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Large-scale distillation is a challenge in many respects. Particularly difficult is the purification by distillation of a compound with limited thermal stability. This article describes various aspects of these difficulties with some possible solutions. Special emphasis is placed on the collaboration of different disciplines to find pragmatic solutions to these challenges. The purification of diketene in quantities of several 1000 ta–1 is an excellent example to illustrate the different requirements. Although the distillation of diketene has been carried out by several companies for many years, there are still some aspects that deserve special attention.

A green, facile, and efficient method for the synthesis of novel 1,2-dihydroacridine-2-carboxamide derivatives was effectively performed via a one-pot pseudo-five component cascade reaction involving 2-chloroquinoline-3-carbaldehyde, 1-phenyl-2-(triphenylphosphoranylidene)ethanone, diketene, and several primary amines in ethanol at 70 °C, in one pot reaction. This novel effective cascade reaction was accomplished probably via a sequence of Wittig reaction/SN reaction/Michael addition/intramolecular C-cyclization and imine hydrolysis. The advantages of this method are operational simplicity, atom economy, short reaction times, facile work-up procedure, and very high yields. [ABSTRACT FROM AUTHOR]

Diketene (4-methylideneoxetan-2-one) is a precursor to the formation of either two molecules of ketene, or allene and CO2 using pyrolysis techniques. It is not known experimentally which of these pathways is followed, or indeed if both are, during the dissociation process. We use computational methods to show that the formation of ketene has a lower barrier than formation of allene and CO2 under standard conditions (by 12 kJ/mol). According to CCSD(T)/CBS, CBS-QB3 and M06-2X/cc-pVTZ calculations the formation of allene and CO2 is favoured thermodynamically under standard conditions of temperature and pressure; however, kinetically the formation of ketene is favoured from transition state theory calculations at standard and elevated temperatures. [ABSTRACT FROM AUTHOR]

We describe the first classic example of green synthesis of pyrrolo[3,4-c]quinolones scaffolds by catalyst-free unusual reaction of diketene, isatin, and primary amines in ethanol in the presence of pyrazole as a promoter for 4 h. The whole structure of the new product was confirmed by X-ray analysis. The overall transformation involves the cleavage and generation of multiple carbon-nitrogen and carbon-carbon bonds. This report represents a simple and straightforward approach for the synthesis of pyrrolo[3,4-c]quinoline-1,3-diones, which has significant advantages like readily available precursors, non-use of toxic solvent, operational simplicity, mild conditions, good atom economy, and excellent yields; therefore it provides a green and sustainable strategy for access to a range of interesting N-containing heterocyclic compounds in medicinal and organic chemistry.

A novel and efficient four component reaction involving diketene, primary amines, aromatic aldehydes and 2-amino-benzimidazole in the presence of I2 in refluxing EtOAc for the synthesis of benzo[4,5]imidazo[1,2-a]-pyrimidine-3-carboxamides is reported. Good yields, mild reaction conditions and facile isolation of products in pure forms are advantageous of this methodology. [ABSTRACT FROM AUTHOR]

Novel and efficient multicomponent reactions (MCRs) involving diketene, ninhydrin (indane-1,2,3-trione) and one primary amine (3CR) or two different primary amines (4CR) were achieved for the successful synthesis of dihydro-4H-indeno[1,2-b]furan-3-carboxamides or tetrahydroindeno[1,2-b]pyrrole-3-carboxamides, respectively. The merits of this method are highlighted by using either commercially available or easily accessible starting materials, operational simplicity, facile workup procedure, efficient usage of all the reactants, tolerance of a variety of functional groups and ability to conduct under un-catalyzed reaction condition. The products were also isolated by just decantation of the solvent, and for the purification column chromatography was non-required. [ABSTRACT FROM AUTHOR]

A facile, efficient and un‐catalyzed approach for the synthesis of new symmetrical highly‐ substituted indeno [1,2‐b]pyrrole derivatives through four‐component reaction, involving, primary amines, diamine, diketene, and ninhydrin in CH2Cl2 at ambient temperature is reported. This approach enjoys merits such as being done in the absence of catalyst at ambient temperature, giving good to excellent yields, completed in short reaction times, and showing a wide functional group tolerance. [ABSTRACT FROM AUTHOR]

Large-scale distillation is a challenge in many respects. Particularly difficult is the purification by distillation of a compound with limited thermal stability. This article describes various aspects of these difficulties with some possible solutions. Special emphasis is placed on the collaboration of different disciplines to find pragmatic solutions to these challenges. The purification of diketene in quantities of several 1000 ta-1 is an excellent example to illustrate the different requirements. Although the distillation of diketene has been carried out by several companies for many years, there are still some aspects that deserve special attention., (Copyright 2024 Mehmet Ogün Biçer, Erik von Harbou, Andreas Klein, Hilke-Marie Lorenz, Christoph Taeschler. License: This work is licensed under a Creative Commons Attribution 4.0 International License.)

