In this thesis, the importance of α,β-unsaturated ketones in pharmaceuticals, functional materials and organic synthesis was highlighted, and the developed synthetic method using these materials in the classical and the newer transition metal-catalyzed chemistry was introduced. It was possible to stabilize the unstable acyl-metal-H complex and suppress the side reaction of decarbonylation via the introduction of the chelating group, but the scope is limited because the chelating groups are always needed for the substrates. Second, by using water as a hydrogen donor with a reducing agent to replace H in the aldehyde, the proton could be supplied stably and a mild state was established without a hydride source like the conventional dangerous silyl hydride.
By forming a stable acyl-nickel-thiopyridine complex, it was possible to effectively suppress R-H decarbonylative side products, which were critical issues in previous transition metal-catalyzed hydroacylation. Desired regio- and stereoselective products can be obtained in the form of α,β-unsaturated and β,γ-unsaturated ketones. Especially, in the case of the terminal alkyne, a product could be afforded in a yield as high as 82%.
Surprisingly, not only simple aryl compounds, but also simple alkyl compounds, which were almost difficult to access through the previous hydroacylation due to weak bonding to the carbonyl carbon, could also be brought into scope through the radical process acil and extended the scope. Through this thesis, it is possible to overcome the challenging part of existing hydroacylation by introducing the concept of hydroacylation using nickel and thioester catalyst at an affordable price under mild conditions and the scope of application is expanded to polymerization and pharmaceutical.
Introduction
According to the different conditions, nucleophilic attack by nucleophiles is thus possible at both the carbonyl carbon and the β-carbon. Due to this vinylogous reactivity, nucleophilic conjugate addition could be easily achieved through the cleavage of unsaturated C–C bond and the formation of new C–C bond, finally approaches to additional substrate could be possible.
Hydroacylation
Comparison of hydroacylation: a hydroacylation with carbon monoxide and water, b hydroacylation with aldehyde, decarbonylative side pathway: c Tusji-Wilkinson decarbonylation reaction. The first alkyne carbonylation using a transition metal was reported by Reppe in 1939, using water as the H source and carbon monoxide as the carbonyl source with nickel catalysts to produce α,β-unsaturated carboxylic acid19-21 (Figure 1.5. a ). Thus, to create environments for easy CO introduction and alkyne introduction, it was necessary to use transition metal catalysts (Ni, Pd, Fe, etc.) for coordination.
With the advent of transition metal-catalyzed functionalization of olefins, the range of unsaturated carbon carbonylation has expanded to include not only α, β-unsaturated ketones, carboxylic acids, amides, esters, aldehydes, and cyclic compounds22. Instead of carbon monoxide, aldehydes appear, which can simultaneously provide a source of H and an acyl source by oxidative addition with a transition metal catalyst. Several strategies have been introduced to suppress the unwanted decarbonylation process i) exchangeable transition metal instead of rhodium, ii) stabilizing effect of chelate groups.
By introducing the phosphine chelating group and effectively stabilizing the intermediate, decarbonylative compds. were somewhat suppressed. Therefore, an intermolecular hydroacylation of non-bonded alkyne still remains a challenge in transition metal catalyzed hydroacylation.
34;Synthesis of α,β-Unsaturated Ketones by Nickel-Catalyzed Aldehyde-Free Hydroacylation of Alkynes" this will be covered in detail. Stereoselective Synthesis of Diacids by the Nickel Cyanide and Phase-Transfer-Catalyzed Carbonylation of Alkynes Dependencies of Product No Dependence. Stereochemistry and optimal stirring speed on the nature of the phase transfer agent.
Synthesis of α,β-unsaturated ketones through nickel-catalysed aldehyde-free
Abstract
Introduction
Metal-catalyzed intermolecular hydroacylation has emerged as a prominent method for rapid access to E-enones through alkyne-aldehyde coupling26-31. This atom-economical method involves the chemoselective activation of an aldehydic C(sp2)-H, and chelating moiety-bearing aldehydes have been applied to prevent decarbonylative side pathways (Figure 2.1.b). Stabilization of an acyl-metal complex assisted by heteroatom chelation is a powerful strategy for obtaining E-enones.
However, the installation and removal of coordination moieties involved additional synthetic steps while reducing the economy of the hydrofunctionalization steps. Although undirected hydroacylation methods have been developed for alkenes or dienes 32–36 , to the best of our knowledge, there is no general hydroacylation method for unactivated terminal alkynes leading to the chelation of moiety-free E -enones. We reasoned that the thioester can act both as a transient thiopyridyl (SPy) ligand and as an acyl component under nickel-catalyzed reductive coupling conditions, leading to the acyl-Ni-SPy complex.
However, the challenges of this predicted reaction process to achieve trace-free alkyne hydroacylation are fourfold: (i) competition with nonconjunctive inter-electrophilic coupling (proton and thioester), (ii) reduction of substrates, (iii) iterative addns. alkynes, and (iv) regioselective and stereoselective issues. Therefore, precise control of reactivity and selectivity is essential for a general approach to the hydroacylation of unactivated terminal alkynes.
Results and discussion
To optimize the reaction conditions, S-(pyridin-2-yl) 4-methoxybenzothioate (1) and 3,3-dimethyl-1-butyne (2) were chosen as model substrates, and a thorough screening of catalysts, reducing agents, additives and solvents were performed (Table 2.1, see also experimental section 2.5.3). The use of 17 mol% Ni catalyst was suitable to provide a stoichiometric 1 equiv of protons to the reaction. No desirable product formation was observed in the absence of the nickel catalyst, Zn or ZnCl2 (entries 6–8).
