Aza-ene Reaction Research Articles

Atom-economic Michael reaction between hydroacridines and arylmaleimides without catalyst/additive

Previously unknown spiroderivatives of 3,1-benzoxazines were synthesized by the reaction of anthranilic acid with cyclic ketones. The interaction of 3,1-spirobenzoxazines with Vilsmeier-Haack reagent (POCl3 (PBr3)/DMF), depending on the amount of formulation agent, leads to the formation of hydroacridones or hydroacridines. Under catalyst- and additive-free conditions, N-arylmaleimides, like Michael's acceptors, are added to the hydroacridines in DMSO to form the corresponding adducts. The reaction proceeds stereoselectively with the formation of a mirror pair of diastereomers, if the products have only two chiral centers. In the presence of three chiral centers in the structure of Michael's adducts, the reaction is not stereoselective. The reaction proceeds by the sp3 hybrid carbon atom under non-catalytic conditions due to the imin-enamine tautomerism of chloro(bromo)hydroacridines. The presented reaction can also be considered as an effective atom-economical aza-ene reaction, which fully meets today's requirements for eco-friendly reaction. The synthesized compounds are potential biologically active substances and can also be used as "building-blocks" for organic synthesis.

Construction of Fully Substituted 2-Pyridone Derivatives via Four-Component Branched Domino Reaction Utilizing Microwave Irradiation.

Microwave irradiation, four-component branched domino reaction of methyl acetoacetate/2,4-pentanedione, diethyl malonate, triethyl orthoformate and amines offering an extremely efficient strategy for the construction of fully substituted 2-pyridone derivatives under sustainable conditions is established. This self-sorting branched domino transformation is proposed to proceed separate through N-nucleophilic addition and imine-enamine tautomerization/condensation reaction generated from enamino ester and diethyl ethoxymethylenemalonate, and then would be subjected to an aza-ene reaction and intramolecular cyclization mechanism to afford the 2-pyridones with only water and ethanol as byproducts. The simple experimental procedure, high bond-forming efficiency, step and atom economy, inexpensive readily available starting materials, moderate to excellent yields, and good functional group compatibility are other noteworthy advantages of this method.

Metal-Free One-Pot Four-Component Cascade Annulation in Ionic Liquids at Room Temperature: Convergent Access to Thiazoloquinolinone Derivatives.

An efficient, eco-friendly, and highly convergent one-pot route to privileged thiazoloquinolinone derivatives has been developed via four-component cascade coupling (4CCC) of α-enolic dithioesters, cysteamine/2-aminothiophenols, aldehydes, and cyclic 1,3-diketones in recyclable [EMIM][EtSO4] ionic liquid at room temperature for the first time. The reaction proceeds via a N,S-acetal formation, Knoevenagel condensation, aza-ene reaction, imine-enamine/keto-enol tautomerization, and intramolecular N-cyclization cascade sequence. The merit of the protocol is highlighted by its efficacy of forming consecutive five new bonds (two C-C, two C-N, and one C-S) and two rings with all reactants being efficiently utilized. The operational simplicity, sustainability, mild conditions, excellent yields, tolerance of wide functional groups, and avoidance of expensive/toxic reagents are additional attributes to this domino four-component protocol. Notably, the products were easily separated from the ionic liquid, and thus the ionic liquid obtained was reused four times without considerable loss of any activity.

Synthesis and insecticidal evaluation of tetrahydroimidazo[1,2- a ]pyridin-5(1 H )-one derivatives

Abstract A series of novel tetrahydroimidazo[1,2-a]pyridine-5(1H)-one derivatives containing a electronegative pharmacophore ( CNO2) were synthesized via practical aza-ene reaction and characterized by 1H NMR, 13C NMR, 19F NMR and HRMS. Preliminary bioassays showed that some of the target compounds exhibited good insecticidal activity against brown planthopper (Nilaparvata lugens) and cowpea aphids (Aphis craccivora) at 500 mg L−1. Among them, compound 11h was active against brown planthopper at 100 mg L−1. The insecticidal activities varied significantly depending on the types and patterns of the substituents, which provided guidance for further investigation on structure modifications.

One-Pot, Three-Component Synthesis of 1,8-Naphthyridine Derivatives from Heterocyclic Ketene Aminals, Malononitrile Dimer, and Aryl Aldehydes

An efficient and versatile method was developed for the access of multisubstituted 1,8-naphthyridine derivatives through a one-pot, three-component protocol from heterocyclic ketene animals, malononitrile dimer, and aryl aldehydes in high yields. The 1,8-naphthyridines were formed via Knoevenagel condensation, aza–ene reaction, imine–enamine tautomerization, and intramolecular cyclization.

