Access to 1‐Phospha‐2‐azanorbornenes by Phospha‐aza‐Diels–Alder Reactions

The unprecedented phospha‐aza‐Diels–Alder reaction between an activated electron‐poor imine and 2H‐phospholes yields 1‐phospha‐2‐azanorbornenes in a highly chemoselective and moderately diastereoselective reaction. The intermediate 2H‐phospholes, which act as dienes, are formed in situ from the corresponding 1H‐phospholes. Theoretical calculations confirm that the phospha‐aza‐Diels–Alder reaction is of normal electron demand. The reactive P?N bond in 1‐phospha‐2‐azanorbornenes can be cleaved by nucleophiles leading to the formation of 2,3‐dihydrophospholes.     

Intramolecular Aza‐Diels‐Alder Cyclization of a Dimerized Citral with Anilines Catalyzed by InCl3

A series of aza‐polycyles containing octahydroacridine core were prepared via an intramolecular aza‐Diels‐Alder reaction of a dimerized citral with various aromatic amines. This reaction is efficiently catalyzed by InCl₃ at ambient temperature to afford the corresponding cyclized products in moderate to good yields.     

Access to Indoles via Diels–Alder Reactions of 5‐Methylthio‐2‐vinylpyrroles with Maleimides

Diels–Alder reactions of 5‐methylthio‐2‐vinyl‐1H‐pyrroles with maleimides followed by isomerization gave tetrahydroindoles in moderate to good yield. Aromatization using activated MnO₂ in refluxing toluene gave the corresponding 2‐methylthioindoles in good yields, and demethylthioation using Raney nickel gave the 2‐H indoles in excellent yields. The protection of the adducts produced aromatization in improved yield, demonstrating the effectiveness of the methylthio group as a protecting group for pyrroles; however, 5‐methylthio‐2‐vinylpyrrole was shown to perform with slightly less efficiency than 2‐vinylpyrrole in Diels–Alder reactions, indicating the protective group was more deactivating than desired. This route toward indoles offers high convergency and conveniently available starting materials that are easily purified. Bis‐methylthioated vinylpyrroles were shown to have potential as highly activated Diels–Alder dienes.     

Catalytic Asymmetric Synthesis of [2,3]‐Fused Indoline Heterocycles through Inverse‐Electron‐Demand Aza‐Diels–Alder Reaction of Indoles with Azoalkenes

An unprecedented catalytic asymmetric inverse‐electron‐demand aza‐Diels–Alder reaction of indoles with in situ formed azoalkenes is reported. A diverse set of [2,3]‐fused indoline heterocycles were achieved in generally good yields (up to 97 %) with high regioselectivity and diastereoselectivity (>20:1 d.r.), and with excellent enantioselectivity (up to 99 % ee).     

Regio‐ and Enantioselective Aza‐Diels–Alder Reactions of 3‐Vinylindoles: A Concise Synthesis of the Antimalarial Spiroindolone NITD609

An asymmetric aza‐Diels–Alder reaction of 3‐vinylindoles with isatin‐derived ketimines has been developed. A series of spiroindolone derivatives were thus obtained in good to excellent yields with excellent enantioselectivity (up to 96 % yield and 99 % ee). Furthermore, the antimalarial compound NITD609 could be obtained in three steps with an overall yield of 40.6 %. Control experiments and operando IR experiments imply a concerted reaction pathway. The regioselectivity and exo selectivity result from π–π interactions between the two indoline rings of the two reactants.     

Synthetic Transformations of Sulfur‐Substituted 4‐Quinolizidinones

Sulfur‐substituted 4‐quinolizidinones, previously prepared by aza‐Diels‐Alder reactions and ring‐closing metathesis, are now subjected to further synthetic transformations. Formal synthesis of cermizine C and 5‐epi‐cermizine C, and some other useful reactions have been achieved.     

A Tunable and Enantioselective Hetero‐Diels–Alder Reaction Provides Access to Distinct Piperidinoyl Spirooxindoles

The active complexes of chiral N,N′‐dioxide ligands with dysprosium and magnesium salts catalyze the hetero‐Diels–Alder reaction between 2‐aza‐3‐silyloxy‐butadienes and alkylidene oxindoles to selectively form 3,3′‐ and 3,4′‐piperidinoyl spirooxindoles, respectively, in very high yields and with excellent enantioselectivities. The exo ‐selective asymmetric cycloaddition successfully regaled the construction of sp³‐rich and highly substituted natural‐product‐based spirooxindoles supporting many chiral centers, including contiguous all‐carbon quaternary centers.     

Palladium‐Catalyzed CH Activation of N‐Allyl Imines: Regioselective Allylic Alkylations to Deliver Substituted Aza‐1,3‐Dienes

A new mode of activation of an imine via a rare aza‐substituted π‐allyl complex is described. Palladium‐catalyzed C(sp³)? H activation of the N‐allyl imine and the subsequent nucleophilic attack by the α‐alkyl cyanoester produced the 1‐aza‐1,3‐diene as the sole regioisomer. In contrast, nucleophilic attack by the α‐aryl cyanoester exclusively delivered the 2‐aza‐1,3‐diene, which was employed in an inverse‐electron‐demand Diels–Alder reaction for heterobiaryl synthesis.     

