Oxidative Coupling Reactions Involving Aldehydes

Transition-metal-catalyzed cross-coupling reaction is a powerful tool for organic synthesis, via the reaction between an electrophile and a nucleophile, which is widely applied in many areas. Compared with the cross-coupling, the oxidative coupling between two nucleophile has more combination, wilder research space, which could provide more choices to construct organic compound. Especially, oxidative coupling of C-H/C-H or C-H/X-H (X=N, O, S....) possesses good atom economy and has attracted much attention. Although some progresses have been made in this emerging field, there still remains great challenge. One of the typical examples is related to the oxidative coupling of aldehyde C-H bond with other C-H or X-H (X=N,O,S....) bonds.Firstly, the thesis reviewed a brief introduction for transition-metal-catalyzed oxidative coupling. Then the development of oxidative coupling involving aldehyde was summarized in details. The research work of this thesis described the oxidative coupling between aldehyde and terminal alkyne, alkene, chainlike secondary amide and the corresponding mechanistic investigation.1. From the synthetic point of view, this work opens up a new avenue for constructing conjugated ynones through zinc-promoted oxidative coupling of simple starting materials aldehydes and terminal alkynes. A variety of functional groups were tolerated on both aldehydes and terminal alkynes. A mechanistic study on the oxidative coupling via operando IR, XANES/EXAFS and DFT calculations techniques was demonstrated. A bimetallic zinc complex was determined to be the active species. Each zinc has two iodides, one aldehyde oxygen and one more O or N ligand coordination. Operando IR study showed that the addition of terminal alkyne to aldehyde occurs quickly to generate propargylic alcohol followed by a relatively slow oxidation by another aldehyde molecule to afford the final ynone. Base on the mechanism understanding, one experiment was designed and the desired ynone could be obtained by using a1:1ratio of the starting aldehyde and terminal alkyne, in which pivalaldehyde was used as an oxidant.2. The first oxidative coupling of alkenes with aldehydes for the construction of a,(3-unsaturated ketones was developed. Under nitrogen atmosphere, readily available alkene and aldehyde derivatives could be converted into the corresponding a,B-unsaturated ketones using CuCl2as the catalyst precursor and TBHP as oxidant. Based on some experiment results, a plausible mechanism was proposed which suggests that this reaction is likely to proceed by a single electron transfer process.3. The first TEMPO-mediated oxidative coupling of alkenes with aldehydes to construct a-carbonyl epoxides was developed. This method is simple, practical and avoids the use of transition metals which complements the classic method for the construction of a-carbonyl epoxides. The TEMPO-adduct aldehayde was confirmed to be the intermediate for this oxidative coupling via Operando IR and the experiment of intermediate verification. According to the racemic desired product, the step of cyclization was thought to maybe go through radical homolytic substitution. Based on above results and DFT calculations, a plausible mechanism was proposed.4. The first oxidative coupling of chainlike secondary amides with aldehydes was developed. Under nitrogen atmosphere, readily available chainlike secondary amide and aldehyde derivatives could be converted into the corresponding imides using FeBr2as the catalyst precursor and TBHP as oxidant. Based on some experiment results, a plausible mechanism was proposed. The proposed reaction pathway is as follows, FeBr2reacts with aldehyde in the presence of TBHP to generate acyl bromide, Fe(III) species and tert-butyl alcohol. Fe(III) species mediates the addition of amide to acyl bromide to afford the desired product along with an equivalent amount of hydrogen bromine which may be oxidized by TBHP to return the bromide source. According to above proposed mechanism, when bromine source was replaced with iodine source, whether could realize that transition-metal-free oxidative coupling of chainlike secondary amides with aldehydes. To our surprise, not only imides, acyl exchange products were also obtained. Secondary amide and aldehyde derivatives could be highly selective converted into the corresponding acyl exchange products using CuCl2as the catalyst precursor and NIS as iodine source.