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Sclareolide was developed as an efficient C-nucleophilic reagent for an asymmetric Mannich addition reaction with a series of N-tert-butylsulfinyl aldimines. The Mannich reaction was carried out under mild conditions, affording the corresponding aminoalkyl sclareolide derivatives with up to 98% yield and 98:2:0:0 diastereoselectivity. Furthermore, the reaction could be performed on a gram scale without any reduction in yield and diastereoselectivity. Additionally, deprotection of the obtained Mannich addition products to give the target sclareolide derivatives bearing a free N-H group was demonstrated. In addition, target compounds 4–6 were subjected to an antifungal assay in vitro, which showed considerable antifungal activity against forest pathogenic fungi.

This study explored the potential of melamine, as the nitrogenating source for the cationization of pulverized quebracho and spruce tannins. The influence of modification conditions on the properties of the coagulants was studied by varying the formaldehyde and melamine ratios with different activation times and temperatures. Based on considerations of charge density and shelf life, the most viable modifications were established as coagulants synthesized with a 1:0.52 formaldehyde to melamine molar ratio at 70 °C. At optimal conditions, the charge density of the quebracho and spruce coagulants was 2.22 meq/g and 1.04 meq/g, respectively, and the residual formaldehyde content in the coagulants was low. The developed synthesis of this study demonstrated a clear advantage over previous methods due to the rapid modification step. X-ray photoelectron spectroscopy (XPS) confirmed the emergence of an amine which signifies a successful Mannich reaction in the coagulant. Although optimal modification conditions for the coagulants were established at 70 °C (5-min activation time), the average molecular weight could not be determined for these conditions. Nevertheless, electrospray ionization mass spectrometry (ESI-MS) and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry measurements revealed that the tannin-based coagulants obtained at lower temperatures (23 °C and 45 °C) possessed low average molecular weight (approx. 800–900 Da). Furthermore, ESI-MS and MALDI-TOF spectra showed that the Mannich modification resulted in the depolymerisation of the quebracho tannin, leading to a reduction in units of higher mass fractions in the synthesized coagulant, which contrasted with the spruce tannin. Jar test experiments with surface and industrial process waters demonstrated that the tannin coagulants enhanced particle settling effectively.

Catalyst-controlled functionalization of unmodified carbonyl compounds is a relevant operation in organic synthesis, especially when high levels of site- and stereo-selectivity can be attained. This objective is now within reach for some subsets of enolizable substrates using various types of activation mechanisms. Recent contributions to this area include enantioselective transformations that proceed via transiently generated noncovalent di(tri)enolate-catalyst coordination species. While relatively easier to form than simple enolate congeners, di(tri)enolates are ambifunctional in nature and so control of the reaction regioselectivity becomes an issue. This Minireview discusses in some detail this and other problems, and how noncovalent activation approaches based on metallic and metal free catalysts have been developed to advance the field.

This study explored the potential for using tannin extract from spruce bark (Picea abies) as a coagulant. Spruce tannins were extracted with hot water and pulverized through spray drying and freeze drying. The pulverized tannins were cationized via the Mannich reaction with formaldehyde and diethanolamine or ethanolamine, and the coagulation performances of the spruce tannin coagulants were compared with an industrially extracted quebracho tannin, which was cationized with the same method. Jar test experiments with kaolin/river water indicated that all of the tannin coagulants were able to enhance particle settling significantly, although the quebracho tannin coagulants were slightly more efficient than the spruce tannin coagulants. Since the phenolic groups play the major role in the modification, the higher coagulation efficiency was probably related to the higher amount of proanthocyanidin in the quebracho tannin, and subsequently the higher cationic charge density obtained for the quebracho tannin coagulants. Nevertheless, the spruce tannin coagulants could still be considered to be effective products because they possessed more stable turbidity and a total surface charge close to zero over a wide dosage range. The ethanolamine was a better amine source, at least for the coagulation of river water with a positive charge demand. Moreover, the study established the importance of charge density as an essential indicator for coagulant performance.

