Chameleonic Reactivity of Vicinal Diazonium Salt of Acetylenyl-9,10-anthraquinones: Synthetic Application toward Two Heterocyclic Targets

Abstract

The nature of products in the diazotization of 1-amino-2-acetylenyl-9,10-anthraquinones strongly depends on the nature of substituents at both the alkyne and at the anthraquinone core. Donor substitution (NHAr, OH) at the fourth position stabilizes the diazonium salt at C1, decelerating electrophilic cyclization at the arylethynyl substituent at C2. This effect allows the replacement of the diazonium with azide group and subsequent closure into isoxazole ring with preservation of the alkyne. In contrast, electrophilic 5-exo-dig cyclizations to condensed pyrazoles is observed for the combination of donor substituents at the aryl alkyne moiety and an OAc substituent at C4. The latter process provides a new synthetic route to 3-ethynyl-[1,9-cd]isoxazol-6-ones that are difficult to access otherwise. DFT calculations suggest that donor substituents have only a minor effect on alkyne and diazonium polarization in the reactant but provide specific transition state stabilization by stabilizing the incipient vinyl cation. This analysis provides the first computational data on electrophilic 5-exo-dig cyclization in its parent form and the nucleophile-promoted version. This cyclization is a relatively fast but endothermic process that is rendered thermodynamically feasible by the enol-keto tautomerization with concomitant aromatization in the five-membered heteroaromatic ring. Computations suggest that the importance of nucleophilic assistance in the transition state for a relatively weak nucleophile such as water is minor because the energy gain due to the Lewis base coordination to the carbocationic center is more than compensated for by the unfavorable entropic term for the bimolecular proces.

The Baldwin rules: revised and extended

“…The necessity of the nucleophile for cyclization was first noted by Overman and Sharp, who found that the 6‐(π‐vinylendo)‐endo‐dig closure occurred only in the presence of the iodide nucleophile . Similarly, alkynyl Richter cyclizations onto aryl diazonium salts are assisted by external species . Interestingly, the regioselectivity for these latter closures can be controlled either with temperature or the nature of the preexisting cyclic core (Scheme ) …”

How to Lose a Bond in Two Ways ― The Diradical/Zwitterion Dichotomy in Cycloaromatization Reactions

“…The factors responsible for the competition between the two cyclization directions were analyzed in detail by using vic ‐acetylenylamino‐9,10‐anthraquinones as the model substrates 35. The high penalty for including a linear sp‐hybridized vinyl cation in a cycle disfavors the “ endo ” closure in the direct cycloaromatization mechanism 36,37.…”

Fundamental and Applied Aspects of the Chemistry of Acetylenylquinones

“…This, in turn, streamlined the synthesis of several analogues. Here, the reactive capacity of the diazo-salts of vic-acetylenyl-9,10-anthraquinones [20] was used to demonstrate that the structure of the transformation products during diazotization of 1amino-2-acetylenyl-9,10-anthraquinones was strongly dependent on the nature of the substituents in the alkynes and the anthraquinone nucleus ( Figure 16).…”