Q3(b). Benzyne from an anthranilic acid, trapped by a tethered furan

Introduction. The left ring is an anthranilic acid (NH₂ ortho to COOH); a 2-methylfuran is tethered to the next ortho position. Diazotisation of an anthranilic acid is the standard way to make benzyne, and the tethered furan traps the benzyne in an intramolecular Diels–Alder reaction to give the oxygen-bridged (1,4-epoxynaphthalene) product.

Reagent A: an alkyl nitrite (isoamyl nitrite, i-C₅H₁₁ONO, or nitrous acid, HONO) in a neutral solvent (DME or dioxane), warmed.

Scheme: Anthranilic acid → zwitterionic diazonium carboxylate → benzyne → furan Diels–Alder adduct (86 % in the reported reaction).

1. Nitrosation. The nitrite gives NO⁺, which is attacked by the NH₂ lone pair; proton transfers and loss of water (as in any diazotisation) give the arenediazonium group, Ar-N+#N.
2. Zwitterion. The ortho COOH loses its proton, giving the inner salt benzenediazonium-2-carboxylate. It must not be isolated dry (it is explosive).
3. Benzyne. On warming, the zwitterion fragments: N₂ and CO₂ leave together, and the two ortho carbons are left with one electron each in in-plane sp² orbitals, which overlap weakly: a strained aryne “triple bond”. Both leaving groups are gases, so the step is irreversible.
4. Diels–Alder. Benzyne has a very low-lying LUMO and is an excellent dienophile. The furan (an s-cis diene) is held next to it by the tether, and a concerted, suprafacial [4πₛ+2πₛ] cycloaddition links C2 and C5 of the furan to the aryne carbons. The furan oxygen becomes the 1,4-oxa bridge, the furan methyl ends up on the bridgehead, and the remaining furan C=C becomes the bridge alkene.
5. Why the acetal. The dioxolane (protected ketone) puts two substituents on the tether carbon; this Thorpe–Ingold (gem-disubstituent) effect favours the folded conformation and makes ring closure fast enough to beat intermolecular reactions of benzyne.

Conclusion. A = isoamyl nitrite (or HONO). Diazotisation gives benzenediazonium-2-carboxylate, which loses N₂ and CO₂ to form benzyne; the tethered furan adds to it by an intramolecular Diels–Alder reaction to give the oxa-bridged tetracycle.

Application. Furan trapping of a benzyne is the classical proof that benzyne exists; aryne Diels–Alder reactions with furans are used to build naphthalene and anthracene frameworks of natural products.