Stereoselective Rhodium‐Catalysed [2+2+2] Cycloaddition of Linear Allene–Ene/Yne–Allene Substrates: Reactivity and Theoretical Mechanistic Studies

Allene–ene–allene ( 2 and 5 ) and allene–yne–allene ( 3 and 7 ) N‐tosyl and O‐linked substrates were satisfactorily synthesised. The [2+2+2] cycloaddition reaction catalysed by the Wilkinson catalyst [RhCl(PPh₃)₃] was evaluated. Substrates 2 and 5 , which bear a double bond in the central position, gave a tricyclic structure in a reaction in which four contiguous stereogenic centres were formed as a single diastereomer. The reaction of substrates 3 and 7 , which bear a triple bond in the central position, gave a tricyclic structure with a cyclohexenic ring core, again in a diastereoselective manner. All cycloadducts were formed by a regioselective reaction of the inner allene double bond and, therefore, feature an exocyclic diene motif. A Diels–Alder reaction on N‐tosyl linked cycloadducts 8 and 10 allowed pentacyclic scaffolds to be diastereoselectively constructed. The reactivity of the allenes on [2+2+2] cycloaddition reactions was studied for the first time by density functional theory calculations. This mechanistic study rationalizes the order in which the unsaturations take part in the catalytic cycle, the reactivity of the two double bonds of the allene towards the [2+2+2] cycloaddition reaction, and the diastereoselectivity of the reaction.     

Microwave-assisted intramolecular [2 + 2] Allenic cycloaddition reaction for the rapid assembly of bicyclo[4.2.0]octa-1,6-dienes and bicyclo[5.2.0]nona-1,7-dienes

Microwave irradiation of alkynyl allenes affords an intramolecular [2 + 2] cycloaddition reaction. This cycloaddition provides an efficient route to bicyclomethylenecyclobutenes. The reaction occurs with complete regioselectivity for the distal double bond of the allene for the selective formation of a variety of hetero- and carbocyclic substrates. Bicyclo[4.2.0]octadienes and bicyclo[5.2.0]nonadienes have been prepared in high yield. [reaction: see text]     

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.     

Palladium-Catalyzed [6+2] Double Allene Annulation for Benzazocines Synthesis

An efficient double allene protocol for the formation of benzazocines has been developed. The reaction constitutes a highly regioselective palladium-catalyzed formal [6+2] annulation of allenyl benzoxazinanones with terminal allenes forming the challenging 8-membered cycles. Decent yields and excellent regioselectivity have been observed under mild conditions with a remarkable Z-stereoselectivity for the exo-cyclic C=C bonds. The synthetic potentials of benzazocine products have been demonstrated.     

Theoretical study on intramolecular allene-diene cycloadditions catalyzed by PtCl2 and Au(I) complexes

The intramolecular [4C+3C] cycloaddition reaction of allenedienes catalysed by PtCl(2) and several Au(I) complexes has been studied by means of DFT calculations. Overall, the reaction mechanism comprises three main steps: (i) the formation of a metal allyl cation intermediate, (ii) a [4C(4π)+3C(2π)] cycloaddition that produces a seven-membered ring and (iii) a 1,2-hydrogen migration process on these intermediates. The reaction proceeds with complete diastereochemical control resulting from a favoured exo-like cycloaddition. Allene substituents have a critical influence in the reaction outcome and mechanism. The experimental observation of [4C+2C] cycloadducts in the reaction of substrates lacking substituents at the allene terminus can be explained through a mechanism involving Pt(IV)-metallacycles. With gold catalysts it is also possible to obtain [4C+2C] cycloaddition products, but only with substrates featuring terminally disubstituted allenes, and employing π-acceptor ligands at gold. However the mechanism for the formation of these adducts is completely different to that proposed with PtCl(2), and consists of the formation of a metal allyl cation, subsequent [4C+3C] cycloaddition and a 1,2-alkyl shift (ring contraction). Electronic analysis indicates that the divergent pathways are mainly controlled by the electronic properties of the gold heptacyclic species (L-Au-C(2)), in particular, the backdonation capacity of the metal center to the unoccupied C(2) (pπ-orbital) of the intermediate resulting from the [4C+3C] cycloaddition. The less backdonation, (i.e. using P(OR)(3)Au(+) complexes), the more favoured is the 1,2-alkyl shift.     

