An efficient synthesis of embelin derivatives through domino Knoevenagel hetero Diels-Alder reactions under microwave irradiation

The synthesis of novel pyrano embelin derivatives has been achieved through domino Knoevenagel hetero Diels-Alder reactions of embelin (1) with paraformaldehyde and electron rich alkenes. This synthetic approach is highly efficient when microwave irradiation is used.     

An efficient synthesis of thiopyrano[5,6-c]coumarin/[6,5-c]chromones through intramolecular domino Knoevenagel hetero Diels-Alder reactions

The synthesis of novel polycyclic thiopyrano coumarin/chromone frameworks through intramolecular domino Knoevenagel hetero Diels-Alder reactions of 4-hydroxy coumarin and its benzo-analogous with S-prenylated aromatic aldehydes was studied. A high degree of chemoselectivity was achieved by the application of microwave irradiation and a solid support.     

Microwave-assisted organocatalytic multicomponent Knoevenagel/hetero Diels-Alder reaction for the synthesis of 2,3-dihydropyran[2,3-c]pyrazoles

A rapid protocol for the multicomponent microwave-assisted organocatalytic domino Knoevenagel/hetero Diels-Alder reaction (DKHDA) has been developed for the synthesis of 2,3-dihydropyran[2,3-c]pyrazoles. The reported procedure could be used for the fast generation of novel substituted 2,3-dihydropyran[2,3-c]pyrazoles with potential anti-tuberculosis activity.     

Zirconium oxide (NP) - ionic liquid as an efficient media for the domino Knoevenagel hetero Diels-Alder reaction with unactivated alkynes

Immobilized ZrO₂-nanopowder (NP) in ionic liquid and different organic solvents was used as a suitable Lewis-acid for the synthesis of polycyclic heterocycles which contains pyran-based skeletons. Reaction of O-propargylated salicylaldehyde with active methylene compounds in the presence of ZrO₂-NP in ionic liquid proceeds via domino Knoevenagel hetero Diels-Alder reaction of unactivated alkynes to construct the pyran skeleton. Comparison with different ionic liquids and organic solvents showed that the best results were obtained with 1-butyl-3-methylimidazolium nitrate [bmim][NO₃] because of short reaction times and high yields. Carrying out the reaction under these conditions has advantages such as: high yields, short reaction times and easy work-up.     

A facile stereoselective synthesis of julolidine hybrid analogs via domino knoevenagel intramolecular hetero Diels–Alder reaction

We have reported here a facile stereoselective synthesis of julolidine hybrid analogs by employing domino Knoevenagel intramolecular hetero Diels–Alder reaction on symmetrical 1,3-diones and unsymmetrical 1,3-diones It was found that the cycloaddition proceeded efficiently under microwave irradiation to afford highly stereoselective cycloadducts in good yields     

Total Synthesis of (+/-)-Leporin A

An efficient synthesis of (+/-)-leporin A (1) has been developed using a tandem Knoevenagel condensation-inverse electron demand intramolecular hetero Diels-Alder reaction to construct the key tricyclic intermediate 3 from pyridone 5 and dienal 6 in one pot in 35% yield. Hydroxylation (71%) of 3 and methylation (77%) of the resulting hydroxypyridone 2 completed the first total synthesis of (+/-)-leporin A (1).     

New types of reactivity of α,β-unsaturated N,N-dimethylhydrazones: chemodivergent diastereoselective synthesis of functionalized tetrahydroquinolines and hexahydropyrrolo[3,2-b]indoles

The indium trichloride-catalyzed reaction between aromatic imines and α,β-unsaturated N,N-dimethylhydrazones in acetonitrile afforded 1,2,3,4-tetrahydroquinolines bearing a hydrazone function at C4 through a one-pot diastereoselective domino process that involves the formation of two C-C bonds and the controlled generation of two stereocenters, one of which is quaternary. This reaction constitutes the first example of an α,β-unsaturated dimethylhydrazone that behaves as a dienophile in a hetero Diels-Alder reaction. The related reaction between anilines, aromatic aldehydes, and methacrolein dimethylhydrazone in CHCl(3) with BF(3)?Et(2)O as catalyst afforded polysubstituted 1,2,3,3a,4,8b-hexahydropyrrolo[3,2-b]indoles as major products through a fully diastereoselective ABB'C four-component domino process that generates two cycles, three stereocenters, two C-C bonds, and two C-N bonds in a single operation.     

