Double Diels-Alder Research Articles

Development of Functional Compounds Using Chemically Unstable Compounds Obtained from Medicinal Plants

Sulfur- or nitrogen-containing compounds from medicinal plants exhibit various biological activities such as anticancer potential. Developing efficient strategies to isolate or synthesize these compounds or their derivatives is a remarkable achievement. We have isolated several sulfur-containing compounds such as tetrahydro-2H-difuro[3,2-b:2',3'-c]furan-5(5aH)-one derivatives from Allium plants. We have devised a unique approach for the rapid preparation of thiopyranones using the regioselective sequential double Diels-Alder reaction; we used a naturally-occurring chemically-unstable intermediate such as thioacrolein, which is produced from allicin, a major component in garlic. The cytotoxicity of the synthetic thiopyranones against cancer stem cells (CSCs) was equal to or higher than that of (Z)-ajoene, the reference compound.

A carbene-stabilized diphosphorus: a triple-bonded diphosphorus (P[triple bond, length as m-dash]P) and a bis(phosphinidene) (P-P) transfer agent.

The reaction of the N,N-diisopropyl bromoiminium salt with excess sodium phosphaethynolate (NaPCO) affords a diphospha-urea 2. Under blue light irradiation (450 nm), carbon monoxide is liberated affording the bis(carbene)P2 adduct 3. Photolysis of a benzene solution of 3 at 365 nm gives rise to the carbene dimer, namely the 1,2-bis(diisopropylamino)ethylene as a cis/trans mixture, along with white and red phosphorus. Under the same experimental conditions, but in the presence of excess 2,3-dimethyl-1,3-butadiene, the classical double Diels-Alder adduct of the triple-bonded diphosphorus P[triple bond, length as m-dash]P was obtained along with the bis(phospholene) formally resulting from a double [4 + 1] reaction of the diene with the bis(phosphinidene) form of P2. A stepwise carbene-carbene exchange reaction also occurs between the monosubstituted aminocarbene of 3 and a cyclic (alkyl)(amino)carbene, possibly involving the transient formation of a diphosphorus analogue of a diazo compound.

The Pursuit of Perphenylterphenyls.

Tetradecaphenyl-p-terphenyl (2) was synthesized from 2,3,5,6-tetraphenyl-1,4-diiodobenzene (11) by two methods. Ullmann coupling of 11 with pentaphenyliodobenzene (9) gave compound 2 in 1.7 % yield, and Sonogashira coupling of 11 with phenylacetylene, followed by a double Diels-Alder reaction of the product diyne 12 with tetracyclone (6), gave 2 in 1.5 % overall yield. The latter reaction also gave the monoaddition product 4-(phenylethynyl)-2,2',3,3',4',5,5',6,6'-nonaphenylbiphenyl (13) in 4 % overall yield. The X-ray structures of compounds 2 and 13 show them to possess core aromatic rings distorted into shallow boat conformations. Density functional calculations indicate that these unusual structures are not the lowest energy conformations in the gas phase and may be the result of packing forces in the crystal. In addition, while uncorrected DFT calculations indicate that the strain energy in compound 2 is approximately 50 kcal/mol, dispersion-corrected DFT calculations suggest that it is essentially unstrained, due to compensating, favorable, intramolecular interactions of its many phenyl rings. An attempted synthesis of tetradecaphenyl-o-terphenyl (4) by reaction of diphenylhexatriyne (14) with three equivalents of tetracyclone at 350 °C gave only the diadduct 2-(phenylethynyl)-2',3,3',4,4',5,5',6,6'-nonaphenylbiphenyl (15) in 17 % yield. Even higher temperatures failed to produce 4 and lowered the yield of 15, perhaps due to rapid decomposition of the starting materials. Ullmann coupling of 3,4,5,6-tetraphenyl-1,2-diiodobenzene (16) and compound 9 also failed to give compound 4.

Development and Applications of Double Diels‐Alder Reaction in Organic Synthesis

AbstractThe class of Double Diels‐Alder (DDA) reactions leading the targets concisely where numerous synthetic pursuits have been rewarded with conceptually novel and streamlined methods. After the tremendous development and discoveries in various Diels‐Alder reactions including its key role applications in many natural products syntheses, the DDA reaction is considered as a growing branch of Diels‐Alder reaction where two consecutive [4+2] cycloadditions trigger the streamlined construction of polycyclic and macrocyclic architectures. In light of the ever‐increasing importance of DDA reactions in chemical sciences, we review the comprehensive studies and recent advances in DDA reactions in organic synthesis. This review summarizes key achievements of DDA for the preparation of macrocyclic, bicyclic, heterocyclic, and polycyclic structures documented since its revelation in 1980 to 2020. Emphasis is put on the synthesis of various structural classes based on the selectivity of the DDA reaction.

