Rhodium N-heterocyclic carbene-catalyzed [4 + 2] and [5 + 2] cycloaddition reactions

[reactions: see text] A rhodium complex of N-heterocyclic carbene (NHC) has been developed for intra- and intermolecular [4 + 2] and intramolecular [5 + 2] cycloaddition reactions. This is the first use of a transition-metal NHC complex in a Diels-Alder-type reaction. For the intramolecular [4 + 2] cycloaddition reactions, all the dienynes studied were converted to their corresponding cycloadducts in 91-99% yields within 10 min. Moreover, up to 1900 turnovers have been obtained for the intramolecular [4 + 2] cycloaddition at 15-20 degrees C. For the intermolecular [4 + 2] cycloadditions, high yields (71-99%) of the corresponding cycloaddition products were obtained. The reaction time and yield were highly dependent upon the diene and the dienophile. For the intramolecular [5 + 2] cycloaddition reactions, all the alkyne vinylcyclopropanes studied were converted to their corresponding cycloadducts in 91-98% yields within 10 min. However, the catalytic system was not effective for an intermolecular [5 + 2] cycloaddition reaction.     

Mechanically facilitated retro [4+2] cycloadditions

Poly(methyl acrylate)s (PMAs) of varying molecular weights were grown from a [4+2] cycloaddition adduct of maleimide with furan containing two polymerization initiators. Subjecting the corresponding PMA (>30 kDa) chains to ultrasound at 0 °C resulted in a retro [4+2] cycloaddition reaction, as observed by gel permeation chromatography (GPC) and UV-vis spectroscopy, as well as labeling of the liberated maleimide and furan moieties with appropriate chromophores featuring complementary functional groups. Similar results were obtained by sonicating analogous polymers that were grown from a thermally robust [4+2] cycloaddition adduct of maleimide with anthracene. The generation of anthracenyl species from these latter adducts allowed for the rate of the corresponding mechanically activated retro [4+2] cycloaddition reaction to be measured. No reduction in the number average molecular weight (M(n)) or liberation of the maleimide, furan, or anthracene moieties was observed (i) for polymers containing the cycloaddition adducts with M(n) < 20 kDa, (ii) for high molecular weight PMAs (M(n) > 60 kDa) featuring terminal cycloaddition adducts, or (iii) when the cycloaddition adducts were not covalently linked to a high molecular weight PMA. Collectively, these results support the notion that the aforementioned retro [4+2] cycloaddition processes were derived from a vectorially opposed mechanical force applied to adducts embedded within the polymer chains.     

Palladium-catalyzed concerted [4 + 1] cyclization of prop-2-yn-1-ones and isocyanides

A palladium-catalyzed [4+1] cycloaddition of prop-2-yn-1-ones with double isocyanides is developed herein.The transformation worked well to produce a series of 2-amino-4-cyanofurans with high efficiency and a broad reaction scope.Based on mechanism studies,it is believed that the palladiumcatalyzed [4+1] imidoylative cycloaddition of prop-2-yn-1-ones was concerted.Treated with a ryl amine and H_2 O,the [4+1] cycloaddition of prop-2-yn-1-ones with double isocyanides provided 2-amino-4-amidylpyrroles efficiently.     

Inverse electron-demand aza-[4+2] cycloaddition reactions of allenamides

An inverse electron-demand aza-[4+2] cycloaddition reaction of allenamides with 1-azadiene is described here. Effects of solvents on diastereoselectivity along with synthetic scopes and mechanistic insights are illustrated. Despite some synthetic limitations, this aza-[4+2] cycloaddition does provide a useful template for the synthesis of aza-glycoside related heterocycles.     

Molecular structures of endo[4+2]π and exo[6+4]π cycloadducts via cycloaddition reaction of n-ethoxycarbonylazepine with 2,5-dimethoxycarbonyl-3,4-diphenylcyclopentadienone

The cycloaddition reaction of N-ethoxycarbonyl-1H-azepine with 2,5-dimethoxycarbonyl-3,4-diphenylcyclopentadienone gave anti-endo [4+2]π and exo [6+4]π cycloadducts. These structures were fully identified by X-ray crystallographic techniques. Mechanism for their cycloaddition reactions are also discussed.     

