Transition metal-catalyzed intermolecular [5+2] and [5+2+1] cycloadditions of allenes and vinylcyclopropanes

Initial examples of the intermolecular Rh(I)-catalyzed [5+2] cycloaddition reaction of bifunctional allenes and vinylcyclopropanes are described. The reactions proceed with facility and in yields of up to 99% with a variety of alkyne-, ester-, styrene-, or cyano-substituents on the allene to afford the corresponding cycloadducts. In the presence of CO, the reaction proceeds to an eight-membered ring cycloadduct and its transannularly closed product, providing the first example of a three-component [5+2+1] cycloaddition with allenes.     

Huisgen's 1,3-Dipolar Cycloadditions to Fulvenes Proceed via Ambimodal [6+4]/[4+2] Transition States

Huisgen's 1960 announcement of the concept of 1,3-dipolar cycloadditions was published the year before Alder's study of the reaction of diazomethane and dimethylfulvene. The diazomethane reaction was studied again in 1970 by Houk et al. and shown to give a [6+4] adduct. Padwa's nitrile ylide cycloaddition to dimethylfulvene (1978) gave [6+4] and [4+2] adducts. We performed computational studies of these reactions with density functional theory (DFT) and show that they involve ambimodal [6+4]/[4+2] transition states that can lead to either type of cycloadduct from one transition state. We dedicate this paper to the extraordinary life and humanity of Rolf Huisgen, and to the undying influence of his discoveries on chemistry.     

Intramolecular [4+2] cycloaddition reactions of enamines and enamides

An attempt to utilize a new strategy for alkaloid synthesis which features the intramolecular [4+2] cycloaddition of enamines and enamides for the construction of the tetracyclic spiroamine skeleton characteristic of the Erythrina alkaloids was unsuccessful, unexpectedly giving a bridged cycloadduct rather than a fused one.     

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.     

Three-component cycloadditions: the first transition metal-catalyzed [5+2+1] cycloaddition reactions

Prompted by our studies of transition metal-catalyzed [4+4], [4+2], [5+2], and [6+2] cycloadditions and by the view that these two-component reactions could be intercepted by a third component of one or more atoms, a new three-component transition metal-catalyzed cycloaddition is described. This new [5+2+1] cycloaddition proceeds in good to excellent yield and with high or complete regioselectivity with a variety of carbonyl-substituted alkynes to give bicyclo[3.3.0]octenone adducts, resulting from transannular closure of the intermediate eight-membered-ring cycloadduct. Effects of concentration, temperature, pressure, and catalyst loading on the efficiency of the reaction are discussed. This process provides access to complex building blocks for synthesis based on simple, readily available components.     

Understanding the nature of the molecular mechanisms associated with the competitive Lewis acid catalyzed [4+2] and [4+3] cycloadditions between arylidenoxazolone systems and cyclopentadiene: a DFT analysis

The molecular mechanisms of the reactions between aryliden-5(4H)-oxazolone 1, and cyclopentadiene (Cp), in presence of Lewis acid (LA) catalyst to obtain the corresponding [4+2] and [4+3] cycloadducts are examined through density functional theory (DFT) calculations at the B3LYP/6-31G* level. The activation effect of LA catalyst can be reached by two ways, that is, interaction of LA either with carbonyl or carboxyl oxygen atoms of 1 to render [4+2] or [4+3] cycloadducts. The endo and exo [4+2] cycloadducts are formed through a highly asynchronous concerted mechanism associated to a Michael-type addition of Cp to the beta-conjugated position of alpha,beta-unsaturated carbonyl framework of 1. Coordination of LA catalyst to the carboxyl oxygen yields a highly functionalized compound, 3, through a domino reaction. For this process, the first reaction is a stepwise [4+3] cycloaddition which is initiated by a Friedel-Crafts-type addition of the electrophilically activated carbonyl group of 1 to Cp and subsequent cyclization of the corresponding zwitterionic intermediate to yield the corresponding [4+3] cycloadduct. The next rearrangement is the nucleophilic trapping of this cycloadduct by a second molecule of Cp to yield the final adduct 3. A new reaction pathway for the [4+3] cycloadditions emerges from the present study.     