Iodine catalyzed mild 4CR protocol for synthesis of Tetrahydroimidazo[1,2-a]pyridines: cascade construction of multiple C–C and C–Hetero bonds

A highly convergent and straight forward synthesis of N-fused heterocycles, including 1,2,3,7-tetrahydroimidazo[1,2-a]pyridine-5-carboxylic acids is successfully achieved via a one-pot four-component cascade reaction utilizing pyruvic acid, aldehydes, diamines and 1,1-bis(methylthio)-2-nitroethylene (BMTNE) in the presence of a catalytic amount of molecular iodine in acetonitrile. The new efficient domino protocol generates two rings by the concomitant formation of C–N (three) and C–C (two) multiple bonds presumably involving a sequence of N,N-acetal formation, Knoevenagel reaction, aza–ene reaction, imine–enamine/keto–enol tautomerization, and N-cyclization as key steps. The merit of this protocol is highlighted by its easily available and economical starting materials, operational simplicity, efficient utilization of all the reactants, clean reaction profile, simple workup procedure, and tolerance of a wide variety of functional groups.

ChemInform Abstract: Catalyst‐Free Concise Synthesis of Imidazo[1,2‐a]pyrrolo[3,4‐e]pyridine Derivatives.

An eco-benign and highly efficient aza–ene reaction for preparing imidazo[1,2-a]pyrrolo[3,4-e]pyridine derivatives from heterocyclic ketene aminals (HKAs) and 2,3-dioxopyrrolidines has been developed in environmentally benign solvent systems, as well as in the absence of any catalyst. The procedures feature excellent yields, short reaction times, a convenient one-pot method, and simple purification that not only minimise the generation of waste but also simplify the work-up procedure.

Catalytic asymmetric aza-ene reaction of 3-indolylmethanols with cyclic enaminones: enantioselective approach to C3-functionalized indoles.

The catalytic asymmetric aza-ene reactions of 3-indolylmethanols with cyclic enaminones and the highly enantioselective aza-ene reactions utilizing cyclic aza-ene components have been established, which directly assemble isatin-derived 3-indolylmethanols and dimedone-derived enaminones into C3-functionalized chiral indoles with one all-carbon quaternary stereogenic center in high yields and excellent enantioselectivities (up to 99% yield, up to 95:5 er).

Catalyst-free concise synthesis of imidazo[1,2-a]pyrrolo[3,4-e]pyridine derivatives

An eco-benign and highly efficient aza–ene reaction for preparing imidazo[1,2-a]pyrrolo[3,4-e]pyridine derivatives from heterocyclic ketene aminals (HKAs) and 2,3-dioxopyrrolidines has been developed in environmentally benign solvent systems, as well as in the absence of any catalyst. The procedures feature excellent yields, short reaction times, a convenient one-pot method, and simple purification that not only minimise the generation of waste but also simplify the work-up procedure.

Four-Component Cascade Heteroannulation of Heterocyclic Ketene Aminals: Synthesis of Functionalized Tetrahydroimidazo[1,2-a]pyridine Derivatives

An efficient and straightforward four-component synthetic protocol has been developed to synthesize imidazo[1,2-a]pyridines and imidazo[1,2,3-ij][1,8]naphthyridine derivatives incorporating medicinally privileged heterosystems from heterocyclic ketene aminals, aldehydes, diketene, and amines via cascade reactions, including diketene ring-opening, Knoevenagel condensation, aza-ene reaction, imine-enamine tautomerization, cyclocondensation, and intramolecular S(N)Ar. This strategy can provide an alternative approach for easy access to the highly substituted imidazo[1,2-a]pyridine derivatives in moderate to good yields using four simple and readily available building blocks under mild conditions. Importantly, the unusual splitting peaks in the (1)H NMR spectra of the products derived from heterocyclic ketene aminals with an o-halogen atom on the aryl ring were explained reasonably by varying the temperature in NMR analysis.

ChemInform Abstract: Application of 2‐(2‐Chloroaroyl)methyleneimidazolidines in Domino and Multicomponent Reaction: New Entries to Imidazo[1,2‐a]pyridines and Benzo[b]imidazo[1,2,3‐ij][1,8]naphthyridines.

Abstract A new strategy for the synthesis of tetrahydroimidazo[1,2-a]pyridines and unusual tetrahydrobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridines has been successfully developed by cascade reactions including Knoevenagel condensation, aza–ene reaction, imine–enamine tautomerization, cyclocondensation/oxidation, and intramolecular SNAr of precursors 2-(2-chloroaroyl)methyleneimidazolidines as new heterocyclic ketene aminals (HKA), which represent a class of polyfunctional scaffolds with four active reaction sites with aromatic aldehydes and malononitrile or ethyl 2-cyanoacetate under mild conditions. In this domino reaction, nine different active sites are involved, and two C–C bonds, two C–N bonds, and two new rings are constructed with all reactants efficiently utilized in the chemical transformation.

