Reaction Of Malonate Research Articles

3-Substituted 6-Azabicyclo[3.1.1]heptanes: Nonclassical Piperidine Isosteres for Drug Discovery.

Advanced analogs of piperidine and smaller homologues of tropane─3-substituted 6-azabicyclo[3.1.1]heptanes─were synthesized on a large scale using readily available bulk reagents. The key step of the approach involved the double alkylation reaction of malonate with cis-2,4-bis(mesyloxymethyl)azetidine-1-carboxylate, in turn easily prepared on up to 1 kg scale. After hydrolysis, N-Boc-6-azabicyclo[3.1.1]heptane-3,3-dicarboxylic acid was obtained (up to 400 g in a single run), which was used as a common intermediate for the preparation of all the title building blocks. In particular, Pb(OAc)4-mediated oxidative decarboxylation of this intermediate gave 2,6-methanopiperidone derivative (up to 400 g scale), while monodecarboxylation gave N-Boc-6-azabicyclo[3.1.1]heptane-3-carboxylic acids as an easily separatable mixture of cis and trans diastereomers (up to 100 g scale). Further functional group transformations gave diastereopure cis- and trans-N-Boc-monoprotected diamines and amino alcohols. Molecular structure analysis using exit vector parameters (EVP) revealed that cis isomers of 3-substituted 6-azabicyclo[3.1.1]heptanes are three-dimensional analogs of common 1,4-disubstituted piperidine chair conformer, whereas trans isomers can be considered as unusual "boat" piperidines.

Continuous‐Flow Enantioselective 1,4‐Addition Reactions of Malonates with Nitroolefins on Ni‐Supported Mesoporous Silica Materials with Co‐feeding of a Chiral Ligand

AbstractA catalytic system is described in which achiral Ni is immobilized on mesoporous silica material with external addition of a chiral modifier enabling continuous‐flow enantioselective reactions with catalyst‐packed bed reactors. Continuous‐flow enantioselective 1,4‐addition reactions of dimethyl malonate with nitroalkenes proceeded with co‐feeding of a chiral diamine ligand, and the corresponding products were obtained in high yields with high enantioselectivities for more than 80 h with a turnover frequency of 3.1 h−1 based on [Ni].

Michael addition reaction of malonates with nitro-olefins catalyzed by 1,1-diaminoazine, a bifunctional hydrogen bonding organocatalyst

Carbon–carbon bond forming processes are central to synthetic organic chemistry, and the Michael addition reaction is a frequently used method for C–C bond formation; 1,1-diaminoazines have been utilised as organocatalysts to facilitate this reaction.

Development of Brønsted Base–Photocatalyst Hybrid Systems for Highly Efficient C–C Bond Formation Reactions of Malonates with Styrenes

Brønsted base–photocatalyst hybrid systems have been developed for reactions of malonates with styrene derivatives. The concept of this process lies in the photo-oxidation of catalytic amounts of the enolate to form reactive radicals that react with alkene double bonds under mild reaction conditions. This is an example of visible-light-activated C–C bond formation reactions of malonates with alkenes to realize high atom economy under very mild reaction conditions without using any transition-metal catalysts.

Bis(imidazolidine)pyridine‐CoCl2: A Novel, Catalytically Active Neutral Complex for Asymmetric Michael Reaction of 1,3‐Carbonyl Compounds with Nitroalkenes

AbstractA neutral bis(imidazolidine)pyridine (PyBidine)‐CoCl2 complex showed catalytic activity for the Michael reaction of malonates with nitroalkenes. The results indicated that a weak amine base aided enolate formation from the neutral complex, in which the N−H proton of the imidazolidine ligand played a significant role.magnified image

Lithium Binaphtholate-Catalyzed Michael Reaction of Malonates with Maleates and Its Application to the Enantioselective Synthesis of Tricarboxylic Acid Derivatives.

The Michael reaction of malonates with maleates afforded the corresponding adducts in high yields with high enantioselectivities (up to 98% enantiomeric excess (ee)) by using dilithium 3,3'-dichlorobinaphtholate as a catalyst. The obtained Michael adducts could be converted to optically active tricarboxylic acid (TCA) derivatives via the Krapcho reaction.

Nickel-Catalyzed Michael Reaction of Malonates and Nitroalkenes

Nickel-Catalyzed Michael Reaction of Malonates and Nitroalkenes

Synthesis of bicyclic lactones via I2-mediated intramolecular tandem C–C/C–O bond formation

The iodine/DMAP-mediated intramolecular tandem C–C/C–O bond forming reaction of malonate bearing alkene moiety proceeded to give bicyclic lactones with good diastereoselectivity in good yield. The mechanistic investigation was also discussed on the basis of various control experimental results.

