Heterocyclic Enamines Research Articles

Adventures in the Chemistry of Multicomponent and Domino Reactions

AbstractThe present personalized account summarizes various cyclization reactions, including multicomponent and domino processes, which are directed towards the synthesis of complex heterocyclic products. Domino Knoevenagel/hetero‐Diels‐Alder reactions provide a synthesis of annulated quinol‐2‐ones. The combination of Knoevenagel reactions with [3+2] cycloadditions of nitrogen ylides afford complex spiroheteriocyclic products. Domino Knoevenagel/enamine cyclization reactions result in the formation of condensed purine analogues. Formal [3+3] cyclizations of pyridinium salts allow for a rapid assembly of bridged heterocyclic systems and include the employment of thioxindoles and cyclohexane‐1,3‐diones as dinucleophilic building blocks. The formal [3+3] cyclization of thioxindoles with fluoroaroyl chlorides, such as 2‐fluorobenzoyl chlorides and 2‐chloropyridine‐3‐carboxylic chloride, give rise to the synthesis of condensed benzothiophenes. The cyclization of heterocyclic enamines with diimines and triazines afford various purine analogues by domino [4+2]/retro [4+2] reactions. The formal [3+3] cyclization of 2,4,6‐tris(trifluoromethyl)‐1,3,5‐triazine with 1,3‐bis(silyloxy)‐1,3‐butadienes afford, depending on the conditions, 2,6‐bis(trifluoromethy)pyrid‐4‐ones or triazaadamantanone derivatives. Heating of 2‐ethynylpyridines with electron‐rich dienes afforded 2‐(2‐methoxyphenyl)pyridines by a domino [4+2]/retro [4+2] process. The reaction of 2‐ethynylpyridines with enones afforded indolizines by a formal [3+3] cyclization. The reaction of trifluoromethyl‐substituted 1,3‐diketones with lithiated alkynes afforded 3‐hydroxy‐pent‐4‐yn‐1‐ones. Formal [5+1] cyclization of the latter with urea afforded trifluoromethyl‐substituted pyridines. The Pd catalyzed formal [3+2] cyclizations of 2,3‐dihalopyridines with imines afforded a series of regioisomeric 4‐ and 7‐azaindoles.

Recyclization of 3‐substituted‐6,8‐dimethylchromones with some heterocyclic enamines: Spectroscopic, quantum calculations (HOMO–LUMO, MEP, NLO), biological evaluation, and ADME investigation

AbstractThe chemical reactivity of some 6,8‐dimethylchromones was studied toward certain heterocyclic enamines. Treatment of carboxaldehyde 1a with the certain enamines proceeded via condensation with concomitant γ‐pyrone ring opening. Reaction of carbonitrile 1b with enamine derivatives proceeded through opening of γ‐pyrone moiety associated with cycloaddition into the nitrile function. A novel angular chromenopyrazolopyridine and chromenopyridopyrimidines were efficiently synthesized from reacting carboxamide 1c with the current enamines. Moreover, frontier molecular orbitals analysis, electronegativity, global hardness, global softness, ionization energy, and HOMO‐LUMO energy gap were calculated by using DFT/B3LYP/6‐311++G(d,p) level. Using the GIAO approach, the 1H and 13C NMR spectra were calculated and showed good agreement with the experimental values. Additionally, the nonlinear optical (NLO) properties of the prepared compounds were found higher than urea. MEP was utilized to ascertain reactive sites within the molecules. The produced compounds exhibited varying degrees of inhibitory effect when tested for their antimicrobial and anticancer properties. The evaluation of ADME (absorption, distribution, metabolism, and excretion) parameters indicated good drug‐like properties of all the investigated compounds.

Adventures in Coumarin Chemistry

AbstractThe cyclization of various nucleophiles, such as 1,3-dicarbonyl compounds, 1,3-bis(silyloxy)-1,3-butadienes, hydrazones, hydroxylamine, amidines, thioglycolic esters, heterocyclic enamines and others, with 4-chlorocoumarins, containing an electron-withdrawing group at position 3, allows for a convenient synthesis of a great variety of benzo[c]coumarins and related fused coumarins. Suzuki–Miyaura reactions of coumarin-derived bis(triflates) result in formation of arylated coumarins with excellent regioselectivity that is controlled by electronic and steric features of the substrate. The combination of Suzuki–Miyaura with lactonization reactions of carba- and heterocyclic substrates allows for the synthesis of benzo[c]coumarins and of other fused coumarins. Domino Michael–retro-Michael–lactonization reactions of 1,3-bis(silyloxy)-1,3-butadienes with chromones provide a convenient access to hydroxylated benzo[c]coumarins. In a related approach, fused coumarins were prepared by domino reactions of heterocyclic enamines with chromone-3-carboxylic acids.1 Introduction2 Reactions of 3-Acceptor-4-chlorocoumarins3 Reactions of Coumarin Triflates4 Synthesis of Fused Coumarins5 Conclusions

In Silico and In Vitro Studies of 4-Hydroxycoumarin-Based Heterocyclic Enamines as Potential Anti-Tumor Agents.

