aza-Diels Alder Cycloaddition Research Articles

Multicomponent synthesis and photophysical properties of meso-thienyl BODIPY-pyrrolo[3,4-b]pyridin-5-ones. An experimental and theoretical study

Seven new pyrrolo[3,4-b]pyridin-5-ones linked to a meso-thienyl BODIPY moiety by an ethynylbenzene π-conjugated system were synthesized in one-pot manner via an Ugi-Zhu reaction coupled to a cascade process [aza Diels-Alder cycloaddition/N-acylation/decarboxylation/dehydration]. The photophysical properties of the polyheterocyclic compounds were evaluated by UV–Vis and fluorescence spectroscopy in five solvents of different polarities. All synthesized products showed two distinct absorption/emission bands, corresponding to both fluorophores separately. The fluorescence intensity of the pyrrolo[3,4-b]pyridin-5-one was the highest in toluene, and it decreased with increasing solvent polarity. On the other hand, the fluorescence intensity of the meso-thienyl BODIPY fragment was insensitive to solvent polarity. The effect of different substituents bonded to the pyrrole ring was evaluated, finding that strong electron-donating groups influence the fluorescence intensity and decay rate of the compounds, even with the presence of a methylene spacer. Moreover, the electronic structure was assessed by DFT and TD-DFT calculations, which reproduced the experimental results reasonably well, showing that the HOMO is located on the pyrrolo[3,4-b]pyridin-5-one core, while the LUMO is on the BODIPY fragment.

I2/DMSO-Promoted Synthesis of Chromeno[4,3-b]quinolines through an Imine Formation/Aza-Diels–Alder/Aromatization Tandem Reaction under Metal-Catalyst- and Photosensitizer-Free Conditions

AbstractA tandem approach was developed for the efficient synthesis of substituted chromeno[4,3-b]quinolines from arylamines and O-cinnamyl salicylaldehydes under metal-catalyst- and photosensitizer-free reaction conditions. Our protocol is based on an inexpensive I2/DMSO system in which molecular iodine first acts as a Lewis acid to promote the formation of the corresponding imine bearing the alkene moiety; then, this species fulfills a second role by catalyzing an intramolecular aza-Diels–Alder cycloaddition to generate the respective tetrahydrochromenoquinoline as an intermediate. Finally, the dual behavior of DMSO as an oxidant and as a solvent proved crucial at this stage, allowing the regeneration of I2 and promoting the aromatization of the tetrahydrochromenoquinoline intermediates to yield the desired 7-aryl-6H-chromeno[4,3-b]quinolines. This protocol is mild and easy to perform, features high step-economy (tandem process) and provides a new access to biologically important nitrogen- and oxygen-containing heterocyclic molecules.

Periselectivity in the aza-Diels–Alder Cycloaddition between α-Oxoketenes and N-(5-Pyrazolyl)imines: A Combined Experimental and Theoretical Study

The thermal 6π aza-Diels-Alder cycloadditions between α-oxoketenes, in situ derived from a thermally induced Wolff rearrangement of 2-diazo-1,3-diketones, and N-(5-pyrazolyl)imines as prototypical electron-rich 2-azadienes lead to two distinct sets of products, essentially as a function of the nature of the α-oxoketenes involved. For instance, cyclic five-membered α-oxoketenes lead preferentially to spiro hydropyridin-4-ones, which involves the α-oxoketenes as the 2π partners at their C═C double bond and the N-(5-pyrazolyl)imines as the 4π partners at their 2-azadiene moiety. In contrast, other cyclic and acyclic α-oxoketenes lead preferentially to 1,3-oxazin-4-ones, which now involves the α-oxoketenes as the 4π partners at their 1-oxadiene moiety and the N-(5-pyrazolyl)imines as the 2π partners at their C═N double bond. A computational modeling study using DFT methods allowed rationalizing this change of periselectivity: the formation of spiro hydropyridin-4-ones is under thermodynamic control while the formation of 1,3-oxazin-4-ones is kinetically controlled, and slightly thermodynamically disfavored in the five-membered ring series. The competing cyclodimerization of the α-oxoketenes is also studied in detail.

Synthesis of Pyrrolo[2,3-c]isoquinolines via the Cycloaddition of Benzyne with Arylideneaminopyrroles: Photophysical and Crystallographic Study.

An efficient and quick access toward a series of (E)-2-arylideneaminopyrroles 6 and to their benzyne-promoted aza-Diels–Alder cycloaddition products is provided. These products are three pyrrolo[2,3-c]isoquinolines 8a–c substituted in position 5 with different electron-acceptor (A) or electron-donor (D) aryl groups. Intermediates and products were obtained in good yields (up to 78 and 84%, respectively), and their structures were determined on the basis of NMR measurements and HRMS analysis. Photophysical properties of 8a–c were investigated, finding good Stokes shift in different solvents, but only the product 8c showed appreciable fluorescence intensity since its 5-aryl group (2,4-Cl2Ph) could favor the twisted intramolecular charge transfer effect. In addition, a riveting relationship between solvent viscosity and fluorescence intensity was found. Structures of 6 and 8 were studied and confirmed by single-crystal X-ray diffraction, observing that their electronic distributions effect the supramolecular assembly but with only long-distance hydrophobic interactions. A CE-B3LYP model was used to study the energetic topology and understand the crystal architecture of compounds as well as find a connection with both the synthetic and photophysical results.

