Angelw: synthesis of functional α - vinyl aldehydes

The functionalized α - vinyl carbonyl compounds are widely found in a variety of natural products, high-performance materials and bioactive compounds (Figure 1) Therefore, the development of new strategies for the synthesis of functionalized α - vinyl carbonyl compounds has become a top priority for synthetic chemists Enolates are often used for the preparation of carbonyl compounds with functional groups, but there are few reports on the preparation of α - vinyl aldehydes from enolates, mainly because it is difficult for enolates to react with electrophilic reagents containing alkenes Transition metal catalyzed coupling reaction of enols or enol equivalents can efficiently synthesize α - vinyl carbonyl compounds (scheme 1, a) Ru and Ni can catalyze the Olefination of α - bromoester to α - vinyl ester (Scheme 1, b) In addition, Macmillan group has successfully developed the co catalysis of Cu and amine for the α - alkenylation of aldehydes to synthesize mono substituted α - vinyl aldehydes (scheme1, c) However, there are some problems in these strategies, such as the complex catalytic system and the need for strong alkaline reaction conditions, which greatly inhibit the synthesis of α - vinyl aldehydes containing multiple carbonyls As the smallest unsaturated carbon ring, cyclopropene is widely used in C-H insertion reaction, X-H insertion reaction and coupling reaction Based on their strong interest in enamine chemistry, the team from Nanyang University of science and technology, Singapore / Teck Peng LOH, Nanjing University of technology and Jiang Yaojia, Nanjing University of technology envisage that cyclopropene can be opened to produce vinyl carbene compounds, which can react with enaminone to form aminocyclopropane intermediate, which can generate selective C-C under the action of catalyst The bond breaks to form vinyl carbonyl compounds The stereoselectivity of the double bond can be controlled by changing the amino protecting group of the ketene Therefore, under mild reaction conditions, Professor Teck Peng LOH of Nanyang University of Technology / Nanjing University of technology in Singapore and Professor Jiang Yaojia of Nanjing University of technology realized the highly regioselective synthesis of functional α - vinyl aldehyde by using the above strategies Relevant research results were published in angelw Chem Int ed (DOI: 10.1002 / anie 201906213) (picture source: angelw Chem Int ed.) (picture source: angelw Chem Int ed.) First, under the condition of N 2 protection, the author took cyclopropene 1a and (E) - 3 - (dimethylamino) - 1-phenylpropyl-2-ene-1-one 2A 'as template substrate, and determined the optimal condition as (table 1) by screening the substrate, catalyst and solvent ）The product 3AA can be obtained in 90% yield and > 99:1 E / Z ratio by using 1.25 mol% RH 2 (OAC) 4 as catalyst and DCE as solvent (picture source: angelw Chem Int ed.) then, under the optimal reaction conditions, the author investigated the substrate range of ketene (Table 2) All kinds of aryl, naphthalene and heterocyclic substituted enaminones and cinnamaldehyde derived enaminones can adapt to the reaction conditions well, and the corresponding products can be obtained with medium to excellent enantioselectivity and excellent stereoselectivity At the same time, all kinds of primary alkyl, middle alkyl, tertiary alkyl substituted and cycloalkyl substituted enaminones have good tolerance, and the corresponding products can be obtained with good yield and excellent enantioselectivity However, N, N-Me, TS substituted ketene amines can not get corresponding products Under the standard conditions, N, n-dimethyl-substituted enolates can obtain the corresponding products in medium yield, and the larger the steric hindrance of the substituents of enolates, the higher the stereoselectivity of the products (image source: angelw Chem Int ed.) then, the author examined the substrate range of cyclopropene (Table 3) Allylidene, naphthyl, adamantyl, benzyl and cyclohexyl substituted cyclopropylenes have good tolerance and can be obtained in medium to good yield, but their stereoselectivity is greatly affected by substituents For isopropyl substituted and cyclopentane substituted CYCLOPROPYLENE, the stereoselectivity of the reaction also decreased significantly Diphenyl substituted, cyclic and unsymmetrical cyclopropene can also adapt to the reaction conditions, but the corresponding products can only be obtained in a low to medium yield (picture source: angelw Chem Int ed.) the author speculated that the possible mechanism (scheme 2): under the action of Rh catalyst, the Rh complex a intermediate formed by ring opening reaction of cyclopropene 1a and the nucleophilic addition reaction of ketene 2A generate the zwitterion intermediate B B undergoes C-C bond rearrangement and cyclization reaction and undergoes intermediate C to intermediate D Due to the influence of the electrical properties of carbonyl and amino group, the C-C bond of D will break selectively, and then the product 3AA will be produced in the process of hydrolysis and deamination Among them, intermediate D can be separated On the other hand, carbene addition reaction may also occur in B, which undergoes intermediate d to form imine ion e, which hydrolyzes to form f in the form of enol and product 3AA (image source: angelw Chem Int ed.) in order to prove the application potential of the reaction, the author carried out gram level reaction and derivative reaction (scheme 3) The results of the extended reaction are good, and 3Na can be obtained in 62% yield Then, the reduction reaction, selective oxidation reaction, olefinization reaction and Paal Knorr reaction were carried out with 3Na as template, and the corresponding derivatives were obtained in good yield At the same time, 3 Na can react with diamine to get Dipyrrole compound 8 Suzuki coupling reaction took place in 3af, and the corresponding products were obtained in 91% yield (photo source: angelw Chem Int ed.) Summary: Nanyang University of technology, Singapore / Teck Peng LOH of Nanjing University of technology and Jiang Yaojia of Nanjing University of technology have successfully developed a new strategy of RH catalyzed high regioselective synthesis of various vinyl aldehyde derivatives At the same time, vinyl aldehydes can be converted into other important compounds by simple derivatization.