A highly regio- and stereoselective formation of bicyclo[4.2.0]oct-5-ene derivatives through thermal intramolecular [2 + 2] cycloaddition of allenes

Thermal [2 + 2] cycloaddition of allenes with an additional multiple bond is described. By simply heating the allenenes or allenynes having a three-atom tether in an appropriate solvent such as dioxane or DMF, the distal double bond of the allenic moiety regioselectively participates in the cycloaddition to form bicyclo[4.2.0]oct-5-ene derivatives in good to excellent yields. In all the reactions of allenenes, the olefin geometry was completely transferred to the cycloadducts. While the reaction of terminal allenes afforded bicyclic cyclobutane derivatives as a single isomer, the cycloaddition of some internal allenes with axial chirality yielded a diastereomeric mixture of cycloadducts. These results are in good accordance with the stepwise mechanism through a biradical intermediate with a coplanar allyl radical.     

Cycloadditions of 1-iminylphosphirane complexes with allenes

A cascade carbonylative ring expansion and [2+2]/[4+2] cycloaddition of strained 1-iminylphosphirane complexes with aryl allenes were reported.The carbonylative ring expansion of 1-iminylphosphirane complexes provides an azaphosphacyclohexone complex intermediate with a C=P double bond.The following [2+2] or dearomatic [4+2] cycloaddition of this intermediate with allenes is modulated by the aryl substituents on the imino carbon.The regioselective [2+2] cycloaddition with 1,1-diarylallene provides an entry to bicyclo[4.2.0]octan-4-one skeletons featuring a four-membered phosphacyclobutane moiety.While dearomatic [4+2] cycloaddition was preferred with less aromatic naphthalene and yielded octahydrochrysene skeleton containing heteroatoms.     

Rhodium‐Catalyzed [(3+2)+2] Carbocyclization of Alkynylidenecyclopropanes with Substituted Allenes: Stereoselective Construction of Tri‐ and Tetrasubstituted Exocyclic Olefins

The development of the stereoselective rhodium‐catalyzed [(3+2)+2] carbocyclization of alkynylidenecyclopropanes (ACPs) with substituted allenes is described. This work demonstrates that activated and unactivated allenes preferentially undergo carbometalation at the distal terminus to generate tri‐ and tetrasubstituted exocyclic olefins with a neutral rhodium catalyst. In addition, this method provides a strategy for the total synthesis of the guaiane family of sesquiterpenes, which are not directly accessible using alkynes as exogenous π‐components. Finally, the preparation of the bicyclo[5.4.0]undecane ring system using a homologated ACP tether serves to further illustrate the versatility of this approach.     

Highly regio- and chemoselective [2 + 2 + 2] cycloaddition of electron-deficient diynes with allenes catalyzed by nickel complexes: a novel entry to polysubstituted benzene derivatives

Diynes 1a-c [X(CH(2)Ctbd1;CCO(2)Me)(2): X = (CH(2))(2), 1a, X = CH(2), 1b and X = O, 1c] undergo [2 + 2 + 2] ene-diyne cycloaddition reactions with a variety of allenes (n-butylallene 2a, phenylallene 2b, (4-chlorophenyl)allene 2c, (4-bromophenyl)allene 2d, (3-methoxyphenyl)allene 2e, 1-naphthylallene 2f, cyclohexylallene 2g and cyclopentylallene 2h) in the presence of Ni(dppe)Br(2) and Zn powder in CH(3)CN at 80 degrees C for 8 h to give the corresponding polysubstituted benzene derivatives 4a-l in good to excellent yields. Under similar reaction conditions, unsymmetrical diynes 5a-c (HCtbd1;CCH(2)XCH(2)Ctbd1;CCO(2)Me) react with allenes 2 to afford exclusively the corresponding meta-isomers 6a-g in 73-86% yields. The catalytic reaction is highly regioselective and completely chemoselective. This synthetic method is compatible with many functional groups such as Cl, Br, and OMe on the phenyl group of the allene moiety and an ether linkage in a diyne moiety. In this catalytic reaction, allenes are synthetically equivalent to terminal alkynes. Interestingly, unsymmetrical diyne 7 (MeCtbd1;C(CH(2))(4)Ctbd1;CCO(2)Me) undergoes 2:1 cocyclotrimerization with allenes 2a and 2g to afford the corresponding polysubstituted benzene derivatives 9a,b in 87% and 82% yields, respectively. A plausible mechanism involving a nickelacycloheptadiene intermediate is proposed to account for this nickel-catalyzed reaction.     

