In Angewandte Chemie International Edition, M. Kevin Brown and co-workers from Indiana University Bloomington reported a type of Suzuki coupling where 10% (Xantphos)CuCl catalyzed reactions between arylboronic esters and aryl iodides to provide biaryls. As in Suzuki coupling, a base was used, and in this case, the choice fell to sodium tert-butoxide. Optimally, the reaction proceeded in toluene at 80 ºC in 15 hours. Both electron-rich and electron-poor iodides and boronic esters were suitable for this process, but steric hindrance in one of the two starting materials needed Cy3PCuCl as the catalyst.
The arylboronic esters can be synthesized from the corresponding arylboronic acids and neopentyl glycol as reported by Aiwen Lei and colleagues from Wuhan University, and (Xantphos)CuCl can be made from CuCl and Xantphos as described by the laboratory of Yasushi Tsuji from Kyoto University. (See the scheme below.) Sodium tert-butoxide can be purchased from chemical companies.
Article: Zhou, Y.; You, W.; Smith, K. B.; Brown, M. K. Angew. Chem., Int. Ed.2014,53, 3475–3479. DOI: 10.1002/anie.201310275.
My notebook traveled between the Netherlands and Germany and underwent a motherboard replacement twice. The precious equipment is now back, and so am I. Let’s look at what the chemistry community has had to offer in recent weeks.
In a communication to Journal of the American Chemical Society, Hisashi Yamamoto and co-workers at the University of Chicago reported a hafnium-catalyzed strategy to enantioselectively epoxidize the olefin group in tertiary allylic and homoallylic alcohols. The optimum reaction conditions involved 10 mol% hafnium(IV) tert-butoxide as the precatalyst, 11 mol% of chiral bis(hydroxamic acid) L1 or L2 as the ligand, and 20 mol% magnesium oxide as an additive. (See the scheme above.) Acid L2 was excellent for more sterically demanding tertiary allylic alcohols. Cumene hydroperoxide (2 equivalents) was the oxidizing agent, and the protocol was performed in toluene at 0 °C for 48 hours. Various tertiary allylic and homoallylic alcohols could be epoxidized with high enantioselectivity in good yield. No such alcohols with a tri- or tetrasubstituted-olefin moiety were, however, tested.
The chiral bis(hydroxamic acid)s were first designed by Yamamoto and colleagues themselves and can be synthesized from a readily available diamine tartrate salt in six steps. (See the scheme below.) Hafnium(IV) tert-butoxide, magnesium oxide, and cumene hydroperoxide are purchasable.
Article: Olivares-Romero, J. L.; Li, Z.; Yamamoto, H. J. Am. Chem. Soc.2013,135, 3411–3413. DOI: 10.1021/ja401182a.
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.
Article: Sadig, J. E. R.; Foster, R.; Wakenhut, F.; Willis, M. C. J. Org. Chem.2012,77, 9473–9486. DOI: 10.1021/jo301805d.