© The Royal Society of Chemistry 2020. In the early 1990s chiral P-thiother ligands emerged as promising ligands in the field of asymmetric catalysis, with the development of many P-thioether ligand families. However, only a few of them have shown a broad reaction and substrate scope. So, compared with other heterodonor ligands such as the widely studied P-N ligands, their impact in asymmetric catalysis was not realised until recently. This has been mainly attributed to the difficulty of controlling the configuration at the sulfur atom when coordinated to the metal. More recently, it has been found that this problem could be solved by a rigorous choice of the ligand scaffold, a process usually aided by mechanistic studies. This allowed the recent discovery of new P-thioether ligand families with a broader versatility, both in reactions and in substrate/reagent scope. This feature article aims to highlight those new P-thioether ligand libraries and the relationship between the structure and catalytic performance.

The organocatalyzed Mannich reaction of unsubstituted and N-aryl-substituted tetrahydroisoquinolines (THIQs) and the Strecker reaction of several N-aryl-substituted THIQs through dehydrogenative C(sp3)–H bond functionalization (cross-dehydrogenative coupling) promoted by organic single electron oxidants DDQ and IBX are presented. The C–H oxidation/Mannich reaction of less reactive N-aryl substituted pyrrolidines is achieved via metal catalyzed photoredox catalysis. Operationally simple procedures provide desired products in an effective and time preserving manner.

Producción Científica, Enantioenriched 3‐amino‐3‐substituted oxindoles have been obtained by addition of different nucleophiles to N‐Boc ketimines derived from isatin catalyzed by chiral bifunctional supported thioureas. The Mannich reaction occurs with excellent enantioselection, but poor diastereoselection when prochiral nucleophiles were used. The supported catalyst were recovered and reused for five times without loss of activity. The mixture of diastereoisomers formed when a prochiral structure was used as nucleophile was converted into a single enantioenriched pyrazolyl derivative., Ministerio de Economía, Industria y Competitividad (Project FEDER-CTQ2014–59870-P), Junta de Castilla y León (Projects FEDER-VA115P17 / VA149G18)

The influence of pH on the Mannich reaction (amino alkylation in the presence of formaldehyde) has been analyzed by liquid chromatography-mass spectrometry (LC-MS) with vanillin (VA) as a model compound and a purified softwood kraft lignin (SKL) as a substrate. The reaction products of VA were studied at pH 5, 7, and 9 at 60 degrees C for 4 h. The Mannich adduct and side reaction products with methylene bridge were found at both pH 7 and 9, while only di-substituted by-products were observed at pH 5. Nitrogen contents determined from blank runs were substantial at pH 5 and negligible at pH 7. In VA or SKL, the resulting N-contents at pH 7 corresponded to a 76 or 62 mol% of the theory, respectively, i.e. based on the available C-5 positions in phenolic guaiacyl units (G-units). In the case of SKL, P-31-NMR analysis confirmed a 77% conversion of all phenolic G-units into their C-5 substituted derivatives. The Mannich reaction should be performed on lignin at pH 7 for 1 h to suppress unwanted side reactions, which could be observed by LC-MS under other pH conditions. The reaction is suitable for fast and reliable determination of reactive C-5-positions in lignin by multiplication of the N-content of the reaction products with a factor of 1.6., QC 20170127

Urea coating was conducted using polylactic acid (PLA) blended with industrial softwood kraft lignin after applying a dip-coating technique. The lignin was pre-functionalized via esterification that increased coat layer hydrophobicity or via amination that created an organically bound nitrogen structure. The PLA film reference had many pores, while the film from the PLA-lignin derivative complex was highly homogeneous and had no pores. The coat thickness was generally adjustable by repeating the coating process reaching up to 81% weight against the urea core. After coating, urea release in water was largely delayed, 20-30 and 6-10 times as long as that of uncoated urea or PLA-coated urea respectively. The coated urea will be a highly effective nitrogen fertilizer due to the controlled release after coating, the slow release from the organically bound nitrogen structure, and the expectedly extra stability against urease hydrolysis and microorganism nitrification after using the lignin structure., QC 20171123

A convenient and scalable synthesis of two unusual amino acid units found in dolastatin 16, dolaphenvaline, and dolamethylleuine, is described. Dolastatin 16, which was first isolated from the sea hare Dolabella auricularia by Pettit, exhibits not only strong inhibition of growth for a variety of human cancer cell lines but also potent antifouling activity against the larvae of the barnacle Balanus amphitrite. The key element of the synthesis is an organocatalytic Mannich reaction to construct two contiguous stereocenters in the amino acid units with almost complete enantio- and diastereoselectivity.

