Verbanone in the synthesis of amidoketones from o-menthane series

A verbanone reaction with acetonitrile under Ritter reaction conditions led to a selective formation of o-menthane derivatives, a mixture of stereoisomeric cis-and trans-8-acetamido-o-menthones. The streoisomers ratio depends on the reaction conditions and the character of acid catalyst used.     

Substituent-controlled domino-Knoevenagel-hetero Diels-Alder reaction—a one-pot synthesis of polycyclic heterocycles

The reaction of 2-(N-alkenyl-N-aryl)amino-4-oxo-4H-1-benzopyran-3-carbaldehyde with dimedone/Meldrum’s acid/4-hydroxycoumarin by heating in ethanol in the presence of pyridine produces polycyclic heterocycles bearing pyridine and pyran rings in a one-pot reaction. The effect of substituents on N-atom of the amino function controls the mode of reaction. Terminal alkenes prefer intramolecular Michael type reaction, but non-terminal alkenes favour Diels-Alder reaction, whereas, under similar condition, 2-(N-alkyl-N-allyl)amino-4-oxo-4H-1-benzopyran-3-carbaldehyde undergoes domino-Knoevenagel-hetero Diels-Alder reaction.     

Temperature vs. time sequences to palliate deactivation in parallel and in series-parallel with the main reaction: parametric study

The calculation of temperature vs. time sequences to palliate catalyst deactivation in an integral reactor has been studied either by maintaining constant the conversion at the reactor outlet in a simple reaction or by maintaining constant the concentration of a given component at the outlet in a complex reaction system. The experimental systems studied, which are a simple one (dehydration of 2-ethylhexanol) and a complex one (isomerization of cis-butene), have kinetic models of the Langmuir-Hinshelwood-Hougen-Watson type for the main reaction and deactivation, with deactivation by coke dependent on the concentration of the reaction components. In the reaction of dehydration of 2-ethylhexanol deactivation occurs in parallel with the main reaction and in the isomerization of cis-butene deactivation occurs in series-parallel with the main reaction. A parametric study has been carried out for both reaction systems. The sequences calculated have been experimentally proven in an automated reaction apparatus.     

A room temperature one-pot Knoevenagel-Chan-Evans-Lam coupling reaction for synthesis of N-aryl-2-Iminocoumarins in bio-mass-derived green solvent 2-methylTHF

An efficient approach for the synthesis of biologically interesting N-aryl-2-iminocoumarins by a copper-catalyzed one-pot procedure has been developed by the reaction of 2-hydroxybenzaldehydes, malononitrile and arylboronic acids using triethylamine as a base in a bio-mass-derived green solvent 2-MethylTHF at room temperature. This protocol allows access to several N-aryl-2-iminocoumarins in high yields in a relatively short period of time under mild reaction conditions. The procedure operates by a simple telescoped process wherein 2-imino-2H-chromene-3-carbonitriles are formed in situ by the reaction of 2-hydroxybenzaldehyde, malononitrile, and TEA. Further a subsequent one-pot reaction of imine with the arylboronic afforded the target compounds. To understand the reaction mechanism, MALDI-ESI studies were performed, which showed the in situ generated iminocoumarins to be in ligation cooper to form a copper-iminocoumarin complex thus facilitating the smooth formation of N-aryl-2-iminocoumarins in the reaction. Overall, this protocol is practically valuable, useful in organic synthesis, shows good functional group tolerance and provides access to a diverse array of N-aryl-2-iminocoumarins derivatives.     

Isocyanide based multicomponent reactions of oxazolidines and related systems

N-Alkyloxazolidines react in a multicomponent reaction with carboxylic acids and isocyanides to give N-acyloxyethylamino acid amides. The previously reported reaction conditions were improved using a design of experiments approach (DoE). Under the optimised conditions, good yields of the N-acyloxyethylamino acid amide products are obtained both via a three- or four-component approach from N-alkylethanolamines, aldehydes/ketones, isocyanides and carboxylic acids. The reaction of oxazolidines without a nitrogen substituent was found to give either the expected Ugi products or the N-acyloxyethylamino acid amides depending on the choice of reaction conditions. Optimised reaction conditions were also developed for the ring-expansion of oxazolidines to morpholin-2-ones via reaction with an isocyanide followed by hydrolysis. The mechanistic pathway of the multicomponent reaction was briefly investigated using an ¹⁸O labelling experiment. The carboxylic acid component can be replaced by a range of other acidic nucleophiles including thiobenzoic acid, thiophenol or 5-phenyltetrazole, which are incorporated via an alternative pathway. These latter reactions can also be applied to 2-aminotetrahydrofurans, 2-aminotetrahydropyrans or 4-hydroxybut-2-one, further extending the structural diversity of the multicomponent reaction products.     

