Reactive Dienophiles Research Articles

Design and Synthesis of Highly Reactive Dienophiles for the Tetrazine–trans-Cyclooctene Ligation

Computation was used to design a trans-cyclooctene derivative that displays enhanced reactivity in the tetrazine-trans-cycloctene ligation. The optimized derivative is an (E)-bicyclo[6.1.0]non-4-ene with a cis-ring fusion, in which the eight-membered ring is forced to adopt a highly strained 'half-chair' conformation. Toward 3,6-dipyridyl-s-tetrazine in MeOH at 25 °C, the strained derivative is 19 and 27 times more reactive than the parent trans-cyclooctene and 4E-cyclooct-4-enol, respectively. Toward 3,6-diphenyl-s-tetrazine in MeOH at 25 °C, the strained derivative is 160 times more reactive than the parent trans-cyclooctene.

ChemInform Abstract: Cationic Gold(I)‐Catalyzed Intermolecular [4 + 2] Cycloaddition Between Dienes and Allenyl Ethers.

Simple allenyl ethers have been shown to be efficiently activated by cationic gold(I) catalysts to form reactive dienophiles in intermolecular Diels-Alder reactions. A range of different dienes give the cycloaddition products in moderate to excellent yields and good selectivity.

Cationic Gold(I)‐Catalyzed Intermolecular [4+2] Cycloaddition between Dienes and Allenyl Ethers

AbstractSimple allenyl ethers have been shown to be efficiently activated by cationic gold(I) catalysts to form reactive dienophiles in intermolecular Diels–Alder reactions. A range of different dienes give the cycloaddition products in moderate to excellent yields and good selectivity.

ChemInform Abstract: 4‐Halogeno‐1,1,1‐trifluorobut‐3‐yn‐2‐one [4 + 2] Cycloadducts and Their Cross‐Coupling with Organozinc Compounds.

AbstractHalogenated trifluoroacetylacetylenes (I) are found to be reactive dienophiles in Diels—Alder reactions under mild conditions.

Domino Diels–Alder reactions of N-methoxyethyl-7-oxa-norbornadiene-2,3-dicarboximide: an elusive, highly reactive dienophile

Flash vacuum pyrolysis (FVP) has been used to generate the novel 7-oxa-norbornadiene-2,3-dicarboxylic imide that in situ gave an unprecedented cycloaddition reaction cascade with the imidofuran, a side-product of FVP. Stereoselectivity of cycloadditions was studied with the aid of density functional calculations, which fully support observed exo/ endo-selectivity.

ChemInform Abstract: Cyclobutenone as a Highly Reactive Dienophile: Expanding Upon Diels—Alder Paradigms.

AbstractSubstrate (II) renders possible the access to various cycloadducts with high diversity.

Synthesis of enantiopure trans‐N‐Boc‐3‐aminobicyclo[2.2.2]octane‐2‐carboxylic acids and their bicyclic 1,3‐amino alcohol derivatives via the [4+2] cycloaddition of 1,3‐cyclohexadiene to a chiral β‐nitroacrylate

The chiral β-nitroacrylate 2 derived from the (R)- or (S)-4-(3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl) benzoic acid 1 acts as a reactive dienophile in a diastereoselective Diels-Alder reaction with 1,3-cyclohexadiene. The major cycloadducts have been isolated and transformed into enantiopure trans(2S,3S)- or (2R,3R)-N-Boc-3-aminobicyclic[2,2,2]octane-2-carboxylic acids 5. The trans-(2S,3S)- or (2R,3R)-N-Boc 3-(hydoxymethyl)-2-aminobicyclic[2,2,2]octane 6 derivatives were also obtained.

ChemInform Abstract: Diels-Alder Reactions Catalyzed by Zeolites.

Abstract Various Zeolite catalysed Diels-Alder reactions of cyclopentadiene, cyclohexadiene and furan with less reactive dienophiles were studied. Exclusive endoselectivity was obtained with Ce-Y zeolite + anhydrous ZnBr2 for cyclopentadiene as well as cyclohexadiene Diels-Alder reactions.

ChemInform Abstract: The Unsymmetrical Silaketal as a Neutral, Removable Tether for Effecting Intramolecular Diels-Alder Reactions.