Graphene oxide covalently functionalized with an organic superbase as highly efficient and durable nanocatalyst for green Michael addition reaction

A highly efficient and durable nanocatalyst comprising graphene oxide (GO) covalently functionalized with an organic superbase, 1,1,3,3-tetramethylguanidine (TMG), was synthesized. Successful anchoring of TMG on the GO surface was corroborated by elemental analysis, Fourier-transform infrared (FT-IR) spectroscopy, thermogravimetric analysis (TGA), X-ray diffraction (XRD) analysis, field-emission scanning electron microscopy (FE-SEM), energy-dispersive x-ray spectroscopy (EDS), and Raman spectroscopy. The synthesized hybrid material (GO–Si–TMG-1) exhibited outstanding catalytic activity, comparable to that of homogeneous TMG. GO–Si–TMG-1 quantitatively promoted Michael addition reaction of malonates to various substituted nitrostyrene derivatives with excellent reaction conversions (100%) and product yields (up to 99%) under mild and green reaction conditions at 30 °C in EtOH–H2O (1:1). Moreover, the catalyst could be easily recovered by filtration and reused for at least seven times without significant decrease in catalytic performance. The catalyst recovered after seven cycles was fully characterized using various analytical techniques. In addition, the stability of the catalyst at high temperature was studied, revealing that the synthesized hybrid material could be easily applied at high temperatures without significant leaching of active sites.

Enzyme-Promoted Direct Asymmetric Michael Reaction by Using Protease from Streptomyces griseus

The direct asymmetric Michael addition of malonates and enones was promoted by protease from Streptomyces griseus for the first time. Yields of up to 84% with enantioselectivities of up to 98% enantiomeric excess (ee) were achieved under optimized conditions. Protease from Streptomyces griseus (SGP) was used for the first time as a biocatalyst in asymmetric Michael reaction of malonates.

A novel homobimetallic nickel complex for the asymmetric direct Mannich reaction of imines: a practical method on a multi-gram scale.

A novel dinuclear Ni complex has been developed for the direct Mannich reaction of malonates with N-tosyl aryl imines with a low catalyst loading (0.1-0.05 mol%) on a preparative scale (5-50 mmol). The structure of the active species was verified via control experiments, ESI-HRMS, and DFT calculations.

Organocatalytic peroxidation of malonates, β-ketoesters, and cyanoacetic esters using n-Bu4NI/t-BuOOH-mediated intermolecular oxidative C(sp3)–O coupling

A new organocatalytic approach for the synthesis of peroxides based on СН activation of a sp3-hybridized carbon atom is reported. Peroxides were prepared in 31–89% yield by the reaction of malonates, β-ketoesters, and cyanoacetic esters with a Bu4NI/tert-butyl hydroperoxide system. The formation of the expected hydroxylation products was not observed. In the discovered reaction, tert-butyl hydroperoxide plays a dual role by acting as the oxidant and the O-reagent for the C–O coupling. The synthesis can be scaled up to generate gram quantities of the target products.

Asymmetric Mannich Reaction of Malonates with Aldimines Using YbIII‐Pybox Complexes Supported on Self‐Assembled Organic–Inorganic Hybrid Silica with an Imidazolium Framework

AbstractYb(OTf)3/iPr‐pybox (3b) immobilized on a self‐assembled organic–inorganic hybrid silica with ionic liquid phase (SAILP) (Catalyst A) behaves as an efficient and recyclable catalyst in the enantioselective Mannich reaction of malonate esters with N‐Boc aldimines to afford the corresponding products in good yields and enantioselectivities. In particular, it has been shown that the use of catalyst A resulted in much superior enantioselectivities in comparison with either 1:2 Yb(OTf)3/3b on a periodic mesoporous organosilica with 10 percent imidazolium framework (catalyst C) or a catalyst comprising 1:1 Yb(OTf)3/3b on SAILP under the same reaction conditions. Catalyst A could be recycled and reused at least four times with only a slight decrease in either catalytic activity or enantioselectivity.

Endohedral Fullerene Derivatives: Tether-Directed Functionalizations and Regioisomer Preferences

Addition reactions have been performed (carbene and addition-elimination, Bingel) on Sc3N@C2nto determine the preferred mono- as well as multiple addition positions both experimentally and via computations. It has been observed that carbene additions lead to many more isomers than the corresponding addition-elimination reactions of malonates (Bingel reaction), which lead to a rather small number of regioisomers. Theory predicts well the Bingel adducts that are observed experimentally and provides a kinetic rationale for the observations.Tethered bis-additions have also been explored, especially on Lu3N@C80, and the results indicate very regioselective bis-additions, with only one bis-regioisomer observed in many cases for bis-carbene additions.These and other results will be presented and discussed within the context of single and multiple functionalization of endohedral fullerene compounds and how the properties of the products can be controlled via functionalization.