A mild and efficient synthesis of a chiral pyridazinone derivative

We found a mild and efficient reaction condition for construction of a chiral 5-methyl-4,5-dihydropyridazin-3(2H)-one from a chiral β-methyl γ-ketocarboxylic acid via the corresponding acid hydrazide without racemization. Furthermore, we demonstrated that this two-step reaction can be attained by one-pot reaction. This method could be applied to various kinds of substrates because of the mild reaction conditions.     

N-Allyl-1,3-oxazines via a facile keto-ene/cyclization tandem reaction

The intramolecular keto-ene/cyclization tandem reaction of γ-N-allylamino ketones is an effective means of producing 1,3-oxazines. The reaction usually requires high temperatures and/or pressures. We discovered that N,N-diallyl amines undergo the reaction at lower temperatures than their monoallyl analogs. An extreme example, 1-N,N-diallylamino-9,10-anthraquinone, undergoes the keto-ene reaction near ambient temperature. In the case of 1-N,N′-dialkylaminoanthraquinones, electron deficient ene components can even be used, allowing the preparation of a broad spectrum of oxazines. Furthermore, the N-allyl-1,3-oxazine can be easily deallylated to produce a 1,3-oxazine that contains a secondary amine.     

Asymmetric synthesis of α,β-substituted γ-amino acids via conjugate addition

The first conjugate addition reaction of organocuprates to N-enoyl oxazolidinone where a N-protected γ-nitrogen atom and an α-methyl group are present into α, β-unsaturated system is described. This reaction gave anti-products in moderate yields and high diastereomeric ratios. The anti-products have two contiguous stereogenic centers, one formed by the conjugate addition reaction and the other by a diastereoselective protonation reaction. The removal of chiral oxazolidinone moiety and N-deprotection of amino group furnished chiral α, β-disubstituted γ-amino acids.     

Chiral base-catalyzed aldol reaction of trimethoxysilyl enol ethers: effect of water as an additive on stereoselectivities

An aldol reaction of trimethoxysilyl enol ether catalyzed by lithium binaphtholate is described. The aldol reaction of trimethoxysilyl enol ether derived from cyclohexanone under anhydrous conditions predominantly afforded the anti-aldol adduct with moderate enantioselectivity, whereas the reaction under aqueous conditions predominantly resulted in the syn-adduct and the enantioselectivity of the syn-adduct was considerably improved. The best enantioselectivity was obtained in the reaction of trimethoxysilyl enol ether derived from 1-indanone with cyclohexanecarboxaldehyde (97% ee (syn)). This is the first example of an aldol reaction of trimethoxysilyl enol ether catalyzed by a chiral base.     

N-Tosylaziridine, a new substrate for chemical fixation of carbon dioxide via ring expansion reaction under atmospheric pressure

N-Tosylaziridine was found to be a useful substrate for cycloaddition reaction with carbon dioxide. The reaction was successfully catalyzed by lithium bromide under atmospheric pressure to give the corresponding five-membered cyclic urethane, N-tosyl-1,3-oxazolidin-2-one, selectively. It was found that electron-donating nature of the substituent at 2-position of N-tosylaziridine accelerated the reaction, and this tendency allowed us to estimate the reaction mechanism.     

A novel carbanion-olefin intramolecular cyclization: synthesis of substituted 2-aroyl-3,4-dihydro-2H-benzopyrans from salicylaldehydes

Utilization of a novel carbanion-olefin intramolecular 6-endo-trig cyclization reaction to provide 2-aroyl-3,4-dihydro-2H-benzopyrans is described. Through a sequence of a Wittig reaction, O-alkylation, and carbanion-olefin intramolecular cyclization, salicylaldehydes were converted into a series of new 2-aroyl-3,4-dihydro-2H-benzopyrans in two steps or in one-pot reaction.     

Application of ortho-chloro-β-aroylthioamides in synthesis(II): an efficient one-pot, three-component synthesis of tricyclic thiochromeno[2,3-b]pyridine derivatives

Tricyclic thiochromeno[2,3-b]pyridine derivatives have been successfully synthesized in an unusual one-pot multicomponent cascade reaction from ortho-halo-β-aroylthioamides, Meldrum's acid, and aromatic aldehydes. The reaction presumably proceeds via Knoevenagel condensation-Michael addition-cyclocondensation-decarboxylation-rearrangement-intramolecular S_NAr reaction sequence. High bond forming efficiency of this reaction makes it attractive for the synthesis of thiochromeno[2,3-b]pyridine derivatives in a single step operation.     

CuO nano-particles supported on silica,a new catalyst for facile synthesis of benzimidazoles,benzothiazoles and benzoxazoles

A facile synthetic route for benzimidazoles, benzothiazoles and benzoxazoles comprising the reaction of corresponding o-phenylenediamine, o-aminothiophenol and o-aminophenol with various aldehydes using silica supported nano-copper (II) oxide as a catalyst has been described. The catalyst exhibited a clean reaction profile with excellent yields in a short reaction time. The catalyst can be recycled effectively after use.     