The present study reports the one-step synthesis of several 3-formyl-4-hydroxycouramin-derived enamines (4a-4i) in good yields (65-94%). The characterization of the synthesized compounds was carried out via advanced analytical and spectroscopic techniques, such as melting point, electron impact mass spectrometry (EI-MS), 1H-NMR, 13C-NMR, elemental analysis, FTIR, and UV-Visible spectroscopy. The reaction conditions were optimized, and the maximum yield was obtained at 3-4 h of reflux of the reactants, using 2-butanol as a solvent. The potato disc tumor assay was used to assess Agrobacterium tumefaciens-induced tumors to evaluate the anti-tumor activities of compounds (4a-4i), using Vinblastine as a standard drug. The compound 4g showed the lowest IC50 value (1.12 ± 0.2), which is even better than standard Vinblastine (IC50 7.5 ± 0.6). For further insight into their drug actions, an in silico docking of the compounds was also carried out against the CDK-8 protein. The binding energy values of compounds were found to agree with the experimental results. The compounds 4g and 4h showed the best affinities toward protein, with a binding energy value of -6.8 kcal/mol.

Ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate in the smiles rearrangement reaction: straightforward synthesis of amino acid derived quinolin-2(1H)-one enamines.

This paper describes the development of 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate compound as a heterocyclic enols containing a Michael acceptor so that it participates in an Ugi-type multicomponent condensation through a Smiles rearrangement in replacement of acid components. The new four-component containing 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate, aldehyde derivatives, amine derivatives and isocyanides process leads readily and efficiently to heterocyclic enamines. This report is an outstanding strategy for the preparation of new biologically structures containing peptidic or pseudo-peptidic with quinolin-2(1H)-one scaffolds.

I2/DMSO-mediated C(sp2)-S bond formation between heterocyclic enamines and triethylammonium thiolates

An efficient I2/DMSO-mediated oxidative dehydrogenative coupling reaction between heterocyclic enamines and triethylammonium thiolates under microwave conditions is reported, by which three different types of biheterocyclic pairs, namely indolin-2-one-pyrazole, indolin-2-one-isoxazole, and indolin-2-one-isothiazole were constructed with high yields through C–H sulfenylation strategies. The present protocol features a wide substrate scope and broad functional group compatibility with I2 as the catalyst and DMSO as both solvent and mild oxidant.

I2/Dmso-Mediated C(Sp2)-S Bond Formation between Heterocyclic Enamines and Triethylammonium Thiolates

I2/Dmso-Mediated C(Sp2)-S Bond Formation between Heterocyclic Enamines and Triethylammonium Thiolates

Synthesis of Purines and Related Molecules by Cyclization ­Reactions of Heterocyclic Enamines

AbstractA great variety of pharmacologically relevant fluorinated purine analogues are available by cyclization reactions of heterocyclic enamines with 1,3-dielectrophiles. The reactions usually proceed with excellent regioselectivities. As electrophiles, 1,3-diketones, enaminones or 3-chloro-2-en-1-ones were used. Other synthetic strategies are based on inverse-electron-demand Diels–Alder reactions of heterocyclic enamines with triazines. Purine analogues were further functionalized by transition-metal-catalyzed CH-coupling reactions or oxidative cyclizations, giving rise to more complex polycyclic products. Amidino-C-glycosides in their reactions with 1,3-dielectrophiles afforded pyrimidine-C-glycosides. Multicomponent reactions of heterocyclic enamines afforded complex products, including spirocyclic derivatives.1 Introduction2 1,3-Diketones3 Enaminones4 3-Chloro-2-en-1-ones5 Triazines6 Transition-Metal-Catalyzed Functionalizations7 Pyrimidine-C-Nucleosides8 Multicomponent Reactions9 Conclusions

Domino Reactions of Chromones with Heterocyclic Enamines

AbstractDomino reactions of heterocyclic enamines with chromone derivatives provides a convenient synthesis of a great variety of annulated heterocyclic ring systems. The course of the reaction depends on the type of substituent located at position 3 of the chromone. Reactions of 3-unsubstituted chromones, 3-nitrochromones, and 3-halochromones proceed by conjugate addition of the carbon atom of the enamine to carbon C-2 of the chromone, ring cleavage, and recyclization via the chromone carbonyl group. In the case of 3-formylchromes, 3-dichloroacetylchromone, 3-perfluoroalkanoylthiochromones, 3-(2-fluorobenzoyl)chromones, and 3-methoxalylchromones the final cyclization proceeds via the carbonyl group located outside the chromone moiety. The functional groups located at the carbonyl group at position 3 of the chromone allow for further synthetic transformations including additional ring closures.Contents1 Introduction2 3-Unsubstituted Chromones3 3-Nitrochromones4 3-Formylchromes5 3-Dichloroacetylchromone6 3-Perfluoroalkanoylthiochromones7 3-Methoxalylchromones8 3-(2-Fluorobenzoyl)chromones9 3-Halochromones10 Chromone-3-carboxylic Acids11 Conclusions

