Allenes and computational chemistry: from bonding situations to reaction mechanisms.

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Allenes and computational chemistry: from bonding situations to reaction mechanisms b Elena Soriano*a and Israel Ferna ńdez*

The present review is focused on the application of computational/theoretical methods to the wide and rich chemistry of allenes. Special emphasis is made on the interplay and synergy between experimental and computational methodologies, rather than on recent developments in methods and algorithms. Therefore, this review covers the state-of-the-art applications of computational chemistry to understand Received 11th December 2013

and rationalize the bonding situation and vast reactivity of allenes. Thus, the contents of this review span

DOI: 10.1039/c3cs60457h

from the most fundamental studies on the equilibrium structure and chirality of allenes to recent advances in the study of complex reaction mechanisms involving allene derivatives in organic and

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organometallic chemistry.

1. Introduction Allene is the common name given to a compound in which one carbon atom has double bonds with each of its two adjacent carbon centres. These species have always fascinated chemists a

ńicos Departamento de Sıńtesis, Estructura y Propiedades de Compuestos Orga ńica General (IQOG, CSIC), Juan de la Cierva, (SEPCO), Instituto de Quı´mica Orga 3, 28006-Madrid, Spain. E-mail: [email protected] b ńica I, Facultad de Ciencias Quı´micas, Departamento de Quı´mica Orga Universidad Complutense de Madrid, 28040-Madrid, Spain. E-mail: [email protected]

Elena Soriano obtained her PhD degree in 2003 at UNED (Madrid) under the supervision of Prof. Paloma Ballesteros. She was a postdoctoral fellow from Gobierno de La Rioja (2005– 2006) and MEC (Juan de la Cierva contract, 2006–2008) working at the Instituto de Investigaciones Biome´dicas ‘‘Alberto Sols’’ (UAM-CSIC). Since 2008, she has held a position as Cientifico Titular del Consejo Elena Soriano Superior de Investigaciones ńica General Cientificas at the Instituto de Quimica Orga (Madrid). Her research interests focus on the application of computational tools to the study of reaction mechanisms (mainly processes catalyzed by transition metals and organocatalysis) and drug design.

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because of the intriguing features of the cumulated diene function, such as the higher reactivity compared to simple alkenes and the peculiar axial chirality of the elongated tetrahedron system. For a long period of time, allenes were considered more as chemical curiosities and highly unstable unsaturated moieties than reliable partners. For this reason, the development of the chemistry of allenes and their synthetic applications has been considerably retarded. However, the chemistry of allenes has experienced a great advancement in the last two decades, as summarized in the monographs by Schuster and Coppola,1

ńdez (Madrid, 1977) Israel Ferna studied Chemistry at the Universidad Complutense of Madrid (UCM). In 2005, he earned his PhD (with honors) at the UCM under the supervision of Prof. Miguel A. Sierra. After that, he joined the Theoretical and Computational Chemistry group of Prof. Gernot Frenking at the ¨t Marburg Philipps Universita as a post-doctoral researcher. At present, I.F. is Profesor ńdez Israel Ferna Contratado Doctor at the UCM. He was awarded the Young Investigator Prize by the Royal Spanish ń Sanz del Rıó Prize in Society of Chemistry in 2009 and the Julia 2011. His current research includes the experimental and computational study of the bonding situations and reaction mechanisms of organic and organometallic compounds with special interest in CC bond forming processes.

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and more recently by Krause and Hashmi.2 They have shown a rich reactivity as well as significant selectivities, which can be efficiently tuned by controlling electronic or steric effects and the nature of the catalysts involved in the transformation.3 This rapid development finds its origin in the usefulness of allenes as intermediates in organic synthesis.4 They can also be found in many natural products, which have provided incentive for their synthesis,5 and are increasingly being incorporated in pharmaceuticals.6 In addition, allenes play a central role in hydrocarbon chemistry,7 and extremely bent allenes are being investigated because of their interesting electronic structure and coordinating properties.8 The fascinating structure of allenes has even caught the attention of chemists interested in molecular materials.9 Regarding organic synthesis, allenes have notably been involved in fields where their use was previously limited, such as asymmetric catalysis10 and transition metal-mediated reactions, where good selectivities have been obtained by modifying the nature of the metal and the associated ligands.11 Typically, key intermediates in the transformations of allenes12 are short-lived and, consequently, difficult to detect and characterize. This means that experimental work in the field often needs to be complemented by theoretical studies. Computational chemistry has been instrumental in assisting experimental chemists in establishing the fundamental properties of the key intermediates and the factors that control the reactivity and selectivity of the transformations involving allenes. In this review, we shall give an overview of the recent advances made on the bonding situation and rich reactivity of allenes by means of computational methods. It is clear from the examples described herein that theory not only assists experimental studies providing insight into reaction mechanisms and pathways in allene chemistry, but also helps in the search of more efficient transformations. First, we shall summarize relevant computational studies on the molecular and electronic structure of allenes and on the effect of substitution on their physicochemical properties (Section 2). Later, some recent examples on the application of computational chemistry to the elucidation of the mechanisms involved in the transformation of allenes into acyclic products will be described (Section 3). Since the main synthetic interest in allenes deals with the formation of carbo- and heterocycles, two sections (Sections 4 and 5) are devoted to illustrate recent successful computational studies on cyclizations and cycloadditions, respectively. Finally, other pericyclic reactions different from cycloadditions are also included in Section 6 to show the ability

Fig. 1

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of computational chemistry to provide insight into the wide variety of reactions that allenes can undergo in organic and organometallic chemistry. Special attention has been paid to rationalize the selectivity of the reactions and the role played by the transition metal-catalyst (when applicable) and the molecular structure.

2. Structure and bonding of allenes Allenes are compounds with the general formula R2CQCQCR2 in which two p-bonds are orthogonal to each other with an ideal C–C–C angle of 1801. In addition, they can be chiral species when substituted, and this property provides additional bonus from the synthetic point of view. The major attraction in the chemistry of allenes arises from the fact that their reactivity and selectivity can be easily tuned by modulating their electronic and steric effects by choosing appropriate substituents.13 Comparative analyses in terms of electronic structure and effect of different substituents on physicochemical properties in the parent allenes and/or heteroallenes have been discussed in the literature.14,15 2.1.