Mechanisms of the Knoevenagel hetero Diels-Alder sequence in multicomponent reactions to dihydropyrans: experimental and theoretical investigations into the role of water

The role of water in a multicomponent domino reaction (MCR) involving styrene, 2,4-pentanedione, and formaldehyde was studied. Whereas anhydrous conditions produced no reaction, the MCR successfully proceeded in the presence of water, affording the targeted dihydropyran derivatives with good yield. The mechanism of this MCR (Knoevenagel hetero Diels-Alder sequence) was studied with and without explicit water molecules using the SMD continuum solvation model in combination with the B3LYP density functional and the 6-311++G** basis set to compute the water and acetone (aprotic organic solvent) solution Gibbs free energies. In the Knoevenagel step, we found that water acted as a proton relay to favor the formation of more flexible six-membered ring transition state structures both in concerted (direct H(2)O elimination) and stepwise (keto-enol tautomerization and dehydration) pathways. The inclusion of a water molecule in our model resulted in a significant decrease (-8.5 kcal mol(-1)ΔG(water)(?)) of the direct water elimination activation barrier. Owing to the presence of water, all chemical steps involved in the MCR mechanism had activation free energies barriers lower than 39 kcal mol(-1) at 25 °C in aqueous solvent (<21 kcal mol(-1) ZPE corrected electronic energies barriers). Consequently, the MCR proceeded without the assistance of any catalyst.     

Efficient one-pot synthesis of benzopyranobenzopyrans and naphthopyranobenzopyrans by domino aldol-type reaction/hetero Diels-Alder reaction of resorcinols and naphthols

The efficient one-pot synthetic approaches for benzopyranobenzopyrans and naphthopyranobenzopyrans are described. The key strategies involve ethylenediamine diacetate-catalyzed cyclization by domino aldol-type reaction/hetero Diels-Alder reaction of resorcinols and naphthols to benzaldehydes with O-allyl ether groups. These reactions provide a rapid route for the synthesis of novel types of polyheterocycles with stereochemically defined quaternary carbon centers.     

Oxidative dimerization of (E)- and (Z)-2-propenylsesamol with O2 in the presence and absence of laccases and other catalysts: selective formation of carpanones and benzopyrans under different reaction conditions

The oxidative dimerization of 2-propenylsesamol to carpanone with O(2) as the oxidant, which probably proceeds as a domino phenol oxidation/anti-β,β-radical coupling/intramolecular hetero Diels-Alder reaction, can be efficiently catalyzed by laccases. Experiments with laccases and other catalysts like a Co(salen) type catalyst and PdCl(2) clearly demonstrate that the diastereoselectivity of the carpanone formation does not depend on the catalyst but on the double-bond geometry of the substrate. With (E)-2-propenylsesamol as the substrate, carpanone and a so far unknown carpanone diastereoisomer are formed in a 9:1 ratio. When (Z)-2-propenylsesamol is used as starting material, carpanone is accompanied by two carpanone diastereoisomers unknown so far in a 5:1:4 ratio. All three carpanone diastereoisomers have been separated by HPLC, and their structures have been elucidated unambiguously by NMR spectroscopy, DFT calculations, and spin work analysis. When the oxidation of 2-propenylsesamol with O(2) is performed in the absence of any catalyst two diastereoisomeric benzopyrans are formed, probably as the result of a domino oxidation/intermolecular hetero Diels-Alder reaction. Under these conditions, carpanone is formed in trace amounts only.     