A one-pot pseudo five-component reaction for the synthesis of 2-aryl-4-hydroxy-4-methyl-6-oxo-N1,N3-dialkylcyclohexane-1,3-dicarboxamide derivatives involving different primary amines, various aromatic aldehydes, and diketene in the presence of triethylamine with high yields is achieved. [ABSTRACT FROM AUTHOR]

A novel five-component strategy involving commercially available diketene, primary amines, malononitrile and various benzaldehydes for the synthesis of densely functionalized 1,4-dihydropyridines in good yields was achieved. The reaction pathway involves a sequential ring-opening of diketene/enamine formation/Knoevenagel-condensation/Michael addition and 6- exo-tet cyclization, resulting in multiple bond-formation events including two C–C and three C–N bonds ultimately leading to the formation of the respective 1,4-dihydropyridines. [ABSTRACT FROM AUTHOR]

We describe the first classic example of green synthesis of pyrrolo[3,4-c]quinolones scaffolds by catalyst-free unusual reaction of diketene, isatin, and primary amines in ethanol in the presence of pyrazole as a promoter for 4 h. The whole structure of the new product was confirmed by X-ray analysis. The overall transformation involves the cleavage and generation of multiple carbon-nitrogen and carbon-carbon bonds. This report represents a simple and straightforward approach for the synthesis of pyrrolo[3,4-c]quinoline-1,3-diones, which has significant advantages like readily available precursors, non-use of toxic solvent, operational simplicity, mild conditions, good atom economy, and excellent yields; therefore it provides a green and sustainable strategy for access to a range of interesting N -containing heterocyclic compounds in medicinal and organic chemistry., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rezvanian and Esfandsar.)

ABSTRACT Derivation of optimal operating policies and runaway boundaries for a semibatch reactor (SBR), when highly exothermic reactions are conducted and hazardous side reactions may occur, is a difficult task because of multiple sources of process uncertainty to be considered (variability in raw materials, catalyst, impurities, model inaccuracies, measurement errors, technological, economic and safety constraints). The present work introduces a new criterion based on failure probability indices related to uncertainty in the runaway boundaries and disturbances of the operating parameters. Such a criterion is used not only to derive more prudent SBR optimal operating policies but also to appreciate rapprochement to critical conditions. An example is provided for an SBR used for conducting the hazardous acetoacetylation of pyrrole with diketene in homogeneous liquid phase catalysis. Both uncertainties in evaluating the runaway boundaries, with a generalized sensitivity criterion, and of the running conditions are used to generate optimal operating strategies, making a satisfactory compromise between the productivity goal and safety requirements. © 2011 Curtin University of Technology and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: A large number of optimization strategies have been developed for semi-batch reactors (SBR) with a fixed or free terminal time, with or without considering various sources of uncertainty. Such strategies account for safety constraints rather empirically determined in the form of parameter thresholds, while safety indices are seldom integrated in the optimization objective function. The present work illustrates how the runaway boundaries, and their confidence region associated to the parameter uncertainty, can be evaluated using the process model and a generalized sensitivity criterion, and how they can be included in the SBR optimization. A concrete example is provided for the SBR used for the acetoacetylation of pyrrole with diketene in homogeneous catalysis, a process known to be of high risk due to the very exothermic side-reactions. While previous studies approached the isothermal SBR, the present work is focused on optimizing the non-isothermal SBR operation. [ABSTRACT FROM AUTHOR]

Diketene (4-methylene-2-oxetanone) is inactive as a carcinogen, although it is more reactive toward nucleophiles than the analogs β-propiolactone and β-butyrolactone, both of which are alkylating agents of known carcinogenicity. In the literature the lack of carcinogenic effects has been ascribed to the rapid hydrolysis of diketene, which could preclude its in vivo alkylating capacity. In this work, the kinetics of the neutral and alkaline hydrolysis of diketene in aqueous and different water–dioxane media have been studied. The following conclusions can be drawn: (i) The neutral hydrolysis of diketene is slightly faster than that of β-propiolactone and β-butyrolactone. (ii) The hydrolysis reaction of diketene is very slow when compared to its alkylation reaction of a DNA-model nucleophile, suggesting that, contrary to earlier results, competitive hydrolysis is not the cause of its lack of carcinogenicity. (iii) The diketene neutral hydrolysis rate constant increases with the water/dioxane ratio, the opposite occurring in base hydrolysis. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

We report an inexpensive method for producing a diverse array of pyrrole amides on a large scale and in good yield. The synthetic sequence allows for the preparation of a number of pyrrole amide derivatives in excellent to moderate yields from commercially available compounds. The diketene adduct, in the presence of an amine nucleophile, provides an excellent method for acetoacetylation. For diversity and versatility, a second method utilizing Meldrum's acid was successfully employed for the preparation of additional acetoacetamide derivatives. Using the Knorr pyrrole synthesis, pyrrole amides were readily prepared from the oxime of the acetoacetamides. [ABSTRACT FROM AUTHOR]

