Multicomponent Synthesis Of Nitrogen-Containing Compounds

Multicomponent Reaction (MCR) is generally defined as a process in which three or more reactants were added simultaneously into one pot to form a product that incorporates structural feature of each reagent. MCRs can form more than one bond at the same time from simple starting materials without isolating intermediates. This kind of reaction has some advantages over classic two component reaction strategies, such as simple procedure, high reaction efficience, low cost, as well as environmentally friendly aspects. However, the reactions with four or more components are quite rare. We have developed some novel 4MCRs, greatly facilitating the manipulation to synthesize primary amines derivatives and urea (or thiourea) derivatives under mild conditions.We reported the first Ferrous Sulfate catalyzed 4CR of carbonyl compounds with alkyl chloroformate, HMDS and Et3SiH to produce protected primary amines. Various aldehydes, ketones, acetals were transformed to their corresponding primary amine with moderate to excellent yield. The mechanism revealed that the byproduct TMSCl which was generated by alkyl chloroformate and HMDS was absolutely necessary in this four-component reaction. Next, we use a catalytic amount of water instead of Ferrous Sulfate to serve as a hydrolyzing agent to decompose byproduct chlorotrimethylsilane (TMSCl) to yield HCl that serves as actual catalyst to promote this four-component reaction. In the presence of 40 mol% of water, a wide variety of nucleophiles, such as silanes,β-keto esters, and ketones have been explored as suitable substrates to give primary amine derivatives in moderate to excellent yield. We also found that no catalyst is needed at all for the four-component reactions with aldehydes bearing hydroxyl groups.Next, we reported a 4CR of aldehydes with isocyanatse (or isothiocyanates), HMDS and a wide variety of nucleophiles to produce ureas (thioureas) derivatives. In the presence of 10 mol% TsOH, many kinds of nucleophiles, such as silane, allylsilane, 2-naphthol, ketones,β-keto esters andβ-diketones can engage in this four-component reaction to give ureas (thioureas) derivatives in moderate to excellent yield. We also designed and synthesized a series of BINOL-based phosphoric acid and evaluated for their ability to catalyzed four-component aldehydes, isocyanate, HMDS and ethyl acetoacetate to give 3,4- dihydropyrimidin-2-ones with up to 84% ee. The reaction of benzyl sulfonamides with sily nucleophiles has been developed in the presence of 10 mol% Tf2NH. The sp3 C-N bond of sulfonamides was cleavaged to generate carbocations, which react with sily nucleophiles including allylsilane, silane, propargylic silane to give alkylation products.