A convenient approach to δ-amino-β-ketoesters by vinylogous Mannich reaction of masked acetoacetates

SiCl₄ is an efficient and selective catalyst for the vinylogous Mannich reaction of linear and cyclic synthetic equivalents of acetoacetate dianion, leading to δ-amino-β-ketoesters in moderate to high yields and complete γ-selectivity; anti-diastereoselectivity was observed by using a γ-methyl-substituted cyclic silyloxydiene.     

Synthesis and nitration of 3-R-4-(2,2,2-trinitroethyl)aminofuroxans

Simple methods for the synthesis of 3-R-4-(2,2,2-trinitroethyl)aminofuroxans were developed based on the Mannich reaction of N,N′-bis(3-R-furoxan-4-yl)methylenediamines with trinitromethane or 3-R-4-aminofuroxans with trinitroethanol or with CH₂O and trinitromethane. The Mannich bases obtained were studied in the nitration reaction, which showed their ability to form nitramines depending on substituents on the furoxan ring.     

Cationic iridium complex is a new and efficient Lewis acid catalyst for aldol and Mannich reactions

A cationic iridium complex [Ir(cod)₂]SbF₆ was found to be a new and efficient Lewis acid catalyst for Mukaiyama aldol and Mannich reactions. Aldehydes react smoothly with silyl enol ethers to give β-siloxy ketones in the presence of 0.5 mol % of [Ir(cod)₂]SbF₆. The reaction of N-alkyl arylaldimines with ketene silyl acetals in the presence of 5 mol % [Ir(cod)₂]SbF₆/P(OPh)₃ gave β-amino esters. After Mannich reaction was complete, stirring of the reaction mixture for 24 h led to cyclization to give β-lactam. The reaction of N-aryl benzaldimine with silyl enol ether derived from acetophenone gave a tetrahydroquinoline derivative as a single diastereomer.     

Enantioselective Mannich reaction of γ-malonate-substituted α,β-unsaturated esters with N-Boc imines catalyzed by chiral bifunctional thiourea-phosphonium salts

A novel enantioselective Mannich reaction of γ-malonate-substituted α, β-unsaturated esters with N-protected arylaldimines was realized by using asymmetric phase-transfer catalysis (APTC). With amino acid-derived bifunctional thiourea-phosphonium salts as a catalyst, a series of enantio-enriched Mannich products could be synthesized under very mild and simple reaction conditions with high yields and enantioselectivities.     

Studies on the mechanism of Mannich reaction involving iminium salt as potential Mannich reagent. III. Furan as pseudo acid component

Structures, heats of formation, and vibrational eigenvalues have been calculated by semiempirical AM 1 quantum mechanical method for the reactants, products, and activated complexes of three Mannich reactions, namely, the reaction between potential Mannich reagent H₂N⁺ = CH₂Cl^? and furan and the conventional Mannich reactions between ammonia, formaldehyde, and furan in neutral and acidic media. It has been found that the Mannich reaction involving the potential Mannich reagent occurs more quickly than do the conventional Mannich reactions in neutral medium; the Mannich reaction in acidic medium proceeds most quickly. The results have been discussed in terms of the orbital match and static electric interaction between some atoms of reactant complexes. © 1995 John Wiley & Sons, Inc.     

Carbon-carbon bond formation via a tandem cationic 2-aza-Cope rearrangement-Lewis acid promoted Petasis reaction

Potassium alkynyltrifluoroborates and potassium (2-phenyl)vinyltrifluoroborates react with N-3-butenyl-(2,2-dichloro-1-propylidene)amine in the presence of BF₃·Et₂O as a Lewis acid to synthesize rearranged Mannich products. The reaction starts with a cationic 2-aza-Cope rearrangement of the imine, followed by the Lewis acid promoted borono-Mannich-type reaction on the rearranged imine to result in a new class of functionalized N-homoallylamines.     

Chemoselective aminomethylation of bifunctional substrates: carbonyl versus phenolic hydroxyl,carbonyl versus pyrazole and pyrrole versus phenolic hydroxyl as competing activating groups

Chemoselectivity in the Mannich reaction for three different types of bifunctional substrates has been investigated. 1-Hydroxy-2-naphthalenylethanone affords either phenolic Mannich bases at high pH (free amines), or ketonic Mannich bases at low pH (amine hydrochlorides), whereas the use of N,N-dimethylmethyleneiminium chloride as a preformed dimethylaminomethylation reagent gave the phenolic Mannich base. 1-Aryl-3-(1H-pyrazol-1-yl)-1-propanones undergo aminomethylation at position 4 of the pyrazole ring, and not at the methylene group α to the carbonyl function, regardless of the reaction conditions. 4-(2,5-Dimethyl-1H-pyrrol-1-yl)phenol is aminomethylated chemoselectively on the pyrrole ring under mild reaction conditions.     

Titanium tetrachloride incorporated crosslinked polystyrene copolymer as an efficient and recyclable polymeric Lewis acid catalyst for the synthesis of Β-amino carbonyl compounds at room temperature

An efficient and eco-friendly procedure for one-pot synthesis of β-amino carbonyl compounds by three-component reaction of aromatic aldehydes, acetophenone, and aromatic amines via a Mannich type reaction using a stable tightly bound complex, titanium tetrachloride incorporated crosslinked polystyrene copolymer (PS/TiCl₄), as a water tolerant, recoverable, and reusable polymeric Lewis acid catalyst in ethanol at room temperature is reported. The complex of the polystyrene and TiCl₄ provides a shelf-stable acidic, water tolerant material, and it is not easily hydrolyzed by water. Our findings thus show a novel and improved modification of the Mannich type reaction in terms of mild reaction conditions, clean reaction profiles, applicability to various substrates using a simple workup procedure which makes this reaction an interesting alternative to previously applied procedures. The recyclability of the catalyst makes this protocol environmentally benign.     

Synthesis of a singly bridged resorcinarene-dimer by Mannich reaction with N,N′-diethylethylenediamine and formaldehyde: self-inclusion of bridging diazahexamethylene unit in methanol

Mannich reaction of resorcin[4]arene with N,N′-diethylethylenediamine and formaldehyde produced a singly bridged resorcinarene-dimer bearing sixteen hydroxyl groups at their peripheral positions, which exists in a closed capsular conformation including the diazahexamethylene bridge chain between the two resorcinarene units in CD₃OD.     

HClO4-SiO2 catalyzed stereoselective synthesis of β-amino ketones via a direct Mannich-type reaction

The HClO₄-SiO₂ catalyzed three-component, one-pot Mannich reaction of ketones, aromatic aldehydes and aromatic amines is carried out in ethanol to afford the corresponding β-amino ketones in good yields and high stereoselectivities in favor of the anti-isomer. Three new compounds are reported.     

Synthesis of non-natural l-alanine derivatives using the aza-Cope–Mannich reaction

Non-natural l-alanine derived trans-octahydrocyclohepta[b]pyrroles were synthesized with high enantiomeric purity using the aza-Cope–Mannich reaction. The study showed that the conditions of the aza-Cope–Mannich reaction and metal catalysed cyclization are mild enough to be applied to the synthesis of molecules with stereocenters, which are prone to racemization. We believe that these compounds will be of interest to medicinal chemists.     

Direct Enantioselective Vinylogous Mannich Reaction of Ketimines with γ‐Butenolide by Using Cinchona Alkaloid Amide/Zinc(II) Catalysts

A direct enantioselective vinylogous Mannich reaction of ketimines with γ‐butenolide has been developed. Good yields and enantioselectivities were observed for the reaction of various ketimines by using a cinchona alkaloid amide/Zn(OTf)₂ catalyst and Et₃N. Both enantiomers of the products could be obtained by using pseudoenantiomeric chiral catalysts.     

Cs2.5H0.5PW12O40 catalyzed diastereoselective synthesis of β-amino ketones via three component Mannich-type reaction in water

A series of insoluble salts of Keggin heteropoly compounds were prepared and used as catalysts for the Mannich-type reaction of benzaldehyde, aniline, and cyclohexanone in water. Among them, Cs_2.5H_0.5PW₁₂O₄₀ showed excellent catalytic activity. Effects of surfactant, catalyst loading and temperature were studied to introduce the best reaction condition. The optimized reaction conditions were extended to Mannich reaction of various aldehydes, ketones, and amines in water. This rapid procedure afforded structurally divers β-amino ketones with major anti diastereoselectivity. Additionally, four new compounds were reported. The catalyst was recovered and reused for subsequent runs.     

