Passerini three-component reaction template

Benzaldehyde, acetic acid and tert-butyl isocyanide combine: the isocyanide adds to the activated carbonyl carbon, acetate traps the nitrilium ion and an O → O acyl transfer gives the α-acyloxy amide.

Mechanism step by step

Aldehyde, carboxylic acid and isocyanide give an α-acyloxy amide

1. Carbonyl activation – Drawn stepwise; in aprotic solvents steps 1–3 are thought to be concerted
2. α-Addition of the isocyanide – The isocyanide carbon attacks the carbonyl carbon: a nitrilium ion
3. Acetate adds – An O-acyl imidate (isoimide) forms
4. Acyl transfer – The hydroxy group adds to the acyl C=O: a five-membered tetrahedral intermediate
5. Collapse – The C=O reforms and the ring C–O bond breaks: the acetyl group has moved O → O
6. Proton transfer – The imidate takes the proton: the amide

Key points

• The first isocyanide multicomponent reaction (Passerini, 1921): aldehyde or ketone + carboxylic acid + isocyanide → α-acyloxy carboxamide.
• Fastest in aprotic solvents at high concentration and third order overall, which supports a non-ionic, H-bonded cyclic transition state (accepted mechanism); the ionic steps drawn here describe polar solvents.
• The isocyanide carbon is attacked twice (α-addition), and the final acyl transfer is irreversible.
• With an amine present the imine reacts instead of the aldehyde: the Ugi reaction (α-acylamino amide).

Drawn with 144 atoms, 20 arrows, 10 shapes – every one editable in MolDraw.

Sources

• Kürti & Czakó, Strategic Applications of Named Reactions in Organic Synthesis, Elsevier 2005 Textbook
• Smith, March's Advanced Organic Chemistry, 8th ed., Wiley 2020, ch. 16 Textbook