Bay-area selective thermal [4+2] and [4+4] cycloaddition reactions of triply linked ZnII diporphyrin with o-xylylene

A triply linked ZnII diporphyrin underwent site-selective cycloaddition reactions with thermally generated o-xylylene to provide a triply linked porphyrin-chlorin hybrid and a triply linked chlorin dimer in moderate yields. The former product is a symmetry-allowed [4+2] cycloadduct, while the latter is a symmetry-forbidden [4+4] cycloadduct. Oxidation of the latter product with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) provided a triply linked diporphyrin fused with a benzocyclooctatriene segment. This oxidized product and above [4+2] cycloadduct were structurally characterized by single crystal X-ray diffraction analysis. The observed site-selectivity is considered to arise from the large MO coefficients at the bay-area in the LUMO of the triply linked diporphyrin. The anomalous thermal [4+4] cycloaddition may be ascribed to the highly conjugated and quite perturbed electronic properties of triply linked ZnII diporphyrin.     

Rh-catalyzed [5+1] and [4+1] cycloaddition reactions of 1,4-enyne esters with CO: a shortcut to functionalized resorcinols and cyclopentenones

We have developed novel Rh-catalyzed [n+1]-type cycloadditions of 1,4-enyne esters, which involve an acyloxy migration as a key step. The efficient preparation of functionalized resorcinols, including biaryl derivatives, from readily available 1,4-enyne esters and CO was achieved by Rh-catalyzed [5+1] cycloaddition accompanied by 1,2-acyloxy migration. When enyne esters had an internal alkyne moiety, the reaction proceeded by a [4+1]-type cycloaddition involving 1,3-acyloxy migration, leading to cyclopentenones.     

Substituent Effects on Fe+-Mediated [4+2] Cycloadditions in the Gas Phase

The Fe⁺-mediated [4+2] cycloaddition of dienes with alkynes has been examined by four-sector ion-beam and ion cyclotron resonance mass spectrometry. Prospects and limitations of this reaction were evaluated by investigating several Me-substituted ligands. Me Substitution at C(2) and C(3) of the diene, i.e., 2-methylbuta-1,3-diene, 2,3-dimethylbuta-1,3-diene, hardly disturbs the cycloaddition. Similarly, variation of the alkyne by use of propyne and but-2-yne does not affect the [4+2] cycloaddition step, but allows for H/D exchange processes prior to cyclization. In contrast, Me substituents in the terminal positions of the diene moiety (e.g., penta-1,3-diene, liexa-2,4-diene) induce side reactions, namely double-bond migration followed by [3+2] and [5+2] cycloadditions, up to almost complete suppression of the [4+2] cycloaddition for 2,4-dimethylhexa-2,4-diene. Similarly, alkynes with larger alkyl substituents (pent-1-yne, 3,3-dimethylbut-1-yne) suppress the [4 + 2] cycloaddition route. Stereochemical effects have been observed for the (E)- and (Z)-penta-1,3-diene ligands as well as for (E,E)- and (E,Z)-hexa-2,4-diene. A mechanistic explanation for the different behavior of the stereoisomers in the cyclization reaction is developed. Further, the regiochemical aspects operative in the systems ethoxyacetylene/pentadiene/Fe⁺ and ethoxyacetylcne/isoprene/Fe⁺ indicate that substituents avoid proximity.     

Lewis acid-catalyzed intermolecular [4 + 2] cycloaddition of 3-alkoxycyclobutanones to aldehydes and ketones