Striking reactivity of ylide-like germylene toward terminal alkynes: [4+2] cycloaddition versus C-H bond activation

The isolable ylide-like N-heterocyclic germylene LGe: (2) {L = CH[(C=CH(2))CMe][N(aryl)](2), aryl = 2,6-(i)Pr(2)C(6)H(3)} shows an unprecedented dual reactivity toward terminal alkynes: its reaction with acetylene leads via [4+2] cycloaddition to the novel intramolecular donor stabilised germylene 3, while conversion of phenylacetylene furnishes the analogous cycloadduct 4 along with a C-H bond activation product, the novel N-donor stabilised alkynyl germylene 5.     

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.     

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.     

Huisgen's 1,3‐Dipolar Cycloadditions to Fulvenes Proceed via Ambimodal [6+4]/[4+2] Transition States

Huisgen's 1960 announcement of the concept of 1,3‐dipolar cycloadditions was published the year before Alder's study of the reaction of diazomethane and dimethylfulvene. The diazomethane reaction was studied again in 1970 by Houk et al. and shown to give a [6+4] adduct. Padwa's nitrile ylide cycloaddition to dimethylfulvene (1978) gave [6+4] and [4+2] adducts. We performed computational studies of these reactions with density functional theory (DFT) and show that they involve ambimodal [6+4]/[4+2] transition states that can lead to either type of cycloadduct from one transition state. We dedicate this paper to the extraordinary life and humanity of Rolf Huisgen, and to the undying influence of his discoveries on chemistry.     

Formal [6+4] cycloaddition of a dicobalt acetylene complex with furan derivatives

An efficient method for constructing a 10-membered carbocycle with an oxygen bridge has been developed on the basis of a formal [6+4] cycloaddition reaction. Under the influence of EtAlCl₂, a dicobalt hexacarbonyl acetylene complex possessing a benzoyloxy group and an allylsilane moiety reacted with furan to give a 11-oxabicyclo[6.2.1]undec-9-ene derivative. On treatment with iodine, the cycloadduct underwent decomplexation followed by rearrangement of the oxygen bridge to afford a 11-oxabicyclo[5.3.1]undeca-1,5-diene derivative.     

Cycloadditions of Diarylgermylenes to a Diazabutadiene [1]

The reaction of tetrakis(2‐tert‐butyl‐4,5,6‐trimethylphenyl)digermene, which dissociates into the germylene molecules 2 in solution, with 1,4‐diisopropyl‐1,4‐diazabuta‐1,3‐diene ( 3 ) furnishes the [4+1] cycloaddition product of 2 to the nitrogen atoms of 3 . Under drastic conditions tetrakis(2,4,6‐triisopropylphenyl)digermene also forms the germylene molecules 6 which react with 3 in a similar fashion to afford the corresponding [4+1] cycloadduct.     

Enantioselective [2+2+2] cycloaddition of ketenes and carbon disulfide catalyzed by N-heterocyclic carbenes

The chiral N-heterocyclic carbene-catalyzed [2+2+2] cycloaddition of ketenes and carbon disulfide was realized to give the cycloadduct of 1,3-oxathian-6-ones in good yields with excellent enantioselectivities.     

Enantioselective Formal [4+2] Cycloadditions to 3‐Nitroindoles by Trienamine Catalysis: Synthesis of Chiral Dihydrocarbazoles

The first enantioselective formal [4+2] cycloadditions of 3‐nitroindoles are presented. By using 3‐nitroindoles in combination with an organocatalyst, chiral dihydrocarbazole scaffolds are formed in moderate to good yields (up to 87 %) and enantioselectivities (up to 97 % ee). The reaction was extended to include enantioselective [4+2] cycloadditions of 3‐nitrobenzothiophene. The reaction proceeds through a [4+2] cycloaddition/elimination cascade under mild reaction conditions. Furthermore, a diastereoselective reduction of an enantioenriched cycloadduct is presented. The mechanism of the reaction is discussed based on experimental and computational studies.     

A new approach to phorbol by [4 + 3] oxyallyl cycloaddition and intramolecular Heck reaction

[formula: see text] A new synthetic strategy for a functionalized tricyclic core of phorbol has been developed by means of a [4 + 3] oxyallyl cycloaddition and subsequent intramolecular Heck reaction. The [4 + 3] oxyallyl cycloadduct 7 was chosen as the B-ring precursor of phorbol. Subsequent elaboration took advantage of its well-defined diastereofacial bias to afford the tricycle 5. This method should be of general value in the construction of 6,7- or 5,7-fused bicyclic systems.     