Preparation of 2-aminosubstituted 3H-imidazo[4,5-c]quinolin-4(5H)-ones by palladium-assisted internal biaryl coupling reaction

Representatives of the 3H-imidazo[4,5-c]quinolin-4(5H)-ones have shown interesting biological activity. We have found 2-aminosubstituted 3H-imidazo[4,5-c]quinolin-4(5H)-one as a potent dipeptidyl peptidase 4 inhibitor. However effective synthesis of this nucleus with various substituents at the 6-9-positions has not been reported. We report herein the development of a novel and efficient synthesis of 2-aminosubstituted 3H-imidazo[4,5-c]quinolin-4(5H)-ones by palladium-assisted internal biaryl coupling reaction. Our optimization of the reaction conditions revealed that the most important factors for this reaction are use of silver carbonate as a base and high reaction temperature.     

E-selective isomerization of stilbenes and stilbenoids through reversible hydroboration

Hydroboration of a mixture of E and Z stilbenes and stilbenoids is followed by an elimination reaction to yield the E isomer with high stereoselectivity. The reaction tolerates aromatic substituents with varying stereoelectronic properties, occurs in one pot, and requires only commercially available reagents. An illustration of the isomerization reaction in a synthesis of resveratrol, a biologically active antioxidant, is presented.     

Microwave-induced domino-Knoevenagel-hetero Diels–Alder reaction—an easy route to di[1]benzopyrano[2,3-b:4′,3′-d]pyridine

MW-irradiation of a well-ground equimolar mixture of 2-(N-alkynyl-N-aryl)aminochromone-3-carbaldehyde and dimedone underwent domino-Knoevenagel-hetero Diels–Alder (DKHDA) reaction for nonterminal alkynes, whereas conventional heating of the above reaction mixture in ethanol in the presence of pyridine accomplished alkyne-carbonyl metathesis (ACM) reaction or both ACM and DKHDA reaction. Here is the first example of an organo-catalyzed ACM reaction.     

Synthesis of unsymmetrical biaryl ureas from N-carbamoylimidazoles: kinetics and application

N-Carbamoylimidazoles dissociate in solution to yield imidazole and an isocyanate that may be reacted with another aryl amine to form an unsymmetrical biaryl urea. This paper investigates the reaction kinetics and the influence of electron withdrawing/donating substituents on the reaction of N-carbamoylimidazoles with aniline. The overall reaction mechanism involves two zwitterionic intermediates, formed during dissociation and upon reaction of the liberated isocyanate with aniline. The rate limiting step for the reaction is a base catalysed proton transfer from the second zwitterionic intermediate. Although electron withdrawing substituents on the aryl group hinder dissociation, they significantly increase reaction rates compared to compounds bearing electron donating substituents. The imidazole liberated upon dissociation catalyses the rate determining step so that reactions of dissociated N-carbamoylimidazoles proceed more rapidly than those involving only isocyanates. In addition, the imidazole eliminates the need for anhydrous reaction conditions. The N-carbamoylimidazole methodology was demonstrated by preparing sorafenib, a biaryl urea kinase inhibitor, in good yield and excellent purity.     

Carbon radical addition to N-sulfonylimines mediated by triethylborane or zinc

The utility of N-sulfonylimines as radical acceptors was investigated under the different reaction conditions such as the stannyl radical-mediated addition reaction, the triethylborane-mediated tin-free radical reaction, and the zinc-mediated aqueous-medium radical reaction. The alkyl radical addition reaction of N-sulfonylimines proceeded effectively without the activation by Lewis acid. These reactions were successfully extended to one-pot reactions for preparing a wide range of amine derivatives.     

Regioselective synthesis of 2-carbonyl furans in a one pot three component reaction

Regioselective synthesis of 2-benzoyl-6,6-dimethyl-6,7-dihydrobenzofuran-4(5H)-ones have been accomplished through a novel protocol involving β-amino enone, N-chlorosuccinimide and dimedone in a one pot catalyst-free reaction at an ambient temperature. On the other hand, the same reaction when conducted with two equivalents of N-chlorosuccinimide under similar reaction conditions, exclusive formation of 2-benzoyl-3-(dimethylamino)-6,6-dimethyl-6,7-dihydrobenzofuran-4(5H)-ones were observed. Simple and metal-free reaction conditions, selective product formation and excellent yields are the advantages of this protocol.     

A novel Barton decarboxylation produces a 1,4-phenyl radical rearrangement domino reaction

A novel 1,4-Phenyl radical rearrangement (1,4-PhRR) is described in a typical Barton decarboxylation procedure. While carrying out this reaction in presence of a N,N-disubstituted β-amino acid derivative, the decarboxyphenyl rearranged derivative is obtained, as well as in presence of β-N,N-acylamide. On the other hand, secondary amines give the β-lactam derivative without rearrangement, as well as N-Fmoc derivatives give the normal decarboxylation reaction. In regards of amines which are far away from the carboxylic group, such as δ-amino acid derivatives, the reaction occur through a typical Barton decarboxylation without rearrangement. The diversity of the reaction proves synthetic usefulness paving the way to interesting biologically active compounds.