Depending on the reaction conditions and the nature of substituents at the triple bond, anionic cyclizations of hydrazides of o-acetylenyl benzoic acids can be selectively directed along three alternative paths, each of which provides efficient access to a different class of nitrogen heterocycles. The competition between 5-exo and 6-endo cyclizations of the "internal" nitrogen nucleophile is controlled by the nature of alkyne substituents under the kinetic control conditions. In the presence of KOH, the initially formed 5-exo products undergo a new rearrangement that involves a ring-opening followed by recyclization to the formal 6-exo-products and rendered irreversible by a prototropic isomerization. DFT computations provide insight into the nature of factors controlling relative rates of 5-exo, 6-endo, and 6-exo cyclization paths, ascertain the feasibility of direct 6-exo closure and relative stability for the anionic precursor for this process, provide, for the first time, the benchmark data for several classes of anionic nitrogen cyclizations, and dissect stereoelectronic effects controlling relative stability of cyclic anionic intermediates and influencing reaction stereoselectivity. We show that the stability gain due transformation of a weak pi-bond into a stronger sigma-bond (the usual driving force for the cyclizations of alkynes) is offset in this case by the transformation of a stable nitrogen anion into an inherently less stable carbanionic center. As a result, the cyclizations are much more sensitive to external conditions and substituents than similar cyclizations of neutral species. However, the exothermicity of such anionic cyclizations is increased dramatically upon prototropic isomerization of the initially formed carbanions into the more stable N-anions. Such tautomerizations are likely to play the key role in driving such cyclizations to completion but may also prevent future applications of such processes as the first step in domino cyclization processes.

Independent of the nature of alkyne substitution, hydrazides of 4‐arylethynyl‐5‐carboxylic acid annealed at the pyrazole scaffold undergo a regioselective base‐catalyzed 6‐endo‐dig cyclization with the formation of pyrazolo[3,4‐c]pyridine‐7‐ones. This behavior contrasts the observation of selective 5‐exo closures in the analogous benzannelated systems and illustrates selective destabilization of the reaction path leading to the formation of a smaller ring. Computational analysis also reveals an important role of prototropic equilibria in rendering the overall cyclization feasible in the strained heterocyclic systems. The switch to the formation of a larger cycle suggests that strategic incorporation of strain can be used as a tool for the efficient control of regiochemistry of nucleophilic cyclizations. Copyright © 2012 John Wiley & Sons, Ltd.

The reaction of methyl o (2 R ethynyl)benzoates with hydrazine affords either fused 4 R methylphthalazin 1 ones or 2 amino 3 R methylideneisoindolin 1 ones. The latter are on treatment with KOH undergo recyclization into the corresponding 4 R methylphthalazin 1 ones.Accessibility and high synthetic potential of aromatic acetylenes determine increasing interest of chemists in this class of compounds. 1 Vicinal functionally substituted aryl acetylenes play a special role. They are highly reactive building blocks in the synthesis of annelated heterocycles, which are promising structures in the search for biologi cally active compounds. 1,2 From the fundamental point of view, they are convenient models for studying the cy clization rules: the dependence of the heterocyclization direction on internal and external factors (nature of sub stituents, substrate structure, electronic and steric effects).We are carrying out systematic studied of the reactivity of vicinal hydrazides of alkynylbenzoic 3-6 and alky nylpyrazolecarboxylic acids. 7,8 Among advantages of the chosen substrates, we consider the presence of two electro philic centers (α and β carbon atoms of the triple bond) and two nucleophilic centers (amine and amide nitrogen atoms of the hydrazide groups), which provide multichan nel transformations.In fact, the study of the reactivity of vicinal alkynylpyr azolecarboxhydrazides showed that the intramolecular ad dition of the functional group follows several directions and depends on the nature of the substituent at the carbon atom of the triple bond. 7, 8 We have recently published the data on the unusual intramolecular heterocyclization of о alkynylbenzhydr azides 5 (Scheme 1).The formation of 2 amino 3 (4 methoxybenzylidene) isoindolin 1 one (see Scheme 1, route a) is quite predict able: it is the product of the nucleophilic attack of the Scheme 1 R = 4 MeOC 6 H 4 (a), 1,5 dimethylpyrazol 4 yl (b) i. NH 2 NH 2 , EtOH.

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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.