Abstract Silaketals, in which reactive dienes and dienophiles are linked, can participate in intramolecular Diels-Alder reactions to produce products with a high degree of stereocontrol and with regiochemistry opposite to that predicted by bond polarization models.

ChemInform Abstract: β-Cyanocyclobutenone as a Highly Reactive Dienophile in Comparison to β-Cyanocyclopentenone.

The thermal [2+2] cycloaddition of alpha-chloroacrylonitrile to allene followed by ozonolysis, then elimination of HCl provides access to the new beta-cyanocyclobutenone 1 (Scheme 1). Diels-Alder reactions of 1 occur very easily at room temperature. The high reactivity of 1 in [4+2] cycloadditions strongly contrasts with the low reactivity of the homologous cyanocyclopentenone 9 (Scheme 4). This is in agreement with calculations (PM3 method).

ChemInform Abstract: (Nitroaryl)sulfinyl-Substituted Allenes. Novel and Convenient Propargyl Alcohol Synthons in (4 + 2)Cycloaddition Chemistry.

(Nitroaryl) sulfinyl-substituted allenes are conveniently prepared by treating propargyl alcohol or methyl 3-hydroxy-2-butynoate with a (nitroaryl) sulfenyl chloride and triethylamine. These activated allenes undergo 4+2 cycloaddition across the C 1 C 2 π-bond. The initially formed allylic sulfoxide readily undergoes a 2,3-sigmatropic rearrangement to produce a stable sulfenate ester that is easily cleaved with thiophilic reagents. The dienophilic reactivity of the (nitroaryl) sulfinyl-substituted allene is much greater than the corresponding propargyl alcohol, and the cycloaddition also proceeds with high regioselectivity

Cyclobutenone as a highly reactive dienophile: expanding upon Diels-Alder paradigms.

Cyclobutenone was employed as a dienophile in Diels-Alder cycloadditions, provide diverse and complex cycloadducts in good yields. Experimental outcomes indicated cyclobutenone to be more reactive than either cyclopentenone or cyclohexenone. In addition, cycloadducts bearing a strained cyclobutanone moiety were able to undergo regioselective ring expansions to produce corresponding cyclopentanones, lactones, and lactams, which are otherwise difficultly obtained by direct Diels-Alder reactions.

ChemInform Abstract: Stereoselectivities of Diels-Alder Cycloadditions of π-Facially Nonequivalent Dienes to MTAD, PTAD, and N-Methylmaleimide: A Theoretical Study.

Abstract 1,2,3,4,9,9-hexachloro-1α,4α,4aα,8aβ-tetrahydro-1,4-methanonaphthalene (1) and 1,2,3,4,9,9-hexachloro-1α,4α,6,7-tetrahydro-1,4-methanonaphthalene (2) undergo π-facially diastereoselective Diels-Alder reactions with 4-methyl- and 4-phenyl-1,2,4-triazoline-3,5-dione [MTAD and PTAD, respectively] and with N-methylmaleimide (NMM). In contrast with the results of AM1 calculations, those obtained via ab initio calculations performed at the HF/3-21G∗ level of theory predict that the computed Diels-Alder transition states are synchronous in all cases studied. Furthermore, these computational results account quantitatively for: (i) the observed π-facial selectivities of the various Diels-Alder reactions studied, (ii) the observed relative lack of dienophilic reactivity of NMM vis-a-vis MTAD and PTAD, and (ii) the observed enhanced diene reactivity of 1 vs. 2 in the reactions studied.

ChemInform Abstract: New Reactivity Patterns in the Diels-Alder Reactivity of Nitrobenzofuroxans.

The reaction of cyclopentadiene with 4-nitro-6-trifluoromethylsulfonylbenzofuroxan 5 in dichloromethane or chloroform proceeds stereoselectively at 0 °C to afford a single compound 6, which is shown to result from an inverse electron-demand Diels–Alder condensation involving the carbocyclic ring of 5 as the diene contributor. However, the adduct 6, whose X-ray structure could be obtained, is not the thermodynamically stable product of the interaction. Keeping a solution of 6 at room temperature results after a few days in the isolation of a new adduct 7a which arises from a regioselective and stereoselective normal electron-demand Diels–Alder condensation involving the C(4)C(5) double bond of 5 as the dienophile contributor. The carbodienic behaviour of 5 as well as the preferred dienophilic reactivity of the C(4)C(5) rather than of the C(6)C(7) double bond, represent two new reactivity patterns in the chemistry of the nitrobenzofuroxans.