Molecular and electronic structure of allenes

As a result of the sp-hybridization of the central C2-atom, the two CH2 groups in the parent unsubstituted allene are perpendicular (1, Fig. 1a),16,17 and consequently the two p-bonds are roughly orthogonal.17 The geminal H-atoms on C1 interact with the remote C2C3 olefinic system, leading to molecular orbitals (MOs) 1e4 (largely C–H density) and 2e4 (largely CQC density). The full ground state (X1A1) electronic configuration is (1a1)2 (1b2)2 (2a1)2 (3a1)2 (2b2)2 (4a1)2 (3b2)2 (p1e)4 (p2e)4.18 The inner 1p4 are unlikely to play a major part in low-lying excited states, owing to their ionization potential being larger than 2p4 by B4.5 eV. Configuration interaction (CI) calculations have provided a consistent picture of the Rydberg assignments in the study of the electronic spectrum of allene.19 Whilst this traditional molecular orbital description explains the general electronic and molecular structure, there are anomalies in both the crystal structures and cycloaddition products involving allenes. Through a basic molecular orbital construction of the p-system, the terminating motifs get an orthogonal conformation (Fig. 1b) (symmetry D2d). A more appropriate description through recent quantum-chemical computations by Walsh et al.20 of the cumulene family confirms that the frontier molecular orbitals (FMOs) are comprised of

(a) Allene, 1. (b) Standard p bonding description of 1 assumes orthogonal p interactions. (c) Helical topology of the FMO.

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Fig. 3

Fig. 2 Frontier orbitals calculated using density functional theory (isovalue 0.015 e Å3). (a) For allene 1, helical degenerate orbitals of symmetry e. (b) The axially chiral (P)-1,3-dimethyl allene maintains the helical characteristics in both the HOMO (left-handed helix) and the HOMO1 (right-handed helix). (c) The two virtual orbitals, LUMO and LUMO+1, are left- and right-handed, respectively.

p-orbitals, but perhaps not what one would expect (Fig. 1c and 2). The allene family (cumulenes with an odd number of linear carbons) has extended FMOs with helical topology. Thus, although the allenes are inherently structurally orthogonal, they display helical orbitals. These orbitals are the linear ¨bius aromatic systems, which also display analogues to the Mo non-linear p interactions (Fig. 2).21 The HOMO-a and HOMO-b (Fig. 1c) of the achiral allenes are a degenerate pair, comprised of right- and left-handed helices orientated 901 from each other. The rotation and polarisation of the p-orbitals of the central carbon atom result in this electronic structure, with visibly helical molecular orbitals (Fig. 2a). The splitting of this degeneracy (achiral allenes) may be achieved chemically by forming an axially chiral allene, thus differentiating the helical MOs. Allene may be axially chiral; the most simple example, 1,3-dimethyl allene, has two stereoisomers, (M) and (P) (or S and R). The axial chirality found in allenes is intimately related to the topology of the frontier orbitals, and has implications for predictions of cycloaddition pathways, structure stability and spectroscopy. Thus, the degeneracy found for the unsubstituted parent allene is removed upon substitutional methylation. The FMOs of the axially chiral (P)-1,3-dimethyl allene (Fig. 2b) are helical. The HOMO of (P)-1,3-dimethyl allene is a left-handed helix. The HOMO1 is found at 0.002 eV below the HOMO, and is right-handed. As expected, the HOMO is inverted to a right-handed helix for the other enantiomer, (M)-1,3-dimethyl allene.


Allenes, bent allenes and carbones.

Closely related structures are the so-called ‘‘bent allenes’’. They are systems with a nonlinear CQCQC framework, and are characterized by slightly deviated orthogonal p-bonds.22,23 Bertrand, Frenking and co-workers suggested that weakening of the p-bonds leads to bending of the CQCQC frame in allenes, which can be regulated on the basis of electron-withdrawing and -donating properties of the substituents or by steric strain.23a,b For instance, cyclic allenes are bent allenes, with CQCQC angles ranging from B1001 to 1701.22 Though there is controversy in assigning allenic character to some of these systems,24 there is general agreement that allenes with zwitterionic character remain as allenes.25 In some cases (Fig. 3), for example in A, due to severe bending, the allene p system is significantly disturbed, and the central carbon atom is no longer sp-hybridized as in typical all-carbon allenes, but attains a unique configuration with two lone pairs of electrons and the two NHC-ligands acting as donor groups.23a Frenking and co-workers studied the electronic structure of systems B (core of A) and described them as divalent C(0) systems (L - C ’ L) (also termed carbodicarbenes, or carbones for L a C due to their resemblance to carbodiphosphoranes).26 These species exhibit a peculiar bonding situation (1) in which the central carbon atom accepts electrons from strong electrondonating groups, (2) with two lone pairs on the central carbon occupying s and p type orbitals, and (3) with high nucleophilicity at the central carbon atom. These compounds are found to be different from carbenes, where the carbon atom has only one s-type lone-pair orbital and a formal oxidation state of two (divalent carbon(II)). The advent of carbodicarbenes in synthetic chemistry has opened new directions in experimental organic chemistry.27–29 Theoretical and experimental studies revealed that the structures and bonding situations of C(CR2)2 allenic systems can be modulated by the nature of the substituents and/or by geometrical constraints that are imposed on carbodicarbenes that are part of a cyclic system.26c,d,28,30 In contrast to allenes, the terminal CR2 groups in bent allenes23a,28 are not orthogonal to each other but twisted with dihedral angles in the range of 30–601 depending on the steric repulsion between the