Cobalt‐Catalyzed Intermolecular [2+2] Cycloaddition between Alkynes and Allenes

An intermolecular [2+2] cycloaddition reaction between an alkyne and an allene is reported. In the presence of a cobalt(I)/diphosphine catalyst, a near equimolar mixture of the alkyne and allene is converted into a 3‐alkylidenecyclobutene derivative in good yield with high regioselectivity. The reaction tolerates a variety of internal alkynes and mono‐ or disubstituted allenes bearing various functional groups. The reaction is proposed to involve regioselective oxidative cyclization of the alkyne and allene to form a 4‐alkylidenecobaltacyclopentene intermediate, with subsequent C?C reductive elimination.     

Intramolecular ketene-allene cycloadditions

[reaction: see text]This report describes intramolecular thermal [2 + 2] cycloadditions between ketenes and allenes. The formation of ketenes and the subsequent cycloadditions occurred under a variety of conditions, affording 7-methylidinebicyclo[3.2.0]heptanones and 7-methylidinebicyclo[3.1.1]heptanones in 45-78% yields. The regioselectivity of the cycloaddition varied with the substitution of the allene, and the yield of cyclized products varied with reaction conditions.     

A new Co(2)(CO8-mediated tandem [5 + 1]/[2 + 2 + 1]-cycloaddition reaction: a one-pot synthesis of tricyclic delta-lactones from cis-epoxy ene-ynes

In the presence of Co2(CO)8 and CO, cis-epoxyalkynes bearing a tether olefin undergo a tandem [5 + 1]/[2 + 2 + 1]-cycloaddition to give tricyclic delta-lactones efficiently in a one-pot operation. The reaction mechanism is proposed to involve a cobalt-coordinated cyclic allene species.     

Structurally novel Bi- and tricyclic beta-lactams via [2 + 2] cycloaddition or radical reactions in 2-azetidinone-tethered enallenes and allenynes

[reaction: see text] Thermolysis of beta-lactam-tethered enallenyl alcohols gave tricyclic ring structures via a formal [2 + 2] cycloaddition of the alkene with the distal bond of the allene, while the tin-promoted radical cyclization in 2-azetidinone-tethered allenynes proceeded to provide bicyclic beta-lactams containing a medium-sized ring. The access to cyclization precursors was achieved by regio- and stereoselective metal-mediated carbonyl allenylation of 4-oxoazetidine-2-carbaldehydes in an aqueous environment.     

Stereoselective Nickel‐Catalyzed [2+2] Cycloadditions of Ene‐Allenes

A stereoselective nickel‐catalyzed [2+2] cycloaddition of ene‐allenes is reported. This transformation encompasses a broad range of ene‐allene substrates, thus providing efficient access to fused cyclobutanes from easily accessed π‐components. A simple and inexpensive first‐row catalytic system comprised of [Ni(cod)₂] and dppf was used in this process, thus constituting an attractive approach to synthetically challenging cyclobutane frameworks under mild reaction conditions.     

Alkenes in [2+2+2] Cycloadditions

Participation of alkenes and allenes in [2+2+2] cycloaddition reactions has attracted much attention recently. This version of the well‐established alkyne cyclotrimerization renders interesting products, such as cyclohexadienes and other polycycles, through cascade processes. Many mechanistic variations are observed when using certain metal complexes as catalysts. The frequent generation of stereogenic centers has prompted the development of efficient asymmetric versions. This Minireview summarizes the efforts reported to date on the use of double bonds as partners in [2+2+2] cyclotrimerizations.     

Enantio‐ and Diastereoselective Synthesis of Chiral Allenes by Palladium‐Catalyzed Asymmetric [3+2] Cycloaddition Reactions

A protocol for the asymmetric synthesis of highly substituted chiral allenes with control of point and axial chirality has been developed. A palladium‐catalyzed [3+2] cycloaddition using readily available racemic allenes gives access to densely functionalized chiral allenes with excellent yields and functional group tolerance. The catalytic asymmetric protocol utilizes a broad range of allenyl TMM (trimethylenemethane) donors to form cyclopentanes, pyrrolidines, and spirocycles with very good control of regio‐, enantio‐, and diastereoselectivity. The chiral allene moiety is shown to be a valuable functional group for rapid elaboration towards complex targets.     

Synthesis of the cyclobutanone core of solanoeclepin A intramolecular allene butenolide photocycloaddition

The compact tricyclic substructure of solanoeclepin A containing the cyclobutanone ring was prepared by using as the key step a highly regioselective intramolecular [2 + 2]-photocycloaddition reaction between one of the [small pi]-bonds of an allene and the CC double bond of a butenolide.     