Abstract: An effective route to functionalized 4,5-dihydro-1H-pyrrol-3-carboxamide derivatives is described. This involves reaction of N-alkyl-3-oxobutanamides, which result from the addition of an amine to the diketene, and a primary amine in the presence of dibenzoylacetylene. The 1,3-dicarbonyl compounds obtained from the addition of an amine to diketene were trapped with a primary amine to produce (Z)-3-(alkylamino)-N 1-alkyl-2-butenamide, which reacts with dibenzoylacetylene to produce 4,5-dihydro-1H-pyrrol-3-carboxamide derivatives. [Copyright &y& Elsevier]

Abstract: An effective route to functionalized furamide derivatives is described. This involves reaction of N-alkyl-3-oxobutanamides, derived from the addition of amines to the diketene, and dibenzoylacetylene in the presence of triphenylphosphoine. The reactive 1:1 intermediate obtained from the addition of triphenylphosphine to dibenzoylacetylene was trapped by OH-acids such as N-alkyl-3-oxobutanamide to produce functionalized furamide derivatives. [Copyright &y& Elsevier]

The reaction of diketene with cyanothioacetamide in dry dioxane in the presence of triethylamine gives triethylammonium 3-cyano-6-methyl-4-oxo-1,4-dihydro-2-pyridinethiolate. The regioselective S-alkylation of this thiolate is a convenient method for the preparation of substituted 4(1H)-pyridones and also derivatives of thiazolo[3,2-a]pyridine and thieno[2,3-b]pyridine. The action of 2-amino-1,1,3-tricyanopropene on this thiolate leads to its transformation into a new heterocyclic system, namely, 5H-pyrido[2′,3′:4,5]thiopyrano[2,3-b]pyridine; treatment with iodine yields the oxidation product, namely, the corresponding bis(2-pyridyl) disulfide. The structure of isopropyl (3-cyano-6-methyl-4-oxo-1,4-dihydro-2-pyridinyl)thioacetate was confirmed by X-ray diffraction structural analysis. [ABSTRACT FROM AUTHOR]

An aldol-type reaction catalyzed by a Ti-(S)-BINOL complex using with a diketene as substrate is described herein. The complex derived from 1.0 molar equivalent of Ti(O-i-Pr)4 and 2.0 molar equivalents of(S)-BINOL gave(S)-isopropyl 5-hydroxy-7-phenyl-3-oxo-6-heptenoate with high enantioselectivity. [ABSTRACT FROM AUTHOR]

Knöevenagel-type reaction between diketene and aldehydes proceeded in the presence of Ti(O-i-Pr)4. This reaction proceeded via titanium enolate derived from Ti(O-i-Pr)4 and diketene. As for the stereoselectivity of the products, E-isomers were produced predominantly in the case of aromatic aldehydes. [Copyright &y& Elsevier]

Enol trichloroacetate of cyclohexanone has been found to react with benzaldehyde in the presence of a catalytic amount of tributyltin methoxide and stoichiometric amount of MeOH to give an aldol adduct. Methanolysis of the in situ generating tin alkoxide of aldol adduct regenerates the tin methoxide, and thus the aldol reaction can proceed catalytically. The use of BINAP·silver(I) complex as an additional catalyst results in formation of optically active aldol products. This catalytic method has been further applied to the asymmetric reaction of diketene with benzaldehyde. [Copyright &y& Elsevier]

Two major compounds are formed in the reaction of 3,5-diamino-4-nitropyrazole with acetoacetic ester: 2-amino-5-methyl-3-nitro-4,7-dihydropyrazolo[1,5-a]pyrimidin-7-one and 3-amino-5-(β-hydroxycrotonyl)amino-4-nitropyrazole. The latter is converted to bicyclic dihydropyrazolo[1,5-a]-pyrimidinone in solutions with heating. [ABSTRACT FROM AUTHOR]

Abstract: 5-Carboxamide substituted 3,4-dihydropyrimidine-2(1H)one derivatives were synthesized in a simple and efficient method from the one-pot four-component reactions of an aliphatic or aromatic amine, diketene, an aromatic aldehyde and urea or thiourea in the presence of p-toluenesulfonic acid as a catalyst under mild reaction conditions at ambient temperature. [Copyright &y& Elsevier]

Abstract: A new, one-pot, four-component reaction for the synthesis of a novel class of highly substituted 1,4-dihydro-1,8-naphthyridine-3-carboxamide derivatives starting from readily available inputs including aliphatic or aromatic amines, diketene, aromatic aldehydes, and 2-aminopyridines in the presence of a catalytic amount of p-toluenesulfonic acid under mild reaction conditions and in good yields at ambient temperature is described. [Copyright &y& Elsevier]

Abstract: A one-pot four-component reaction of an aliphatic or aromatic amine, diketene, an aromatic aldehyde and 1,3-diphenyl-1H-pyrazol-5-amine in the presence of p-toluenesulfonic acid as a catalyst has been developed. In this reaction, a new class of fully substituted pyrazolo[3,4-b]pyridine-5-carboxamide derivatives is produced under mild reaction conditions and in good yields at ambient temperature. [Copyright &y& Elsevier]