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substituents.26c,d,30a,29 The bending of allene is attributed to the weakening of p-bond strength across the allene. However, allene 6, which is characterized by push–push interactions, exhibits a linear structure,26d,e thus suggesting that the CQCQC bonding environment should be better considered as a donor–acceptor interaction instead of an allenic bond. The latter example clearly illustrates the controversy in the current understanding of the bonding situation in bent allenes. In conclusion, allenes, R2CQCQCR2, and carbodicarbenes, R2C - C ’ CR2, are two extreme bonding situations for these species. A recent work by Bharatam et al.31 has reported the computational analysis of a series of amino-substituted allenes (1–6, Fig. 3) to elucidate their bent vs. linear character. Three different electronic structural environments are competing in these systems: (I) with orthogonal p bonds as in allenes, (II) with p conjugated systems with one lone pair on the central carbon atom similar to typical carbenes (i.e. divalent carbon(II)), and (III) a bent allene character with two lone pairs on the central carbon atom as in carbones (i.e. divalent C(0) systems). Electronic structure analyses proved that the CQC p bond strength decreases with an increase in the NH2 substitution, so that the orthogonality of the p orbitals in 6 is very weak and tends to bend when symmetry is broken. A delicate balance between the weak p bonds and sp2 rehybridization exists in allenes substituted with electrondonating groups. Upon reducing the symmetry across the central carbon atom, this balance tilts toward sp2 structures. This delicate balance dictates the CQCQC angle of substituted allenes, and hence, a unique opportunity is available to stabilize systems with varying angles across the central carbon. NBO analysis also suggested that charge accumulation at the central C increases with an increase in the number of NH2 groups. Other computed parameters, such as proton affinities, the nucleophilicities and their gradual change as a function of increasing amino substitution, support the observed changes in allene vs. divalent C(0) character of the species.31 Finally, it should be noted that, although most of the current literature deals with carbones with different stabilizing ligands, some studies suggest that replacing carbon in carbodicarbenes with the heavier homologues Si–Pb leads to highly interesting ylidones that share some of the characteristics of their parent compounds.32 QC bond rotation. Seeger et al. studied the CQC 2.1.1. CQ rotational process in allene through a C2v bent planar transition structure. The barrier through the 1A1 state was shown to require 76.4 kcal mol1,33 which does not concur with the experimental value of ca. 46 kcal mol1.34 Indeed, the rotational transition state was reported to proceed through a 1A2 singlet biradical state with a lower computed barrier of 50.1 kcal mol1.33 A slightly lower value has been reported by Rauk et al.35 (48.0 kcal mol1) at the MP3/6-31G**//RHF/3-21G level. Ruedenberg et al. also characterized the transition structure for the internal rotation of allene, computing a barrier of 45.1 kcal mol1,36 in agreement with the experimental barriers for 1,3-dimethyl- and 1,3-di-tert-butylallene (46.2 and 46.9 kcal mol1,

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respectively).34 Schleyer and co-workers reported (B3LYP/TZP and CASSCF(4,4) methods) a similar allene internal rotation barrier (44.6 kcal mol1).37 As in alkenes,38 the presence of electron-donor groups is expected to reduce significantly the CQC rotational barriers in allenes. Thus, the results for 1–6, by using open and close shell wave functions,31 indicate that the rotation in 1–3 may proceed via open shell singlet diradical transition states. Despite that, only for 1 the corresponding open shell singlet diradical TS (B54 kcal mol1 at the UMP2-(full)/6-31+G* level) is preferred over the close shell TS (B72 kcal mol1 at the MP2(full)/ 6-31+G* level). For 2 and 3, open shell singlet diradical TSs (50.0 and 50.5 kcal mol1, respectively) are found to be higher in energy than the respective close shell singlet TSs (33.6 and 24.7 kcal mol1). These data suggest a crossover from open to close shell TS on mono- (2) and diamino (3) substituted allenes. On further increasing the number of amino substitutions from 4 to 6, open-shell TSs could not be located on the potential energy surface. Moreover, the barrier for the CQC rotation in 4 (26.3 kcal mol1 at the G2MP2 level) is comparable to that of 3 but much smaller than that in 1 and 2, whereas much smaller values were computed for 5 and 6 (15.7 and 16.4 kcal mol1, respectively). These data suggest that the weakening of the p-bond is due to increased electron delocalization from the NH2 groups. The gradual decrease in the CQC rotational barriers in 1–6 supports the suggestion by Bertrand that the p strength in allene gradually decreases with an increase in the electron donation, which, in turn, suggests gradual conversion from allenic (1) to donor–acceptor bond (6), as concluded above from MO analysis. The extra electron density from the lone pairs of the substituent amino groups being ‘‘pushed’’ reaches the p* orbital of allene and, hence, weakens the p bonds. Even in 6, where linearity is preferred, the CQC p bond strength is weak.29 2.1.2. Isomerization of allene. Three stable molecules exist with the simple chemical formula C3H4: cyclopropene, allene (propadiene), and propyne (methylacetylene).39 There are several stable and unstable isomers on the potential energy surface (Scheme 1), which have been studied by theoretical methods.

Scheme 1

Plausible isomerization pathways of allene 1.


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Yoshimine and co-workers first described detailed ab initio calculations of the ground state surface of C3H4.40 They investigated the lowest energy pathways involving intermediate geometries and transition states and suggested the following sequence of reaction paths: allene (CH2QCQCH2) - 1,2-H shift - vinylmethylene (CH2QCH–CH:) - ring closure cyclopropene - 1,2-H shift/ring opening - propenylidene (H3C–CHQC:) - 1,2-H shift - propyne (H3C–CRCH). These studies confirmed the initial proposal of Walsh and co-workers41 that the allene–propyne isomerization takes place via the cyclopropene intermediate. The height of the isomerization barrier was found to be 65.80 kcal mol1 above the zeroenergy level of propyne, which itself lies 0.72 kcal mol1 below allene. The barrier for the 1,3-H shift leading directly from allene to propyne was calculated to be much higher (94.98 kcal mol1). Further higher-level ab initio studies were later performed,42 and the allene–propyne isomerization was re-examined by Davis et al. at the G2-(B3LYP) level.43 The atomic and molecular hydrogen loss channels were computed by Mebel et al. (CCSD(T)/6-311+G(3df,2p)//B3LYP/6-311G(d,p)) along with calculations of the lowest excited states.44 The most detailed account of the C3H4 isomerization in the ground state was given by Miller and Klippenstein in 2003,45 who calculated microcanonical rate coefficients using the Rice–Ramsperger–Kassel–Marcus theory, and predicted phenomenological rate constants for various competing reactions. They confirmed the isomerization mechanism suggested by Yoshimine and co-workers (except that propenylidene does not appear to be a stable intermediate and vinylmethylene is only a metastable species) and calculated the highest barrier on the reaction path to be 66.75 kcal mol1 with respect to allene related to the initial 1,2-H migration step from allene to vinylmethylene. Similarly, the direct 1,3-H shift path from allene to propyne exhibits a much higher barrier (88.76 kcal mol1). The energies for the atomic hydrogen loss processes to produce the propargyl radical were computed to be similar, 89.23 and 89.95 kcal mol1, for allene and propyne, respectively.46 Other relevant results are the molecular hydrogen loss from cyclopropene producing the most stable C3H2 isomer (cyclopropadienylidene) which requires an 83.73 kcal mol1 barrier with respect to cyclopropene, but the latter itself resides 22.44 kcal mol1 above allene. Noteworthily, the endoergicities of the singlet CH2 + C2H2 and CH3 + C2H product channels involving carbon– carbon bond cleavages computed at a similar G2M(MP2) level of theory are 108.61 and 122.73 kcal mol1, respectively. Jackson et al.44a also investigated surfaces for several excited electronic states of allene and deduced a scenario for the

Scheme 2

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internal conversion to the vibrationally excited electronic ground state.47 2.2.

