MgBr2‐Mediated Ionic Diels–Alder Reaction of Acetals of α,β‐Unsaturated Aldehydes and Ketones with 1,3‐Dienes

A facile, mild, and efficient methodology for the ionic Diels–Alder reaction of acetals of α,β‐unsaturated ketones and aldehydes as dienophiles with various 1,3‐dienes employing MgBr₂ as the Lewis acid catalyst to furnish corresponding Diels–Alder adducts at ambient temperature is described.     

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     

DFT Studied Hetero‐Diels–Alder Cycloaddition for the Domino Synthesis of Spiroheterocycles Fused to Benzothiazole and Chromene/Pyrimidine Rings in Aqueous Media

Structurally diverse spiroheterocycles; spiro[pyrimido[2,1‐b ]benzothiazole‐3,3′‐chromene]‐2′,4′‐dione, spiro[pyrimido[2,1‐b ]benzothiazole‐3,5′‐pyrimidine]‐2′,4′,6′‐trione, and spiro[pyrimido[2,1‐b ]benz‐thiazole‐3,2′‐cyclohexane]‐1′,3′‐dione have been synthesized by an environmentally benign, efficient, and facile one‐pot pseudo‐four component reaction of 2‐aminobenzothiazoles with aromatic aldehydes and cyclic β‐diketones in aqueous medium. The process involves hetero‐Diels–Alder cycloaddition and provides facile access to spiroheterocycles fused with potentially interesting biologically active scaffolds. The configuration of hetero‐Diels–Alder cycloadduct has been ascertained through density functional theory calculations.     

Metalloporphyrin‐Based Hypercrosslinked Polymers Catalyze Hetero‐Diels–Alder Reactions of Unactivated Aldehydes with Simple Dienes: A Fascinating Strategy for the Construction of Heterogeneous Catalysts

We describe a novel and intriguing strategy for the construction of efficient heterogeneous catalysts by hypercrosslinking catalyst molecules in a one‐pot Friedel–Crafts alkylation reaction. The new hypercrosslinked polymers (HCPs) as porous solid catalysts exhibit the combined advantages of homogeneous and heterogeneous catalysis, owing to their high surface area, good stability, and tailoring of catalytic centers on the frameworks. Indeed, a new class of metalloporphyrin‐based HCPs were successfully synthesized using modified iron(III) porphyrin complexes as building blocks, and the resulting networks were found to be excellent recyclable heterogeneous catalysts for the hetero‐Diels–Alder reaction of unactivated aldehydes with 1,3‐dienes. Moreover, this new strategy showed wide adaptability, and many kinds of homogeneous‐like solid‐based catalysts with high catalytic performance and excellent recyclability were also constructed.     

A Facile Synthesis of Bridged‐tricyclic Skeletons via Intramolecular Diels‐Alder Reaction of Cyclic 1,3‐Dienes Containing an α,β‐Unsaturated Ester

Intramolecular Diels‐Alder reaction (IMDA) precursors are easily available starting from addition of ester functionalized zinc‐copper reagents to cyclohexadienyl‐ and cycloheptadienylirontricarbonyl cation salts. The resulting cyclic 1,3‐dienes containing an α,β‐unsaturated ester functionality underwent smoothly IMDA reaction to afford bridged tricyclic compounds. Bridged heterotricyclic skeletons were also available via IMDA reaction of cyclic 1,3‐dienes bearing an imine or aldehyde functionality.     

Copper‐Catalyzed Aminothiolation of 1,3‐Dienes via a Dihydrothiazine Intermediate

Heteroatom‐containing organic molecules are of particular interest to medicinal chemists and materials scientists. A strategy to reach these architectures via direct difunctionalization of abundant 1,3‐dienes is especially attractive. Herein, we describe the development of a regio‐ and diastereoselective 1,4‐aminothiolation of 1,3‐dienes with a sulfur diimide reagent, a copper catalyst, and alkyl Grignard reagents. This unique protocol provides remote nitrogen and sulfur functionalities with high levels of stereocontrol. The reaction proceeds via a tandem hetero‐Diels–Alder cycloaddition of N,N′‐bis(benzenesulfonyl)sulfur diimide with 1,3‐diene followed by copper‐catalyzed Grignard substitution. Mechanistic studies support a copper catalyzed formation of an unprecedented [10‐S‐4] sulfurane that reductively eliminates to afford a 3,6‐dihydrothiazine, which is selectively converted to 1,4‐aminothiols.     