Facile One-Pot Synthesis and Crystal Structure of 2:1 Adducts of Myrcene (or Ocimene) with Benzoquinones

One-pot tandem oxidation and double Diels-Alder reaction of myrcene or ocimene with in situ generated 1,4-benzoquinone or 1,2-benzoquinone at 0°C for 1.5 h yielded polyalkylated 1,4,4a,5,8,8a,9a,10a-octahydro-9,10-anthracenediones and bis(alkylated) 9,10-phenanthrenedione respectively. The structure of novel bis-adduct from ocimene, (1R,4aR,5S,8aS,9aS,10aR)-rel- 1,4,4a,5,8,8a,9a,10a-octahydro-2,6-dimethyl-1,5-bis(3-methyl-2-buten-1-yl)-9,10-anthracenedione, was elucidated through single crystal X-ray analysis.

Synthesis and application of 3,4,7,8-tetrakis-exo-methylenecycloocta-1,5-diene as a versatile Diels-Alder diene: synthesis of V-shaped cyclooctatetraene fused acenes.

V-shaped molecules with a cyclooctatetraene (COT) core and rigid acene wings are an interesting class of compounds from the point of view of synthetic challenge and their applications in various fields such as photonics and molecular electronics. A new Diels-Alder diene, namely 3,4,7,8-tetrakis-exo-methylenecycloocta-1,5-diene (1), has been synthesized on a multigram scale by the debromination of 1,4,5,8-tetrakis-bromomethylcycloocta-1,3,5,7-tetraene (2) using either zinc powder or NaI. Compound 1 was used as a Diels-Alder diene with various dienophiles to yield the corresponding double Diels-Alder adducts. The Diels-Alder adducts have a COT core and dihydroaromatic wings which were aromatized with a variety of reagents. The methodology described herein provides a direct and shorter route for the synthesis of COT fused with rigid aromatic wings (V-shaped) compared to the existing iterative multistep synthesis of such compounds.

Revisiting Kekulene: Synthesis and Single-Molecule Imaging.

Four decades after the first (and only) reported synthesis of kekulene, this emblematic cycloarene has been obtained again through an improved route involving the construction of a key synthetic intermediate, 5,6,8,9-tetrahydrobenzo[m]tetraphene, by means of a double Diels–Alder reaction between styrene and a versatile benzodiyne synthon. Ultra-high-resolution AFM imaging of single molecules of kekulene and computational calculations provide additional support for a molecular structure with a significant degree of bond localization in accordance with the resonance structure predicted by the Clar model.

One-pot synthesis of [6-5-6] tricyclic products via a double Diels-Alder/Nazarov tandem reaction of unsymmetrically substituted cross-conjugated diynones

A highly concise one-pot method towards biologically pertinent compounds having a [6-5-6] tricyclic framework has been established. The multicomponent reaction utilizes a tandem, double Diels-Alder cycloaddition followed by a Nazarov reaction to furnish the [6-5-6] backbone. This method produces three fused rings evolving from the construction of five new carbon-carbon bonds, a quaternary carbon, and stereogenic centers in a one-pot reaction. The products are produced with excellent regio- and diastereocontrol.

Crystal structure of 5,7,12,14-tetra-hydro-5,14:7,12-bis-([1,2]benzeno)-penta-cene-6,13-dione.

The lattice of 5,7,12,14-tetra-hydro-5,14:7,12-bis-([1,2]benzeno)-penta-cene-6,13-dione, C34H20O2, at 173 K has triclinic (P-1) symmetry and crystallizes with four independent half-mol-ecules in the asymmetric unit. Each mol-ecule is generated from a C17H10O substructure through an inversion center at the centroid of the central quinone ring, generating a wide H-shaped mol-ecule, with a dihedral angle between the mean planes of the terminal benzene rings in each of the two symmetry-related pairs over the four mol-ecules of 68.6 (1) (A), 65.5 (4) (B), 62.3 (9) (C), and 65.8 (8)° (D), an average of 65.6 (1)°. This compound has applications in gas-separation membranes constructed from polymers of intrinsic microporosity (PIM). The title compound is a product of a double Diels-Alder reaction between anthracene and p-benzo-quinone followed by de-hydrogenation. It has also been characterized by cyclic voltammetry and rotating disc electrode polarography, FT-IR, high resolution mass spectrometry, elemental analysis, and 1H NMR.