A new approach for the synthesis of fluorescent pyrido[1,2-a]benzimidazoles

A facile synthesis of new pyrido[1,2-a]benzimidazoles through a one-pot multicomponent reaction of malononitrile, electron-deficient aryl aldehydes and heterocyclic enamines followed by a nitrous acid release under mild condition, is reported. Depending on the substituents on heterocyclic enamine, newly synthesized products have been obtained either as an inseparable mixture of regioisomers or as a single regioisomer. A plausible mechanism can be proposed for the formation of pyrido[1,2-a]benzimidazoles via this unfamiliar transformation with the HNO2 extrusion. The structures of all title compounds were elucidated using spectroscopic methods and physical characteristics involving single crystal X-ray diffraction and TOF-MS measurements. In addition, among all the products, CN- and CF3-substituted ones showed promising absorption and fluorescent properties.

Chemical behavior of 4,9‐dimethoxy‐5‐oxo‐5H‐furo[3,2‐g]chromene‐6‐carboxaldehyde towards carbon nucleophilic reagents

AbstractThe chemical behavior of 6‐formylkhellin (1) was investigated toward a variety of carbon nucleophiles. Treatment of aldehyde 1 with cyanoacetamide, N‐benzylcyanoacetamide produced pyridine‐3‐carboxamides 3 and 4. Treatment of carboxaldehyde 1 with malononitrile dimer and 1H‐benzimidazol‐2‐ylacetonitrile gave 1,6‐naphthyridine 5 and pyrido[1,2‐a]benzimidazole 6, respectively. Some novel pyrazolo[3,4‐b]pyridine 7, pyrido[2,3‐d]pyrimidines 8 and 9 were synthesized from the ring opening ring closure reactions of carboxaldehyde 1 with certain heterocyclic enamines. In addition, reaction of carboxaldehyde 1 with certain cyclic enols produced a variety of products. Treatment of carboxaldehyde 1 with 1,3‐cyclohexanediones gave xanthene‐1,8‐diones 19 and 20. Reaction of carboxaldehyde 1 with 5‐methyl‐2,4‐dihydro‐3H‐pyrazol‐3‐one proceeds in 1:2 M ratio producing pyrazolo [4′,3′:5,6]pyrano[2,3‐c]pyrazole derivative 22. Carboxaldehyde 1 reacted with certain heterocyclic compounds containing active methylene groups to give the corresponding condensation products 22‐27. The synthesized compounds were screened in vitro for their antimicrobial activity and showed high to moderate activities against the tested microorganisms.

Synthesis of Thio and Selenoethers of Cyclic β-Hydroxy Carbonyls and Amino Uracils: A Metal-Free Regioselective I2 /DMSO Mediated Reaction

A simple and practical method has been developed using I2/DMSO for the construction of C−S and C−Se bonds in pharmaceutically important cyclic β-hydroxy carbonyls such as 4-hydroxy-6-methyl-2H-pyran-2-one, 4-hydroxy-1-methylquinolin-2(1H)-one, quinoline-2,4-diol and heterocyclic enamines such as amino uracil and amino pyrazole derivatives under mild reaction conditions. A series of thio and seleno ethers have been synthesized directly from thiols and selenols in the presence of in situ iodonium ion generated from the I2/DMSO combination in good to very good yields. This metal-free dehydrogenative C−S and C−Se coupling reaction goes via C(sp2)-H bond activation and works under conventional as well as microwave heating. Under microwave conditions, reactions complete within 15 minutes with very good yields.

Synthesis of [1,2-a]-fused tricyclic dihydroquinolines by palladium-catalyzed intramolecular C–N cross-coupling of polarized heterocyclic enamines

Synthesis of [1,2-a]-fused tricyclic dihydroquinolines by palladium-catalyzed intramolecular C–N cross-coupling of polarized heterocyclic enamines

ChemInform Abstract: Base‐Promoted Transannulation of Heterocyclic Enamines and 2,3‐Epoxypropan‐1‐ones: Regio‐ and Stereoselective Synthesis of Fused Pyridines and Pyrroles.

AbstractThe microwave‐assisted reaction of N‐aryl 4‐aminofuranones (VI) with epoxypropanones (II) leads to desired furo[3,2‐b]pyridines (VII).

