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.     

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.     

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).     

Molecular Iodine Catalyzed One‐pot Aza‐Diels‐Alder Reaction under Solvent‐free Conditions

Catalyzed by molecular iodine at room temperature, under solvent‐free conditions, a two component aza‐Diels‐Alder cyclization of N‐vinyl‐2‐pyrrolidinone with N‐arylimine gave tetrahydroquinoline derivatives in good yields and high stereo‐selectivity. And three components aza‐Diels‐Alder reaction of N‐vinyl‐2‐pyrrolidinone, anilines and indole‐3‐carbaldehydes under the same condition afford only cis‐product in good yields.     

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.     

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 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.     

Stereoselective Synthesis of Polycycles Containing an Aziridine Group: Intramolecular aza‐Diels–Alder Reactions of Unactivated 2H‐Azirines with Unactivated Dienes

Vinyl azide with a pendent diene can undergo thermal decomposition to a related azirine intermediate, which was used immediately in an intramolecular aza‐Diels–Alder reaction to furnish an aziridine‐containing trans‐fused tricyclic core structure with excellent stereoselectivity. The method provides a facile entry to complex polycyclic alkaliods which can be further elaborated by ring‐opening reactions and ring expansion of the aziridine moiety, as well as by dihydroxylation of the alkene group.     

N,N′‐Dioxide/Nickel(II)‐Catalyzed Asymmetric Inverse‐Electron‐Demand Hetero‐Diels–Alder Reaction of β,γ‐Unsaturated α‐Ketoesters with Enecarbamates

N,N′‐Dioxide/nickel(II) complexes have been developed to catalyze the inverse‐electron‐demand hetero‐Diels–Alder reaction of β,γ‐unsaturated α‐ketoesters with acyclic enecarbamates. After detailed screening of the reaction parameters, mild optimized reaction conditions were established, affording 3,4‐dihydro‐2H‐pyranamines in up to 99 % yield, 99 % ee and more than 95:5 d.r. The catalytic system was also efficient for β‐substituted acyclic enecarbamates, affording more challenging 2,3,4‐trisubstituted 3,4‐dihydro‐2H‐pyranamine with three contiguous stereogenic centers in excellent yields, diastereoselectivities, and enantioselectivities. The reaction could be scaled up to a gram scale with no deterioration of either enantioselectivity or yield. Based on these experiments and on previous reports, a possible transition state was proposed.     

First synthesis of 2‐(2,4,4‐trimethyl‐3,4‐dihydro‐2H‐benzo[h]chromen‐2‐yl)‐1‐naphthol and 3‐(2,4,4‐trimethyl‐3,4‐dihydro‐2H‐benzo[g]chromen‐2‐yl)‐2‐naphthol from 1‐ and 2‐naphthol derivatives

Two new structurally isomeric, 2‐(2,4,4‐trimethyl‐3,4‐dihydro‐2H‐benzo[h]chromen‐2‐yl)‐1‐naphthol ( 1 ) and 3‐(2,4,4‐trimethyl‐3,4‐dihydro‐2H‐benzo[g]chromen‐2‐yl)‐2‐naphthol ( 3 ) have been synthesized from 2‐acetyl‐1‐naphthol and ethyl‐3‐hydroxy‐2‐naphthoate, respectively, involving Grignard reaction, dehydration of the corresponding tertiary alcohols, and hetero Diels–Alder dimerization. The two benzochromenes ( 1 and 3 ) have been fully characterized by IR, NMR, and HRESIMS data. Their structures are further supported by crystallography of their corresponding acetates ( 2 and 4 ). J. Heterocyclic Chem., (2011).     

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.     

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.     

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.     

Stereoselective synthesis of pyrano[3,2‐c]‐ and furano[3,2‐c]quinolines: Gadolinium chloride catalyzed one‐pot aza–Diels–Alder reactions

A simple and efficient method for the cis‐selective synthesis of pyrano‐ and furano[3,2‐c]quinolines via gadolinium chloride catalyzed one‐pot aza–Diels–Alder reaction is described. Solvent conditions played a major role in affecting the diastereoselectivity of the products. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 21:351–354, 2010; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20612     

Diastereodivergent Catalysis Using Modularly Designed Organocatalysts: Synthesis of both cis‐ and trans‐Fused Pyrano[2,3‐b]pyrans

Both enantiomers of cis‐ and trans‐fused 3,4,4a,8a‐tetrahydro‐2H,5H‐pyrano[2,3‐b]pyran‐7‐carboxylates have been obtained in high diastereoselectivities and enantioselectivities from the same starting materials using a tandem inverse‐electron‐demand hetero‐Diels–Alder/oxa‐Michael reaction catalyzed by modularly designed organocatalysts (MDOs). Diastereodivergence was achieved in these reactions through the direct control of the stereochemistry of the bridgehead atoms of the fused ring using new MDOs self‐assembled from both enantiomers of proline and cinchona alkaloid thiourea derivatives.     

A Pyrene‐Linked Cavity within a β‐Barrel Protein Promotes an Asymmetric Diels–Alder Reaction

A unique π‐expanded reaction cavity tethering a polycyclic moiety which provides a platform for substrate binding was constructed within the robust β‐barrel structure of nitrobindin (NB). NB variants with cavities of different sizes and shapes are coupled with N ‐(1‐pyrenyl)maleimide ( Pyr ) to prepare a series of NB‐ Pyr conjugates. The orientation of the pyrene moiety is fixed within the cavity by the coupling reaction. The fluorescent quenching analysis of NB‐ Pyr indicates that azachalcone ( aza ), which is a dienophile for a Diels–Alder (DA) reaction, is efficiently incorporated within the pyrene‐linked reaction cavity by the aromatic interaction. The DA reaction between aza and cyclopentadiene proceeds within the reaction cavity of NB‐ Pyr in the presence of Cu^II ion in high yield and high enantio‐ and regioselectivity.     

Indium Trichloride Catalyzed Diels–Alder Reaction: Synthesis of Novel 5‐Butyl‐11a‐aryl‐4a,5,11,11a‐tetrahydro‐11bH‐indolo[3,2‐c]quinoline‐1,4‐dione

Hetero Diels–Alder reaction of 3‐butyliminomethyl‐2‐aryl‐1H‐indoles (Schiff's base) 1 with p‐benzoquinone 2 affords six novel 5‐butyl‐11a‐aryl‐4a,5,11,11a‐tetrahydro‐11bH‐indolo[3,2‐c]quinoline‐1,4‐diones 3 in good yields. All the reactions proceeded with complete diastereoselectivity giving only one product in each case, which was characterized on the basis of its elemental analyses and spectral data (IR, ¹H NMR, and Mass).     

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.     

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 .     

Enantioselective Addition of Cyclic Enol Silyl Ethers to 2‐Alkenoyl‐Pyridine‐N‐Oxides Catalysed by CuII–Bis(oxazoline) Complexes

Asymmetric reactions involving (E)‐3‐aryl‐1‐(pyridin‐2‐yl‐N‐oxide)prop‐2‐en‐1‐ones and cyclic enol silyl ethers show good yields and excellent enantioselectivities (up to 99.9 % ee) when catalysed by bis(oxazoline)–Cu^II complexes. Different reaction pathways can be followed by different enol silyl ethers: with 2‐(trimethylsilyloxy)furan, a Mukaiyama–Michael adduct is obtained, whereas a hetero Diels–Alder cycloadduct was formed by using (1,2‐dihydronaphthalen‐4‐yloxy)trimethylsilane. In the latter reaction, the absolute configuration of the product is consistent with a reagent approach to the less hindered Re face of the coordinated substrate in the reactive complex.