A new entry to the synthesis of substituted azetidines: [2+2] cycloaddition reaction of four-membered endocyclic enamides to ketenes

The first example of a [2+2] cycloaddition reaction of a four-membered endocyclic enamide (2-azetine) to dichloroketene is described and constitutes a new entry to the synthesis of substituted azetidines. Preliminary studies concerning the Baeyer-Villiger oxidation of the [2+2] cycloadduct revealed an unusual regioselectivity. The synthesis of a new azetidine-3-carboxylic acid derivative from the [2+2] cycloadduct is also presented.     

Interesting behavior of alpha,beta-unsaturated oximes in intramolecular [4 + 2] cycloaddition reactions

[structure: see text] Intramolecular [4 + 2] cycloaddition using alpha,beta-unsaturated oximes was explored. The reactions proceeded under unusually facile conditions to furnish the nitrones. The latter were subsequently reacted with DMAD to afford [3 + 2] cycloaddition products.     

Intramolecular photochemical dioxenone-alkene [2 + 2] cycloadditions as an approach to the bicyclo[2.1.1]hexane moiety of solanoeclepin A.

A synthesis of the bicyclo[2.1.1]hexane substructure of solanoeclepin A (1), the most active natural hatching agent of potato cyst nematodes, was approached via an intramolecular [2 + 2] photocycloaddition. Aldehyde 12 containing the dioxenone chromophore served as a useful starting material, allowing the synthesis of a variety of photocycloaddition substrates via Grignard addition or via a Nozaki-Hiyama-Kishi reaction. Photolysis of the unsubstituted alkene 14 led to the expected crossed cycloadduct bicyclo[2.1.1]hexane 15 according to the so-called rule of five. However, several functionalized alkenes 18, 20, and 31 exhibited a complete reversal of cycloaddition regioselectivity, providing straight cycloadducts bicyclo[2.2.0]hexanes 21-26 and 4, respectively. Their structures were proved by a combination of extensive NMR measurements, X-ray analyses, and subsequent retro-aldol reactions. The latter de Mayo process allowed the formation of spiro-[3.5]nonane 35 and spiro[3.4]octane 36 as well as the cyclobutanes 37 and 38. Finally, the cyclization of the more rigid lactone precursor 28 occurred in high yield in the desired fashion with complete regio- and stereoselectivity to give 3 containing the core bicyclo[2.1.1]hexane skeleton of the natural product.     

[4+2] Cycloaddition Reactions Between 1,8‐Disubstituted Cyclooctatetraenes and Diazo Dienophiles: Stereoelectronic Effects,Anticancer Properties and Application to the Synthesis of 7,8‐Substituted Bicyclo[4.2.0]octa‐2,4‐dienes

A detailed examination of [4+2] cycloaddition reactions between 1,8‐disubstituted cyclooctatetraenes and diazo compounds revealed that 4‐phenyl‐1,2,4‐triazole‐3,5‐dione (PTAD) reacts to form either 2,3‐ or 3,4‐disubstituted adducts. The product distribution can be controlled by modulating the electron density of the cyclooctatetraene. Unprecedented [4+2] cycloadditions between diisopropyl azodicarboxylate (DIAD) and 1,8‐disubstituted cyclooctatetraenes are also described and further manipulation of a resulting cycloadduct uncovered a new pathway to the synthetically challenging bicyclo[4.2.0]octa‐2,4‐diene family. Variation of the substituents resulted in a range of compounds displaying selective action against different human tumour cell types.     

First cobalt(I)-catalyzed [6 + 2] cycloadditions of cycloheptatriene with alkynes

[reaction: see text] The CoI2(dppe)/Zn/ZnI2 system effectively catalyzes the [6 + 2] cycloaddition of cycloheptatriene with terminal alkynes to afford 7-alkyl-bicyclo[4.2.1]nona-2,4,7-trienes in fair to excellent yields. The catalyst proved to be tolerant toward functional groups such as ketone, sulfone, ester, ketal, ether, alcohol, imide, and nitrile. The enantioselective cycloaddition of CHT and phenylacetylene with BINOL phosphoramidite ligand 4 afforded the cycloadduct 3a (R = Ph) in 91% yield and 74% ee.