Ruthenium carbenes as catalysts in stereoselective ene–yne metathesis/Diels–Alder and ene–yne metathesis/Diels–Alder/cross coupling multicomponent reactions

An ene–yne cross metathesis of silyl substituted alkynes and alkenes followed by a Diels–Alder reaction of the metathesis product 2-silyl-1,3-dienes has been developed. The dienes thus prepared in situ were shown to participate in highly diastereoselective Diels–Alder reactions. In one case the silicon substituted Diels–Alder cycloadduct was subsequently used without isolation and purification in a Hiyama cross coupling reaction. The cross coupling reactions enable these silicon dienes to be used as synthons for a variety of other dienes.     

Diels–Alder Reactions of 1,2‐Azaborines

Diels–Alder reactions employing 1,2‐azaborine heterocycles as 1,3‐dienes are reported. Carbocyclic compounds with high stereochemical and functional complexity are produced, as exemplified by the straightforward two‐step synthesis of an amino allyl boronic ester bearing four contiguous stereocenters as a single diastereomer. Whereas electron‐deficient dienophiles undergo irreversible Diels–Alder reactions, a reversible Diels–Alder reaction with the less electron‐deficient methyl acrylate is observed. Both the N and the B substituent of the 1,2‐azaborine exert significant influence on the [4+2] cycloaddition reactivity as well as the aromatic character of the heterocycle. The experimentally determined thermodynamic parameters of the reversible Diels–Alder reaction between 1,2‐azaborines and methyl acrylate correlate with aromaticity trends and place 1,2‐azaborines approximately between furan and thiophene on the aromaticity scale.     

The Asymmetric Hetero‐Diels–Alder Reaction in the Syntheses of Biologically Relevant Compounds

The hetero‐Diels–Alder reaction is one of the most powerful transformations in the chemistry toolbox for the synthesis of aza‐ and oxa‐heterocycles embodying multiple stereogenic centers. However, as compared to other cycloadditions, in particular the dipolar cycloadditions and the Diels–Alder reaction, the hetero‐Diels–Alder reaction has been much less explored and exploited in organic synthesis. Nevertheless, this powerful transformation has opened up efficient and creative routes to biologically relevant small molecules and different natural products which contain six‐membered oxygen or nitrogen ring systems. Recent developments in this field, in particular in the establishment of enantioselectively catalyzed hetero‐Diels–Alder cycloadditions steered by a plethora of different catalysts and the application of the resulting small molecules in chemical biology and medicinal chemistry research, are highlighted in this Minireview.     

Diels-Alder Reactions of Ethyl α-Bromoacrylate with Open-chain Dienes——Synthesis of Ethyl 1,3-/1,4-Cyclohexadienecarboxylates

The Diels‐Alder reactions of ethyl α‐bromoacrylate 1 with open‐chain dienes 2 were conducted under thermal or Lewis acid‐catalysis conditions. In most cases, the cyclic adducts of 1‐bromocyclohex‐3‐enecarboxylates 3 were formed in high yields with good regio‐ and stereoselectivity. Subsequent E2‐elimination by treatment with DBU provided the corresponding 1,3‐ or 1,4‐cyclohexadienecarboxylates depending on the relative configuration of the products. Starting from myrcene (7‐methyl‐3‐methyleneocta‐1,6‐diene) the reaction sequence afforded the ester precursor of Georgywood with good yields.     

