The hexadehydro-Diels–Alder reaction

Abstract

Summary o-Benzynes (arynes) are among the most versatile of all reactive (short-lived) intermediates in organic chemistry. These species can be trapped to give products that are valuable from the perspective of both fine (pharmaceuticals) and commodity (agrochemicals, dyes, polymers, etc.) chemicals. Here we show a fundamentally new strategy that unites a de novo generation of benzynes, through the title hexadehydro-Diels–Alder (HDDA) reaction, with their in situ elaboration into structurally complex benzenoid products. In the HDDA reaction a 1,3-diyne is engaged in a [4+2] cycloisomerization with a third (pendant) alkyne–the diynophile–to produce the highly reactive benzyne intermediate. The metal- and reagent-free reaction conditions for this simple, thermal transformation are notable. The subsequent and highly efficient trapping reactions increase the power of the overall process. Finally, we provide examples of how this de novo benzyne generation approach allows new modes of intrinsic reactivity to be revealed.

Transfer Hydrogenation vs Nucleophilic Addition: Aryne Reaction with Alcohols

“…The expected alcohol nucleophilic addition to aryne (Scheme 1, right) was found to be second-order with respect to the alcohol (Figure 1), and consequently is favored only at high concentration of the latter. This computational result is consistent with early success where alcohols were used as solvents, and is also consistent with Hoye's and Lee's earlier results where large excess of alcohols was typically used [11][12]. Interestingly, this mechanistic rationale is in good agreement with a half-century-old finding from Bunnett that alcohol addition to arynes comes with accumulation of negative charge on aryne[4].…”

“…Meanwhile, it also sparked another curiosity standing equally elusive, that is, whether the lack of reactivity of aliphatic carboxylic acids and primary carboxyamides with arynes [7] could be explained by the same model. In fact, if one compares Hoye's and Lee's results [11,12] where acetic acid underwent nucleophilic addition to arynes with Larock's conditions [7] where no synthetically meaningful yield was obtained, it follows that the former success can be, at least partially, attributed to the excess and higher concentration of AcOH [15] which in turn might suggest higher-order kinetics with respect to the acid. It remains questionable as to why phenols behave differently from aliphatic alcohols in the nucleophilic addition with arynes, and why aromatic carboxylic acids behave differently from aliphatic ones [7].…”

Chemical Activation in Azide and Nitrene Chemistry: Methyl Azide, Phenyl Azide, Naphthyl Azides, Pyridyl Azides, Benzotriazoles, and Triazolopyridines

“…The case of an unusually reactive benzyne derivative was reported recently. [3] The aryne was formed in an intramolecular [2þ4] cycloaddition reaction of a triyne and estimated to be exothermic by ,50 kcal mol À1 (1 kcal mol À1 ¼ 4.186 kJ mol À1 ), and it is suggested that this excess energy is the reason for the increased reactivity. [4] contradictory and inconclusive results.…”

“…[12][13][14] Temperatures above 10008C are required to decompose the unactivated methylenimine to HCN under these conditions. [21] CH 3 …”

Benzene construction via organocatalytic formal [3+3] cycloaddition reaction

“…In a different direction for substituted benzene synthesis, the benzene core is newly formed. Representative methods include transition metal-catalyzed [2 þ 2 þ 2] or [4 þ 2] reactions such as acetylene trimerizations developed by Reppe et al [9][10][11] In this cycloaddition approach, partial or complete intramolecular reaction is usually indispensable to ensure the regio-selectivity.…”