Rapid Assembly of Functionalized 2H-Chromenes and 1,2-Dihydroquinolines via Microwave-Assisted Secondary Amine-Catalyzed Cascade Annulation of 2-O/N-Propargylarylaldehydes with 2,6-Dialkylphenols.

An efficient, secondary amine-catalyzed cascade annulation of 2-O/N-propargylarylaldehydes with 2,6-dialkylphenols was established to access biologically relevant functionalized 2H-chromenes and 1,2-dihydroquinolines tethered with a synthetically useful p-quinone methide scaffold in high yields under microwave irradiation and conventional heating conditions. The microwave-assisted strategy was convenient, clean, rapid, and high yielding in which the reactions were completed in just 15 min, and the yields obtained were up to 95%. This highly atom-economical domino process constructed two new C-C double bonds and a six-membered O/N-heterocyclic ring in a single synthetic operation. Its mechanism process was rationalized as involving sequential iminium ion formation, nucleophilic addition, and intramolecular annulation steps. Furthermore, the synthesized 2H-chromene derivatives were transformed into valuable indeno[2,1-c]chromenes, 5H-indeno[2,1-c]quinolines, and oxireno[2,3-c]chromene via a palladium-catalyzed double C-H bond activation process and epoxidation, respectively.

Diversity-Oriented Synthesis of Benzo[f][1,4]oxazepine-, 2H-Chromene-, and 1,2-Dihydroquinoline-Fused Polycyclic Nitrogen Heterocycles under Microwave-Assisted Conditions.

An efficient, diversity-oriented synthesis of oxazepino[5,4-b]quinazolin-9-ones, 6H-chromeno[4,3-b]quinolines, and dibenzo[b,h][1,6]naphthyridines was established involving a substrate-based approach under microwave-assisted and conventional heating conditions in high yields (up to 88%). The CuBr2-catalyzed, chemoselective cascade annulation of O-propargylated 2-hydroxybenzaldehydes and 2-aminobenzamides delivered oxazepino[5,4-b]quinazolin-9-ones involving a 6-exo-trig cyclization-air oxidation-1,3-proton shift-7-exo-dig cyclization sequence. This one-pot process showed excellent atom economy (-H2O) and constructed two new heterocyclic rings (six- and seven-membered) and three new C-N bonds in a single synthetic operation. On the other side of diversification, the reaction between O/N-propargylated 2-hydroxy/aminobenzaldehydes and 2-aminobenzyl alcohols delivered 6H-chromeno[4,3-b]quinolines and dibenzo[b,h][1,6]naphthyridines involving sequential imine formation-[4 + 2] hetero-Diels-Alder reaction-aromatization steps. The influence of microwave assistance was superior to conventional heating, where the reactions were clean, rapid, and completed in 15 min, and the conventional heating required a longer reaction time at a relatively elevated temperature.

A microwave-assisted intramolecular aminopalladation-triggered domino sequence: an atom economical route to 5,10-dihydroindeno[1,2-b]indoles.

A microwave-assisted, palladium(II)-catalyzed cascade reaction of 2-alkynylanilines tethered with an α,ß-unsaturated carbonyl moiety was established to access 5,10-dihydroindeno[1,2-b]indoles in high yields (up to 84%) in a short reaction time. This operationally simple cascade process shows 100% atom economy and allows the construction of two new five-membered rings and two new (1 C-C and 1 C-N) bonds in a single synthetic attempt. The mechanistic pathway of this reaction is visualized involving intramolecular aminopalladation (5-endo-dig) followed by carbopalladation (olefin insertion) and protonolysis steps. A systematic comparison between microwave irradiation and conventional heating methods was also performed to demonstrate the supremacy of the microwave-assisted approach. This domino reaction requires no protecting groups for the amino group and the palladium catalyst needs no ligands. To the best of our knowledge, this is the first report on microwave-assisted nucleopalladation-initiated cascade transformation.

Microwave-Assisted Copper(II)-Catalyzed Cascade Cyclization of 2-Propargylamino/Oxy-Arylaldehydes and O-Phenylenediamines: Access to Densely Functionalized Benzo[f]Imidazo[1,2-d][1,4]Oxazepines and Benzo[f]Imidazo[1,2-d][1,4]Diazepines.