Structure and bonding of metal–allene complexes

Allenes have a rich coordination and organometallic chemistry. It has been well established that allenes can form transition metal complexes with one of their CQC bonds to give Z2 (or less frequently Z1) complexes.48,49 Upon coordination, allenes are activated and can participate in various organometallic reactions, for example, insertion into M–R bonds, oxidative coupling with other unsaturated substrates,50 nucleophilic addition,51 abstraction,52 electrophilic addition,53 and insertion reactions.54 As for the olefin-metal bond, the Dewar–Chatt–Duncanson molecular orbital picture can be applied to describe the bonding situation of the complexes as a synergistic combination of s-donor and p-acceptor interactions between the metal and the CQC p-system. The shortened allene carbon-metal distance that can be observed has been explained in terms of an additional interaction between the filled metal d-orbital and the p*-orbital of the uncomplexed CQC. Thus, metal - ligand back-donation weakens (lengthens) the CQC bond (as in olefinmetal complexes), and consequently, the substituents will bend away from the metal. There has been controversy on the relative p- and s-description of bonding. Whether a complex lies closer to the p- or the s-description will depend on the relative extents of ligand - metal (p - d) and metal - ligand (d - p*) electron density transfer and this, in turn, will be determined by the nature and oxidation state of the metal, by the number and nature of the ancillary ligands and by the allene’s substituents. To our knowledge, a systematic analysis of the metal–allene bonding by computational calculations has not been performed to date. However, a variety of allene–metal complexes have been characterized by quantum calculations in the studies of metal-catalysed transformations.55 It should also be noted that allenes exhibit diverse coordination chemistry, and the presence of a pair of adjacent metals introduces a number of additional coordination modes for allene itself, in which either one or both sites of unsaturation can be involved in the bonding.56 On the other hand, the increasing relevance of gold-catalysis to synthesis has prompted the study of gold-complexes and bonding in detail.57 Depending on the substituents on the allene, different structures can be formed. For cationic gold(I) complexes (Scheme 2), the structure of type 8 represents a similar contribution of the two carbon atoms of the double bond in the coordination with the metal center, but distorted structures with a major contribution of the central or external carbon atom can be favoured by the presence of electron-donating or electron-withdrawing

Possible structures for the interaction of an allene and a gold metal center.


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groups, respectively. The second category can also be represented by different structures such as s-allylic cation 9, zwitterionic carbenes 10, or Z1-coordinated bent allenes 11. Remarkably, if the allene is chiral, the stereochemical information is conserved if the interaction gives structures of type 8 or Z1-coordinated bent allenes 11. However, the chirality of the allene is lost in structures of type 9 and 10 with the three carbons and their substituents in the same plane. In spite of the limited experimentally derived geometries, it has been established that Z2-allene ground-state structures, having preferential binding of gold to the less substituted CQC bond of the allene, undergo facile (DGa = 8.9–11.4 kcal mol1) allene p-face exchange consistent with staggered Z1-allene intermediates and/or transition states.58 In contrast, the literature is rich in calculated structures, many of them being slipped Z2-allene complexes of type 8. A computational study by Gandon, Fensterbank, Malacria and co-workers on the interaction of allenes with gold complexes59 suggests that the structures are highly dependent on the nature of the allene substituents as well as on the properties of the particular gold complex employed. The interaction between 1,3-dimethyl allene and [AuPMe3]+ or AuBr3 (Fig. 4a and b) gives Z2-structures (type 8) 12 and 15, and two different isomers, 13 and 16, which are very close in energy. Moreover, s-allylic cations (type 9) 14 and 17 were also observed, being more stabilized for the AuBr3 system 17 than for [AuPMe3]+ 14 (relative energies of 2.1 and 6.1 kcal mol1 above the most stable isomers, 15 and 12, respectively). A Z1-coordinated bent allene (type 11) 18 was observed in the AuBr3 system but not with cationic [AuPMe3]+. The effect of the allene substituents in the interaction with [AuPMe3]+ was also analysed by replacing a methyl group by acetate in the allene moiety. In this case, a s-allylic cation structure (type 9) 20 was found to be the ground state (Fig. 4c). This species is 3.8 kcal mol1 more stable than the Z2-coordinated structure 19. This differential behaviour compared to 12 or 14 has been explained in terms of the electron-donor properties of the

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Scheme 3 Interconversion between gold complexes of a cyclopropyl allene (relative Gibbs energy in kcal mol1; the activation barrier is indicated over the arrow). Geometry of TS23–24 is also depicted.

acetate group, which are reflected in the short C–O distance (1.31 Å) in species 20. Moreover, the transformation of species of type 19 into the other possible isomers shows low enthalpy barriers, in the range of 0.1–2.4 kcal mol1. Different computational studies have revealed similar results. For instance, for cyclopropylallenyl esters, Toste et al. found that the formation of allylic cations was exergonic and proceeded via low-lying transition states (Scheme 3).60 Likewise, complex 25 transforms exothermically into the virtually planar allylic cation 26 via a transition state lying 3.4 kcal mol1 above the ground state (Scheme 4).61 The latter rearranges in a slightly exothermic fashion into the most severely twisted allylic cation 27 at an enthalpic cost of 3.1 kcal mol1. ´s and Toste on alleneTwo independent studies by Lledo diene systems allow for further insight into ligand effects.62,63 The transformation of the pertinent Z2-allene complexes into gold-stabilized allylic cations is moderately exergonic to quite endergonic. In terms of kinetics, it is somewhat faster with phosphines and phosphites than with an N-heterocyclic carbene. As described above, the structures and bonding in allenic systems can be modulated by the nature of the substituents and/or by geometrical constraints. Since carbones (R2C C ’ CR2) possess two donor–acceptor bonds and a bare carbon atom that retains its four valence electrons as two lone pairs,

Fig. 4 Structures of the localized minima for the different gold–allene systems (relative energies in kcal mol1).

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Scheme 4 Interconversion between gold complexes of a cyclopropyl allene (relative enthalpies in kcal mol1; the activation barriers are indicated over the equilibrium arrows).

they are very strong Lewis bases and may bind to two Lewis acids. Recently, Frenking and Esterhuysen have investigated the coordination modes of one and two AuCl species with allenes R2CQCQCR2 (with R = H, F, NMe2), N-methylsubstituted N-heterocyclic carbene (NHCMe), and carbones of the type carbodiphosphorane C(PPh3)2 and carbodicarbene C(NHCMe)2, in order to elucidate the differences in the chemical behaviour between allenes, carbenes and carbones. The results showed that complexation by one or two AuCl groups can discriminate between compounds with divalent carbon(0) character and allenes on the basis of their coordination mode: carbones bind one and two AuCl species in the Z1 mode, whereas allenes bind them in a Z2 fashion. Compounds with latent divalent carbon(0) character can coordinate in more than one way, with the dominant mode indicating the degree of carbone or allene character.64 The calculated structures of the mono- and diaurated tetraaminoallenes reveal that they exhibit a chameleon-like behaviour, showing features of both allenes and divalent C(0) species. 2.3.