Highly stereo and chemoselective synthesis of tetra and pentacyclic frameworks using Solid-State Melt Reaction (SSMR)

Benzopyran fused tetra and pentacyclic frameworks have been synthesized by the domino Knoevenagel hetero Diels–Alder (DKHDA) reaction using various 1,3-diones with O-allylated salicylaldehydes and O-propargylated salicylaldehydes in a solvent and catalyst free condition via Solid-State Melt Reaction (SSMR). The reaction requires only a single step operation thus providing potentially bioactive polycyclic heterocycles in high yields.     

Multicomponent synthesis of 6H-dibenzo[b,d]pyran-6-ones and a total synthesis of cannabinol

A multicomponent domino reaction that affords 6H-dibenzo[b,d]pyran-6-ones is reported. The overall transformation consists of six reactions: Knoevenagel condensation, transesterification, enamine formation, an inverse electron demand Diels-Alder (IEDDA) reaction, 1,2-elimination, and transfer hydrogenation. Both the diene and dienophile for the key inverse electron demand Diels-Alder (IEDDA) step are generated in situ by secondary amine-mediated processes. In most cases, the yields (10-79%) are considerably better than those obtained using a stepwise process. This methodology is employed in a concise total synthesis of cannabinol.     

Chiral hetero Diels-Alder products by enantioselective and diastereoselective zirconium catalysis. Scope,limitation, mechanism,and application to the concise synthesis of (+)-Prelactone C and (+)-9-deoxygoniopypyrone

Catalytic asymmetric hetero Diels-Alder (HDA) reactions using a chiral zirconium complex have been developed. The reactions of aldehydes with Danishefsky's dienes proceeded smoothly to afford the corresponding pyranone derivatives in high yields with high diastereo- and enantioselectivities in the presence of a chiral zirconium complex, which was prepared from zirconium tert-butoxide, (R)-3,3'-diiodobinaphthol or its derivative, a primary alcohol, and a small amount of water. It is noted that 2,3-trans-pyranone derivatives were obtained with remarkably high diastereo- and enantioselectivities in the reaction with 4-methyl Danishefsky's diene. This is the first example of catalytic asymmetric trans-selective hetero Diels-Alder reactions of aldehydes. Furthermore, asymmetric HDA reactions with 4-benzyloxy Danishefsky's dienes were conducted to afford 2,3-cis-pyranone derivatives in high selectivities. Isolation of an intermediate of this asymmetric hetero Diels-Alder reaction indicated that the reaction proceeded in a stepwise cycloaddition pathway. Finally, these catalytic, asymmetric hetero Diels-Alder reactions were successfully applied to concise syntheses of biologically important natural pyranone derivatives, (+)-Prelactone C and (+)-9-deoxygoniopypyrone.     

An expedient microwave-assisted, solvent-free, solid-supported synthesis of pyrrolo[2,3-d]pyrimidine-pyrano[5,6-c]coumarin/[6,5-c]chromone derivatives by intramolecular hetero Diels-Alder reaction

A rapid synthesis of pyrrolo[2,3-d]pyrimidine annulated pyrano[5,6-c]coumarin/[6,5-c]chromone derivatives has been accomplished in good yields via an intramolecular domino hetero Diels-Alder reaction using microwave irradiation under solvent-free, solid-supported conditions.     

2-(N-Allylaminomethyl)cinnamaldehydes as substrates for syntheses of aza-polycycles via intramolecular cycloaddition reactions

Syntheses of a variety of aza-polycycles employing 2-(N-allylaminomethyl)cinnamaldehydes derived from Morita–Baylis–Hillman adducts of acrylates via intramolecular 1,3-dipolar cycloaddition, or Aza-Diels–Alder or domino Knoevenagel/hetero Diels–Alder cycloaddition reactions are described. Whereas the Aza-Diels–Alder afforded a mixture of cis- and trans-isomers of substituted 1,2,3,4,4a,5,10,10a-octahydrobenzo[b][1,6]naphthyridines, the 1,3-dipolar cycloaddition and domino Knoevenagel/hetero Diels–Alder were diastereoselective to produce exclusively cis-derivatives of 1,2,3,4,4a,6,7,8,9,9a-decahydro-1H-pyrido[3,4-b]pyrrolizine-8a-carboxylates and 3,4,4a,5,7,8,9,10b-octahydro-1H-chromeno[3,4-c]pyridin-10(2H)-ones, respectively.     