Acyclic as well as cyclic aliphatic terminal alkynes underwent the reaction to give the corresponding vinyl ketones (33-38) in moderate yields, although cyclopropyl- and cyclopentyl-derived alkynes gave the reduced yields. 2-Ethynylthiophene and 3-ethynylthiophene underwent the reaction smoothly to obtain the corresponding products (55, 56) in 39% and 58% yields, respectively. We were delighted to find that the reaction was feasible with ethisterone, a gynecological disease treatment agent, to yield 58 in 56%.
When TEMPO was added under standard reaction conditions, the desired hydroacylation was completely terminated and an acyl-TEMPO adduct (65) was isolated in 70% yield. This study proves the involvement of an acyl radical intermediate during the course of the reaction (Figure 2.2.a). Surprisingly, acyl-TEMPO adduct formation was also observed using Zn and ZnCl2 in the absence of any nickel catalyst, indicating its role in the generation of acyl radicals from the thioester via single electron transfer (SET).
First, a reaction performed using deuterium oxide (3.0 equiv) resulted in the formation of the product with 64% and 33% [D] incorporation at the β and α positions, respectively, of unsaturated ketone [D]-3. The use of deuterated nickel(II) perchlorate hexahydrate resulted in the comparable ratio of ~1.9:1 (see also experimental section 2.5.5). To confirm the non-involvement of solvent molecules, we performed the hydroacylation reaction using deuterated THF, and no D incorporation was detected in the final product.
The use of terminally deuterated alkyne [D]-2 for the Ni-catalyzed reductive coupling reaction also demonstrated H–D exchange due to the weak acidity of the terminal alkyne41,42. The reaction is initiated by the formation of an acyl radical and a thiopyridyl anion through single-electron reduction of a redox-active thioester promoted by Zn and ZnCl2. Engagement of the acyl group with intermediate A directs the formation of acyl-Ni(II)-thiopyridyl complex B.
Conclusion
The SPy anion undergoes a sequential ligand exchange reaction with the nickel(I)X precatalyst to yield Ni(I)SPy complex A, which is generated in situ by the reduction of the Ni(II) precatalyst by zinc. Protodemetalation of nucleophilic vinyl Ni(II) type D using water yields the desired E-enone38. The reduction of LnNi(II)X2 (X = Spy-, OH-) species E by zinc regenerates the active Ni(I) species A to complete the catalytic cycle.
Experimental
- General Information
- Preparation of Thioesters
- Optimization Studies
- X-ray Single Crystal Diffraction Data
- Deuterium Labeling Experiments
- Experimental Procedures
- Characterization Data
After the reaction was complete, the mixture was diluted with additional DCM (100 mL) and washed with a saturated aqueous solution of NaHCO3 (50 mL 2) and brine (50 mL 2). The residue was purified by flash column chromatography (hexane/EtOAc = 1:1) to give the title compound S1 (white solid, 1.38 g, 63%). After the reaction was complete, the mixture was diluted with additional DCM (50 mL) and washed with saturated aqueous NaHCO3 solution (30 mL 2) and brine (30 mL 2).
The residue was purified by flash column chromatography (hexane/EtOAc = 1:1) to yield the title compound S28 (a yellow oil, 148 mg, 83%). Crystal structures of compound 27 and compound 67 were solved by the direct method and refined by full-matrix least-squares calculations using the SHELXTL program package.50 Thermal ellipsoids were shown with 50% probability. The O-D stretching peak appears at a lower frequency than the O-H peak due to the higher mass of deuterium, as shown in Eq.
When an FTIR spectrum is plotted as absorbance versus wavenumber, the integrated area of a peak is proportional to the product of the population and the integrated absorption coefficient (or oscillator strength) of the corresponding species (or functional group). This set of mole fractions of three different water species (D2O, HOD, and H2O) shows that the substitution reaction proceeded as expected. After completion of the reaction, the mixture was purified by flash column chromatography (hexane/EtOAc = 95:5) to give the title compound 3 (a colorless oil, 35 mg, 81%).
After completion of the reaction, the mixture was purified by flash column chromatography (hexane/EtOAc = 9:1) to yield the title compound 40 (a white solid, 35 mg, 69%). After completion of the reaction, the mixture was purified by flash column chromatography (hexane/EtOAc = 1:1) to yield the title compound 58 (a white solid, 263 mg, 59%).
The cinchona primary amine-catalyzed asymmetric epoxidation and hydroperoxidation of α,β-unsaturated carbonyl compounds with hydrogen peroxide. Asymmetric catalytic epoxidation of α,β-unsaturated carbonyl compounds with hydrogen peroxide: additive-free and broad substrate range. Design of novel chiral phase transfer catalysts with dual functions for highly enantioselective epoxidation of α,β-unsaturated ketones.
New one-pot three-component coupling reaction with trimethylsilylmethyl-phosphonate, acyl fluoride and aldehyde through Horner-Wadsworth-. Access to multifunctionalized benzofurans by arylnickelation of alkynes: efficient synthesis of the antiarrhythmic drug amiodarone. Nickel-catalyzed highly regioselective hydrocyanation of terminal alkynes with Zn(CN)2 using water as a hydrogen source.
Dilatometric studies of reaction volumes for the formation of nickel(II) complexes in aqueous solution. Oxygen as a Single Oxidant for Two Steps: One-Pot Baseless Alcohol Oxidation with Pd(II) and Arylation to Halogen-Intact β-Aryl α,β-Enones. Synthesis of α,β-unsaturated ketones by rhodium-catalyzed carbonylation arylation of internal alkynes with arylboronic acids.