Diels–Alder reaction of α-tropolone and electron-deficient dienophiles prompted by Et 3N or silica gel: a new synthetic method of highly functionalized homobarrelenone derivatives

A Diels–Alder reaction of α-tropolone and electron-deficient dienophiles prompted by Et 3N or silica gel was performed. Reaction with the highly reactive dienophile, N-methylmaleimide, proceeded smoothly in the presence of Et 3N or silica gel to yield adducts as a mixture of endo and exo isomers. Both catalysts accelerated endo/ exo isomerization of the product, and detailed examination of the reaction using hinokitiol and N-methylmaleimide revealed that isomerization proceeds via an intramolecular path without retro Diels–Alder reaction. Successful cycloaddition reactions were established with six other dienophiles: acrylonitrile, methyl acrylate, ethyl vinyl ketone, dimethyl fumalate, dimethyl malate, and dimethyl acetylenedicarboxylate, and the corresponding adducts were obtained in good to moderate yields.

Is anthracene cofactor or spectator for the thermolysis of anthracenyl acylnitroso cycloadducts in the presence of a diene?

Acylnitroso species are very reactive dienophiles broadly used in organic synthesis. They are traditionally prepared from the oxidation of hydroxamic acids at low temperature. When this strategy fails, acylnitroso compounds may be generated from other stable sources, for example, their (9,10-dimethyl)anthracenyl cycloadducts. The thermolysis of such compounds performed in the presence of a diene leads generally to the corresponding hetero Diels–Alder (HD–A) cycloadduct in high yield with concomitant release of anthracene. The most widely accepted mechanism is the postulated slow release of acylnitroso via a retro Diels–Alder process, although the anthracenyl acylnitroso cycloadducts bear intrinsic structural features suggesting another pathway, that is, an exchange process. By using computational chemistry, we have hereby clarified the exact role of anthracene in this reaction.

Benzofurans as Efficient Dienophiles in Normal Electron Demand [4 + 2] Cycloadditions

Dearomatization of electron-poor benzofurans is possible through involvement of the aromatic 2,3-carbon-carbon double bond as dienophile in normal electron demand [4 + 2] cycloadditions. The tricyclic heterocycles thereby produced bear a quaternary center at the cis ring junction, a feature of many alkaloids such as morphine, galanthamine, or lunaridine. The products arising from the reaction have been shown to depend on different factors among which the type of the electron-withdrawing substituent of the benzofuran, the nature of the reacting diene, and the method of activation. In the presence of all-carbon dienes, the reaction yields the expected Diels-Alder adducts. When thermal activation is insufficient, a biactivation associating zinc chloride catalysis and high pressure is required to generate the cycloadducts in good yields and high stereoselectivities, for instance, when cyclohexadiene is involved in the process. The use of more functionalized dienes, such as those bearing alkoxy or silyloxy substituents, also shows the limits of the thermal activation, and hyperbaric conditions are, in this case, well-suited. The involvement of Danishefsky's diene induces a competition in the site of reactivity. The aromatic 2,3-carbon-carbon double bond is unambiguously the most reactive dienophile, and the 3-carbonyl unit becomes a competitive site of reactivity with benzofurans bearing substituents prone to heterocyloaddition, in particular under Lewis acid activation. The sequential involvement of both the aromatic double bond and the carbonyl moiety as dienophiles is then possible by using an excess of diene under high-pressure activation. In line with the experimental results, DFT computations suggest that the Diels-Alder process involving the aromatic double bond is preferred over the hetero-Diels-Alder route through an asynchronous concerted transition state. However, Lewis acid catalysis appears to favor the heterocycloaddition pathway through a stepwise mechanism in some cases.

