Ureas from Boc-Protected Amines

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.

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:

• Article: Spyropoulos, C.; Kokotos, C. G. J. Org. Chem. 2014, 79, 4477–4483. DOI: 10.1021/jo500492x.
• National and Kapodistrian University of Athens.
• Christoforos Kokotos’s research group.

Benzimidazoles and Quinazolinones: Palladium-Catalyzed Amination and Aminocarbonylation

Many drugs and natural products around us contain benzimidazole scaffolds, for example, albendazole (Albenza, GlaxoSmithKline) and tiabendazole (Mintezol, Merck & Co.), and quinazolinone ones, for instance, febrifugine and halofuginone. Michael Willis and co-workers at the University of Oxford in a collaboration with Pfizer have developed a microwave-assisted palladium-catalyzed benzimidazole synthesis with carboximidoyl chlorides and amines as substrates. (See the scheme above.) The reaction condition involved 5 mol% palladium(II) acetate as the precatalyst, 7 mol% Ad₂Pn-Bu, also known as cataCXium A, as the ligand, and sodium tert-butoxide as the base in trifluorotoluene as the solvent. The procedure tolerated a wide range of substituents, but aromatic amines rendered benzimidazoles in more moderate yields. Carboximidates could replace the carboximidoyl chlorides although a higher reaction temperature and a longer reaction time were necessary and only anilines could be applied. The method still permited diverse functional groups. The reaction mechanism begins with nucleophilic substitution by the amine at the carboximidoyl or carboximidate carbon to give the corresponding imidine as the reaction intermediate, followed by intramolecular palladium-catalyzed amination.

The chemists have also conceived a palladium-catalyzed quinazolinone synthesis with carboximidates having bromide on the ortho position of the benzene ring and amines as precursors. The reaction condition this time comprised a slightly higher precatalyst loading and a higher concentration of the ligand under 1 atm of carbon monoxide. Cesium carbonate and toluene replaced sodium tert-butoxide as the base and trifluorotoluene as the solvent respectively, and conventional heating substituted the microwave irradiation. The reaction mechanism now starts with palladium-catalyzed aminocarbonylation to create an amide intermediate that then undergoes cyclization under basic environment. This synthetic approach also allowed a variety of substituents even though incorporation of alkylamines needed a higher temperature.

The carboximidoyl chlorides can be prepared from the commercially available corresponding anilines by synthesis of the amides with acyl chlorides and conversion of these amides to carboximidoyl chlorides by applying phosphorus pentachloride. (See the scheme below.) The carboximidates can be synthesized from the anilines and orthoesters with an acid catalyst or by heating. Palladium(II) acetate, cataCXium A, sodium tert-butoxide, and cesium carbonate are all in the market.

Teleportation gates:

• Article: Sadig, J. E. R.; Foster, R.; Wakenhut, F.; Willis, M. C. J. Org. Chem. 2012, 77, 9473–9486. DOI: 10.1021/jo301805d.
  
• University of Oxford.
• Michael Willis’s research group.
• Microwave chemistry on Wikipedia.