One Pot Synthesis of Medicinally Important cis‐2‐Methyl‐4‐amino substituted‐1,2,3,4‐tetrahydroquinolines

A simple synthesis of medicinally important cis‐2‐methyl‐4‐azapan‐2‐one‐1,2,3,4‐tetrahydroquinolines/cis‐9‐(2‐methyl‐1,2,3,4‐tetrahydroquinolin‐4‐yl)‐9H‐carbazole was reported. Multicomponent one pot synthesis with anilines and N‐vinylcaprolactam/N‐vinyl carbazole via imino Diels‐Alder reaction by using antimony trichloride as catalyst and acetonitrile as solvent was employed. NMR technique (2D) was used to study the regio‐ and stereo‐chemistry of newly synthesized compounds. The cis diastereo‐selectivity of the products was predicted by COSY and NOESY studies.     

Synthesis of New Pyrano[2′,3′: 5,6]chromeno[4,3‐b]quinolin‐4‐ones via Aza‐DielsAlder Reaction

New pyrano[2′,3′: 5,6]chromeno[4,3‐b]quinolin‐4‐ones have been synthesized by intramolecular aza‐Diels? Alder reaction of the azadienes generated in situ from aryl amines and 8‐formyl‐7‐(prop‐2‐ynyl)2,3‐disubstituted chromones using CuFe₂O₄ nanoparticles as a catalyst in DMSO at 80–90° in good‐to‐excellent yields. Particularly valuable features of this methodology include simple implementation, inexpensive and reusable catalyst, and good yields. The structures were established by spectroscopic data and further confirmed by X‐ray diffraction analysis of one of the products.     

Intramolecular Aza‐Diels–Alder Reactions of ortho‐Quinone Methide Imines: Rapid,Catalytic, and Enantioselective Assembly of Benzannulated Quinolizidines

Aza‐Diels–Alder reactions (ADARs) are powerful processes that furnish N‐heterocycles in a straightforward fashion. Intramolecular variants offer the additional possibility of generating bi‐ and polycyclic systems with high stereoselectivity. We report herein a novel Brønsted acid catalyzed process in which ortho‐quinone methide imines tethered to the dienophile via the N substituent react in an intramolecular ADAR to form complex quinolizidines and oxazinoquinolines in a one‐step process. The reactions proceed under very mild conditions, with very good yields and good to very good diastereo‐ and enantioselectivities. Furthermore, the process was extended to a domino reaction that efficiently combines substrate synthesis, ortho‐quinone methide imine formation, and ADAR.     

Applications of Dainshefsky's Dienes in the Asymmetric synthesis of Aza‐Diels‐Alder Reaction

Asymmetric hetero‐Diels‐Alder (AHDA) reactions provide a multitude of opportunities for the highly efficient, regio‐ and stereoselective construction of various heterocycles in enantiomerically pure form. The asymmetric aza‐Diels‐Alder (A‐aza‐DA) reaction using diversely hetero‐dienophiles and hetero‐dienes have been increasingly developed as a valuable method for the synthesis of functionalized nitrogen ring systems. The purpose of this review is to give a detailed discussion of the A‐aza‐DA reaction particularly, the stereoselective reactions of imines as dienophiles with Dainshefsky dienes to obtain optically pure aza‐Diels‐Alder products. The development of stereoselective variants of the reaction make use of imines as the dienophile and Dainshefsky dienes is at the forefront of these studies. This review updates the A‐aza‐DA reactions covering the literature from 1972 till date     

Asymmetric Synthesis of Both Enantiomers of Protected 5‐Hydroxynorvaline by Hetero‐Diels‐Alder Addition of ethyl 2‐Nitrosoacrylate to (R)‐ and (S)‐1‐Phenylbutyl Vinyl Ether

Both enantiomers of protected 5‐hydroxynorvaline were prepared by hetero‐Diels‐Alder addition of ethyl 2‐nitrosoacrylate to readily available (R)‐ and (S)‐1‐phenylbutyl vinyl ether and a further three‐step manipulation. Attempted synthesis of (±)‐vigabatrin from protected (±)‐5‐hydroxynorvaline was unsuccessful.     

Palladium‐Catalyzed C?H Activation of N‐Allyl Imines: Regioselective Allylic Alkylations to Deliver Substituted Aza‐1,3‐Dienes

A new mode of activation of an imine via a rare aza‐substituted π‐allyl complex is described. Palladium‐catalyzed C(sp³) H activation of the N‐allyl imine and the subsequent nucleophilic attack by the α‐alkyl cyanoester produced the 1‐aza‐1,3‐diene as the sole regioisomer. In contrast, nucleophilic attack by the α‐aryl cyanoester exclusively delivered the 2‐aza‐1,3‐diene, which was employed in an inverse‐electron‐demand Diels–Alder reaction for heterobiaryl synthesis.     

