aza-Michael Addition Reaction Research Articles

Access to Fluoropyrrolidines by Intramolecular Aza-Michael Addition Reaction

Study of the intramolecular aza-Michael addition reaction from an aminofluorovinylsulfone opens a new route for the synthesis of pyrrolidine derivatives. An unexpected diastereoselective cyclization reaction was observed, leading preferentially to the anti-N-benzylpyrrolidine sulfone. The resulting sulfone was reacted with aldehydes to access β-substituted α-fluoroalkenyl pyrrolidines in one step.

Spectroscopic analysis of methacrylate groups introduced on silica particle surfaces by the aza-Michael addition reaction

We modified silica nanoparticles with a N′-(3-trimethoxysilylpropyl)diethylenetriamine (TPDT) silane coupling agent, which has one primary and two secondary amino groups in each molecule, to introduce amino groups on silica surfaces. After surface modification of silica, we used an acrylate group containing 3-(acryloyloxy)-2-hydroxypropyl methacrylate (AHM) to introduce free radical polymerizable methacrylate groups by the aza-Michael addition reaction. Fourier transform infrared spectroscopy (FTIR), elemental analysis (EA), liquid state 1H and 13C nuclear magnetic resonance spectroscopy (NMR) and solid state cross polarization magic angle spinning (CP/MAS) 29Si NMR were used to investigate the effects of various reaction conditions on the degree of reaction between the N-H groups of the TPDT-modified silica surface and the acrylate groups of AHM. We found that approximately 48% of the N-H groups of the TPDT-modified silica surface reacted with the acrylate groups of AHM, compared with approximately 83% of the N-H groups of pure TPDT reacting with the acrylate groups of AHM at the same reaction conditions. This lower degree of the aza-Michael addition reaction between the N-H groups of the TPDT grafted on the solid silica particle versus the N-H groups of pure TPDT, both with acrylate groups of liquid AHM, may be caused by the lower mobility of the N-H groups of the grafted TPDT on the solid silica particle and the higher steric hindrance caused by the solid silica particle.

Highly Active Kenaf Bio-Cellulose Based Poly(hydroxamic acid) Copper Catalyst for Aza-Michael Addition and Click Reactions

Bio-heterogeneous kenaf cellulose supported poly(hydroxamic acid) Cu(II) complex and corresponding copper nanoparticles ([email protected]) were synthesized and characterized. Cellulose supported poly(hydroxamic acid) copper nanoparticles was successfully applied to the Aza-Michael addition reaction of amines with α,β-unsaturated carbonyl/cyano compounds and poly(hydroxamic acid) Cu(II) complex was applied to the Click reactions of organic azides with alkynes in presence of sodium ascorbate as highly active catalysts under mild reaction conditions. The copper nanoparticles (50 mol ppm) selectively boosted Aza-Michael addition reaction to give the corresponding alkylated products in up to 96 % yield, whereas poly(hydroxamic acid) Cu(II) complex (0.25 mol%) efficiently promoted Click reaction to give the corresponding 1,2,3-triazoles in up to 94 % yields. Excellent reusability of the supported copper catalysts were found with no significant loss of catalytic activity for several cycles having high turnover number (TON) 18000 and turnover frequency (TOF) 3000 h−1 in the Aza-Michael addition reaction.

Structural sensitivity of peptoid-based low molecular mass organogelator

A new class of peptoid-based low molecular mass organogelators was prepared by the aza-Michael addition reaction. The gelation was observed only for tert-butyl group substituted peptoid in chlorinated solvents including chloroform, 1,2-dichloroethane, and 1,2-dichlorobenzene. Interestingly, the peptoids with methyl, ethyl, n-propyl, n-butyl, and isobutyl groups did not exhibit gelation, indicating unique structural sensitivity of organogelation. The compound reported here is one of the simplest low molecular mass organogelators prepared so far. The physical properties, spectral data, and ab initio calculation suggest that nanofibrous morphology developed through the intermolecular hydrogen bonding of peptoid molecules plays a crucial role in organogelation. This study provides insights in designing various peptoid-based small molecule organogelators, and suggests that a minute structural difference should affect the formation of organogels significantly.