Intermolecular [4 + 2] cycloaddition between 3-alkoxycyclobutanones and aldehydes or ketones by the activation with boron trifluoride etherate is reported. The carbonyl compounds are inserted into the less substituted C2-C3 bond of the cyclobutanone ring of 6-alkyl-2-oxabicyclo[4.2.0]octan-7-ones to afford 1-alkyl-5,7-dioxabicyclo[4.4.0]decan-2-one derivatives regioselectively (>99:1) and diastereoselectively. On the other hand, [4 + 2] cycloaddition of 3-ethoxy-2,2-dialkylcyclobutanones at low temperature proceeds at the more substituted C2-C3 bond to yield 3,3-dialkyl-6-ethoxy-2,3,5,6-tetrahydro-4H-pyran-4-one derivatives with high regioselectivities. This [4 + 2] cycloaddition is developed into a one-pot synthesis of tri- or tetrasubstituted dihydro-gamma-pyrones from 3-ethoxycyclobutanones which are readily prepared from acid chloride and ethyl vinyl ether. The two regioselectivities observed in ring-opening of cyclobutanones can ascribe to thermodynamic stabilities of zwitterionic intermediates generated from tetrahydropyran-fused cyclobutanones and 3-ethoxycyclobutanones.     

Computational study on the reaction mechanism of the key thermal [4 + 4] cycloaddition reaction in the biosynthesis of epoxytwinol A

[reaction: see text] The key [4 + 4] cycloaddition in the biosynthesis of epoxytwinol A has been established by theoretical calculations to comprise of three processes. The first step is formation of the C8-C8' bond generating a biradical intermediate. Next, rotation about the C8-C8' bond occurs, and finally the C1-C1' bond is formed. Biradicals stabilized by conjugation and two hydrogen bonds are essential for realization of this rare thermal [4 + 4] cycloaddition.     

[4 + 2]-Cycloadditionen mit inversem Elektronenbedarf,XVII. Oxepin und 2,7-Dimethyloxepin als Dienophile bei Diels-Alder-Cycloadditionen mit inversem Elektronenbedarf

[4 + 2] Cycloadditions with Inverse Electron Demand, XVII. Oxepin and 2,7-Dimethyloxepin as Dienophiles in Diels-Alder Cycloadditions with Inverse Electron Demand The cycloaddition reactions of oxepin ( 1 ) with the tetrazine 3 and the triazine 12 yield the dihydrooxepino[4,5-d]pyridazine 5 and the oxepino[4,5-c]pyridine 13 , resp., via [2 + 4] cycloaddition as well as the phthalazine 9 and the isoquinoline 14 , resp., most probably via [6 + 4] cycloaddition. On the contrary, 2,7-dimethyloxepin ( 15 ) only gives the products 16 and 20 , which result from [2 + 4] cycloaddition. Oxidation of 16 by silver(I) oxide leads to the oxepino[4,5-d]pyridazine 17 , which as well as 20 in hydrochloric acid rearranges to the pseudoazulenes 19 and 21 , resp.     

Synthetic studies and mechanistic insight in nickel-catalyzed [4+2+1] cycloadditions

A new nickel-catalyzed procedure for the [4+2+1] cycloaddition of (trimethylsilyl)diazomethane with alkynes tethered to dienes has been developed. A broad range of unsaturated substrates participate in the sequence, and stereoselectivities are generally excellent. Stereochemical studies provided evidence for a mechanism that involves the [3,3] sigmatropic rearrangement of divinylcyclopropanes.     

Catalytic Enantioselective [10+4] Cycloadditions

The first peri‐ and stereoselective [10+4] cycloaddition between catalytically generated amino isobenzofulvenes and electron‐deficient dienes is described. The highly stereoselective catalytic [10+4] cycloaddition exhibits a broad scope with high yields, reflecting a robust higher‐order cycloaddition. Experimental and computational investigations support a kinetic distribution of intermediate rotamers dictating the enantioselectivity, which relies heavily on additive effects.     

An exploratory study of type II [3 + 4] cycloadditions between vinylcarbenoids and dienes

The intramolecular type II [3 + 4] cycloaddition between vinylcarbenoids and furans is a practical method for the construction of 5-oxo-10-oxatricyclo[6.2.1.0(4,9)]undeca-3, 8(11)-dienes, containing two anti-Bredt double bonds. These tricyclic systems are well functionalized for eventual elaboration to the natural product CP-263,114. The rhodium-stabilized vinylcarbenoids are generated by dirhodium tetracarboxylate catalyzed decomposition of vinyldiazoacetates. The [3 + 4] cycloaddition is generally considered to occur by a tandem cyclopropanation/Cope rearrangement, although evidence is presented that with these substrates the [3 + 4] cycloaddition may occur in a concerted manner.     

