R1 and R2 = H, alkyl, aryl
R3 = alkyl, aryl, alkoxy
X = Cl, OSu, symmetrical anhydride
The base is usually sodium carbonate or sodium bicarbonate.
The solvent may be 1,4-dioxane, THF, acetone, DCM, ether, acetonitrile, and others. I use dioxane.
Introduction
In the classical Schotten-Baumann Reaction, an amine or alcohol reacts with an acyl halide to produce an amide. "Schotten-Baumann conditions" also refers to the most common method of preparing carbamates from amines and chloroformates, mixed anhydrides, or dicarbonates in aqueous base/organic solvent. This article deals with the latter. The amine is dissolved in aqueous base and cooled on an ice bath. The acylating agent is dissolved in the organic solvent and this solution added dropwise to the aqueous. The reaction is usually allowed to run overnight.
Installing Carbamate Protecting Group
Carbamate protecting groups, such as Boc, Fmoc, Z, and Alloc are usually installed under Schotten-Baumann conditions.
The Electrophiles
All of these electrophiles will get the job done. The choice of electrophile depends on byproduct profile, cost/availability, stability in storage, and handling characteristics (e.g. melting point).
| Protecting group | Electrophile |
| Boc | (Boc)2O, Boc-ON |
| Fmoc | Fmoc-OSu, Fmoc-Cl |
| Z | Z-Cl, Z-OSu |
| Alloc | Alloc-Cl |
Chloroformates
Chloroformates are the original carbamate-forming reagents. Fmoc-Cl, Z-Cl, and Alloc-Cl are used to install Fmoc, Z and Alloc protecting groups, respectively. Chloroformates are usually the cheapest option. The issue with chloroformates is that if the pH drops below the amine pKa, the chloroformate will react with the carboxylate instead of the amine, activating the carboxylate resulting in amide coupling. Product may be contaminated with dipeptides which may be difficult to remove. Keep the pH above 9 to avoid this issue.
Mixed carbonates
Examples include Fmoc-OSu and Z-OSu (they're almost always the OSu carbonate). These are more stable in storage than the chloroformates. Product tends not to be contaminated with much dipeptide. However, Fmoc-OSu is known to yield Fmoc-beta-alanine as a byproduct due to a base-mediated Lossen rearrangement. The Fmoc-beta-alanine may be difficult to remove. This issue may be avoided by using a slight deficit of the Fmoc-OSu (e.g. 0.97eq).
Dicarbonates
Boc2O, ("Boc anhydride", di-tert-butyl dicarbonate) a symmetrical anhydride, is used to convert amines to Boc-protected amines. The byproducts are carbon dioxide, isobutylene, and maybe tert-butanol. The first two are gaseous. tert-Butanol is low-boiling. Unfortunately, Boc2O is a low-melting solid (23oC). It will probably melt during shipping and once it refreezes it will be difficult to remove from the container without first melting in a warm water bath. Boc2O is sold in containers with a lot of head space because it slowly decomposes on prolonged storage, releasing CO2.
Reaction of Z-Cl with an amine to produce a Z-protected amine
Reaction of Boc2O with an amine to produce a Boc-protected amine
Acetylation of an amine with acetic anhydride or acetyl chloride