ChemInform Abstract: An Unexpected Double Diels—Alder Reaction of (E)‐2‐Bromo‐4‐aryl‐1,3‐pentadiene Involving [1,5]‐Hydrogen Migration and HBr Elimination: Synthesis of Bicyclo[2.2.2]octene Derivatives.

An unexpected double Diels-Alder (DDA) reaction of (E)-2-bromo-4-aryl-1,3-pentadiene was developed and resulted in a series of butterfly-like bicyclo[2.2.2]octene derivatives in moderate to good yields without the need for a metal catalyst. The proposed mechanism involves a [1,5]-sigmatropic hydrogen migration and HBr elimination. Through this decisive [1,5]-hydrogen shift step, the electronic properties and steric hindrance of the conjugated diene substrate are completely altered and the DDA reaction of this potential diene synthon is successfully achieved.

An unexpected double Diels-Alder reaction of (E)-2-bromo-4-aryl-1,3-pentadiene involving [1,5]-hydrogen migration and HBr elimination: synthesis of bicyclo[2.2.2]octene derivatives.

An unexpected double Diels-Alder (DDA) reaction of (E)-2-bromo-4-aryl-1,3-pentadiene was developed and resulted in a series of "butterfly-like" bicyclo[2.2.2]octene derivatives in moderate to good yields without the need for a metal catalyst. The proposed mechanism involves a [1,5]-sigmatropic hydrogen migration and HBr elimination. Through this decisive [1,5]-hydrogen shift step, the electronic properties and steric hindrance of the conjugated diene substrate are completely altered and the DDA reaction of this potential diene synthon is successfully achieved.

Synthesis of Bistetrahydroquinolines as Potential Anticholinesterasic Agents by Double Diels-Alder Reactions

The tetrahydroquinoline ring system is a unit found in many biologically active natural products and pharmacologically relevant therapeutic agents. A new series of bistetrahydroquinolines (bis-THQs) was synthesized using imino Diels-Alder reactions between dialdehydes, anilines and N-vinyl-2-pyrrolidone (NVP). The notable features of this procedure are mild reaction conditions, greater selectivity and good yields of products. In addition, the inhibitory activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) of some selected derivatives is reported. The feasible binding modes of these active compounds, within AChE and BuChE binding sites, were predicted by molecular docking experiments and their binding affinity was estimated by means of free energy calculations through the MM-GBSA approximation.

N-Alkyldinaphthocarbazoles, Azaheptacenes, for Solution-Processed Organic Field-Effect Transistors

Substituted N-alkyldinaphthocarbazoles were synthesized using a key double Diels-Alder reaction. The angular nature of the dinaphthocarbazole system allows for increased stability of the conjugated system relative to linear analogues. The N-alkyldinaphthocarbazoles were characterized by UV-vis absorption and fluorescence spectroscopy as well as cyclic voltammetry. X-ray structure analysis based on synchrotron X-ray powder diffraction revealed that the N-dodecyl-substituted compound was oriented in an intimate herringbone packing motif, which allowed for p-type mobilities of 0.055 cm(2) V(-1) s(-1) from solution-processed organic field-effect transistors.

ChemInform Abstract: Pericyclic Reactions of 2-Pyrones with Nonconjugated Dienes. Conformational Analysis of the Double Diels-Alder Adducts by Molecular Mechanics Calculation.

Pericyclic reactions of 5-methoxycarbonyl-2-pyrone (Ic) with nonconjugated dienes (IIa-j) were investigated. The diene (Ic) reacted readily with IIa-j to give [4+2]π cycloadducts (IIIa-j) that lost carbon dioxide to afford intramolecular double Diels-Alder (DDA) adducts (V). The structures of these adducts were determined from spectral evidence. The reactivity of the addends and the regiochemistry of the primary adducts are discussed on the basis of modified neglect of diatomic overlap (MNDO) calculation data. The relative stability of the twistene- and isotwistene- type compounds and the conformation of some isotwistene-type compounds are discussed on the basis of the molecular mechanics (MM2) calculation data.

ChemInform Abstract: Double Diels-Alder Cycloadditions of 2(1H)-Pyridones Acting as Dienophiles.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Crystallographic Evidence for Cyclopropane Ring Formation in Isotwistenes Obtained by Thermal Cascade Reactions of Cyclopentadienone with Acyclic Conjugated Dienes

The molecular structure of the double Diels-Alder (DDA) adduct derived from three-step thermal cascade reactions of 2,5-bis(methoxycarbonyl)-3,4-diphenylcyclopentadienone with ethyl sorbate is elucidated by single crystal X-ray analysis. The structural features and the reaction mechanism of the adduct are discussed on the basis of density functional theory (DFT) calculation results.