A convenient and scalable synthesis of two unusual amino acid units found in dolastatin 16, dolaphenvaline, and dolamethylleuine, is described. Dolastatin 16, which was first isolated from the sea hare Dolabella auricularia by Pettit, exhibits not only strong inhibition of growth for a variety of human cancer cell lines but also potent antifouling activity against the larvae of the barnacle Balanus amphitrite. The key element of the synthesis is an organocatalytic Mannich reaction to construct two contiguous stereocenters in the amino acid units with almost complete enantio- and diastereoselectivity.

In the category of microorganism, fungi are considered as the special class of microbes responsible for opportunistic pathogenic infections in humans species. Due to the side effects of commercially available antifungal drugs and the emergence of new drug resistant fungal species in the past few years has forced the researchers to search for novel and efficient antifungal drug molecules. The 1,3,4-oxadiazoles scaffold is associated with diverse biological activities. The multipurpose use of the Mannich bases in pharmaceutical chemistry provoked us to prepare a new series of 1,3,4-oxadiazole Mannich bases derivatives, as antifungal agents. Herein we report Molecular sieves and Ultrasound assisted synthesis of novel series of Mannich bases of the 5-substituted 1,3,4-oxadiazole-2-thiones by amino methylation with paraformaldehyde and substituted primary / secondary amines and their evaluation for antifungal activity .The structures of the newly synthesized compounds were determined by IR, NMR and Mass spectral study. The synthesized compounds exhibited interesting moderate to excellent antifungal activity against Candida albicans (NCIM 3557),Candida albicans(NCIM3471), Candida glabrata(NCIM3237), Cryptococcus neoformans (NCIM 3542),Cryptococcus neoformans(NCIM 3378),Aspergillus fumigates(NCIM 902), Aspergillus niger( NCIM 628) using Flucanazole as a standard reference drug. The synthesised compounds 6d, 6f ,6g, 6h and 6j exhibited promising antifungal activity as fungi static agents

The amination of industrial softwood kraft lignin was conducted using the Mannich reaction to modify the lignin structure for value-added applications. To understand the reaction mechanism and to quantify the amount of amine groups that were introduced, different types of NMR analyses were performed. The lignin was also pretreated by phenolation to increase its reactivity and the amount of the amine groups that were introduced. The Mannich reaction was very selective at the C-5 position of the guaiacyl units and complete under acidic conditions with similar to 11-fold amounts of reagents of dimethylamine and formaldehyde over either model lignin (4-hydroxy-3-methoxyacetophenone, HMAP) or industrial spruce kraft lignin (LignoBoost lignin, LBL). For LBL, 28 amine groups were introduced over 100 aromatic rings. By weight, the nitrogen content was 2.5%. The animated lignin was found to possess a higher molecular mass, reaching a Mp of 4.9 x 10(3) Da compared to the original 319 x 10(3) Da, and with a considerably increased dispersibility, especially in a dilute aqueous solution of hydrochloric acid (pH = 3), namely 5.2 mg/ml. With a preceding phenolation treatment, which increased the amount of phenolic aromatic rings available for the Mannich reaction, an introduction of 42 amine groups over 100 aromatic rings, or a nitrogen content of 4.8%, was obtained, which caused a further increase of the molecular mass to 5.1 x 10(3) Da (Mp) and of dispersibility in the aqueous solution of hydrochloric acid up to 32.0 mg/ml. The aminated lignins with or without the phenolation pretreatment formed very stable colloidal suspensions in water, with large particle sizes (391 and 39 nm), high zeta potentials (31.6 and 27.2 mV), and large charge densities (1.6 and 1.2 x 10(-7) equiv./ml, respectively). The potential value-added applications of these modified lignins with high amine contents include use as surfactant chemicals, polycationic materials and slow-release fertilisers, among o, QC 20140404. Updated from manuscript to article in journal.