Synthesis of angular triquinanes from 1-Alkynylbicyclo[3.2. 0]hept-2-en-7-ones. A tandem alkoxy-cope ring Expansion/Transannular ring closure reaction

Addition of ethenyllithium reagents to the carbonyl group of dialkyl squarate-derived 1-alkynylbicyclo[3.2.0]hept-2-ene-7-ones (15), followed by a TBAF workup, results in a low-temperature anion-accelerated alkoxy-Cope rearrangement which proceeds by way of a strained cyclic allene intermediates (e.g.,17). This leads to the formation of angularly fused triquinanes (e.g., 20) in which each of the rings is functionally differentiated. Bicyclo[6.3. 0]undecadienones (e.g., 36) are the major products when the reactions are quenched with aqueous bicarbonate rather than TBAF. Under analogous conditions 2-alkylidene-1-alkynylbicyclo[3.2. 0]heptan-7-ones also give bicyclo[6.3.0]undecadienones by a mechanism that was established to involve a 1,5-hydrgen shift in a strained allene intermediate. The synthetic scope and mechanism of these and related transformations are discussed.     

Strain and reactivity: electrophilic addition of bromine and tribromide salts to cyclic allenes

The kinetics and the products of the bromination of several cyclic allenes, from C(9) to C(13) (1 a-e), with tetrabutylammonium tribromide (TBAT) and Br(2) have been investigated in 1,2-dichloroethane (DCE) and methanol. The first product of the interaction between the allene and Br(2) is a 1:1 pi complex. The stability constant of this complex, determined at 25 degrees C for allene 1 a, is 7.4 M(-1). The comparison of this value with those reported for several alkenes and alkynes further support the hypothesis of the existence of sizeable structural effects on the stability of these complexes. The negative values of the apparent activation energy for the reaction of allenes 1 a-e with Br(2) in DCE demonstrate the involvement of these complexes as essential intermediates along the reaction coordinate. Different stereochemical behavior was observed in the bromine addition on going from the strained 1,2-cyclononadiene to the larger compounds. Furthermore, a solvent-dependent stereochemistry has been observed for each compound. The kinetic and product distribution data have been interpreted in terms of the influence of the strain on the nature of the intermediate and by considering the competition between pre-association and ion-pair pathways on going from aprotic to nuclophilic solvents or when nucleophilic bromide ions are added. Ab initio (MP2/6-311+G**) and density functional (B3LYP/6-311+G**) computations of 1:1 Br(2) complexes showed that the association energies of allene x Br(2) and ethene x Br(2) complexes are nearly the same but are greater than that of acetylene x Br(2) complexes. Allene x 2 Br(2) complexes are more stable than their ethene x 2 Br(2) counterparts. Br(2) x allene x Br(2) structures, in which the bromine molecules interact either with a single allene double bond or individually with both double bonds, are not preferred significantly over alternatives with Br(2)...Br(2) interactions. As a result of the entropy, the association of bromine with unsaturated hydrocarbons is usually unfavorable in the gas phase (except at extremely low temperatures); complexes are observed in solution (under ambient conditions), since the entropy loss is reduced as a result of restricted translation and rotation and possible association to the solvent. The 1,2-cycloheptadiene x Br(2) > 1,2-cyclononadiene x Br(2) > 1,3-dimethylallene x Br(2) association energies increase with ring strain.     

Access to substituted cyclobutenes by tandem [3,3]-sigmatropic rearrangement/[2 + 2] cycloaddition of dipropargylphosphonates under Ag/Co relay catalysis

We present herein an unconventional tandem [3,3]-sigmatropic rearrangement/[2 + 2] cycloaddition of simple dipropargylphosphonates to deliver a range of bicyclic polysubstituted cyclobutenes and cyclobutanes under Ag/Co relay catalysis. An interesting switch from allene–allene to allene–alkyne cycloaddition was observed based on the substitution of the substrates, which further diversified the range of compounds accessible from this practical method. Significantly, preliminary biological screening of these new compounds identified promising candidates as suppressors of cellular proliferation.

In situ generation of allenes through [3,3]-sigmatropic rearrangement of propargylphosphonates. Divergent allene–allene or allene–alkyne cycloaddition by Ag/Co relay catalysis. Products as promising suppressors of cellular proliferation.