Catalytic Asymmetric Inverse‐Electron‐Demand Hetero‐Diels−Alder Reactions

In this review, the recent developments in catalytic asymmetric inverse‐electron‐demand hetero‐Diels−Alder reaction, which is recognized as one of the most powerful routes to construct highly functionalized and enantioenriched six‐membered heterocycles, are described. The article is organized on the basis of different kinds of electron‐deficient heterodienes, including α,β‐unsaturated ketones/aldehydes, o‐benzoquinones, α,β‐unsaturated imines, N‐aryl imines, o‐benzoqinone imides, and other aza‐olefins.     

A Catalyst‐Enabled Diastereodivergent Aza‐Diels–Alder Reaction: Complementarity of N‐Heterocyclic Carbenes and Chiral Amines

Highly efficient and diastereodivergent aza‐Diels–Alder reactions have been developed to access either diastereomeric series of benzofuran‐fused δ‐lactams and dihydropyridines in nearly perfect stereoselectivity (d.r. >20:1, >99 % ee for all examples). The complementarity of N‐heterocyclic carbene and chiral amine as the catalyst was demonstrated for the first time, together with an excellent level of catalytic efficiency (1 mol % loading).     

Stereoselective Synthesis of 2,6‐Disubstituted Tetrahydropyridines Via Aza‐Diels‐Alder Reactions

Abstract

The aza‐Diels‐Alder reactions of (E)‐2‐(phenylthio)‐1,3‐pentadiene (2) with iminium salts gave the 2,6‐disubstituted tetrahydropyridines 3–8. Factors influencing the stereochemistry and reactivity of these reactions were also studied.     

Synthesis of a poly(vinyl ether) containing a benzocyclobutene moiety and its reaction with dienophiles

1‐Benzocyclobutenyl vinyl ether (1) was easily prepared by the elimination reaction of hydrogen bromide from 1‐benzocyclobutenyl 1‐bromoethyl ether obtained by 1‐bromobenzocyclobutene and ethylene glycol via two steps in a good yield. Cationic polymerizations of 1 was carried out at −78°C for 2 h in toluene in the presence of BF₃OEt₂ as an initiator to give quantitatively the corresponding polymers (2) as white solids. As a model reaction of the polymer reaction of 2 with dienophiles, the Diels–Alder reactions of 1‐methoxybenzocyclobutene with maleic anhydride (MA) in toluene at 100–140°C for 3 h were carried out to obtain the corresponding Diels–Alder adduct quantitatively at 140°C. The polymer reactions of 2 with MA and N‐phenylmaleimide (MI) in toluene were carried out to yield the corresponding Diels–Alder adduct polymers in good yields. The degree of introduction of the dienophile could be controlled by temperature, and the unreacted benzocyclobutene moiety could further react with another benzocyclobutene moiety or dienophile. The properties (solubilities, T_g, and temperature of 10% weight loss) of the polymers obtained from the polymer reaction were quite different from those of 2. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 59–67, 1999     

Electropolymerizable Terthiophene S,S‐Dioxide‐Fullerene Diels‐Alder Adduct for Donor/Acceptor Double‐Cable Polymers

The preparation of a novel fullerene‐thiophene derivative by Diels‐Alder addition of terthiophene S,S‐dioxide was demonstrated. Extrusion of SO₂ from the adduct is an effective process that yields a stable cyclohexadiene‐1,4‐bisthiophene–C₆₀ adduct in good isolable yield. The product has been accurately characterized and opens the way to synthesize new C₆₀ derivatives “via” Diels‐Alder methodology without the possibility of cycloreversion. Electrochemical and spectroscopic properties of this macromolecule were studied and supported by theoretical calculations to interpret its electronic structure. The first approach to the electropolymerization of this macromonomer produces donor‐acceptor molecular wires providing a new and versatile way to fullerene‐based double cable polymers.

     

Reactivity of 4‐Phenyl‐1,2,4‐triazoline‐3,5‐dione and Diethylazocarboxylate in [4+2]‐Cycloaddition and Ene Reactions: Solvent,Temperature, and High‐Pressure Influence on the Reaction Rate

We have studied the solvent, temperature, and pressure influences on the reaction rates of cyclic and acyclic N=N bonds in the Diels–Alder and ene reactions. The transfer from N‐phenylmaleimide ( 9 ) to a structural analogue, 4‐phenyl‐1,2,4‐triazoline‐3,5‐dione ( 2 ), is accompanied by the rate increase in five to six orders of magnitude in the Diels–Alder reactions with cyclopentadiene ( 4 ) and 9,10‐dimethylanthracene ( 5 ), whereas the transfer from dimethyl fumarate ( 10 ) to diethyl azodicarboxylate ( 1 ) increases only in one to two orders of magnitude. The ratio of the reaction rate constants ( 2 + 4 )/( 1 + 4 ) is very large (5.2 × 10⁷) and almost the same (5.3 × 10⁷) as in the ene reactions with tetramethylethylene ( 7 ), ( 2 + 7 )/( 1 + 7 ). It has been observed that the N=N bond in reagent 2 has strong electrophilic, and its N–N moiety in the transition state has nucleophilic properties, which results from the analysis of the solvation enthalpy transfer of reagents, activated complex, and adduct in the Diels–Alder reaction of 2 with anthracene 22 .