Consequences on chirality transfers

The stereoselective generation of axial chiral allenes and axis-tocenter transformation of allenes without loss of chirality are still challenging.65 This strategy has been widely used to reach complex enantiopure structures. Until now, only a limited number of asymmetric versions of different reactions of allenes have been

Scheme 5

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reported. Chiral allenes must be stable to racemization under the experimental conditions. This requirement is crucial; otherwise, no chirality transfer could be envisaged. Extensive structural and mechanistic studies are therefore necessary for elucidating the interactions of allenes with catalysts as well as the origin of the stereocontrol during those transformations.66 A variety of enantioselective transformations of chiral allenes have been reported in the last five years, both in metal-free conditions67 and in transition metal-catalysed reactions,68 such as Rh-catalysed monoallylation of chiral allenes with chirality transfer69 or aziridination of chiral allenes followed by nucleophilic ring-opening to form stereoselective stereotriads with three contiguous stereodefined carbon centers,70 Zn-mediated Michael addition,71 Pd-catalysed decarboxylative amination,72 and Ag-catalysed cycloisomerization,73 among others. In the enantioselective cyclopropanation of allenes with methyl aryldiazoacetates mediated by Rh2(S-DOSP)4 (28), the calculations (B3LYP/LANL2DZ level) have revealed an asynchronous TS which would place partial positive charge at the central carbon atom of the allene during the reaction.74 The mechanistic model justifies (Scheme 5) the high diastereoselectivity observed for monosubstituted allenes, wherein a group, R1, projects away from the reaction center, while a hydrogen (R2 = H) projects directly toward it. 1,1-Disubstituted allenes provide lower yields. Substitution with silicon on the allene substrate has a strong accelerating b-silicon effect on the reaction through hyperconjugation. For more complex stepwise processes, where the allene coordinates to the metal, the mechanism is less obvious and predictable. The apparent ease by which Z2-allene gold complexes rearrange into planar or virtually planar allylic cations implies that the stereochemical information of the starting allene can be lost. However, gold-catalysed reactions in which enantioenriched allenes transform into enantioenriched products have been reported, suggesting that a given reaction of a Z2-allene complex can be even faster than the formation of planar allylic cations or even that twisted (chiral) allylic cations may be involved. Enantioselective gold-catalysed reactions have been more profusely reported than reactions involving other metals as catalysts.75 Accordingly, more computational mechanistic studies have been performed.

Rh-catalysed enatioselective cyclopropanation of allenes.


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to a transfer of chirality. This transfer should be even more efficient as the substitution of the allene increases.


Scheme 6

Gold complexes of 1,3-dimethylallene.

The cyclisation of chiral a- and b-heteroallenes in the presence of gold(I) or gold(III) salts provides the corresponding 5- and 6-membered heterocycles with axis-to-center transfer of chirality.76,77 The nucleophilic attack at species of type 32, 33 or 34 is crucial to account for the transfer of chirality (Scheme 6). Indeed, although the stereochemical information is kept in complexes 32, it becomes lost when planar allylic cations 34 are formed. Even if these species are not strictly planar, their rotation barrier is so low that racemization of the starting allene is expected to be much faster than any other reaction process (vide infra).78 On the other hand, twisted allylic cations 33 are chiral species which keep the memory of the chirality of the starting material. Concerted racemization of such complexes is expected to be easier than that of Z2-allene complexes, but more difficult than that of virtually planar allylic cations, leaving a good chance for another elementary step to take place. As noted above, DFT calculations have revealed that for 1,3-dimethylallene, coordination to the central carbon atom is enthalpically disfavoured (by 6.1 kcal mol1, Fig. 4), and the concerted racemization reactions require quite high enthalpies of activation.59 This may account for the good chirality transfers observed with 1,3-dialkyl or 1-phenyl-3-alkyl allenes,77 the nucleophilic addition being faster than these competitive processes. However, the presence of an electron-donating group at the allene can modify this trend, which besides involves low-lying transition states for interconversions (0.01–3.4 kcal mol1). For vinylallenes, the corresponding allylic cation constitutes the ground state, and due to conjugation these species can also be considered as pentadienyl cations exhibiting helical chirality.79 In the case of trisubstituted allenes (Fig. 5), no planar structure was found. Besides, the ground states are the twisted complexes 36 or 39. Therefore, it seems clear that the 1,3-allylic strain is a critical feature to ensure chirality transfer because it prevents the formation of planar cations and also slows down the racemization of allenes. Because twisted structures retain the stereochemical information of the substrate, a reaction that requires the formation of C2-coordinated allenes may give rise

Fig. 5 Selected examples of gold complexes of trisubstituted allene ([Au] = Au(PMe3); relative enthalpies in kcal mol1).

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3. Formation of acyclic compounds by addition reactions In the last few decades, allenes have been recognized as synthetically highly useful precursors for the synthesis of acyclic products (olefins, 1,3-dienes, enynes, and allenes). These transformations can be uncatalysed or, most frequently, mediated by organocatalysts or by metal-catalysts. Thus, upon coordination, allenes are activated and can participate in various organometallic reactions, for example, insertion into M–R bonds, oxidative coupling with other unsaturated substrates, C–H activation, nucleophilic addition and abstraction reactions, and electrophilic addition reactions. Since the most relevant computational studies in this area concern the addition reactions, we have focused mainly on this type of transformations.80 3.1.

Electrophilic and nucleophilic additions

The bromination of allenes is an important reaction for generating key intermediates in the synthesis of natural products.81 Chiappe et al. have reported experimental and computational (MP2/6-311+G** and B3LYP/6-311+G**) evidence for the involvement of p complexes along the reaction coordinate for bromine addition to allenes, showing that the pre-equilibrium formation of these complexes between unsaturated compounds (alkenes, alkynes and allenes) and Br2 is a general phenomenon. The existence of these charge-transfer complexes formed from the reaction of allenes with bromine in various solvents was firstly derived from their UV spectra. However, no direct determination of the structures of the complexes has been obtained due to their instability. The most stable form of the 1 : 1 complex of allene with bromine is, according to calculations, similar to the 1 : 1 bromine complexes of ethene and acetylene investigated previously,82 i.e. exhibiting the Br2 moiety perpendicular to the C–C bond (species 41 in Fig. 6).