Malaria is a global health problem, with an estimated 300–500 million new clinical cases and 1–2 million fatalities reported annually. Almost 90% of the incidences of malaria and deaths from the disease occur in sub-Saharan Africa. Since malaria affects mainly the poor, it is not profitable for pharmaceutical companies to develop new treatments; thus malaria is classified as a „neglected‟ or „orphan disease‟. Malaria in humans, transmitted by female Anopheles mosquitoes, is caused by four species of Plasmodium, of which P. vivax is the most common malaria parasite, while the most severe form of malaria is caused by P. falciparum. These protists, the targets of antimalarial drugs, gradually develop resistance to malarial drugs. For example, quinine from the bark of the cinchona tree was the first drug against malaria. When it became obsolete in the 1940s it was replaced by chloroquine (CQ), a synthetic analogue, which is also reaching a stage of obsolescence. Many of the subsequently developed drugs are structurally related to chloroquine; thus they are or will soon be ineffective. Artemisinin, developed from an ancient Chinese herbal medication for fever, is the latest antimalarial drug of choice. It is structurally unrelated to aminoquinoline, but resistance has already been observed in East Asia. Derivatives – including artesunate, dihydroartemisinin, artemether and arteether – are often used in combination with other antimalarial compounds to increase the half-life of a drug and delay the development of resistance to it. Because flavonoids are not detected in human blood after oral administration (i.e. are not bioavailable), it is difficult to explain the plethora of biological activities and beneficial dietary effects reported for flavonoids. The low bioavailability of polyphenols is explained by their poor absorption in the intestines and their rapid enzymatic degradation in blood. Furthermore, according to the Lipinski rules, most commercially available drugs

An efficient method for the synthesis of beta-hydroxy and beta-amino ketones from allylic alcohols catalyzed by Ru(5-C5Ph5)(CO)2Cl is described. The influence of the stereoelectronic properties of the catalyst on the reaction outcome has been studied. Optimization of the reaction conditions supressed the formation of undesired side products such as saturated ketones, benzyl alcohols, and a,beta-unsaturated ketones. Several aromatic and aliphatic allylic alcohols have been reacted with a large variety of aldehydes or imines to produce beta-hydroxy ketones or beta-amino ketones, respectively, in yields up to 99%. Based on experimental data, a mechanism via ruthenium alkoxides and ruthenium aldoxides is proposed. In addition, a C-bound ruthenium enolate has been characterized., 5

Amination of lignin conducted simply by Mannich reaction is an important mean for lignin structural and value upgradation. However, there is a lack of powerful analysis for quantification of the amine groups introduced and at the meantime for supplement of structural information about e.g. binding positions and side reactions etc. Various types of NMR analysis have thus been performed for the analysis of Mannich reaction products from lignin model, 4-hydroxy-3-methoxyacetophenone (HMAP), and from industrial spruce Kraft lignin. As revealed by NMRs, the reaction was very selective at C-5 position of guaiacyl lignin units and complete under acidic conditions with 11-fold amounts of reagents of piperidine (PIP) or dimethylamine (DMA) and formaldehyde over HMAP. No side reactions took place at the aromatic structure. For industrial lignin, 13.5 (by PIP) and 15 (by DMA) nitrogen atoms were introduced per 100 aromatic rings. Using other analytical methods, the aminated lignin was found with higher molecular weights, reaching Mp of 5.06kDa from the original 3.92kDa by DMA modification, and with a sharp increased solubility especially in acetic acid aqueous solution, 31.2 mg/ml after DMA modification. A preceding phenolation of the lignin resulted in a 70% increase of available aromatic rings and an introduction of 56 amine groups over 100 original aromatic rings after Mannich reaction by using DMA, which caused increases of molecular weights to 5.11kDa (Mp) and of solubility in acetic acid aqueous solution up to 77.2 mg/mL. Potential applications of these modified lignins of high values include many applications in different fields such as surfactant chemicals, polycationic materials and slow released fertilizers etc., QC 20140901

Metal-proline complexes of various metals like Zn, Cd, Hg, and Pb were found to be good catalysts for direct Mannich reaction in water medium at room temperature, smoothly affording the β-amino carbonyl compounds in excellent yields. Among the catalyst cadmium-proline complex gave high yield in lesser time. All the catalysts were easily separated from the reaction mixture by water extraction and among this cadmium -proline complex was found to be most stable and can be recycled five times without losing its catalytic activity.

Metal-proline complexes of various metals like Zn, Cd, Hg, and Pb were found to be good catalysts for direct Mannich reaction in water medium at room temperature, smoothly affording the β-amino carbonyl compounds in excellent yields. Among the catalyst cadmium-proline complex gave high yield in lesser time. All the catalysts were easily separated from the reaction mixture by water extraction and among this cadmium -proline complex was found to be most stable and can be recycled five times without losing its catalytic activity.