Double Diels−Alder Strategies to Soluble 2,9- and 2,9,6,13-Tetraethynylpentacenes, Photolytic [4 + 4] Cycloadditions, and Pentacene Crystal Packing

Four new classes of organic solvent soluble ethynylpentacene derivatives (2,9-, 2,10-, 2,6,9,13-, 2,6,10,13-) have been prepared by complementary, versatile, double Diels-Alder strategies. Functional groups on the A, C, and E rings can be manipulated to increase the solubility, modulate the electronics, and alter the solid-state packing. Cycloaddition reactions with diene 2 and 1,4,5,8-anthradiquinone (3) or ortho-quinodimethane 19 with 1-butyl-3-methylimidazolim iodide (18) as the iodide source (a significant improvement over NaI) and benzoquinone (20) followed by in situ aromatization afforded the quinones 4, 5, 21, and 22, respectively. For the 2,9- and 2,10- families, a one-pot desilylation/triflation was developed. Palladium(0) coupling and reductive aromatization afforded 2,9-di(triisopropylsilylethynyl)pentacene (10) and 2,10-di(triisopropylsilylethynyl)pentacene (11), respectively. Photodimerization of these pentacenes afforded the air-stable [4 + 4] cycloaddition pentacene precursors (tetrakisnaphthotricyclo[4.2.2.22,5]dodecanes, 12-15). Thermal cycloreversion of the dimers ( approximately 13 J/g, approximately 4 kcal/mol) produces the parent pentacenes (10 or 11). The tetrasubstituted family utilized a parallel route with extra versatility as the timing of the Grignard and palladium(0) coupling step may be varied depending upon the functional group combinations desired. The subsequent reactions provided the tetraethynylpentacenes 28-30, 33-35 (para-isomers), and 38 (meta-isomer). X-ray crystallography analysis of 28, 29, and 33 revealed various pi-pi stacked packing motifs that differ from the unfavorable herringbone pattern of pentacene.

Approaches to Open Fullerenes: Synthesis and Thermal Stability of cis-1 Bis(isobenzofuran) Diels−Alder Adducts of C60

In a quest to form wider openings within the cage of the fullerene C60 through controlled bond-breaking reactions, we have examined the double saturation of adjacent C=C bonds within a six-membered ring of C60. We have investigated the double Diels-Alder cycloaddition of two tethered isobenzofurans to the fullerene C60. We obtained cis-1 adducts in good yields after reacting the methylene- or quinoxaline-tethered bis(isobenzofuran) precursors 2a-k with parent 3,6-dihydro-1,2,4,5-tetrazine (3b). The X-ray structure of the methylene-tethered bis(isobenzofuran)-C60 adduct 4b has been obtained; four-eclipsed substituents are held rigidly by the bicyclic addends. The cis-1 bis(isobenzofuran) bisadducts 4b and 4e-j are kinetically far more stable toward thermal retro-Diels-Alder fragmentation than are mono(isobenzofuran) adducts of C60, in solution and in the solid state as determined by 1H NMR spectroscopy or thermogravimetric analysis. A methodology for the reversible solubilization of other fullerene derivatives based on this work is also presented.

Microwave-Assisted Diels-Alder Reaction of 2H-Pyran-2-ones with Maleimides towards Fused Bicyclo[2.2.2]octenes

An efficient, green access to functionalized and highly constrained heteropolycyclic derivatives via a microwave-assisted cycloaddition reaction is reported. The double Diels-Alder reaction of a series of 2H-pyran-2-ones with maleimide and its N-substituted derivatives takes place in an aqueous mixture (and in some cases as neat reaction) to give a variety of fused bicyclo[2.2.2]oct-7-enes.

A Highly Pyramidalized Cage Alkene Formed via the Double Diels−Alder Cycloaddition of syn-4,5,13,14-Bis(dehydro)octafluoroparacyclophane to Anthracene

[reaction: see text] A double Diels-Alder reaction of the formal syn-bis(dehydro)octafluoroparacyclophane with anthracene leads to formation of a novel cage compound that contains a highly pyramidal double bond. The measures of pyramidality of this double bond constitute what appear to be the highest combined values of psi and phi (34.3 degrees and 33.5 degrees, respectively) yet reported to have been determined by X-ray crystallography. This cage compound, although stable indefinitely as a crystalline compound in air, exhibits the high reactivity with both triplet and singlet O2 in solution that is characteristic of such highly pyramidal pi systems.