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.     

Enantioselective Nitroso‐Diels–Alder Reaction and Its Application for the Synthesis of (−)‐Peracetylated Conduramine A‐1

Cu^I‐catalyzed enantioselective nitroso‐Diels–Alder reactions (NDA reactions) of 2‐nitrosopyridine with various dienes are presented. The [CuPF₆(MeCN)₄]/Walphos‐CF₃ catalyst system is best suited to catalyze the NDA reaction of various dienes by using 2‐nitrosopyridine as a dienophile. In most of the cases studied, cycloadducts are obtained in quantitative yield with very good to excellent enantioselectivities. Based on DFT calculations, a model to explain the stereochemical outcome of the NDA reaction is presented. Finally, an efficient short synthesis of (?)‐peracetylated conduramine A‐1 by applying the enantioselective NDA reaction as a key step 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     

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.     

Catalytic Asymmetric Inverse‐Electron‐Demand Oxa‐Diels–Alder Reaction of In Situ Generated ortho‐Quinone Methides with 3‐Methyl‐2‐Vinylindoles

The first catalytic asymmetric inverse‐electron‐demand (IED) oxa‐Diels–Alder reaction of ortho‐quinone methides, generated in situ from ortho‐hydroxybenzyl alcohols, has been established. By selecting 3‐methyl‐2‐vinylindoles as a class of competent dienophiles, this approach provides an efficient strategy to construct an enantioenriched chroman framework with three adjacent stereogenic centers in high yields and excellent stereoselectivities (up to 99 % yield, >95:5 d.r., 99.5:0.5 e.r.). The utilization of ortho‐hydroxybenzyl alcohols as precursors of dienes and 3‐methyl‐2‐vinylindoles as dienophiles, as well as the hydrogen‐bonding activation mode of the substrates met the challenges of a catalytic asymmetric IED oxa‐Diels–Alder reaction.     

Radical Cation Diels‐Alder Reactions of Non‐Conjugated Alkenes as Dienophiles by Electrocatalysis

Radical cation Diels‐Alder reactions provide a powerful method for the construction of six‐membered ring systems between both electron‐rich dienes and dienophiles. However, the most recent examples of this class have been limited to β‐methylstyrenes as dienophiles; the use of non‐conjugated alkenes remains challenging. The present study describes the serendipitous development of novel radical cation Diels‐Alder reactions by electrocatalysis that use non‐conjugated alkenes as dienophiles. The key to successful transformation involves highly substituted cyclohexenyl radical cations that are stable enough to be reduced by intermolecular single electron transfer.     

Synthesis and application of novel imidazole and 1H-tetrazolic acid containing catalysts in enantioselective organocatalyzed Diels–Alder reactions

Herein we report studies on the organocatalytic Diels–Alder reaction using a variety of catalysts capable of activating α,β-unsaturated carbonyl compounds for reactions with dienes. The structurally attractive catalysts 4 and 14 were utilized in the enantioselective organocatalytic Diels–Alder reactions. Catalyst 4 provided the products in fair yields and more importantly in good enantioselectivities of up to 83% ee. Catalyst 14 was synthesized in high yield and was assessed in the enantioselective organocatalytic Diels–Alder reaction. Catalyst 14 proved to be a highly active and selective catalyst providing the products in high yield and high enantioselectivities up to 95% ee.     

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.     

Cationic Chiral Pd‐Catalyzed “Acetylenic” Diels–Alder Reaction: Computational Analysis of Reversal in Enantioselectivity

The highly enantioselective Diels–Alder reaction of acetylenic dienophiles is shown to be effectively catalyzed by cationic chiral palladium complexes. Not only the degree but also the sense of enantioselectivity critically depends on the steric demand of ligands. Computational analyses indicate that the steric demand does not affect the endo/exo‐selectivity but the enantioface selectivity of dienes.     

