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Large-size macrocycles are synthesizedviathe type-II Alder–ene reaction of arynes generatedviathe hexadehydro Dies–Alder reaction. 

Substituent-dependent reactivity and selectivity in the intramolecular reactions of arynes tethered with an allene are described. With a 1,3-disubstituted allene moiety, an Alder–ene reaction of an allenic C–H bond is preferred over a [2 + 2] cycloaddition, whereas a [2 + 2] cycloaddition of the terminal π-bond of the allene is preferred with a 1,1-disubstituted allene. With a 1,1,3-trisubstituted allene-tethered aryne, an Alder–ene reaction with an allylic C–H bond is preferred over a [2 + 2] cycloaddition. 

Multicomponent reactions (MCRs) constitute a powerful synthetic tool to generate a large number of small molecules with high atom economy, which thus can efficiently expand the chemical space with molecular diversity and complexity. Aryne-based MCRs offer versatile possibilities to construct functionalized arenes and benzo-fused heterocycles. Because of their electrophilic nature, arynes couple with a broad range of nucleophiles. Thus, a variety of aryne-based MCRs have been developed, the representative of which are summarized in this account. 1 Introduction 2 Aryne-Based Multicomponent Reactions 2.1 Trapping with Isocyanides 2.2 Trapping with Imines 2.3 Trapping with Amines 2.4 Insertion into π-Bonds 2.5 Trapping with Ethers and Thioethers 2.6 Trapping with Carbanions 2.7 Transition-Metal-Catalyzed Approaches 3 Strategies Based on Hexadehydro Diels–Alder Reaction 3.1 Dihalogenation 3.2 Halohydroxylation and Haloacylation 3.3 Amides and Imides 3.4 Quinazolines 3.5 Benzocyclobutene-1,2-diimines and 3H-Indole-3-imines 3.6 Other MCRs of Arynes and Isocyanides 4 Conclusion 

A unique aryne-based Alder-ene reaction to form benzocyclobutene is described. In this process, the thermodynamic barrier to form a four-membered ring is compensated by the relief of the strain energy of an aryne intermediate. On the other hand, the driving force to overcome the high kinetic barrier is provided by the gearing effect of the bulky substituent at the ortho -position of the ene-donor alkene. To maximize the steric strain by the ortho -substituent, a structural element for internal hydrogen bonding is installed, which plays a crucial role for both the hexadehydro Diels–Alder and the Alder-ene reactions. DFT calculations show that the bulky hydrogen bonding element lowers the activation barrier for the Alder-ene reaction by destabilizing the intermediate, which is due to the severe bond angle distortion. The preferred formation of cis -isomers can also be explained by the extent of bond angle distortion.