Fig. 6 Geometries (MP2/6-311+G**) of 1 : 1 and 2 : 1 complexes of Br2 with allene.


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The most stable structures of the 2 : 1 complexes of allene with bromine are 42 (C2) and 45 (C2v), but their preferences over 43 and 44 are less. The trimolecular complex can be regarded as a combination of the T-shaped 1 : 1 complex with an additional bromine molecule perpendicular to the first one. The fragment of the monomolecular T-shaped complex donates electron density into the empty s orbital of the second bromine molecule through the p and p* orbitals. It was pointed out that a 1 : 2 complex may resemble a bromonium ion with Br3 as the anion. Hence, in ionizing solvents the formation of bromonium or bromirenium ions from the trimolecular complexes will additionally be strongly favoured energetically. Comparison of computational and experimental evidence strongly suggests the involvement of a pre-association mechanism in the reaction of allenes with bromine and shows that a competition between pre-association, free-ion, and ion-pair pathways is a general feature of the electrophilic bromination of unsaturated compounds. The authors also analysed how the steric strain of the allene (cyclic) affects the reactivity. N-Bromosuccinimide (NBS) promotes, as an electrophilic reagent, bromination under soft conditions.83 Alcaide et al. have recently reported the chemo-, regio- and stereoselective bromination and ring expansion of lactam-tethered allenols to cyclic a- or b-ketoamides, through controlled C–C bond cleavage of the b- or g-lactam nucleus.84 At the corresponding TSs, while the Br+ cation is essentially transferred to the central sp carbon atom of the allene group, ring expansion is delayed. The addition of the Br+ cation to the central sp carbon atom of the allene group leads to the formation of a carbocationic sp2 C5 center, which induces concomitant ring expansion (Scheme 7). The presence of a bulky substituent can control the stereochemistry of the reaction. Whereas the a-sulfenylation of aldehydes85 and b-addition of a,b-unsaturated carbonyl compounds via sulfa-Michael reaction86 have been successfully performed, the g addition of unsaturated carbonyl compounds was a challenge until Trost and Li described the umpolung addition at g-carbon catalysed by Ph3P.87 Later on, the asymmetric synthesis of g-thioester by addition of thiols to allenoates catalysed by chiral bisphosphine TangPhos has been recently reported by Sun and Fu.88 Chen et al. have performed DFT calculations (PCM/B3LYP/ 6-311++G(d,p)//B3LYP/6-31G(d,p)) to get more insight into the activation mode of TangPhos (49) and its implication on the enantioselectivity.89 The uncatalysed addition occurs at the b-carbon atom via a stepwise process involving C–S bond formation and proton transfer from S to g-carbon which generates

Scheme 7

NBS-catalysed ring expansion of 2-indolinone-tethered allenols.


Review Article

Scheme 8 TangPhos-catalysed asymmetric g addition of thiols to allenoates.

the corresponding b-thioester. TangPhos-catalysed asymmetric g addition proceeds through three steps: the rate-limiting nucleophilic attack of thiol on g-carbon of allenoate after the barrierless addition of TangPhos to b-carbon, the proton transfer firstly from P of TangPhos to the carbonyl O of allenoate, and then to the b-carbon. Finally, TangPhos and the product g-thioester are liberated (Scheme 8). As nucleophilic catalyst, P2 forms a strong covalent bond with the b-carbon which shifts the positive charge of C2, leaving C3 as the electrophilic center for g addition. The regioselectivity is consequently altered. As Lewis base, P1 deprotonates thiol enhancing the nucleophilicity of S and facilitates the proton transfer to b-carbon as a medium. 3.2.

Activation of the allene by an electrophilic metal

Transition metals, in particular those from groups 10–12, exhibit significant efficacy for catalysing the formation of carbon–carbon and carbon–heteroatom bonds. Complexes and salts derived from late transition metals Au (gold(III) and cationic gold(I)), Pt and Pd have shown an exceptional ability to promote a variety of organic transformations of unsaturated precursors. These processes result from the peculiar Lewis acid properties of these metals: the alkynophilic character of these soft metals and the p-acid activation of unsaturated groups promote the intra- or intermolecular attack of a nucleophile. Maseras et al. have reported computational studies (PBE0/ 6-31G(d,p)/SDD) into the [NHC]Au(I)-catalysed intermolecular hydroalkoxylation reactions of allenes.90 The regioisomer formed by attack of the alkoxy group on the methylated end of the allene is computed to be thermodynamically more stable, but its formation is kinetically less favourable. However, this result is not in agreement with the experimental observations (hydration of mono-, 1,1-, 1,3-substituted, and trisubstituted allenes was achieved in moderate yields). In most cases only the product of the attack of water on the less hindered terminal carbon was obtained.91 Because allene hydroalkoxylation was calculated to be irreversible (i.e., under kinetic control),

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Scheme 9

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[NHC]Au(I)-catalysed hydroalkoxylation reaction of allenes.

the authors considered that a further Au(I)-catalysed interconversion of the regioisomeric allylic ether products can occur. This rearrangement proceeds via the formation of a cyclic acetoxonium intermediate (60) in a process electronically similar to a metal catalysed Cope rearrangement, which is predicted to be more facile than the initial allene hydroalkoxylation reaction (Scheme 9). Thus, the preferred path involves the nucleophilic attack of the alcohol onto the more substituted terminal carbon atom from the outer-sphere of the gold-coordinated allene (as proposed by Widenhoefer78a and in contrast to the inner-sphere mechanism proposed by Yamamoto)92 and protonolysis of the s Au–C bond, followed by a gold-catalysed regioisomerisation between the two possible allyl ethers. These DFT calculations suggested that the concentration of the alcohol might be important for the formation of one or the other regioisomer, which is in agreement with the results obtained by Horino et al.,93 who observed that the use of an excess of alcohol was essential to improve the regioselectivity towards the addition to the more substituted carbon of the allenic system. This concept has been proven more recently by Lee et al. in a study where the gold(I)-catalysed isomerization of tert-allylic ethers to primary allylic ethers was retarded by excess of alcohol.94 Despite all the studies on the intermolecular reaction of allenes with alcohols in the presence of gold complexes, and the understanding of the factors that influence the regiochemistry of the addition, the enantioselectivity of the reaction remains an unsolved challenge. No transfer of chirality is observed in this process, which is quite different from the closely related hydroamination reaction.95 Regarding hydroamination reactions, although the enantioselective intermolecular hydroamination of allenes would be an efficient method for the synthesis of a-chiral allylic amines, only one example has been reported, which requires internal allenes. This methodology has a limited scope, and provides only moderate levels of enantioselectivity.96,97 On the basis of experimental and computational studies, Toste et al.98 proposed a mechanistic picture of the gold(I)catalysed hydroamination of allenes (Scheme 10). The computational studies suggest an outer-sphere mechanism where a