Bioinspired Intramolecular Diels–Alder Reaction: A Rapid Access to the Highly‐Strained Cyclopropane‐Fused Polycyclic Skeleton

A bioinsipred gold‐catalyzed tandem Diels–Alder/Diels–Alder reaction of an enynal and a 1,3‐diene, forming the highly‐strained benzotricyclo[3.2.1.0^2,7]octane skeleton, was reported. In contrast, a Diels–Alder/Friedel–Crafts tandem reaction occurred instead when silver salts were used as the catalyst. Although both reactions experienced the similar Diels–Alder reaction of a pyrylium intermediate with a 1,3‐diene, they have different reaction mechanisms. The former proceeded with a stepwise Diels–Alder reaction, while the latter one with a concerted one.     

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.     

Competition between Hetero‐Diels‐Alder and Cheletropic Additions of Sulfur Dioxide to 2‐Substituted Buta‐1,3‐dienes. Synthesis of 2‐(1‐Naphthyl)‐ and 2‐(2‐Naphthyl)buta‐1,3‐diene

Chloroprene (=2‐chlorobuta‐1,3‐diene; 4b ) and electron‐rich dienes such as 2‐methoxy‐( 4c ), 2‐acetoxy‐( 4d ), and 2‐(phenylseleno)buta‐1,3‐diene ( 4e ) refused to equilibrate with the corresponding sultines 5 or 6 between −80 and −10° in the presence of excess SO₂ and an acidic promoter. Isoprene ( 4a ) and 2‐(triethylsilyl)‐( 4f ), 2‐phenyl‐( 4g ), and 2‐(2‐naphthyl)buta‐1,3‐diene ( 4i ) underwent the hetero‐Diels‐Alder additions with SO₂ at low temperature. In contrast, 2‐(1‐naphthyl)buta‐1,2‐diene ( 4h ) did not. With dienes 4a, 4g , and 4i , the hetero‐Diels‐Alder additions with SO₂ gave the corresponding 4‐substituted sultine 5 with high regioselectivity. In the case of 4g +SO₂⇄ 5g , the energy barrier for isomerization of 5g to 5‐phenylsultine ( 6g ) was similar to that of the cheletropic addition of 4g to give 3‐phenylsulfolene ( 7g ). The hetero‐Diels‐Alder addition of 4f gave a 1 : 4 mixture of the 4‐(triethylsilyl)sultine ( 5f ) and 5‐(triethylsilyl)sultine ( 6f ). The preparation of the two new dienes 4h and 4i is reported.     

Asymmetric Photocatalysis by Intramolecular Hydrogen‐Atom Transfer in Photoexcited Catalyst–Substrate Complex

3‐(2‐Formylphenyl)‐1‐pyrazol‐1‐yl‐propenones undergo an asymmetric photorearrangement to benzo[d]cyclopropa[b]pyranones with up to >99 % ee, which is catalyzed by a bis‐cyclometalated rhodium catalyst in the presence of visible light. Mechanistic experiments and DFT calculations support a mechanism in which a photoexcited catalyst/substrate complex triggers an intramolecular hydrogen‐atom transfer followed by a highly stereocontrolled hetero‐Diels–Alder reaction. In this reaction scheme, the rhodium catalyst fulfills multiple functions by 1) enabling visible‐light π→π* excitation of the catalyst‐bound enone substrate, 2) facilitating the hydrogen‐atom transfer, and 3) providing the asymmetric induction for the hetero‐Diels–Alder reaction.     

An Enantioselective Inverse‐Electron‐Demand Imino Diels–Alder Reaction

The imino Diels–Alder reaction is an efficient method for the synthesis of aza‐heterocycles. While different stereo‐ and enantioselective inverse‐electron‐demand imino Diels–Alder (IEDIDA) reactions have been reported before, IEDIDA reactions including electron‐deficient dienes are unprecedented. The first enantioselective IEDIDA reaction between electron‐poor chromone dienes and cyclic imines, catalyzed by zinc/binol complexes is described. The novel reaction provides a facile entry to a natural product inspired collection of ring‐fused quinolizines including a potent modulator of mitosis.     