Synthesis, Characterization and Catalytic Application of MCM 41 Supported Phenanthrolinium Dibromide Catalyst for Aza-Michael Addition Reaction in Aqueous Medium

MCM-41 immobilized phenanthrolinium dibromide (phen-MCM-Br2) was easily prepared and applied as an efficient heterogeneous catalyst for aza-Michael addition of aromatic amines to α,β-unsaturated nitriles and nitro compounds in water. The catalyst was characterized by CHN, TGA, FT-IR, SEM, EDAX, XRD, BET, and TEM. It could be simply recovered and reused several times without significant loss of catalytic activity.

Synthesis and characterization of a magnetically separable novel Fe3O4@L-DOPA@CuII nanocatalyst (L-DOPA = L-3,4-dihydroxyphenyylalanine): Asymmetric aza-Michael addition reaction

The synthesis and characterization of new copper(II)-L-3,4-dihydroxyphenyylalanine based magnetically separable nanocatalyst, namely Fe3O4@L-DOPA@CuII (L-DOPA=L-3,4-dihydroxyphenyylalanine), are described. The catalyst has been characterized by physicochemical studies. We have studied the application of this new catalyst for asymmetric aza-Michael addition reaction. This catalyst could simply be separated and recovered from the reaction mixture with the assistance of an external magnet and reused several times.

Pd-Catalyzed α-Arylation of Sulfones in a Three-Component Synthesis of 3-[2-(Phenyl/methylsulfonyl)ethyl]indoles

A novel four-step domino process for the synthesis of 3-[2-(aryl/alkylsulfonyl)ethyl]indoles starting from readily available 2-iodoanilines is reported. The domino reaction is based on the intramolecular palladium-catalyzed α-arylation of sulfones, which was combined with both intermolecular aza-Michael and Michael addition reactions using vinyl sulfones as the electrophile. The domino process produced good yields and tolerated the presence of substituents with different electronic properties on the aniline ring. In addition, density functional theory (DFT) calculations were carried out to gain more insight into the formation of the observed indole derivatives.

Chromatography-free stereoselective synthesis of (R)-3-benzylpiperidine

The present study describes aza-Michael addition reactions of 4-aroylpent-4-enoic acids with (R)-phenylglycinol. Subsequent spontaneous lactamization yielded the corresponding piperidin-2-ones, which can selectively crystallize in very high diastereomeric purity. These are useful intermediates in the stereoselective syntheses of diverse 3-benzylpiperidines, as herein demonstrated by a chromatography-free and straightforward Gram-scale synthesis of (R)-3-benzylpiperidine hydrochloride.

A green and convenient approach toward benzimidazole derivatives and their antimicrobial activity

Abstract N-Alkylated benzimidazole derivatives have been synthesized via the aza-Michael addition reactions of 1H-benzimidazoles to α,β-unsaturated compounds in water and palladium acetate obviously promoted these transformations. The reported method, overcoming the inactivation of palladium under the equivalent nitrogenous conditions, has the advantages of convenient manipulation, atom-economy, as well as environmental friendliness. The bioactive results showed that butyl 3-(5,6-dimethyl-1H-benzo[d]imidazol-1-yl)propanoate (3c) exhibited excellent inhibitory activity against Bacillus subtilis (MIC = 16 μg/mL) and Bacillus proteus (MIC = 8 μg/mL). Therefore, this process would facilitate the construction of various potential bioactive compounds based on the benzimidazole scaffold under mild conditions.