A library of 1,3-disubstituted indoles has been prepared via an iterative Mannich reaction sequence. The first Mannich reaction with secondary amines and formaldehyde preferentially yields 3-aminomethyl indoles, while the second Mannich reaction introduces an additional aminomethyl group at the N1-position of the indole ring. A library of 25 substituted indoles has thus been prepared in moderate to good yields with purity., QC 20100525

Tall fescue (Festuca arundinacea Schreb.) is often infected by the endophytic fungus, Acremonium coenophialum (Morgan-Jones and Gams) The fungus produces ergo peptide alkaloids, especially ergovaline. Consumption of endophyte-infected (ED fescue forage by cattle decreases serum prolactin and average daily weight gains, which results in economic losses for producers. Anecdotal reports suggest cattle with fescue toxicosis may not respond to vaccination. Hyperprolactinemia decreases cell-mediated and humoral immune responses in mice. Therefore, steers grazing EI or endophyte-free (EF) fescue forages were vaccinated to assess humoral immune responses. Steers grazing EI fescue exhibited classical clinical signs of fescue toxicosis, and mounted humoral immune responses to vaccination, despite hyperprolactinemia. Lymphocyte proliferation responses to mitogens in mice fed EI diets were similar to mice fed EF diets. Production of interferon gamma and interleukin-4 was higher by splenocytes from mice fed EI diets, whereas interleukin-2 tended to be lower. Fescue toxicosis may stimulate T helper cell 2 subset of CD4⁺ T cells. The TH2 subset may augment humoral immune responses to vaccination.

A series of sixteen target compounds involving primarily methylene ethylene and methyleneoxy spacers between the heterocyclic portion and halogenated phenyl portion were prepared and submitted for screening. The chemistry and biological screening results are described. None of the compounds exhibited useful chemotherapeutic activity. (Author)

Exploratory investigations in several series of amines were conducted with the view of obtaining optimum conditions as well as representatives examples for biological screening. Difficulties encountered with either the reactivity of some of the amines or the stability of some of the products prevented completion of this initial goal. Where such areas of difficulty arose further work will be required. A series of 6-(substituted benzyl)-2,4-diamino-5,6,7,8-tetra-hydropyrimido (4,5-d) pyrimidines has been prepared and is in the process of being submitted for screening. (Author)

Five new high explosives, all nitramines, were synthesized by means of the Mannich reaction. The condensation of 3,3,3-trinitropropyl amine and trinitroethanol, followed by postnitration, gave N-2,2,2-trinitroethyl-N-3,3,3- trinitropropyl nitramine. The condensation of 2 moles of 3,3,3-trinitropropyl amine with 1 mole of 2,2-dinitro-1,3-propanediol, followed by postnitration, gave 1,1,1,4,6,6,8,11,11,11-decanitro-4,8-diaza-undecane. The condensation of 3, 3,3-trinitropropyl amine with 2,2,4,4-tetranitro-1,5-pentanediol gave N-3,3,3- trinitropropyl-3,3,5,5-tetranitropiperidine. The condensation of 3,3,3- trinitropropyl amine with 2,2-dinitropropanol, followed by postnitration, gave N-3,3,3-trinitropropyl-N-2,2-dinitropropyl nitramine. The condensation of 3,3- dinitrobutyl amine with trinitroethanol, followed by postnitration, gave N3,3- dinitrobutyl-N-2,2,2-trinitroethyl nitramine. The use of the heat of explosion per unit weight was proposed as a criterion of explosive power to supplement the predicted lead-block and ballistic-mortar values. The contribution to the molar heat of explosion and molecular weight was tabulated for a large number of structural groups. The heat of explosion per unit volume was calculated for a number of high explosives and for some structural changes. RDX was desensitized with a 10% coating of a copolymer of 2,2-dinitrobutyl acrylate (90%) and 2- nitrobutyl acrylate (10%). A method of predicting the crystal density of explosive compounds is under development.

A method for the synthesis of novel phosphorylated aminoacetals was developed. The latter are involved in Mannich reaction as amine component with calix[4]resorcinol and formaldehyde to form tetrasubstituted macrocycles containing four acetal groups and four phosphonate (phosphine oxide) fragments on the "upper" rim of molecule with high yields. © 2013 Copyright Taylor and Francis Group, LLC.

A method for the synthesis of novel phosphorylated aminoacetals was developed. The latter are involved in Mannich reaction as amine component with calix[4]resorcinol and formaldehyde to form tetrasubstituted macrocycles containing four acetal groups and four phosphonate (phosphine oxide) fragments on the "upper" rim of molecule with high yields. © 2013 Copyright Taylor and Francis Group, LLC.