Manganese(I)‐Catalyzed C−H Activation/Diels–Alder/retro‐Diels–Alder Domino Alkyne Annulation featuring Transformable Pyridines

Complexity‐increasing Domino reactions comprising C?H allenylation, a Diels–Alder reaction, and a retro‐Diels–Alder reaction were realized by a versatile catalyst derived from earth‐abundant, non‐toxic manganese. The C?H activation/Diels–Alder/retro‐Diels–Alder alkyne annulation sequence provided step‐economical access to valuable indolone alkaloid derivatives through a facile organometallic C?H activation manifold with transformable pyridines.     

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.     

6‐Methylenebicyclo[3.2.1]oct‐1‐en‐3‐one: A Twisted Olefin as Diels–Alder Dienophile for Expedited Syntheses of Four Kaurane Diterpenoids

6‐Methylenebicyclo[3.2.1]oct‐1‐en‐3‐one, a twisted and highly reactive enone, was prepared for the first time by elimination of its bromide precursor. Its reactions as a dienophile with several dienes in Diels–Alder reactions proceeded smoothly to provide tricyclic and tetracyclic adducts, which allowed short syntheses (10–11 steps) of four kurane diterpenoids including 11β‐hydroxy‐16‐kaurene, 11α‐hydroxy‐16‐kaurene, liangshanin G, and gesneroidin B.     

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.     

Reaction energetics on long‐range corrected density functional theory: Diels–Alder reactions

The possibility of quantitative reaction analysis on the orbital energies of long‐range corrected density functional theory (LC‐DFT) is presented. First, we calculated the Diels–Alder reaction enthalpies that have been poorly given by conventional functionals including B3LYP functional. As a result, it is found that the long‐range correction drastically improves the reaction enthalpies. The barrier height energies were also computed for these reactions. Consequently, we found that dispersion correlation correction is also crucial to give accurate barrier height energies. It is, therefore, concluded that both long‐range exchange interactions and dispersion correlations are essentially required in conventional functionals to investigate Diels–Alder reactions quantitatively. After confirming that LC‐DFT accurately reproduces the orbital energies of the reactant and product molecules of the Diels–Alder reactions, the global hardness responses, the halves of highest occupied molecular orbital (HOMO)‐lowest unoccupied molecular orbital (LUMO) energy gaps, along the intrinsic reaction coordinates of two Diels–Alder reactions were computed. We noticed that LC‐DFT results satisfy the maximum hardness rule for overall reaction paths while conventional functionals violate this rule on the reaction pathways. Furthermore, our results also show that the HOMO‐LUMO gap variations are close to the reaction enthalpies for these Diels–Alder reactions. Based on these results, we foresee quantitative reaction analysis on the orbital energies. © 2012 Wiley Periodicals, Inc.     

Asymmetric Diels–Alder and Inverse‐Electron‐Demand Hetero‐Diels–Alder Reactions of β,γ‐Unsaturated α‐Ketoesters with Cyclopentadiene Catalyzed by N,N′‐Dioxide Copper(II) Complex

Highly enantioselective Diels–Alder (DA) and inverse‐electron‐demand hetero‐Diels–Alder (HDA) reactions of β,γ‐unsaturated α‐ketoesters with cyclopentadiene catalyzed by chiral N,N′‐dioxide–Cu(OTf)₂ (Tf=triflate) complexes have been developed. Quantitative conversion of β,γ‐unsaturated α‐ketoesters and excellent diastereoselectivities (up to 99:1) and enantioselectivities (up to >99 % ee) were observed for a broad range of substrates. Both aromatic and aliphatic β,γ‐unsaturated α‐ketoesters were found to be suitable substrates for the reactions. Moreover, the chemoselectivity of the DA and HDA adducts were improved by regulating the reaction temperature. Good to high chemoselectivity (up to 94 %) of the DA adducts were obtained at room temperature, and moderate chemoselectivity (up to 65 %) of the HDA adducts were achieved at low temperature. The reaction also featured mild reaction conditions, a simple procedure, and remarkably low catalyst loading (0.1–1.5 mol %). A strong positive nonlinear effect was observed.     