Convergent Synthesis Strategy of Novel Fused Azines: 1H-15N HMBC NMR as a Tool for Assertion of the Site Selectivity of Aza-Michael Addition Reaction

A unified convergent strategy has been developed for the facile synthesis of a series of novel fused azines bearing a phenothiazine moiety based on the aza-Michael addition reaction of an enaminone derivative to a variety of different heterocyclic amines under microwave irradiation conditions. The results of this study revealed that new methods are required to allow for the simple and efficient analysis of the fused azine products of this reaction other than single-crystal X-ray crystallography. With this in mind, 1H–15N HMBC experiments were used in the current study to allow for the unambiguous structural characterization of the fused azine products. These results provided further support in favor of the proposed structures and allowed for the resolution of several discrepancies reported in the literature regarding the structural characterization of these compounds. Keywords: Microwave irradiations, pyrazolo[1, 5-a]pyrimidines, triazolo[1, 5-a]pyrimidine, pyrimido[1, 2-a]benzimidazole, 1H-15N HMBC.

Highly Enantioselective Aza-Michael Reaction between Alkyl Amines and β-Trifluoromethyl β-Aryl Nitroolefins.

The aza-Michael addition reaction is a vital transformation for the synthesis of functionalized chiral amines. Despite intensive research, enantioselective aza-Michael reactions with alkyl amines as the nitrogen donor have not been successful. We report the use of chiral N-heterocyclic carbenes (NHCs) as noncovalent organocatalysts to promote a highly selective aza-Michael reaction between primary alkyl amines and β-trifluoromethyl β-aryl nitroolefins. In contrast to classical conjugate-addition reactions, a strategy of HOMO-raising activation was used. Chiral trifluoromethylated amines were synthesized in high yield (up to 99 %) with excellent enantioselectivity (up to 98 % ee).

ChemInform Abstract: Chiral Phosphoric Acid Catalyzed Asymmetric Synthesis of 2‐Substituted 2,3‐Dihydro‐4‐quinolones by a Protecting‐Group‐Free Approach.

Chiral 2-substituted 2,3-dihydro-4-quinolones were synthesized based on the chiral phosphoric acid catalyzed intramolecular aza-Michael addition reaction using N-unprotected 2-aminophenyl vinyl ketones as substrates in good yields with high enantioselectivities.

Chiral Phosphoric Acid Catalyzed Asymmetric Synthesis of 2-Substituted 2,3-Dihydro-4-quinolones by a Protecting-Group-Free Approach.

Chiral 2-substituted 2,3-dihydro-4-quinolones were synthesized based on the chiral phosphoric acid catalyzed intramolecular aza-Michael addition reaction using N-unprotected 2-aminophenyl vinyl ketones as substrates in good yields with high enantioselectivities.

Exploring the post-polymerization modification of side-chain amino acid containing polymers via Michael addition reactions

An efficacious protocol for the aza-Michael addition of a C-terminus modified phenylalanine side-chain containing polymer (Michael donor) was demonstrated with various Michael acceptors. The aza-Michael addition reactions were carried out at 50°C in anhydrous methanol, which is a protic solvent, to enhance the advancement of the reactions. 1H and inverse gated 13C NMR spectroscopy were utilized to qualitatively deliver comprehensive data on the reaction progress. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) provided quantitative information about the modification of the polymer. The extent of change in the aza-Michael addition varied with different Michael acceptors and decreased in the order of acrylate>acrylamide>methacrylate. The present study opens up a library of polymers with functional modifications in the side-chain.

Design and synthesis of novel oxetane β3-amino acids and α, β-peptides

The study describes synthesis of (S)- and (R)-oxetane-β3-amino acid (β3-Oaa) monomers from diacetone glucose (DAG). The oxetane ring is prepared by a nucleophilic cyclization reaction, wherein, the C-3 and C-4 stereocenters of DAG represent the C-2 and C-1 of oxetane ring, respectively. The hydroxy methyl group generated from C-1/C-2 was used for the ring formation, and C-5/C-6 of DAG were used for the introduction of amine and ester groups via aza-Michael addition reaction on the α, β-unsaturated ester. The stereochemistry at the newly created amine center was defined through modified Mosher method. The (S)-β3-Oaa monomer and l-Ala were used for the synthesis of regular 1:1 was converted into α, β-peptides. The conformational analysis of the peptides revealed the presence of 11/9-helical patterns from the NMR, CD and MD studies.