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Scheme 10

Mechanism for hydroamination of 61 with Ph3PAuNTf2.

monomeric bent allene–gold complex is the rate-determining transition state (TS1) in the catalytic cycle, which is supported by kinetic evidence. The overall reaction exhibits zeroth-order dependence on the concentration of the nucleophile, suggesting that nucleophilic addition must occur after the rate-determining step. In addition, the pseudo-first-order dependence on the concentration of allene and Ph3PAuNTf2 suggests that the catalytic species is monomeric and that the ratio of allene to catalyst in the transition state is 1 : 1. Thus, the inner-sphere mechanism, proposed by Yamamoto,92 where the nucleophile coordinates to the gold center prior to or during allene activation is unlikely. The reaction proceeds via a two-step no-intermediate mechanism and involves a second transition state occurring immediately after the rate-determining step which is not planar but axially chiral. Importantly, the observed dependence of the degree of chirality transfer on the concentration of the nucleophile suggests that a pathway proceeding through a traditional two-step pathway involving a planar intermediate (66) is also available. Thus, the reaction coordinate can bifurcate following TS1, leading to TS2 or intermediate 66. At higher nucleophile


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concentrations, addition of the nucleophile is fast and the two-step no intermediate pathway is favoured, leading to higher levels of chirality transfer. At lower concentrations of the nucleophile, TS1 leads to the planar intermediate 66 with loss of chirality. The operating reaction mechanism is a continuum between a traditional two-step process with loss of chirality and a two-step no-intermediate process with retention of stereochemistry. In 2008, Toste and co-workers postulated the involvement of a diaurated intermediate in the gold-catalysed cycloisomerization of 1,5-allenynes on the basis of DFT calculations (see Section 4).99 ´ et al. provided experimental support for a Subsequently Gagne diaurated reaction intermediate involved in Au(I)-catalysed intramolecular hydroarylation of allenes,100 whose structure resembles that of the intermediate proposed by Toste. More recently, Bandini and co-workers reported an enantioselective intramolecular binuclear gold(I) complex catalysed allylic alkylation of indole with allylic alcohol, presumably via a diaurated reaction intermediate with dual activation of the CQC bond and the hydroxy group.101 Che et al. have investigated the intermolecular reaction of allene with indole via mono- or diaurated intermediates.102 Their experimental and computational results revealed that the reaction mechanism involving intermolecular nucleophilic addition of free indole to gold-activated allene is more likely than intramolecular cyclization via a diaurated intermediate with dual activation of allene and indole (Scheme 11). Thus, the cationic gold(I) coordinates to the allene to give intermediate 69 and this coordination facilitates the nucleophilic attack on the allene by free indole to generate intermediate 71 via transition state TS70–71. Subsequent protonolysis of 71 affords the desired product (72) and regenerates the catalyst.

Review Article

Other remarkable reactions of allene derivatives under goldcatalysed conditions with high yield and specificity are the transformations of an allene derivative to an acyclic conjugated system.103 Most of these processes involve a sigmatropic rearrangement, where a C–O or C–H bond cleavage takes place as a mandatory step. Recently, the easy isomerization of a specific class of allenes to conjugated dienes using suitable solvents and reagents has been reported. Although allenamide derivatives isomerize to 2-amido conjugated dienes when heated in acetonitrile solution,104 Ting et al. reported the isomerization of several alkyl-substituted unactivated allene derivatives to 1,3-butadiene systems under metal-catalysed conditions, such as Au(III) using nitrosobenzene as an additive.105 Das et al. proposed a bimolecular pathway that can rationalize not only the energetics of the reaction but also the stereoselectivity and regioselectivity associated with the metal-free process.106 This mechanistic pathway may be considered as a tandem ene–retro-ene process involving two consecutive steps, rather than a path via a concerted antarafacial [1,3]-H shift mechanism. DFT calculations (PBE0/6-31G**/(aug)-ccpVDZ) by the same group107 suggest that the Au(III)-catalysed isomerisation of substituted allene 73 to conjugated diene 77 (Scheme 12) takes place through activation of the allene by Au(III), followed by migration assisted by an additive (nitroso compound) of the hydrogen atom from the substituent alkyl group of the allene moiety to its central sp-hybridized carbon atom. The unbound nitroso compound acts as a better proton transferring agent in the isomerization process and utilizes its own nitrogen atom to carry the proton. Also in agreement with the experiment,

Scheme 11 Gold-catalysed intermolecular reaction of allene with indole via a monoaurated intermediate.


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Scheme 12 Au(III)-catalysed isomerization of substituted allene to a conjugated diene in the presence of nitrosobenzene.

the calculation suggests that Au(I) is not very effective to carry out the isomerization smoothly under similar reaction conditions. 3.3.

Addition of element–element to allenes

3.3.1. Transition metal-catalysed 1,2-addition of element– element to allenes. The wide variety of transformations reflect the multireactivity of the allene moiety due to the two existing orthogonal p-bonds. A remarkable progress has been made toward the development of transition metal-catalysed reactions with allenes as precursors, as noted along this review.108–112 Among the transition metals, palladium catalysts have been most widely investigated and proven to be extremely advantageous in allene chemistry113 since the first described synthetic application in the 1980s.114 Thus, palladium-catalysed cross-coupling reactions of allenyl halides with organometallic species R–Met or of allenylmetal species with organohalides R–X are reliable and well-known methods for the synthesis of highly substituted derivatives which keep the allene group. Synthetically more important are smooth palladiumcatalysed addition reactions of allenes, which produce alkenes as reaction products without the cumulene p-system. Nucleophilic additions to allenes occur on either 1- or 3-position depending on their substituents, which leads to a- or g-adducts.115–118 From a mechanistic viewpoint, the formation of the adducts can be described as follows: R–X, for example, an organic halide, adds oxidatively to a palladium(0) catalyst, which forms the palladium species 79; it then undergoes a carbopalladation with the allene119 to generate regioselectively a Z3-allylpalladium intermediate 80 (in equilibrium with the less stable s-vinylpalladium species, Scheme 13). Finally, a nucleophilic attack by Nu leads to the expected adducts 81