Intramolecular pyridone/enyne photocycloaddition: partitioning of the [4 + 4] and [2 + 2] pathways

Intramolecular photocycloaddition (>290 nm) between a 1,3-enyne and a 2-pyridone is far more selective than the intermolecular version; a three-atom linkage both controls regiochemistry and separates the [2 + 2] and [4 + 4] pathways. All four head-to-head, head-to-tail, tail-to-head, and tail-to-tail tetherings have been investigated. Linkage via the ene of the enyne leads to [2 + 2] products regardless of alkene geometry, whereas linkage through the yne results in [4 + 4] cycloadducts. The bridged 1,2,5-cyclooctatriene products of [4 + 4] cycloaddition are unstable and undergo a subsequent [2 + 2] dimerization reaction.     

Regioselectivity Switch in Palladium‐Catalyzed Allenylic Cycloadditions of Allenic Esters: [4+1] or [4+3] Cycloaddition/Cross‐Coupling

The first Pd‐catalyzed asymmetric allenylic [4+1] cycloaddition was successfully developed. Alternatively, tuning the Pd catalyst switched the reactivity toward an unprecedented [4+3] cycloaddition/cross‐coupling. Ligands play a vital role in controlling the reaction pathway, allowing highly selective access to different products from identical substrates. Biological evaluation of the obtained compounds led to the discovery of new antitumor targets. A possible mechanism is proposed, suggesting two interesting catalytic cycles for the cycloaddition with palladium‐butadienyls. This study also demonstrated the potential and utility of allenic esters as 1,4‐biselectrophiles and C₄ synthons for participating in cycloaddition reactions.     

Nickel-catalyzed dehydrogenative [4 + 2] cycloaddition of 1,3-dienes with nitriles

Pyridines, which comprise one of the most important classes of the six-membered heterocyclic compounds, are widely distributed in nature, and the transition-metal-catalyzed [2 + 2 + 2] cycloaddition reaction of two alkynes and a nitrile is one of the most powerful methods for preparing versatile, highly substituted pyridine derivatives. However, the lack of chemo- and regioselectivity is still a crucial issue associated with fully intermolecular [2 + 2 + 2] cycloaddition. The present study developed the Ni(0)-catalyzed intermolecular dehydrogenative [4 + 2] cycloaddition reaction of 1,3-butadienes with nitriles to give a variety of pyridines regioselectively.     

Intermolecular transition metal-catalyzed [4 + 2 + 2] cycloaddition reactions: a new approach to the construction of eight-membered rings

Transition metal-catalyzed cycloaddition reactions represent powerful methods for the construction of complex polycyclic systems. We have developed a new intermolecular metal-catalyzed [4 + 2 + 2] cycloaddition of heteroatom-tethered enyne derivatives with 1,3-butadiene. This study demonstrates that excellent selectivity can be obtained for the heterocycloaddition adducts through the judicious choice of silver salt. The development of the tandem rhodium-catalyzed allylic substitution [4 + 2 + 2] cycloaddition provides a convenient three-component coupling that circumvents the prior formation of the enyne derivative. Finally, the introduction of a stereogenic center at C-2 leads to a diastereoselective cycloaddition, which provides a powerful new method for the construction of bicyclic octanoid ring systems applicable to target directed synthesis.     

Intramolecular Benzyne–Phenolate [4+2] Cycloadditions

An intramolecular benzyne–phenolate [4+2] cycloaddition is reported. Benzyne precursors, having vicinal halogen‐sulfonate functionalities, linked with a phenol(ate) by various tether groups undergo efficient intramolecular [4+2] cycloaddition by treatment with either Ph₃MgLi or nBuLi for halogen–metal exchange to form various benzobarrelenes.     

4 + 1] cycloaddition of N-heterocyclic carbenes with vinyl isocyanates

[reaction: see text] N-Heterocyclic carbenes have been found to undergo [4 + 1] cycloaddition with various vinyl isocyanates to afford functionalized hydroindolone products.