Unexpected cyclization route for o-ethynylbenzoic acids hydrazides in the presence of base

Abstract

The reaction of o-ethynylbenzoic acids hydrazides with base has been studied. In the presence of a strong donor substituent (1,5-dimethylpyrazol-4-yl) it has been found that an unusual cyclization route occurs to give the corresponding benzopyridazinone instead of the expected isoindolinone.The high synthetic potential of polyfunctional aryl-and hetarylacetylenes ensures the unabated interest of chemists in this class of compound. Vicinal functionally substituted aryl-and hetarylacetylenes are very convenient synthons in the preparation of condensed heterocycles which are promising biologically active compounds [1].In fact, a study of the reactivity of vicinal hydrazides of acetylenylbenzoic and pyrazolylcarboxylic acids has shown that the presence of the α-and β-carbon atoms of the triple bond and the two nucleophilic centers ("amine" and "amide" nitrogen atoms) in the hydrazide group guarantee many outcomes for their reactions [2,3]. Recent investigations of the heterocyclization of vic-acetylenylpyrazolecarboxylic acid hydrazides led to the unexpected result that oxidative coupling of the molecule occurs along with formation of a condensed diazepinone ring (which, in itself, was seen for the first time) [4].In addition, the very limited number of previous investigations of aromatic series compounds does not reveal the full picture of even the basic dependence of the heterocyclization route for unsaturated hydrazides. Study of the cyclization of the vic-acetylenylbenzoic acid hydrazides series is limited to just two examples [2,3]. This circumstance, together with the marked effect of the nature of the substituent at the triple bond carbon atom on the reaction course [4], led us to broaden the range of acetylenyl substituents in a series of ortho-acetylenylbenzoic acids hydrazides.The synthesis of the starting o-acetylenylbenzoates 1a,b was carried out by treating methyl o-iodobenzoate with the corresponding terminal alkynes under copper-palladium catalysis conditions [5] using the system (Pd(PPh 3 ) 2 Cl 2 , CuI, NEt 3 ) in 67-97% product yield.

Tuning Selectivity of Anionic Cyclizations: Competition between 5-Exo and 6-Endo-Dig Closures of Hydrazides ofo-Acetylenyl Benzoic Acids and Based-Catalyzed Fragmentation/Recyclization of the Initial 5-Exo-Dig Products

“…Our recent communication reported cyclizations of two hydrazides of o -acetylenyl benzoic acids bearing p -methoxyphenyl and 1,5-dimethylpyrazol-4-yl substituents at the alkyne moiety (Scheme ). Although we observed the 5-exo-dig cyclization with the formation of ( Z )-2-amino-3-(4-methoxybenzylidene)isoindolin-1-one (67%) in the first case, cyclization of the pyrazolyl derivative unexpectedly yielded the product of a formal 6-exo-dig cyclization, 4-((1,5-dimethyl-1 H -pyrazol-4-yl)methyl)phthalazin-1(2 H )-one, in 70% yield …”

Strain control in nucleophilic cyclizations: reversal of exo‐selectivity in cyclizations of hydrazides of acetylenyl carboxylic acids by annealing to a pyrazole scaffold

“…Bifunctional nucleophiles are particularly interesting because the selectivity of intramolecular attack at the triple bond is sensitive to the variations in the nature of the alkyne substituents and reaction conditions. For example, hydrazides of vic ‐acetylenyl benzoic acids can yield benzopyrrolidones, benzopyridazones or benzodiazinones – three promising biologically active types of annealed heterocycles with a wide spectrum of pharmacological activity . The multichannel reactivity originates from the presence of two nucleophilic centers of different nature (the amide and the amine nitrogens) and the possibility of selective targeting α‐acetylenic and β‐acetylenic carbons (Fig.…”