Control of the Regio‐ and Stereoselectivity in Diels–Alder Reactions with Quinone Boronic Acids

It all adds up: The dienophilic reactivity of 2-methyl-substituted quinones has been substantially increased by the introduction of a boronic acid substituent, which makes them equivalent to a highly reactive quinone. The Diels–Alder reactions of these quinones are followed by spontaneous and stereoselective protodeboronation to give the trans-fused adducts. The boron group is a temporal regiocontroller and leads to the uncommon meta adduct.

Diversity‐Oriented Synthesis of Enantiomerically Pure Steroidal Tetracycles Employing Stille/Diels–Alder Reaction Sequences

Various steroid analogues were synthesized by Stille coupling of bicyclo[4.3.0]nonenylstannanes cis-/trans-8 and 14 with cyclohexenol triflates 17 and 18 and subsequent Diels-Alder reactions of the resulting dienes. The enantiomerically pure bicyclo[4.3.0]nonenylstannanes cis- and trans-8 were prepared in good yields via the enol triflates cis- and trans-7, obtained from the bicyclo[4.3.0]non-2-en-3-one 5. The alkenylstannane 14 was obtained from the [2+2] cycloadduct 10 a produced from addition of dichloroketene to the enantiomerically pure and protected bishydroxycyclohexadiene 9 a (65 %). Treatment of 10 a with diazomethane, reduction of the dichloromethylene group, and trapping with tributyltin chloride after lithium-for-bromine exchange, yielded the bicyclo[4.3.0]nonenylstannane 14 (23 % over four steps). Stille couplings provided the tricyclic dienes cis-/trans-19 in good yields (73-77 %), whereas the tricyclic diene 20 was obtained in only 34 % yield at best. Diels-Alder reactions of trans-19 with various reactive dienophiles yielded the novel steroidal compounds trans-21 to trans-26 with complete diastereoselectivity. Heating the dienes cis-19 or 20 with maleic acid derivatives provided the corresponding tetracycles cis-23alpha,beta and 27alpha,beta with a cis-C,D ring junction, each as mixtures of two diastereomers. Less reactive dienophiles required higher temperatures to promote the relevant cycloaddition with trans-19 to furnish several stereoisomeric forms of trans-28 and trans-29 in significantly lower yields (31-45 %). The selected steroid analogues trans-22 and trans-23 were deprotected in two steps by using acid catalysis to provide trans-31 and trans-33 (91 and 80 % over two steps). Cyclopropanation of trans-30 yielded the cyclopropasteroid analogue 34 (74 %), treatment of which with trifluoroacetic acid furnished the cyclopropasteroid 35 and the 2-methyl-substituted steroid analogue 36 in 40 and 12 % yield, respectively. Aromatic B-ring steroids 38 (69 %) and 39 (5 %) were accessed by dehydrogenation of trans-24 with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

Cobalt-Catalyzed Cyclotrimerization of Alkynes: The Answer to the Puzzle of Parallel Reaction Pathways

To understand some experimental data at odds with the computed mechanism of the CpCo(L2)-catalyzed [2 + 2 + 2] cyclotrimerization of ethyne, DFT computations were carried out following the fate of methyl- and hydroxycarbonyl-substituted alkynes to give the corresponding arenes. The key intermediate in all cases is a triplet cobaltacyclopentadiene obtained by oxidative coupling of the corresponding CpCo(bisalkyne) complex and subsequent spin change via a minimum energy crossing point (MECP). From that species, two different catalytic cycles lead to an arene product, depending on the nature of the alkyne and other ligands present: either alkyne ligation to furnish a cobaltacyclopentadiene(alkyne) intermediate or trapping by a sigma-donor ligand to generate a coordinatively saturated cobaltacyclopentadiene(PR3) complex. The former leads to the CpCo-complexed arene product via intramolecular cobalt-assisted [4 + 2] cycloaddition, whereas the latter may, in the case of a reactive dienophile (butynedioic acid), undergo direct intermolecular [4 + 2] cycloaddition to generate a cobaltanorbornene. The bridgehead cobalt atom is then reductively eliminated after another change in spin state from singlet to triplet. The necessary conditions for one or the other mechanistic pathway are elaborated.