Organo-catalytic [4+2] Aza Diels Alder Cycloaddition Reaction in an Environmentally Benign Solvent System

Green chemistry brings an attention on a research work emerging from scientific innovations regarding toxic waste acquaintance and it make the use of principles that reduces the use or generation of hazardous materials in an intermediate as well as final steps of Organic synthesis or Chemical progression. Researchers can significantly diminish the hazard to human health as well as environment by following all the valuable philosophy of green chemistry. The most simple way in application of green chemistry in pharmaceuticals is to use efficient, reproducible, eco-friendly, non-hazardous green solvents and green catalysts in synthesis of Organic Moiety, drug intermediates and in researches concerning synthetic chemistry. Organic catalyst brings an exceptional advantage considering the principles of “green chemistry” in Environment as well as economic point of view. Solvents states major serving of the environmental concert of a process and also impact safety and health issues. Water has been found to be very efficient green Solvent and thus can replace many poisonous and harmful solvents. Cycloaddition reactions are fundamental and substantial part of organic chemistry in research. Research work on the aza Diels alder cycloaddition reactions in aqueous systems would be green pathway for organic processes and will definitely protect health as well as environment from toxic materials.

One-pot and catalyst-free synthesis of pyrroloquinolinediones and quinolinedicarboxylates

A method for the catalyst-free synthesis of pyrroloquinolinediones and quinolinedicarboxylates is developed through a one-pot synthesis involving denitrogenation of azide, benzisoxazole formation, aza-Diels–Alder cycloaddition, and dehydrative aromatization.

ChemInform Abstract: Indium(III) Chloride/Silica Gel Catalyzed Synthesis of Pyrazolo[3,4‐b]pyrrolo[3,4‐d]pyridines.

Abstract A facile synthesis of pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine was developed through an Aza-Diels–Alder reaction of pyrazoylimines with maleimides in the presence of 20% wt InCl3/silica gel in the sealed tube. Based on the metal catalyst scanning study, silica gel impregnated with indium trichloride was found to be the suitable catalyst to improve the Aza-Diels–Alder cycloaddition. In comparison with Bronsted–Lowery acetic acid condition, the Lewis acidic metal catalyst is more efficient for the Aza-Diels–Alder reaction.

Indium(III) chloride/silica gel catalyzed synthesis of pyrazolo[3,4-b]pyrrolo[3,4-d]pyridines

A facile synthesis of pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine was developed through an Aza-Diels–Alder reaction of pyrazoylimines with maleimides in the presence of 20% wt InCl3/silica gel in the sealed tube. Based on the metal catalyst scanning study, silica gel impregnated with indium trichloride was found to be the suitable catalyst to improve the Aza-Diels–Alder cycloaddition. In comparison with Brønsted–Lowery acetic acid condition, the Lewis acidic metal catalyst is more efficient for the Aza-Diels–Alder reaction.

Synthesis of cyclic analogues of hexamethylenebis(3-pyridine)amide (HMBPA) in a one-pot process

A series of cyclic analogues of hexamethylenebis(3-pyridine)amide was prepared based upon a Ugi-3CR and aza-Diels–Alder reaction as a post-functionalization in a one-pot process. A simple condensation of commercially available diamine and aldehydes followed by isonitrile α-addition provides the oxazole intermediates, finally an aza-Diels–Alder cycloaddition and ring-opening using maleic anhydride provides the desired compounds in modest overall yields in approximately 40min using microwaves as the heat source and scandium(III) triflate as a catalyst.

Development of a mild and versatile directed cycloaddition approach to pyridines.

The aza-Diels–Alder cycloaddition of 1,2,4-triazines with alkynes offers a rapid and convenient method for the synthesis of highly substituted pyridines, but often requires harsh conditions and long reaction times. The present study offers a solution to these limitations by use of a temporary tether established by a Lewis acid–base complexation of in situ generated alkynylboranes and triazines bearing a Lewis basic donor. The cycloaddition reactions take place within 20 min at 40 °C and provide direct access to a broad range of pyridines with complete and predictable regiocontrol. The carbon—boron bond can be further functionalised by cross-coupling allowing further functionality to be introduced after cycloaddition.

One-Pot Synthesis of Nuevamine Aza-Analogues by Combined Use of an Oxidative Ugi Type Reaction and Aza-Diels–Alder Cycloaddition

A rapid and efficient one-pot synthesis of a series of four novel nuevamine aza-analogues is described based on the oxidative Ugi-type reaction and aza-Diels–Alder reaction as post-functionalization. A simple IBX-mediated oxidation of a secondary amine followed by isonitrile α-addition and finally an aza-Diels–Alder cycloaddition provides the desired compounds in excellent overall yields considering the short reaction time, atom economy, and the molecular complexity of the final products. This protocol presents a highly attractive procedure for the rapid generation of fused polyheterocycles.

