A One-Pot Asymmetric Synthesis of Homoallylic Amines via Indium-Mediated Allylation of Hydrazones

Abstract

Homoallylic amines are an important structural element of natural products and valuable synthetic building blocks in organic syntheses. The nucleophilic addition of organometallic reagents to the C=N bond is a straightforward method for the synthesis of homoallylic amines. However, due to the low reactivity of imines toward nucleophiles, more reactive nucleophiles are required for the addition reaction. Thus, there are some drawbacks to such methods including aza-enolization and competitive formation of side products. Some organometallic reagents such as allylsilanes and allylboronates have been successfully employed for the formation of homoallylic amines. Employing allylindium reagents for the synthesis of homoallylic amines is attractive as indium reagents have low toxicity and low basicity and are stable to moisture and air. Recently, various methodologies for the enantioselective allylation of imines in the presence of chiral ligands have been developed. However, the synthesis of chiral ligands is frequently difficult and requires multi-step synthesis. Diastereoselective allylation of imines bearing a chiral auxiliary is a reliable and efficient method for the synthesis of optically pure homoallylic amines. Several chiral imines have been developed for indium-mediated allylations. Since Loh and co-workers’ report, chiral N-aliphatic imines, which are derived from amino acid derivatives such as (S)-valinol and (R)-phenylglycinol, have been used for diastereoselective allylations. Yus and co-workers developed a method for the synthesis of optically pure homoallylic amines via chiral Nsulfinyl imines. Chiral imines have also been widely employed. Among the chiral imine derivatives, chiral hydrazones are the choice of chiral auxiliary due to advantages that include ease of preparation, high reactivity, and high selectivity. Although (S)-1-amino-2-methoxymethylpyrrolidine and (S)-4-phenylmethyl-oxazolidin-2-one-derived hydrazones have been employed for indium-mediated diastereoselective allylations, these auxiliaries have some drawbacks such as the use of expensive and toxic reagents and multiple steps for their synthesis. Herein, we wish to report a one-pot stereoselective allylation of aldimines bearing an L-proline moiety to afford chiral homoallylic amine derivatives in a highly stereoselective manner. A one-pot asymmetric reaction that involves aldehydes, chiral hydrazides, and an allyindium species is attractive since the reaction is simple and easy to perform as well as being both eco-friendly and rapid. Benzaldehyde was chosen as a model substrate, and Zn(ClO4)2·6H2O was chosen as the catalyst since it is known to be an efficient promoter for the formation of hydrazones. We examined the one-pot allylation with benzaldehyde, a chiral L-proline-derived hydrazide, allyl bromide and indium in the presence of 1 mol % Zn(ClO4)2 in methanol at room temperature. The reaction proceeded smoothly and was complete in 2 h affording 87% of the allylated product with a 60:40 dr (Table 1, entry 1). The reaction rate was much faster than that of the reaction performed without a catalyst (15 h). This result suggests that Zn(ClO4)2·6H2O promotes the formation of hydrazone as well as assists in the allylation of the resulting hydrazone. The same reaction performed using allyl iodide instead of allyl bromide at room temperature gave an 85% chemical yield of the product with no stereoselectivity (entry 3). However, the reaction time was shortened. As the reaction temperature was lowered, the stereoselectivity increased. When performed at −20 C, the reaction was complete in 10 h with high diastereoselectivity (entry 5). Upon changing from methanol, a polar solvent, to nonpolar solvents such as toluene, dichloromethane, or chloroform, the reaction did not proceed at −20 C. With optimized reaction conditions in hand, we investigated the scope of the reaction with various aldehydes. The results are presented in Table 2. The reaction with aromatic aldehydes that were substituted with an electron-donating