Diels‐alder reaction of 1‐methyl‐3,6,8‐trinitro‐2‐quinolone

1‐Methyl‐3,6,8‐trinitro‐2‐quinolone (1) behaved as the dienophile in Diels‐Alder reactions with dienes. When cyclopentadiene was used, cycloadduct 4 was obtained, which was then aromatized on treatment with triethylamine. In the reaction of 1 with hydrazone of 2‐butenal, phenanthridine derivative 7 was produced.     

Scandium(III)‐Zeolites as New Heterogeneous Catalysts for Imino‐Diels–Alder Reactions

This study demonstrates the first zeolite‐catalyzed synthesis of piperidine derivatives, including peptidomimetics and indoloquinolizidine alkaloids. The approach developed utilizes a highly effective one‐pot reaction cascade, through imine formation and imino‐Diels–Alder reactions, promoted by scandium‐loaded zeolites as a heterogeneous catalyst. The methodology described benefits from very low catalyst loadings (≤5 mol % of Sc^III), commercially and readily available starting materials, and mild reaction conditions. Furthermore, the Sc^III‐zeolite catalyst can be readily reused more than 10 times without any loss in efficiency.     

Development of Domino Processes by Using 7‐Silylcycloheptatrienes and Its Analogues

7‐Silyl‐ and 7‐silylmethylcycloheptatrienes were shown to react with acylnitroso reagents at room temperature, through their norcaradiene forms, to generate the corresponding cycloadducts 5 a – b and 6 a – b as single diastereomers. The course of the reaction was dramatically modified by changing the reaction conditions. Using a polar medium, functionalized cyclohexa‐1,3‐dienes 7 a – b and bicyclic compounds 13 a – b were instead generated, incorporating one or two amino groups. Similar behavior was observed by using other dienophiles, including triazolinedione, but also activated aldehydes and ketones. A tentative mechanism has been proposed to rationalize the formation of both classes of products that relies on a domino process involving four consecutive elementary steps, in this order: 1) electrocyclic process, 2) hetero‐Diels–Alder reaction, 3) cyclopropane ring opening, and 4) hetero‐Diels–Alder reaction. Trapping of the cationic intermediate and isolation of the primary cycloadduct provide support for this hypothesis. An enantioselective version of the cascade using cycloheptatriene 4 b and aldehydes and ketones, under copper(II) catalysis was also carried out, leading to cyclohexa‐1,3‐dienes 21 , 28 , and 30 with enantioselectivities up to 93 % ee. Finally, elaboration of the intermediates above has been carried out, opening a straightforward access to sugar mimics 42 – 43 and complex polycyclic systems 36 and 39 .     

Enantioselective Synthesis of Arene cis‐Dihydrodiols from 2‐Pyrones

An enantioselective chemical synthesis of arene cis‐dihydrodiols has been realized from 2‐pyrones through sequential ytterbium‐catalyzed asymmetric inverse‐electron‐demand Diels–Alder (IEDDA) reaction of 2‐pyrones and retro‐Diels–Alder extrusion of CO₂. By using this strategy, a series of substituted arene cis‐dihydrodiols can be obtained efficiently with high enantioselectivity (>99 % ee in many cases). Based on this strategy, efficient and concise asymmetric total syntheses of (+)‐MK7607 and 1‐epi‐(+)‐MK7607 were accomplished.     

1,4‐Cyclohexadienes—Easy Access to a Versatile Building Block via Transition‐Metal‐Catalysed Diels–Alder Reactions

1,4‐Cyclohexadiene derivatives are easily accessed via transition‐metal cycloadditions of 1,3‐dienes with alkynes. The mild reaction conditions of several transition‐metal‐catalysed reactions allows the incorporation of various functional groups to access functionalised 1,4‐cyclohexadienes. The control of the regiochemistry in the intermolecular cobalt‐catalysed Diels–Alder reaction is realised utilising different ligand designs. The functionalised 1,4‐cyclohexadiene derivatives are valuable building blocks in follow‐up transformations. Finally, the oxidation of the 1,4‐cyclohexadienes can be accomplished under mild conditions to generate the corresponding arene derivatives.