A highly efficient microwave-assisted copper(II)-catalyzed cyclization cascade was established starting from readily accessible O/N-propargylated 2-hydroxy or 2-aminobenzaldehydes and o-phenylenediamines to synthesize densely functionalized imidazo[1,2-d][1,4]oxazepines and imidazo[1,2-d][1,4]diazepines in high yields (up to 93%). This one-pot two-step process was found to be highly atom economical (-H2O, -H2) and operationally simple and enabled the generation of two new heterocycle rings (seven- and five-membered) and three new C-N bonds in a single synthetic operation. These reactions well tolerated a variety of substituents including electron-donating and electron-withdrawing groups and furnished the desired fused heterocycles in high yields under microwave irradiation in a very short reaction time. The mechanism of the established protocol involves sequential imine formation-intramolecular cyclization-air oxidation followed by 7-exo-dig cyclization steps. A comparative study between the microwave-assisted approach and conventional heating was also performed to demonstrate the advantages of the microwave-assisted protocol in terms of high yield and shorter reaction time.

Microwave-assisted one-pot two-step imine formation-hetero-Diels-Alder-detosylation/aromatization sequence: direct access to dibenzo[b,h][1,6]naphthyridines.

A microwave-assisted, copper-catalyzed, one-pot, two-step reaction is established to access functionalized [1,6]naphthyridines in high yields (up to 96%) starting from 2-(N-propargylamino)benzaldehydes and arylamines. This rapid and operationally simple sequential reaction allowed the construction of two new heterocyclic rings and three new (2 C-C and 1 C-N) bonds in a single synthetic operation. This reaction tolerated various electron-donating and electron-withdrawing substituents well and delivered the desired products in a shorter reaction time under microwave irradiation. This reaction proceeds through a sequential imine formation, intramolecular [4 + 2] hetero-Diels-Alder reaction, and air oxidation, followed by detosylation-aromatization steps.

Direct Access to Bridged Tetrahydroquinolines and Chromanes via an InCl3-Catalyzed Sequential Three-Component Cascade.

A sequential three-component cascade process was developed for the synthesis of bridged tetrahydroquinolines and chromanes bearing 2,6-methanobenzo[d][1,3]diazocine and 2,6-methanobenzo[g][1,3]oxazocine scaffolds, respectively, in good yields from readily available materials. The InCl3-catalyzed reaction progressed via enamine formation, Michael addition, intramolecular cyclization, and intramolecular iminium ion cyclization steps. Notably, this high atom economic approach (-2H2O) allowed the generation of four new bonds (1 C-C and 3 C-N or 1 C-C, 1 C-O and 2 C-N) and two heterocyclic rings in a single operation.

Regioselective synthesis of tetrahydroquinolines via syn- and anti-nucleopalladation-initiated cascade processes.

Palladium(ii)-catalyzed regioselective syn-chloropalladation and anti-acetoxypalladation-initiated cascade processes were developed for the synthesis of functionalized tetrahydroquinolines. A series of N-propargyl arylamines tethered with an α,ß-unsaturated carbonyl scaffold underwent atom economical cascade reactions to deliver chloro- and acetoxy-substituted tetrahydroquinolines bearing an exocyclic double bond in high yields. A mechanism is proposed for these cascade processes involving a sequential syn-chloropalladation or anti-acetoxypalladation of alkynes followed by intramolecular olefin insertion (6-exo-trig) and protonolysis steps. The reaction was completely regioselective and the terminal aryl/alkyl group of the propargyl moiety dictated the regiochemistry of the initial nucleopalladation. The role of the bidentate nitrogen ligand is crucial to trigger the acetoxypalladation-initiated cascade sequence in contrast to the chloropalladation-initiated process.

Diastereoselective ABB' Three-Component Synthesis of Highly Functionalized Spirooxindoles Bearing Five Consecutive Asymmetric Carbons.

The synthesis of spirooxindoles bearing tetrahydro-4 H-cyclopenta[ b]furan framework was established starting from isatin-derived aldehydes and 2 equiv of 1,3-dicarbonyl compounds involving a piperidine-catalyzed ABB' three-component domino process. This reaction was highly diastereoselective affording a single diastereomer of spirooxindoles with five consecutive asymmetric carbons including spiro and tetrasubstituted carbon centers. In addition, this waste-free (-2H2O) reaction showed high atom economy and step economy by creating four new bonds, including three C-C bonds and one C-O bond, and two rings (one carbo- and one heterocyclic) in a single operation. The mechanism of this three-component domino process involved sequential Knoevenagel condensation-Michael addition-intramolecular oxa-Michael addition-intramolecular aldol reactions.

Heterogeneous Amberlyst-15-catalyzed synthesis of complex hybrid heterocycles containing [1,6]-naphthyridine under metal-free green conditions.

