Facile Synthesis of Aza-Baylis-Hillman Adducts of Cycloalkenones: FeCl3-Mediated Direct Amination of Baylis-Hillman Alcohols

Abstract

The Baylis-Hillman adducts of cycloalkenones have been used widely in organic synthesis. The synthesis of BaylisHillman adducts from the reaction of cycloalkenones and aldehydes has been carried out with a variety of catalyst system including the use of TMPDA or DMAP. However, the synthesis of aza-Baylis-Hillman adducts of cycloalkenones was not reported much. Direct synthesis of azaBaylis-Hillman adducts from the reaction of cycloalkeneones and N-tosylimines was examined by using DMAP or N-heterocyclic carbene catalyst very recently. However, the methods suffer from low yields of products and the use of special catalyst. In addition, these direct methods require the preparation of N-tosylimines, which could be hydrolyzed to some extent into the corresponding aldehydes and tosylamide during the separation of N-tosylimine and during the next Baylis-Hillman reaction, and this makes the separation of product tedious and lowers the yield. Recently, direct amination of allylic, benzylic and/or propargylic alcohols has received much attention, which could be achieved directly using sulfonamide derivatives with the aid of AuCl3, MoCl5, [Ir(COD)Cl]2, Bi(OTf)3/ KPF6, or FeCl3. In these contexts, we decided to develop a practically efficient synthetic method of N-tosyl aza-BaylisHillman adducts of cycloalkenones by adopting benzylic amination protocol (vide infra, Scheme 1). Starting material 1a was prepared by the known method, and examined for amination reaction with tosylamide under various conditions. When AuCl3 was used (5 mol%, rt, 24 h) the reaction was sluggish and observed the formation of product 2a in low yield (30%). The use of p-TsOH (5 mol%, rt, 24 h) showed similar results (ca 10% of 2a and ca 30% of remaining 1a). Fortunately, the use of FeCl3 (5 mol%) produced the desired product 2a in 88% isolated yield (rt, 12 h, Scheme 1). Although FeCl3-catalyzed amidation reaction of allylic/benzylic alcohol system was published very recently, the successful synthesis of N-tosyl aza-BaylisHillman adduct 2a in high yield from the easily available Baylis-Hillman alcohol could be highly influential in BaylisHillman chemistry. Encouraged by the results various representative BaylisHillman adducts were prepared and examined for FeCl3catalyzed amination reaction with TsNH2 and methanesulfonamide (Table 1). As shown in Table 1, the reactions of Baylis-Hillman adducts derived from 2-cyclohexen-1-one, 4,4-dimethyl-2-cyclohexen-1-one, and 2-cyclopenten-1-one provided the corresponding aza-Baylis-Hillman adducts 2a-i in good yields (80-93%). The substituent of the aryl moiety did not affect much on the reaction. Methanesulfonamide showed similar reactivity (entry 5). However, when we used Scheme 1