A New Approach for Supramolecular Iminium Catalysis

An alternative modular strategy has been developed for hydrogen-bond-mediated supramolecular iminium catalysis (SIC). To improve the efficiency of traditional iminium ion catalysis and provide a new approach to asymmetric catalysis, we recently developed a new concept which aims to activate iminium ions. To expand the scope of SIC, we reported here a rationally designed strategy involving the dual activation of both iminium ions and the nucleophilic partner that provides new opportunities for improving the reactivity and designing new reactions. We analyzed the different reaction rates of the addition reaction of malonate to alpha,beta-unsaturated aldehyde catalyzed by traditional iminium ion catalysis and supramolecular iminium catalysis by the means of H-1 NMR monitoring of the reaction conversions and comparison of the isolated yields. Moreover, different carboxylic acids were employed in iminium catalytic Michael addition reaction of malonate to alpha,beta-unsaturated aldehyde to test our hypothesis. General speaking, by using this novel supramolecular iminium catalysis, the enantioselectivities of the Michael addition products are excellent (93%similar to 95%) with moderate to good yields (61%similar to 86%), meanwhile, all these reactions were rather slow and only 33%similar to 57% conversions were obtained even after 7 days in the presence of traditional iminium ion catalysis. Further reducing the catalyst loading to 5 mol%, the reaction proceeded smoothly to give a >90% conversion with 94% ee after 12 h. The results revealed that the use of less acidic acid which generates lower concentration of iminium ion associated with stronger anion-binding stabilized conjugate base gives faster reaction rate. The experimental results indicate a new approach for SIC which involves an anion-exchange process between anion-binding stabilized carboxylate ion and malonate. The self-assembled supramolecular system has higher reactivity, better efficiency and greater turnover numbers. This general strategy has the potential to be applied in many iminium catalytic nucleophilic addition reactions and might provide new opportunities for designing new asymmetric reactions. The further study is currently underway in our laboratory.

ChemInform Abstract: Highly Efficient Catalytic Enantioselective Mannich Reaction of Malonates with N‐tert‐Butoxycarbonyl Imines by Using Yb(OTf)3/Pybox Catalyst at Room Temperature.

AbstractA highly efficient Mannich reaction of Boc‐aldimines with benzyl malonate is described using Yb(OTf)3 and a chiral pybox ligand as catalysts.

Mechanistic study of asymmetric Michael addition of malonates to enones catalyzed by a primary amino acid lithium salt

A mechanistic study was carried out for the asymmetric Michael addition reaction of malonates to enones catalyzed by a primary amino acid lithium salt to elucidate the origin of the asymmetric induction. A primary β-amino acid salt catalyst, O-TBDPS β-homoserine lithium salt, exhibited much higher enantioselectivity than that achieved with the corresponding catalysts derived from α- and γ-amino acids for this reaction. Detailed studies of the transition states with DFT calculations revealed that the lithium cation and carboxylate group of the β-amino acid salt catalyst have important roles in achieving high enantioselectivity in the Michael addition reaction of malonates to enones.

Ytterbium-Catalyzed Enantioselective Mannich Reaction of Malonates

Ytterbium-Catalyzed Enantioselective Mannich Reaction of Malonates

ChemInform Abstract: Chiral Calcium Iodide for Asymmetric Mannich‐Type Reactions of Malonates with Imines Providing β‐Aminocarbonyl Compounds.

AbstractA chiral air‐ and moisture‐stable calcium iodide catalyst, generated in situ from CaI2 and pybox‐ligands, is developed.

Organocatalytic enantioselective conjugate addition–cyclization domino reactions of o-N-protected aminophenyl α,β-unsaturated aldehydes

A highly enantioselective synthesis of biologically useful tetrahydroquinolines has been developed through the asymmetric organocatalytic conjugate addition–cyclization reaction of malonates with o-N-protected aminophenyl α,β-unsaturated aldehydes using a diphenylprolinol TMS ether as an organocatalyst followed by reductive deoxygenation. This novel protocol allows for the formation of 4-substituted chiral tetrahydroquinolines, which are not easily accessible using other methodologies, in good yields with high enantioselectivities (up to >99% ee).