Angelw: chemical selective α, β - dehydrogenation of saturated amides by maulide group, University of Vienna, Austria

At present, the methods of constructing α, β - unsaturated carbonyl system mainly include carbonylation and olefin cross metathesis Kingsbury and cram's pioneering results on the synergistic heat elimination of alkylsulfoxide inspired the follow-up research of similar selenium oxide elimination; Saegusa ITO oxidation is another method commonly used in the synthesis of α, β - unsaturated carbonyl system; Stahl and other research groups developed a greener oxidant for catalytic reaction However, the above methods usually involve two-step reactions or are limited to (cyclic) ketones Subsequently, Nicolaou et al Also reported the use of 2-iodoylbenzoic acid (IBX) to oxidize ketones into corresponding α, β - ketene In addition to ketones and aldehydes, the difficulty of direct dehydrogenation of other carbonyl compounds (such as esters and amides) is that their α - site acidity is significantly reduced The new house group reported the method of dehydrogenation of zinc enol compounds under palladium catalysis (scheme 1a), which is suitable for total synthesis; Dong guangbin group realized the desaturation of N-acyl lactam (scheme 1b) through two-point combination activation process; recently, Huang Yong group reported the desaturation of γ, δ - unsaturated amide catalyzed by iridium under specific conditions (scheme 1A 1c) Recently, the team of Nuno maulide, University of Vienna, Austria, reported the chemical selective α, β - dehydrogenation of amides in angew Chem Int ed., which can be completed at room temperature and has wide applicability (DOI: 10.1002/anie.201808794) It is assumed that selenic acid (phseo ­ 2H) has enough nucleophilic property to attack the intermediate of ketoneimine to produce enamine compound 2, and then α - selenide 3 obtained by [1,3] - σ rearrangement of 2 is eliminated in situ and finally α, β - dehydrogenation product (scheme 1) is obtained (picture source: angelw Chem Int ed.) firstly, the author screened the reaction conditions with amide 1A as the substrate (Table 1) The yield of α - and β - dehydrogenation products 4A was lower than 50% in the initial experiment, and the by-products α - hydroxylamide 5 and α - selenidamide 6 appeared in the reaction After a series of experiments, the author found that when DESs Martin oxidant (DMP) was added, 4A was obtained in 73% yield under the action of phseo2h and et3n, and no other by-products were formed (entry 5) (image source: angelw Chem Int ed.) after getting the best reaction conditions, the author turned his attention to explore the substrate range of the reaction (scheme 2) All the amides derived from tertiary amides and aniline have good tolerance, and the reaction conditions can also tolerate alkynes, trifluoromethyl and other groups Different cinnamamides can also be prepared by this method α - substituted amides can also be dehydrogenated to indene 4f, cyclobutenamide 4G and 1,3-diene 4H In addition, tert amides with other N-substituents, such as dibenzyl, morpholine, piperidine and azacycloheptane, can also be dehydrogenated successfully In the presence of more reactive carbonyl structures such as esters and ketones, amides can also be selectively dehydrogenated In addition, the amides derived from the natural products oleic acid and dehydrocholic acid can also be used to separate and selectively generate dehydrogenated products The antidepressants citalopram and 13 membered lactam were also dehydrogenated to 4Z and 4AA (picture source: angel Chem Int ed.) in order to further study the selectivity of the reaction, the author used the substrate containing both secondary amide and tertiary amide to carry out the reaction, resulting in 4AB (scheme 3a), the product of partial dehydrogenation of tertiary amide Next, in order to illustrate the practicability of dehydrogenation products, the author made a double hydroxylation of unsaturated amide 4N to get product 7 (scheme 3b); in addition, harutyunyan and his colleagues reported the reaction of 4N and etmgbr to get product 8 (scheme 3C) by asymmetric conjugation addition The method was also applied to the synthesis of piperine (13) (scheme 3D) Next, the mechanism of α, β - dehydrogenation was studied After the replacement of phseo 2H with phseoh selenite, α - selenide amide 6 and α - hydroxylation product 5 were obtained It is speculated that [1,3] - σ rearrangement took place in the intermediate 2 'obtained by the attack of phseoh on ketenimide, thus forming 6 and 5 (scheme 4a) When DMP is replaced by acetic anhydride, a mixture of 6 and 4a is formed, which shows that DMP is very important in the process of reaction (scheme4b) DMP can oxidize 6 to unsaturated amide 4a, so the author speculates that DMP may play a dual role of capturing phseoh and oxidizing 6 (scheme 4C) When h 218 o was added for labeling experiment, 18 O-labeled unsaturated amides were formed, which indicated that the intermediate of ketene imine might be attacked by H 2O or ACO released by DMP to produce a mixture of ketene amines and enols (scheme 4D) (picture source: angelw Chem Int ed.) conclusion: the team of Nuno maulide reported the selective α, β - dehydrogenation of amides under mild conditions Its strategy depends on electrophilic activation and Se mediated in-situ selective dehydrogenation The method has good functional group tolerance, can selectively dehydrogenate amide in the presence of ester and ketone, and can also be used in the synthesis of natural product piperine.