Base-promoted transannulation of heterocyclic enamines and 2,3-epoxypropan-1-ones: regio- and stereoselective synthesis of fused pyridines and pyrroles.

Base-promoted transannulation of heterocyclic enamines and 2,3-epoxypropan-1-ones has been successfully achieved, providing a new access to structurally diverse fused pyridines and pyrroles with excellent regio- and stereoselectivity. Treatment with N-aryl 4-aminofuran-2(5H)-ones and 2,3-epoxypropan-1-ones under microwave heating resulted in functional furo[3,2-b]pyridines in good yields. The N-aryl 4-aminopyrrol-2(5H)-ones bearing an electron-withdrawing group engaged in the reaction afforded pyrrolo[3,2-b]pyridines, whereas their counterparts with an electron-neutral or an electron-donating group underwent a different reaction pathway to form pyrrolo[3,2-b]pyrroles through C-C bond cleavage.

Acylation of the enamino tautomer of 2-azaspiro[4.5]deca-1,6,9-trien-8-ones with 5-arylfuran-2,3-diones. Crystal and molecular structure of (2Z,5Z)-3-Hydroxy-5-(6,9-dimethoxy-3,3-dimethyl-8-oxo-2-azaspiro[4.5]deca-6,9-dien-1-ylidene)-1-phenylpent-2-ene-1,4-dione

5-Arylfuran-2,3-diones reacted with heterocyclic enamines of the 2-azaspiro[4.5]deca-1,6,9-trien-8-one series to give products of β-CH-acylation of the enamino fragment. The structure of (2Z,5Z)-3-hydroxy-5-(6,9-dimethoxy-3,3-dimethyl-8-oxo-2-azaspiro[4.5]deca-6,9-dien-1-ylidene)-1-phenylpent-2-ene-1,4-dione was proved by X ray analysis.

Reactions of Methyl Acetylenecarboxylate with Heterocyclic Enamines: [2+2] Cycloadditions in Polar and Non-Polar Solvents

Reactions of Methyl Acetylenecarboxylate with Heterocyclic Enamines: [2+2] Cycloadditions in Polar and Non-Polar Solvents

Five-membered 2,3-dioxoheterocycles: XCIV. Recyclization of 4,5-diaroyl-1H-pyrrole-2,3-diones under the action of 3-aminopyrazolo[3,4-b]pyridine. Crystal and molecular structure of substituted pyrido[2′,3′:3,4]pyrazolo[1,5-a]pyrimidine

Aryl-4,5-diaroyl-1Н-pyrrole-2,3-diones react with 3-amino-4,6-dimethyl-2Н-pyrazolo(3,4-b)- pyridine affording N-aryl-2,3-diaroyl-8,10-dimethylpyrido (2',3':3,4)pyrazolo(1,5-a)pyrimidine-4-carboxamides. DOI: 10.1134/S1070428013080186 In reactions of 4,5-diaroyl-1Н-pyrrole-2,3-diones with nucleophiles several reaction pathways can be realized depending on the structure of the nucleophiles. Recycli- zations were described of 4,5-diaroyl-1Н-pyrrole-2,3- diones under the action of arylamines (2) and substituted hydrazines (3) involving the carbon atoms in the position 5 and the carbonyl group of the aroyl substituent in the position 4 of 1Н-pyrrole-2,3-diones, and also spiro- bisheterocyclization under the action of acyclic (1) and heterocyclic (4) enamines involving the carbon atoms in the position 5 and the carbonyl group of the aroyl substitu- ent in the position 5 of 1Н-pyrrole-2,3-dionesов. No pub- lished data exist on the reactions of these pyrrolediones with NH,NH-1,3-binucleophiles. At boiling a solution in anhydrous toluene of 1-aryl-4,5-diaroyl-1H-pyrrole-2,3-diones Iа-Ih (5) and 3-amino-4,6-dimethyl-2Н-pyrazolo(3,4-b)pyridine (II) (6) in a ratio 1:1 during 2-3 h (TLC monitoring) we obtained in good yields N-aryl-2,3-diaroyl-8,10- dimethylpyrido(2',3':3,4)-pyrazolo(1,5-a)pyrimidine-4- carboxamides IIIа-IIIh,** whose structure was proved

ChemInform Abstract: Enols as Feasible Acid Components in the Ugi Condensation.

AbstractA high‐yielding three‐component reaction of imines, heterocyclic enols, and isocyanides is described to give a variety of heterocyclic enamines.

Enols as Feasible Acid Components in the Ugi Condensation

Heterocyclic enols are used for the first time as acid components in an Ugi-type multicomponent condensation. For that purpose, we have chosen enols containing a Michael acceptor, in order to facilitate an irreversible rearrangement of the primary Ugi adduct. The new four-component process leads readily and efficiently to heterocyclic enamines containing at least six elements of diversity.