Synthesis of temperature and pH/CO2 responsive homopolymer bearing oligo(ethylene glycol) unit and N,N-diethylamino ethyl group and its solution property

A homopolymer strategy was developed to synthesize temperature and pH/CO2 stimulus-responsive homopolymers. A new class of acrylamide monomers bearing oligo(ethylene glycol) unit and N,N-diethylaminoethyl group were designed and prepared through Aza-Michael addition reaction followed by amidation with acryloyl chloride using amino group as a linkage to connect oligo(ethylene glycol), N,N-diethylaminoethyl, and polymerizable double bond groups together. Subsequently, the corresponding homopolymers containing oligo(ethylene glycol) unit and N,N-diethylaminoethyl group in each repeated unit were prepared via RAFT polymerization with controlled molecular weights and relatively narrow molecular weight distributions. The lower critical solution temperature (LCST) of homopolymer was examined to be influenced by molecular weight, salt concentration, and pH value of aqueous solution. The LCSTs of homopolymers could be tuned in a wide temperature window by changing pH value of aqueous solution and it increased with the decrease of pH value. Particularly, CO2 gas as a unique pH stimulus can also reversibly adjust the solubility of homopolymer without the addition of acids or bases.

Thermoresponsive Homopolymer Tunable by pH and CO2.

A new acrylamide monomer bearing isopropylamide and N,N-diethylamino ethyl groups in the side chain, i.e., N-(2-(diethylamino)ethyl)-N-(3-(isopropylamino)-3-oxopropyl)acrylamide (DEAE-NIPAM-AM), was synthesized through Aza-Michael addition reaction followed by amidation with acryloyl chloride. The homopolymers, poly(N-(2-(diethylamino)ethyl)-N-(3-(isopropylamino)-3-oxopropyl)acrylamide)s [poly(DEAE-NIPAM-AM)], with controlled molecular weights and relatively narrow molecular weight distributions were then prepared via RAFT polymerization. The lower critical solution temperature (LCST) of the homopolymer was examined to be influenced by molecular weight, salt concentration, and pH value of aqueous solution. The LCST of the homopolymer could be tuned in a wide temperature window by changing the pH value of aqueous solution, and it increased with the decrease of pH value. Particularly, CO2 gas as a unique pH stimulus can also reversibly adjust the solubility of homopolymer without the addition of acids or bases.

One-pot consecutive catalysis by integrating organometallic catalysis with organocatalysis.

The present study integrates two types of catalysis, namely, organometallic catalysis and organocatalysis in one reaction pot. In this process, the product of the first catalytic cycle acts as catalytic component for next catalytic cycle. The abnormal N-heterocyclic carbene-copper-based organometallic catalyst acts as an efficient catalyst for a click reaction to provide triazole, which, in turn, acts as an efficient organocatalyst for different organic transformations, for example, aza-Michael addition and multicomponent reactions, in a consecutive fashion in the same reaction pot.

ChemInform Abstract: Facile Synthesis of Indolines by a Tandem Nitro‐Reduction Aza Michael Addition Reaction.

ChemInform Abstract: Facile Synthesis of Indolines by a Tandem Nitro‐Reduction Aza Michael Addition Reaction.

A facile synthesis of β-amino carbonyl compounds through an aza-Michael addition reaction under solvent-free conditions

An efficient and eco-friendly process for the synthesis of β-amino carbonyl compounds was introduced in this paper. The oxanorbornene β-amino esters and β-enamine esters were successfully prepared from oxabornene and amines by using solvent-free aza-Michael addition reaction in the absence of any catalyst. Oxanorbornene β-amino esters were the major product at room temperature, but higher temperature (e.g. 90 °C) led to the formation of β-enamine esters. In addition, all of the target compounds were characterized by IR, 1H NMR, 13C NMR, and HR-MS. A possible reaction pathway was also proposed.