Ureas from Boc-Protected Amines

Figure 15

In the Journal of Organic Chemistry, Christoforos Kokotos and his student, Constantinos Spyropoulos, from National and Kapodistrian University of Athens described a one-pot synthesis of ureas from amines protected by tert-butyloxycarbonyl (Boc) group. Treating a Boc-protected amine with 2-chloropyridine (3 equivalents) and triflic anhydride in dichloromethane at room temperature for 50 minutes led to an isocyanate that generated a urea upon addition of 9 equivalents of another amine. This mechanism was proposed after the researchers could isolate the isocyanate intermediate in one reaction, but I doubt whether the secondary amines protected by the Boc group, for example, for the urea with a piperidine motif below, form isocyanates. Various ureas were formed within 1 to 20 hours after the addition of the second amine. The ureas below show the idea of the substrate scope.

Figure 16

No strong base was required and no epimerization occurred in this methodology so that the use of chiral substrates like amino acids is tolerated. The problem is that 9 equivalents of the amine nucleophile were necessary so that the excess had to be recycled via acid-base extraction. Kokotos and Spyropoulos recovered 78% to 85% of the amine.

Boc-protected amines either are commercially available or can be synthesized. 2-Chloropyridine and triflic anhydride can be bought from the market.

Teleportation gates: