Synthesis of a New Series of N‐Mannich Bases and Polyhydroxy Mannich Bases of Pharmaceutical Interest Related to Isatin and Its Schiff Bases

The reaction of isatin 1 with benzaldehyde and a sec‐amine or the appropriate aldimine afforded the N‐Mannich bases 2 – 3 and the bis‐base 4 . Treatment of 1 with glutaric dialdehyde and morpholine gave the bis‐base 5 . Mannich reaction of the Schiff bases 6a – f derived from 1 , led to the new Mannich bases and bis‐bases 7 – 9 . The use of N‐methyl‐D‐glucamine as the amine component in the Mannich reaction with 6b – f led to the polyhydroxy Mannich bases 11 – 13 .     

Synthesis and Reactivity of Mannich Bases. XVIII. Reaction of Dithiocarbamic Acid Salts With Mannich Bases Derived from Ortho-Hydroxyacetophenones

The reaction of Mannich bases derived from ortho-hydroxyacetophenones with N,N-dialkyldithiocarbamic acid salts result in the formation of the corresponding dithiocarbamic acid esters via an amine moiety replacement when the process is conducted in cold water. Attempts to carry out the synthesis in refluxing ethanol-water mixture led to the insertion of carbon sulfide at the C—N bond in Mannich bases. N-Aryldithiocarbamic acid salts afforded on reaction with the above-mentioned Mannich bases only bis-(2-(2-hydroxybenzoyl)ethyl)thioethers.     

Vicinal N,C-difluorination of secondary polynitroalkylamine Mannich bases

The direct fluorination of Mannich bases containing nitro groups in one or two alkyl substituants in the position relative to the amine nitrogen gives previously unreported vicinal N,C-difluorides.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 7, pp. 1692–1693, July, 1991.     

Synthesis and characterization of Mannich bases of lawsone and their anticancer activity

Abstract

Natural and synthetic naphthoquinones are known for a large number of biological activities. Lawsone (2-hydroxy-1, 4-naphthoquinone) is a simplest naturally occurring compound obtained from dried henna (Lawsonia inermis) leaves. In literature, some lawsone derivatives have been reported to exhibit anticancer activity. Hence, a clean and facile one-pot protocol was developed for the synthesis of new aminonaphthoquinones derived from lawsone by three-component Mannich reaction, at room temperature for potential anti-cancer application. Herein we present a small library of Mannich bases with different amines and aromatic aldehydes with moderate to high yield. Synthesized compounds were characterized using various spectroscopic techniques. The anticancer activity (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay) along with nuclear morphology assessment (4′,6-diamidino-2-phenylindole or DAPI staining), apoptosis assessment (acridine orange/ ethidium bromide staining), hemolysis and DNA ladder assay evaluated on human liver carcinoma cell line HepG2 are presented.     

Pesticidal Mannich Bases Derived from Isatinimines

Mannich bases from isatinimines and isatin hydrazones are synthesized for evaluation of their pesticidal activities. Among all the prepared Mannich bases only N-dimethylaminomethyl-3-(p-bromophenyl)iminoindol-2-one exhibited herbicidal activity in pre- and post-emergent tests.     

Utility of Ketonic Mannich Bases in Synthesis of Some New Functionalized 2‐Pyrazolines

The styryl ketonic Mannich base 2 has been used as a precursor in the synthesis of 2‐pyrazolines having a basic side chain at C‐3 and a phenolic Mannich base at C‐5. Treatment of the bis(styryl ketonic bases) 6a and 8a with phenylhydrazine affords the bis(3‐functionalized 2‐pyrazolines) 7 and 9 . The transamination between the styryl keto base 10 and 4‐aminoantipyrine leads to 12 , which reacts with piperazine to give 13 . N‐Nitrosation of the sec‐Mannich bases 15a – d followed by reductive cyclization affords 2‐pyrazolines 17a – d . The keto base 14b has been used for the synthesis of 2‐pyrazolines having a phenolic Mannich base at C‐3 and its reaction with 3,5‐dimethyl‐1H‐pyrazole affords 23 . The alkylation of 3‐methyl‐1‐phenyl‐2‐pyrazolin‐5‐one with the bis(Mannich base) 25 was investigated.     

A Novel Method for Biomimetic Synthesis of Mannich Bases

Since the early studies of Mannich, Mannich reaction has become an important tool for the synthesis of new compounds. Mannich bases can be either directly employed or used as intermediates. In this work, the one‐carbon unit transfer reaction of tetrahydrofolate coenzyme was initiated. 1,3‐Dimethylimidazolidine as a new tetrahydrofolate coenzyme model at formaldehyde oxidation level was used to react with ketone having active hydrogen atoms and amine to give the corresponding Mannich base in good yield by a covert Mannich reaction. A novel method for biomimetic synthesis of various Mannich bases is provided.     

The use of amino acids in the mannich reaction

Amino acids have been found to participate as the amine component in the Mannich reaction with both ketones and phenols. The phenolic Mannich bases may be cyclized with sulfuric acid to 1,2-dihydro-4(3/H)isoquinolones. In the presence of thionyl chloride the same Mannich bases undergo lactonization to benz[f]-1,4-oxazepin-4(3H)ones.     

四环素C-2位Mannich反应的研究

报道了四环素C-2位与伯胺、仲胺反应形成Mannich碱的简便方法:四环素盐酸盐在甲醇和水溶液中与伯胺反应,生成二级Mannich碱;四环素在叔丁醇中与仲胺反应,生成三级Mannich碱。合成了10个化合物,其中8个未见报道,并对所合成化合物的结构进行了表征。     

Synthesis and characterization of some N‐mannich bases of [1,2,3]triazoloquinolines

Some novel N‐Mannich bases of [1,2,3]‐triazolo[4,5‐f] and [4,5‐h]quinolines were synthesized following the classical experimental procedure for Mannich base preparation: triazoloquinoline with formaldehyde and secondary amine. Tricyclic nuclei were obtained starting from two protected isomeric amino‐quinolines, which were nitrated, reduced and diazotated. Two N‐anilinomethyltriazoloquinolines were also synthesized via the N‐hydroxymethyl intermediate.     

Mannich aminomethylation of flavonoids and anti-proliferative activity against breast cancer cell

We herein report Mannich aminomethylation of variously structural flavonoids and their biological evaluation against human breast cancer cell. Mannich reaction showed that substitution at C-6 position depends on amine basicity and C-ring feature of flavonoids. All five flavonoid substrates reacted with strong amine bases to afford the bis(6,8-aminomethyl) derivatives, while with weak amines, the different products were obtained dependently on structural characteristic of flavonoid. 3-OH and 3-O-substituted groups on the C-ring exhibited the deactivated aminomethylation at C-6 position, whereas substitution at this position was independent on bond feature at C-2 and C-3 on the C-ring. Screening anti-proliferative activity showed six flavonoids possessed activity against breast cancer cell, MDA-MB-231. Among them, the flavonoids, luteolin (2) and 3′,4′,5,7-tetrahydroxy-6,8-bis(pyrrolidin-1-ylmethyl)-3-rutinosylflavone (3a), displayed the highest anti-proliferative activity with the lowest IC₅₀ values.     

N-Alkylation of Pyrazoles with Mannich Bases Derived from ortho-Hydroxyacetophenones

The involvement of Mannich bases derived from ortho-hydroxyacetophenones in amine-exchange reactions with pyrazole and methyl- and/or halogen-substituted pyrazoles was studied. The corresponding -(pyrazol-1-yl)ethyl ketones resulted in excellent yield and were characterized by elemental analysis, IR, and ¹H and ¹³C NMR spectroscopy.     

Synthesis of mannich bases of bioactive benzylphenols

2,4-Bis(1,1-dimethyl)-6-[(4-methoxyphenyl)methoxymethyl]phenol ( 4 ), prepared by oxidation of 2,4-bis(1,1-dimethylethyl)-6-[(4-methoxyphenyl)methyl]phenol ( 1 ) with silver oxide in methanol, reacts with secondary amines in boiling toluene to give Mannich bases ( 6 ) related to the biologically active o-benzylphenol. Mannich basis of the isomeric p-benzylphenol ( 7 ) were prepared by reaction of amines with the p-quinone methide formed by oxidation of 7 .     

Controlling Stereoselectivity in the Aminocatalytic Enantioselective Mannich Reaction of Aldehydes with In Situ Generated N‐Carbamoyl Imines

A simple and convenient method for the direct, aminocatalytic, and highly enantioselective Mannich reactions of aldehydes with in situ generated N‐carbamoyl imines has been developed. Both α‐imino esters and aromatic imines serve as suitable electrophilic components. Moreover, the judicious selection of commercially available secondary amine catalysts allows selective access to the desired stereoisomer of the N‐tert‐butoxycarbonyl (Boc) or N‐carbobenzyloxy (Cbz) Mannich adducts, with high control over the syn or anti relative configuration and almost perfect enantioselectivity. Besides the possibility to fully control the stereochemistry of the Mannich reaction, the main advantage of this method lies in the operational simplicity; the highly reactive N‐carbamate‐protected imines are generated in situ from stable and easily handled α‐amido sulfones.     

Synthesis and characterization of some novel cyanonitrosyl complexes of chromium(I) with Mannich bases,aromatic aldehyde oximes and syn-phenyl-2-pyridylketoxime

Some new low-spin hexacoordinated cyanonitrosyl complexes of Cr¹ of the type [Cr(NO)(CN)₂(L)₂(H₂)], where L is an aromatic aldehyde oxime or Mannich base, have been prepared by the interaction or K₃[Cr(NO)(CN)₅]· H₂O with L in aqueous AcOH, and characterized by a range of physico-chemical techniques, I.r. data suggest that all the oxime derivatives and Mannich bases act as monodentate ligands by coordinating through the aromatic nitrogen. TMC 2564     

Photo- and thermochromic mannich bases. 1. Mannich bases from 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 2-naphthols

Mannich bases exhibiting photo- and thermochromic properties in solutions were synthesized from 3,5-di-tert-butyl-4-hydroxybenzaldehyde and 2-naphthols. An investigation of an acetyl derivative of methylenequinone, modeling a product of photo- and thermochromic transformations, proved that the color change of solutions of the Mannich bases is due to reversible dissociation into colored methylenequinones and morpholine. On the basis of data of x-ray diffraction analysis of one of the Mannich bases, characteristics of their molecular structure were determined, and reasons were stated for their effect on the dissociation mechanism.     

Addition of Lithium Reagents of N,N-Dialkylsulfonamides to Mannich Bases

The addition of metallated N,N-dialkyl-sulfonamides 1 to Mannich bases 2, leading to N,N-dialkylamides of 4-(N′,N′-dialkylamino)-2-hydroxy-2-phenylbutanesulfonic acids (4) is described.     

Synthesis of Mannich bases of 5-hydroxynapthalene-1,8-carbolactone as potential antifungal or antitumor agents

Mannich bases of 5-hydroxynaphthalene-1,8-carbolactone 1 were prepared from various secondary amines or bulky primary amines and formaldehyde. They were isolated in almost all cases as hydrochlorides. These derivatives were submitted to in vitro antifungal and cytotoxic assays. The antifungal assays were performed against three strains of yeasts and five strains of human pathogenic fungi. Two of the tested compounds, 2i and 2j, exhibited interesting antifungal activities against Candida albicans and Candida tropicalis. The cytotoxic activity was evaluated towards L 1210 leukemia cells. Almost all of the Mannich bases had shown significant activity against this tumor cell line as values of IC50 less than or equal to 4 micrograms/ml are considered interesting. Only one derivative 2 developed better cytotoxicity than the parent compound 1.     

Synthesis and Biological Activity of Novel Furan/Thiophene and Piperazine‐Containing (Bis)1,2,4‐triazole Mannich Bases

Series of novel furan/thiophene and piperazine‐containing 1,2,4‐triazole Mannich bases and bis(1,2,4‐triazole) Mannich bases have been conveniently synthesized via Mannich reaction with triazole Schiff bases, various piperazine derivatives, and formaldehyde as intermediates in good yields. Their structures were characterized by melting points, ¹H NMR, ¹³C NMR, IR and elemental analysis. The preliminary bioassay showed that most compounds exhibited significant in vitro and in vivo fungicidal activity against several test plant fungi. Among 32 new compounds, the trifluoromethyl‐containing compounds showed superior activity than the methyl‐containing ones. Several compounds, such as F8 , F9 , F10 , G5 , H7 , H8 , I3 and I4 , were comparable with some commercial fungicides against different fungi during the present study and could be further structurally optimized. Meanwhile, several compounds showed good herbicidal activity against Brassica campestris at 100 µg/mL and KARI inhibitory activity at 200 µg/mL. However, compounds exhibited poor insecticidal activity against oriental armyworm at 200 µg/mL in the preliminary studies. The research results will provide useful information for the design and discovery of new agrochemicals with novel heterocyclic structures.     

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.