Byproduct‐Catalyzed Four‐Component Reactions of Aldehydes with Hexamethyldisilazane, Chloroformates, and Nucleophiles in Acetonitrile Leading to Protected Primary Amines, β‐Amino Esters, and β‐Amino Ketones

Abstract

Multicomponent reactions are a very powerful tool for the construction of complex organic molecules by using readily available starting materials. While most of the multicomponent reactions discovered so far consist of three components, the reactions with four or more components remain sparse. We have successfully developed several four-component reactions using a catalytic amount of water as a hydrolyzing agent to decompose byproduct chlorotrimethylsilane (TMSCl) to yield secondary byproduct HCl that serves as a catalyst. In the presence of 40 mol % of water, the four-component reaction of aldehydes with hexamethyldisilazane (HMDS), chloroformates, and silylated nucleophiles proceeds smoothly at room temperature to give a range of protected primary amines in moderate to excellent yields. Importantly, a wide variety of protic carbon nucleophiles, such as beta-keto esters, beta-diketones, and ketones, have further been explored as suitable substrates for the synthesis of protected beta-amino esters and beta-amino ketones that are useful building blocks for various pharmaceuticals and natural products. These four-component reactions proceed through a pathway of tandem nitrogen protection/imine formation/imine addition, and the decomposition of byproduct TMSCl, generated in the first step of nitrogen protection, with water results in the formation of secondary byproduct HCl, a strong Brønsted acid that catalyzes the following imine formation/imine addition. Taking advantage of the fact that alcohols or phenols are also able to decompose byproduct TMSCl to yield secondary byproduct HCl, no catalyst is needed at all for the four-component reactions with aldehydes bearing hydroxy groups.

Improving the Atom Efficiency of the Wittig Reaction by a “Waste as Catalyst/Co‐catalyst” Strategy

“…Most recently, Tian and co-workers reported an indirect method for utilization of the TMSCl byproduct that was generated in a tandem nitrogen protection/imine formation/imine addition reaction. [13] That process needed the addition of water to hydrolyze the TMSCl byproduct from the reaction of hexamethyldisilazane (HMDS) and chloroformate to produce the active catalyst, HCl, for the following two steps. To the best of our knowledge, only the two examples are reported in the literature that utilize the byproduct of an upstream step to catalyze the downstream reaction in a tandem reaction, and the use of waste generated in the first step of a catalystic asymmetric reaction as catalyst/ co-catalyst in the enantioselective reaction step has not yet been reported.…”

“…A serial of functional groups such as ketones, nitro groups, halogen atoms, and terminal alkene groups tolerated the reaction conditions of the conjugate reduction step, thus illustrating the excellent chemoselectivity of this novel organocatalytic transformation. [18] Different phosphoranes 1 were also evaluated using aldehyde 2 c ( Table 1, entries [13][14][15][16][17][18]. Generally, the more stable the phosphorane 1, the slower the reaction rate in the Wittig reaction step.…”

Yb(OTf)3‐catalyzed One‐Pot Three Component Synthesis for Tertiary Amines

“…It is cheap, stable, commercially available, and easy to handle. HMDS has also been employed in organic synthesis as a nitrogen source instead of harmful and odorous ammonia …”

Improving the Atom Efficiency of the Wittig Reaction by a “Waste as Catalyst/Co‐catalyst” Strategy

“…However, the use of two equivalents of In 0 as the reducing agent and five equivalents of aldehyde to achieve high overall yield, together with the fact that the same aza‐Diels–Alder reaction was reported to work well in methanol without any catalyst,12 made the whole transformation less atom‐economical. Most recently, Tian and co‐workers reported an indirect method for utilization of the TMSCl byproduct that was generated in a tandem nitrogen protection/imine formation/imine addition reaction 13. That process needed the addition of water to hydrolyze the TMSCl byproduct from the reaction of hexamethyldisilazane (HMDS) and chloroformate to produce the active catalyst, HCl, for the following two steps.…”