An efficient green protocol for the synthesis of complex hybrid heterocycles containing [1,6]-naphthyridine and coumarin/pyrazole moieties was established, involving an intramolecular [4 + 2] hetero Diels-Alder reaction as the key step. The biologically significant 12,13-dihydro-6H-benzo[h]chromeno[3,4-b][1,6]naphthyridin-6-ones and 6,10-dihydro-5H-benzo[h]pyrazolo[3,4-b][1,6]naphthyridines were synthesized starting from 2-(N-propargylamino)-arylaldehydes and 3-aminocoumarins or 3-methyl-1-aryl-1H-pyrazol-5-amines in the presence of an Amberlyst-15 catalyst in PEG-200 in good yields. The easy access to diverse complex molecules in a single operation from readily available starting materials, a commercially available, transition metal-free and recyclable catalyst, the use of a green solvent, a very high atom economy and the release of water as the only side product are the highlights of this protocol.

Synthesis of 6,12-Epiminodibenzo[b,f][1,5]diazocines via an Ytterbium Triflate-Catalyzed, AB2 Three-Component Reaction.

An efficient and selective procedure for the synthesis of epiminodibenzo[b,f][1,5]diazocines involving a AB2 three-component reaction is developed. Two equivalents of suitably substituted 2-aminoarylaldehydes reacted with arylamines in the presence of Yb(OTf)3 to afford the desired products in high yields. The reaction is highly atom-economic and waste-free, in addition to allowing the generation of two heterocyclic rings and four C-N bonds in a single operation. Significantly, this approach is complementary to the existing literature procedures, affording arylamine-derived products that could not be accessed previously. A plausible mechanism is proposed involving an imine formation-intermolecular annulation-intramolecular iminium ion cyclization sequence.

Palladium-catalyzed intramolecular oxypalladation-initiated cascade: solvent-dependent chemodivergent approach to functionalized benzazepines and tetrahydroquinolines.

Palladium-catalyzed, solvent-dependent intramolecular oxypalladation-triggered domino sequences of internal alkynes bearing tethered nucleophilic carboxylic ester and electrophilic enone functionalities were developed for the chemodivergent synthesis of two completely distinct biologically significant complex molecules including isochromenone-fused benzazepines and isobenzofuranone-fused tetrahydroquinolines/chromanes in a single synthetic operation.

Oxidant-free, three-component synthesis of 7-amino-6H-benzo[c]chromen-6-ones under green conditions.

An oxidant-free three-component synthesis of biologically significant 7-amino-6H-benzo[c]chromen-6-ones was established involving a Sc(OTf)3 catalyzed three-component reaction between primary amines, ß-ketoesters and 2-hydroxychalcones under green conditions. In this strategy, both the B and C rings of 6H-benzo[c]chromen-6-ones were constructed simultaneously starting from acyclic precursors by generating four new bonds including two C-C, one C-N and one C-O in a single synthetic operation. The mechanism of this sequential cascade process involves the initial formation of a ß-enaminone intermediate followed by Michael addition with 2-hydroxychalcone, intramolecular cyclization, dehydration, lactonization and aromatization steps. Unlike the related literature approaches, this reaction delivered the products without the addition of any external oxidants to achieve the key aromatization step.

Palladium-Catalyzed Regioselective Syn-Chloropalladation-Olefin Insertion-Oxidative Chlorination Cascade: Synthesis of Dichlorinated Tetrahydroquinolines.

A palladium catalyzed cascade process involving syn-chloropalladation, intramolecular olefin insertion, and oxidative C-Cl bond formation reactions was demonstrated for the synthesis of dichlorinated tetrahydroquinolines in high yields (up to 93%). The N-propargyl arylamines having a tethered α,ß-unsaturated carbonyl moiety underwent a regioselective syn-chloropalladation followed by a Heck-type reaction to deliver the tetrahydroquinoline scaffold. The rare insertion of the second chlorine atom was rationalized comprising a PdII/IV catalytic cycle and oxidative cleavage of the C-PdII bond.

Direct Access to 9-Chloro-1H-benzo[b]furo[3,4-e]azepin-1-ones via Palladium(II)-Catalyzed Intramolecular syn-Oxypalladation/Olefin Insertion/sp2-C-H Bond Activation Cascade.

An efficient Pd(II)-catalyzed cascade approach was established for the synthesis of 9-chloro-1H-benzo[b]furo[3,4-e]azepin-1-ones starting from N-propargyl arylamines having a pendant α,ß-unsaturated ester scaffold. The mechanism of this sequential process involved intramolecular syn-oxypalladation followed by olefin insertion and ortho sp2-C-Cl bond formation reactions. This high atom- and step-economical cascade sequence generated two heterocycle rings and three new bonds in a single synthetic operation.