Synthesis of α-CF3-substituted γ,δ-didehydro lysine derivatives

An efficient and selective access to novel α-CF₃-substituted γ,δ-didehydro lysine derivatives and their phosphorus analogues has been developed via the Cu-catalyzed Mannich reaction of α-amino α-propargyl α-trifluoromethyl carboxylates or phosphonates with different secondary amines and paraformaldehyde.     

A tandem Diels–Alder/Mannich approach to the synthesis of AE and ABE ring analogues of Delphinium alkaloids

The one-pot TiCl₄ catalysed Diels–Alder/Mannich reaction of α-cyanoaminoacrylates with 2-silyloxy-1,4-butadienes gives 6-keto-3-azabicyclo[3.3.1]nonane-1-carboxylates. Reduction of the ketone and alkylation of the resultant alcohol gives 6-alkoxy-3-azabicyclo[3.3.1]nonanes mimicking the AE rings of a number of Delphinium and Aconitum alkaloids, with the same stereochemistry as the natural products.     

Formation of a vanillic Mannich base — theoretical study

One-pot anti-Mannich reaction of vanillin, aniline and cyclohexanone was successfully catalyzed by ionic liquid triethanolammonium chloroacetate, at room temperature. Yield of the obtained Mannich base was very good and excellent diastereoselectivity was achieved. Mechanism of the reaction was investigated using the density functional theory. The reaction started with a nucleophilic attack of aniline nitrogen at the carbonyl group of vanillin. The intermediate α-amino alcohol formed in this way was further subjected to protonation by the triethanolammonium ion yielding the imminium ion. Theoretically, the obtained imminium ion and the enol form of cyclohexanone can build the protonated Mannich base via the anti and syn pathways. The chloroacetic anion spontaneously abstracts the proton yielding the final product of the reaction anti 2-[1-(N-phenylamino)-1-(4-hydroxy-3-methoxyphenyl)]methylcyclohexanone (MB-H). The syn pathway requires lower activation energy but the anti pathway yields a thermodynamically more stable product, which implies that the examined Mannich reaction is thermodynamically controlled.     

Direct Mannich reaction mediated by Fe(Cp)2PF6 under solvent-free conditions

Fe(Cp)₂PF₆ (5 mol %) efficiently catalyzed Mannich reaction of aldehydes, anilines, and ketones under solvent-free condition to give β-amino-ketones in high yield (up to 94%) within 30 min with anti-isomer in excess. Simple experimental conditions and product isolation procedure makes this protocol potential for the development of clean and environment-friendly strategy for the synthesis of β-amino-ketones.     

Synthesis of pyrazole- and thiazole-annulated 3-R-1,5-dinitro-3-azabicyclo[3.3.1]nonanes

The previously unknown 3-R-1,5-dinitro-3-azabicyclo[3.3.1]nonanes fused to the pyrazole or thiazole rings were synthesized by the reductive cyclization of m-dinitroindazoles and benzothiazoles. The method is based on the reduction of carbon-carbon bonds in the benzene ring, which are activated by the meta-nitro groups, with NaBH₄ followed by the Mannich reaction with formaldehyde and primary amines.     

Anti-selective direct asymmetric Mannich reaction catalyzed by protease

The anti-selective direct asymmetric Mannich reaction of (hetero) aromatic aldehydes, 4-anisidine and O-protected hydroxyacetones for the synthesis of stereodefined anti-β-amino-α-hydroxycarbonyl compounds was developed. Protease type XIV from Streptomyces griseus (SGP) was used as a biocatalyst in 1,4-dioxane/phosphate buffer under mild reaction conditions. The excellent diastereoselectivities of up to >99:1 (anti/syn) and good enantioselectivities of up to 90% ee were achieved. This method provides a more sustainable complement to chemically catalyzed anti-selective direct asymmetric Mannich reactions.     

A quantum-chemical study on the Mannich reaction with polynitromethanes

According to the results of SCF-CNDO/2 computation, we propose employing the “ladder weighting summation” to define a G_e index which is used to measure the relative magnitude of the nucleophilicity of the relevant amine and pseudo acid components in a Mannich reaction. We also put forward an A_e index to measure the relative magnitude of the electrophilicity of methyleneamine cationic species in the same reaction. A combined use of both G_e and A_e indices is suggested to evaluate the feasibility of a Mannich reaction for the polynitromethanes and the stability of the products. These results are consistent with those conclusions drawn from “soft-hard acid-base theory”.