An efficient synthesis of 2,3-diaryl-2-azabicyclo[2.2.2]octan-5-ones and their acetylcholinesterase inhibitory activity

Abstract A series of substituted 2,3-diaryl-2-azabicyclo[2.2.2]octan-5-ones have been prepared by an efficient three-component aza-Diels–Alder cycloaddition reaction in water catalyzed by layered α -zirconium hydrogen phosphate ( α -ZrP) and sodium calix[4]arene sulfonates bearing pendant short aliphatic chains. The 18 synthesized compounds were assayed for acetylcholinesterase inhibition using mouse acetylcholinesterase.

Synthesis of Nuevamine Aza-Analogues by a Sequence: I-MCR–Aza-Diels–Alder–Pictet–Spengler

A series of nuevamine aza-analogues were prepared in moderate to good yields in two reaction steps. The synthetic strategy involves an isonitrile-based multicomponent reaction, including an aza-Diels–Alder cycloaddition and Pictet–Spengler reaction as postcondensation.

Domino routes to substituted benzoindolizines: tandem reorganization of 1,3-dipolar cycloadducts of nitrones with allenic esters/ketones and alternative cycloaddition–palladium catalyzed cyclization pathway

Reactions of C-(4-oxo-4 H[1]benzopyran-3-yl)- N-phenyl nitrones ( 7) with allenic esters ( 8a– c) and allenic ketones ( 18a– d) furnish benzoindolizines ( 9a– k, 19a– d) in good yields. The formation of benzoindolizines is postulated to involve regioselective addition of 1,3-dipole to C2–C3 π bond of allenic esters/ketones followed by domino transformation of the cycloadducts, which involve an intramolecular aza Diels–Alder reaction in the intermediate C. DFT calculations of various parameters for diene and dienophile components in the proposed intermediate C have revealed that conformational constraints imposed by the alkyl groups (R=Me, Et) favor intramolecular aza-Diels–Alder cycloaddition. An alternative domino route to benzoindolizines ( 9a, d, g) involving sequential one-pot cycloaddition of azadienes ( 22a– c) with silyl-enol ether ( 23) followed by palladium(0)-catalyzed Heck coupling reaction has also been developed. Both these approaches represent novel domino routes for the synthesis of benzoindolizines.

Remarkable effects of titanium tetrachloride in diastereoselective aza Diels–Alder cycloaddition: synthesis of ( S)-piperazic acid

Titanium tetrachloride-mediated aza Diels–Alder cycloaddition using a chiral diene and an aza dienophile proceeds in highly diastereoselective manner to form a dehydropiperazic acid derivative in high yield, and diastereoselectivity of the reaction depends on the quantity of titanium tetrachloride.

Resin-bound 4-phenyl-1,2-dihydroquinoline (DHQ): a new safety-catch linker for solid-phase organic synthesis (SPOS)

A new safety-catch linker has been developed for combinatorial solid-phase chemistry. Azidomethyl-polystyrene, obtained by nucleophilic substitution of chloromethyl-polystyrene, undergoes an acid promoted Schmidt rearrangement. The resulting polymer-bound iminium participates in an aza Diels–Alder cycloaddition, which leads to a supported dihydroquinoline (DHQ resin). The acylated form of the DHQ resin is stable under basic, acidic and mild reducing agents. The cleavage proceeds in two steps (i) oxidative aromatization leading to an activated quinolinium and (ii) nucleophilic displacement of the quinoline resin. The overall process is high yielding and efficient.

Intramolecular Michael‐Type Addition of Azadienes to 1,4‐Naphthoquinones Instead of Aza‐Diels—Alder Cycloaddition: A Synthesis of Ascididemin.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Intramolecular Michael-type addition of azadienes to 1,4-naphthoquinones instead of Aza-Diels–Alder cycloaddition: a synthesis of ascididemin

α,β-Unsaturated hydrazones tethered by an amino group to 1,4-naphthoquinone or quinoline-5,8-dione do not react by intramolecular aza-Diels–Alder cycloaddition. Instead, these substrates cyclize to form benzo[b]acridine-6,11-dione or pyrido[2,3-b]acridine-5,12-dione derivatives, respectively. This route leads to a highly concise synthesis of the pyridoacridine alkaloid ascididemin.

New synthesis of pyridoacridines based on an intramolecular aza-Diels–Alder reaction followed by an unprecedented rearrangement†

The synthesis of pyridoacridines related to the ascididemins can be performed by an intramolecular aza-Diels–Alder cycloaddition of an α,β-unsaturated hydrazone to a quinone followed by an unprecedented rearrangement to yield benzo- or pyrido-[b]acridine-6,11-diones.