Recent progress in a chiral multinucleating system utilizing tartaric acid esters

In order to develop a practical method for the construction of chiral molecules, we have designed a novel chiral reaction system possessing multi‐metal centers utilizing tartaric acid ester as a chiral auxiliary. Based on this concept, we have developed an asymmetric 1,3‐dipolar cycloaddition reaction of azomethine imines, an asymmetric hetero Diels‐Alder reaction of nitroso compounds, an asymmetric Diels‐Alder reaction of o‐quinodimethanes. Furthermore, an asymmetric nucleophilic addition of alkynylzinc reagents, prepared in situ from dialkylzinc and 1‐alkynes, to nitrones was achieved with high level of stereocontrol. In the last case, the addition of methylzinc salt of a product‐like racemic hydroxylamine was found to be effective for unprecedented enhancement of enantioselectivity. © 2010 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 10: 173–187; 2010: Published online in Wiley InterScience ( www.interscience.wiley.com ) DOI 10.1002/tcr.201000002     

Metallaaromatics Containing Main‐group Heteroatoms

Metallaaromatics are metallacycles that are derived from the formal replacement of a carbon atom in the framework of organic aromatics with a metal fragment. As an important subclass of metallaaromatics, metallaaromatics that contain main‐group heteroatoms have attracted considerable attention. In the past ten years, we have developed several new methods to construct metallaaromatics as well as those containing main‐group heteroatoms, such as metallapyridine, metallapyridinium, metallapyridyne, metallafuran, metallabenzothiazole, metallabenzoxazole, metallabenzthiophene, aza‐metallapentalene and some novel tricyclic/tetracyclic metallaaromatics. In addition, interesting reactions such as the first hetero‐Diels Alder reaction between 1‐metalla‐1,3‐dienes and nitriles, the first intramolecular nucleophilic aromatic substitution (S_NAr) reaction of metallabenzene, and the first iodine‐mediated electrophilic cyclizations of a metallabenzene complex were demonstrated. In this account, recent and novel approaches for their synthesis and property analyses are summarized. The structural diversity and unique properties of metallaaromatics containing main‐group heteroatoms will strongly inspire further investigation of these species and provide a wide range of potential applications.     

Stereoselectivity in the Diels‐Alder Cycloadditions of a Facially Dissymmetric Bicyclo[2.2.2]octadiene‐Grafted Maleic Anhydride with Exocyclic Butadienes. Unexpected Facial Selectivity in the Cycloaddition with 2,3,5,6‐tetramethylidenebicyclo[2.2.2]octene

The Diels‐Alder cycloadditions of facially dissymmetric maleic anhydride 1 with facially nonequivalent exocyclic 1,3‐butadienes(dimethylidenebicyclo[2.2.2]octene 3 and 2,3,5,6‐tetramethylidenebicyclo[2.2.2]‐octene ( 4 )) were investigated. In each cycloaddition, the reaction occurred via the course in which 1 added exclusively by its syn‐face (same face as the etheno‐bridge) onto either π‐face of the exocyclic 1,3‐butadiene systems to produce only two of the four possible stereoisomeric monocycloadducts ( 8a / 8b and 9a / 9b ). In the Diels‐Alder cycloaddition of 1 with bis‐exocyclic butadiene 4 , however, both monocycloadducts 9a and 9b underwent subsequent cycloaddition with distinctive facial selectivity to produce the C_s‐symmetric bis‐cyclohexanobarrelene 10a as only bis‐cycloadduct.     

Diastereoselective synthesis of cis-fused pyrano[4,5-c]pyrrole derivatives via microwave-accelerated intramolecular Knoevenagal hetero Diels–Alder reaction

The synthesis of enantiomerically pure pyrano[4,5-c]pyrroles has been accomplished by the intramolecular hetero Diels–Alder reaction of enantiomerically pure N-allyltetheredalkenyl aldehydes with various 1,3-diones. The reaction led to the formation of cis-fused enantiomerically pure pyrano[4,5-c]pyrroles in excellent yield under mild conditions and the products were characterized by spectroscopic data.     

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.