Application of 2-(2-chloroaroyl)methyleneimidazolidines in domino and multicomponent reaction: new entries to imidazo[1,2- a]pyridines and benzo[ b]imidazo[1,2,3- ij][1,8]naphthyridines

A new strategy for the synthesis of tetrahydroimidazo[1,2- a]pyridines and unusual tetrahydrobenzo[ b]imidazo[1,2,3- ij][1,8]naphthyridines has been successfully developed by cascade reactions including Knoevenagel condensation, aza–ene reaction, imine–enamine tautomerization, cyclocondensation/oxidation, and intramolecular S NAr of precursors 2-(2-chloroaroyl)methyleneimidazolidines as new heterocyclic ketene aminals (HKA), which represent a class of polyfunctional scaffolds with four active reaction sites with aromatic aldehydes and malononitrile or ethyl 2-cyanoacetate under mild conditions. In this domino reaction, nine different active sites are involved, and two C–C bonds, two C–N bonds, and two new rings are constructed with all reactants efficiently utilized in the chemical transformation.

Modulating the Reactivity of Heterocyclic Ketene Aminals in MCR: Selective Construction of Tetrahydrobenzo[b]imidazo[3,2,1-ij][1,8]naphthyridines

Two new kinds of tetrahydrobenzo[b]imidazo[3,2,1-ij][1,8]naphthyridine derivatives have been successfully synthesized by cascade reactions including Knoevenagel condensation, aza-ene reaction, imine-enamine tautomerization, cyclocondensation, and intramolecular S(N)Ar of precursors 2-(2-chloroaroyl)methyleneimidazolidines with aromatic aldehydes and ethyl acetoacetate or Meldrum's acid under mild conditions, respectively. These studies highlighted the concept of a substrate-design approach to the development of novel multicomponent reactions by simply incorporating an o-halo group into the aryl ring of 2-benzoylmethyleneimidazolidine as new synthons. In this domino reaction, at least six different active sites are involved; two C-C bonds, two C-N bonds, and two new rings are constructed with all reactants efficiently utilized in the chemical transformation.

Catalytic and enantioselective aza-ene and hetero-Diels–Alder reactions of alkenes and dienes with azodicarboxylates

Lewis acids such as Cu(OTf)(2), Zn(OTf)(2), Yb(OTf)(3) and Nd(OTf)(3) catalyze the aza-ene reaction of alkenes with azodicarboxylates, giving the allylic amination adducts. The use of bis(2,2,2-trichloroethyl)azodicarboxylate as the amination reagent and Cu(OTf)(2) and Yb(OTf)(3) as the catalysts gave the aza-ene reaction of different alkenes, leading to the corresponding allyl amines in high yields. Chiral copper complexes prepared from Cu(OTf)(2) and chiral bisoxazoline ligands were found to catalyze the enantioselective aza-ene reaction of azodicarboxylates with alkenes and the hetero-Diels-Alder reaction with cyclopentadiene, giving the corresponding aza-ene- and hetero-Diels-Alder adducts, respectively, in good yields and moderate enantioselectivities.

Synthesis of the necine bases (±)-macronecine and (±)-supinidine via an aza-ene reaction and allylsilane induced ring closure

An aza-ene reaction has been used for the first time for the synthesis of two 5-membered lactam-hydrazides, each with a built-in allylsilane terminator for further elaboration. One of the lactam-hydrazides was transformed via an allylsilane-hydrazonium ion ring closure to a fused tetrahydropyrazole which may be considered as a mono-nitrogen analog of the biologically significant necine bases. A density functional theoretical study (B3LYP/6-21G*) was undertaken to provide insight into the factors that favor a synclinal transition structure of the hydrazonium ion intermediate leading to the tetrahydropyrazole. This stereocontrolled synthesis served as a model for the multi-step conversion of the other lactam-hydrazide, the substituted 2-pyrrolidinone, to necine bases (±)-supinidine and (±)-macronecine. An allylsilane-aldehyde ring closure formed the key step in the synthesis of these natural products.