Ethylenediamine diacetate (EDDA)-catalyzed one-pot synthesis of tetrahydroquinolines by domino Knoevenagel/hetero Diels–Alder reactions from 1,3-dicarbonyls

This paper describes new and efficient synthetic approaches for biologically interesting tetrahydroquinoline analogues. The key strategies involve the ethylenediamine diacetate-catalyzed cyclization of 1,3-dicarbonyls to aminobenzaldehydes through domino Knoevenagel/hetero Diels–Alder reactions. These reactions provide a rapid route for the synthesis of novel polycycles with the tetrahydroquinoline moiety.     

Efficient synthesis of polycycles bearing prenylated, geranylated, and farnesylated citrans: application to 3′-prenylrubranine and petiolin D regioisomer

Efficient synthetic routes for biologically interesting polycycles with prenylated, geranylated, and farnesylated citrans were developed from several trihydroxybenzenes with prenyl, geranyl, and farnesyl groups on the benzene rings. Ethylenediamine diacetate-catalyzed cyclization by a domino aldol-type/electrocyclization/H-shift/hetero Diels-Alder reaction of prenylated, geranylated, and farnesylated trihydroxybenzenes with citral or trans,trans-farnesal provided a variety of tetracycles bearing prenylated, geranylated, and farnesylated citrans. The mechanistic pathway for regio- and stereochemistry of synthesized polycycles was described. As an application of this methodology, 3′-prenylrubranine and petiolin D regioisomer were first synthesized.     

Domino Knoevenagel/Diels-Alder sequence coupled to Suzuki reaction: a valuable synthetic platform for chemical biology

A small library of peculiar biphenyl and terphenyl-containing spirocyclic triones has been synthesized in parallel by combining the organocatalytic three-component domino Knoevenagel/Diels-Alder sequence to Suzuki coupling. This methodology is fast, general and serves as a platform to gain access to novel chemical tools to probe protein-protein interactions.     

Synthesis and domino reactions of polymethylene-3-cyanopyridine-2(1Н)-thiones

A new and facile three-component method was developed for the synthesis of polymethylene-3-cyanopyridine-2(1Н)-thiones by the domino Knoevenagel → Michael → heterocyclization → dehydrogenation reaction from cycloalkanones, cyanothioacetamide, and polymethoxy-substituted benzaldehydes. The final dehydrogenation step was found to involve arylidenecyanothioacetamide. The resulting pyridinethiones and 4-chloroacetoacetic ester were introduced into the domino S_N2 → Thorpe-Ziegler → Guareschi-Thorpe reaction to synthesize tetracyclic dipyridothiophenes. Starting from these compounds, 8,9-polymethylenepyranothienodipyridines were also synthesized by the domino Knoevenagel → Michael → hetero-Thorpe-Ziegler reaction. Furthermore, a method for the synthesis of thienodipyridine annulated to the steroid skeleton is proposed.     

A very efficient synthesis of 1,8-diazaanthraquinones

The reaction between 1-dimethylamino-1-azadienes and 2,6-dibromobenzoquinone gave excellent yields of the corresponding double hetero Diels-Alder cycloadducts. 3-Substituted azadienes directly gave aromatic 1,8-diazaanthraquinone derivatives, while 4-substituted azadienes led to 1,8-dimethylamino-1,4,5,8-tetrahydro-1,8-diazaanthraquinones, which were aromatized under thermal conditions.