyclization. The X-ray crystal structure of compound 10 has been determined and this shows that the C3 to N4 bond is no longer than in normal tertiary amides, as has been obsered with other N-acylated azoles.

Azabicyclo[3.2.0]heptan-7-ones (carbapenams) from pyrrole

The azabicyclo[3.2.0]heptan-7-ones 4, 10, 16 and 24 have been prepared from pyrrole. The same general approach has been used for all these derivatives; namely, substitution of pyrrole at the 2- and 5-carbon atoms, catalytic hydrogenation to produce pyrrolidine-2-acetic acid derivatives, and cyclisation using tris(1,3-dihydro-2-oxobenzoxazol-3-yl)phosphine oxide 6. The catalytic hydrogenation of 2,5-disubstituted pyrroles gives only the corresponding cis-2,5-disubstituted pyrrolidines. The hydrogenation proceeds more easily when the nitrogen atom bears a tert-butoxycarbonyl substituent. The N-tert-butoxycarbonylpyrroles 8 and 21 bearing an α-substituent in the acetate side chain were hydrogenated with a high degree of facial stereoselectivity. This allowed the 6-phthalimidoazabicyclo[3.2.0]heptan-7-one 24 to be isolated as a single diastereoisomer. The X-ray crystal structure of a precursor, the triester, 22a, has been obtained.

Reactions of Azovinylphosphonates with Nucleophilic Alkenes and Heterocycles: Synthesis of Tetrahydropyridazine-3-phosphonate and 2-Substituted-1-hydrazonoethylphosphonate Derivatives

Transient azovinylphosphonates, generated in situ by base induced dehydrohalogenation of the corresponding 2-bromo- and 2-chloro-acetylphosphonate- tertbutoxycarbonyl hydrazones are intercepted by electron rich alkenes and heterocycles in hetero Diels-Alder reactions, producing tetrahydopyridazine-3-phosphonates or open chain α-hydrazono phosphonates.

Reaction of pyrroles with ethyl 2-nitroso- and 2-azo-propenoates, and with ethyl cyanoformate N-oxide: a comparison of the reaction pathways

The reaction of ethyl 2-nitrosopropenoate 2a with 1-methylpyrrole, 2,5-dimethylpyrrole and 2,5-diphenylpyrrole has been investigated. In every case the products result from highly regioselective attack at C-2 of the pyrrole by the electrophile. The azopropenoate esters 2b and 2c react similarly with pyrroles, to the extent that even 1 -(triisopropylsilyl)pyrrole is attacked exclusively at the 2-position by the azo ester 2b. In contrast, the nitrile oxide ethyl cyanoformate N-oxide 12 reacts at the 3-position of 2,5-dimethyl- and of 2,5-diphenyl-pyrrole. The reactions of the nitroso and azo esters with pyrroles are interpreted as Diels–Alder cycloadditions with inverse electron demand.