The aza–ene or the Michael addition? Examination of an unusual substituent effect on the reaction of heterocyclic ketene aminals with ethyl propiolate

Heterocyclic ketene aminals having at least one secondary amino group underwent the aza–ene reaction with ethyl propiolate under various conditions to yield the corresponding adducts, which were readily transformed into the δ-lactam fused heterocyclic products with or without the aid of sodium ethoxide in refluxing ethanol, while the ester- and cyano-substituted tertiary enediamines acted as the strong Michael donor to add to ethyl propiolate in a polar or a protic solvent. The unusual substituent effect on the reactivity and mechanism was discussed.

A systematic study of reaction of heterocyclic enamines with electrophilic alkynes: a simple and efficient synthetic route to 2-pyridinone-fused heterocycles

The reaction of heterocyclic enamines with ethyl propiolate and diethyl acetylenedicarboxylate has been systematically studied. In contrast to their heterocyclic ketene aminal analogues, heterocyclic enamines reacted with electrophilic alkynes via the Michael addition pathway rather than the aza-ene reaction mechanism. In the presence of a strong base such as sodium ethoxide and sodium hydride, the resulting Michael addition products underwent cyclocondensation reaction readily to produce 2-pyridinone-fused heterocycles in good to excellent yield.

5-Membered heterocyclic allylsilanes in synthesis: Generation via aza-ene reaction and application to the synthesis of a bicyclic 1,2-dinitrogen analogue of naturally occurring pyrrolizidines

A cyclic hydrazide containing an allylsilane functionality obtainable by an aza-ene reaction provides ready access to a bicyclic 1,2-dinitrogen compound related to naturally occurring pyrrolizidines.

The aza-ene reaction of heterocyclic ketene aminals with activated carbonyl compounds: a novel and efficient synthesis of γ-lactam-fused diazaheterocycles

Reactions of heterocyclic ketene aminals with activated carbonyl compounds are strongly influenced by the structure of the heterocycle moiety. Six-membered heterocyclic ketene aminals with or without an N-methyl group such as 3 and 4 underwent efficient addition and consecutive cyclocondensation reactions with diethyl oxomalonate 9 to produce γ-lactam-fused pyrimidine derivatives 10 and 11 in moderate to excellent yield. For the five-membered enediamines, however, those compounds without any N-substituent such as 6 underwent the same reaction slowly and no reaction at all was observed with N-methyl and N,N′-dimethyl-substituted analogs 7 and 8. Heterocyclic ketene aminals 3 also reacted with glyoxylic acid esters 17 to afford 8-aroyl-7-hydroxy-6-oxo-1,2,3,4,6,7-hexahydropyrrolo[1,2-a]pyrimidines 18 in good yield. No asymmetric induction was found, however, when (1R,2S,5R)-(–)-menthyl glyoxylate 17b was employed as a chiral substrate. An aza-ene reaction mechanism involving heterocyclic ketene aminals as the aza-ene component (H–N–CC) has been proposed. The effects of intramolecular hydrogen bonding and heterocyclic ring size on the reactivity are also discussed.

The aza-ene reaction of heterocyclic ketene aminals with enones: an efficient and simple synthetic route to fused di- and tri-heterocycles

Heterocyclic ketene aminals bearing a secondary amino moiety acted as hetero-ene components to react with a number of enones under very mild conditions. The reaction of five- and six-membered heterocyclic ketene aminals 5 and 8 with methyl vinyl ketone proceeded effectively through the aza-ene addition, imine–enamine tautomerization and intramolecular cyclization to give good yields of 8-aroyl-5-hydroxy-5-methyl-1,2,3,5,6,7-hexahydroimidazo[1,2-a]pyridines 6 and 9-aroyl-6-hydroxy-6-methyl-1,2,3,4,7,8-hexahydroxy-6H-pyrido[1,2-a]pyrimidines 9, respectively. When methyl vinyl ketone was present in excess, preliminarily formed product 6 underwent a second aza-ene reaction followed by intramolecular cyclization and water-participating debenzoylation, to yield the cisoid-4,9-dihydroxy-4,9-dimethyl-1,2,5,6,6a,7,8,10α-octahydro-4H,9H-imidazo[1,2,3-ij][1,8]naphthyridin-10α-ylium benzoate 7 as the sole product. In refluxing acetonitrile, heterocyclic ketene aminals 5 underwent aza-ene addition and cyclocondensation reaction with a number of substituted α,β-unsaturated ketones to afford 1,2,3,7-tetrahydroimidazo[1,2-a]pyridine derivatives 23 while tricyclic imidazo[1,2-a]quinoline derivatives were easily obtained when 2-benzylidene-cyclohexanone and -cyclohexane-1,3-dione were used as enophiles. The effect of the structures of heterocyclic ketene aminals, particularly of the intramolecular hydrogen bond, on the aza-ene reactivity is also discussed.