1,3-Dipolar cycloaddition template

Benzyl azide and acetylene give a 1,2,3-triazole (Huisgen); a nitrone and styrene give a 5-phenylisoxazolidine, each in one concerted step.

Mechanism step by step

Azides and nitrones add across π bonds: [3+2] cycloadditions to five-membered rings

1. Azide + alkyne – Huisgen cycloaddition: four π electrons of the dipole and two of the alkyne
2. Nitrone + alkene – O bonds to the substituted carbon: the 5-substituted isoxazolidine

Key points

• A 1,3-dipole (4π electrons over three atoms) plus a dipolarophile (2π): [π4s + π2s], six electrons, thermally allowed and suprafacial.
• FMO: either HOMO(dipole)–LUMO(dipolarophile) or the reverse can dominate; the larger coefficients set the regiochemistry.
• Stereospecific: the geometry of the alkene is kept in the ring (cis stays cis).
• Thermal azide–alkyne additions give 1,4/1,5 mixtures with terminal alkynes; Cu(I) catalysis (CuAAC, “click”) gives only the 1,4-triazole by a stepwise route.

Drawn with 72 atoms, 9 arrows, 4 shapes – every one editable in MolDraw.

Sources

• Woodward & Hoffmann, Angew. Chem. Int. Ed. Engl. 1969, 8, 781 Review
• Fleming, Molecular Orbitals and Organic Chemical Reactions, Wiley 2010 Textbook
• Clayden, Greeves & Warren, Organic Chemistry, 2nd ed., OUP 2012, ch. 34 Textbook