Chem Soc Rev

and/or 82 depending on the individual substrates and reaction conditions. The isolation of Z3-allylpalladium intermediate120 and its structural characterization by using X-ray analysis support this mechanism. A broad range of reagents possessing an element–element or an element–carbon s bond has been used as reaction partners in palladium-catalysed additions to allenes.116–118,121 Typical elements involved are B, Si, Ge, Sn, S, and Se, which result in products that are valuable intermediates in organic synthesis, such as vinyl and allyl silanes, boranes, or stannanes. Many silaboration reactions of allenes have been studied by the groups of Ito and Suginome,122 Tanaka,123 and Cheng,124 who disclosed efficient regio- and stereoselective transformations of monosubstituted allenes. The mechanism proposed for the regioselective silaboration of allenes122 on the basis of a DFT study125 suggests that the reaction proceeds exothermically and the rate-determining step is the coordination and insertion of allene into the Pd–B bond of the Pd complex that generates a s-allylic complex (87, Scheme 14). The selective insertion of the electron-deficient CQC bond provides the most stable s-allylic complex, which converts into the p-allylic complex while maintaining the O–Pd coordination. This orientation in the p-allylic complex facilitates the reductive elimination, which leads to the regioselective product in a transformation occurring under kinetic control. The most extensively studied additions of E–E bonds to allenes are those involving Si–Sn bonds, because the silylstannanes are easy to be handled and the addition products are easy to be isolated.126 On the basis of Mitchell’s pioneering work on the silastannylation of allenes,127 RajanBabu and co-workers128,129 developed a modified protocol that led to significantly higher regioand stereoselectivities. An interesting regioselectivity was found when the silyl group is exclusively attached to the internal sp-carbon atom of the nonsubstituted, monosubstituted and 1,1-disubstituted allenes.127,130 The position to which the stannyl group was attached depends remarkably upon the substituents on the allene as well as the silylstannane. Remarkably, the silyl group prefers the internal sp-carbon atom, while the stannyl favours the substituted sp2-carbon atom kinetically and the terminal nonsubstituted one thermodynamically. The reaction mechanism of silastannation of allenes was proposed to proceed via oxidative addition, allene insertion into the Pd–Si bond to provide the p-allylpalladium species, and final reductive elimination.128 Based on the theoretical studies on the Pd(0)-catalysed allene silaboration125 and alkyne silastannation,131 Wang et al. carried out theoretical calculations (B3LYP/6-311-G(d)/LANL2DZ) for a model of Pd(0)-catalysed allene silastannation reaction

Scheme 13 Additions to allenes via carbopalladations.

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Scheme 14

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Palladium-catalysed regioselective silaboration of allene.

Scheme 15 Silastannylations vinylsilanes.

of

allenes,

leading

to

functionalized

(Scheme 15).132 The results suggested that the reaction pathway proceeds via (a) oxidative addition of Si–Sn to Pd(PH3)2, (b) dissociation to form complex 89, (c) allene coordination and insertion into the Pd–Si bond, (d) isomerization from s-allyl 90 to p-allyl complex 91, and (e) reductive elimination to give the final product Z-93. The rate-determining step is the allene insertion into the Pd–Si bond. The s-allylpalladium (internal) insertion product is favoured over the s-vinylpalladium (terminal) insertion product during the allene insertion into Pd–Si bond, which might be related to the different orientation of the electron transfer in terminal-insertion and internal-insertion. The Pd–Si bond is favoured over Pd–Sn for allene insertion mainly due to the higher Si–C bond strength compared to Sn–C bonds. Regarding the regioselectivity in methylallene silastannation, the calculations revealed that the Si–Sn bond addition to the internal CQC bond is preferred kinetically and to the terminal one thermodynamically, in agreement with the experiment. The same group has also reported the bis-selenation of allenes catalysed by Pd complexes.133 Palladium-catalysed bisselenation of allenes in the presence of CO was first reported in 2005.134 Highly regioselective addition products are obtained with two selenyl groups attached to the terminal CQC of the allenes. This regioselectivity is special, because the addition of Si–Si, Sn–Sn, Si–Sn, B–B, and B–Si bonds to allenes generates


organic compounds with two functional groups added to the internal carbon–carbon double bond of allenes.126 The calculations (hybrid B3LYP and pure BP86 functionals) suggested that the most favoured reaction pathway proceeds via (a) oxidative addition of Se–Se to Pd(PH3)2 to generate the cis complex Pd(SeMe)2(PH3)2, (b) dissociation of PH3 to form cis-Pd(SeMe)2(PH3), (c) isomerization of the cis complex to the complex trans-Pd(SeMe)2(PH3), (d) allene coordination and insertion into the Pd–Se bond of trans-complex using the internal carbon atom attached to the selenyl group, (e) isomerization from the s-allyl to the p-allyl complex, and (f) reductive elimination to give the final product (Z)-CH2QC(SeMe)CH2(SeMe). With the PH3 ligand, allene insertion and reductive elimination constitute the rate-determining steps, while the rate-determining step is the reductive elimination process with the slightly bulkier PMe3, which highlights the importance of the ligand effect. For methylallene, the Z and E isomers of the Se–Se bond addition products (Scheme 16) are formed in a competitive way, in agreement with experiment. Similar selectivity was observed in the dithiolation of monosubstituted allenes under similar reaction conditions.135 Palladium-catalysed carbonylations of allenes in the presence of carbon monoxide provide a straightforward access to various synthetically important a,b-unsaturated carbonyl compounds.136 In the last decade, alternative strategies were developed that avoided the use of the toxic carbon monoxide. As alternatives, Cheng and co-workers137 and later Mapp’s group138 have reported acylborations, acylsilylations and acylstannations of allenes with high regio- and stereoselectivity. Likewise, the palladium-catalysed 1,2-addition of selenol ester 104 to monosubstituted allenes 103 afforded functionalized allyl selenides 105 in good yields and with excellent Z selectivities, as observed by Kambe et al.139 DFT calculations provided support for the mechanism depicted in Scheme 17, where formation of 108 is kinetically and thermodynamically the most favoured pathway, thus accounting for the observed regio- and stereoselectivity. Because of the Lewis acidic character of trivalent organoboron compounds, the diboration of allenes140,141 should provide addition products that have unique reactivity relative to related silicon and tin derivatives. The palladium-catalysed diboration of prochiral allenes (109) with bis(pinacolato)diboron using the enantiopure TADDOL-derived ligands 110 enables an efficient and highly

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Scheme 16 Regioselective bis-selenation of methyl-allene catalysed by Pd. The reductive elimination transition states TSZ-101 and TSE-102 are depicted, the former being only 1.0 kcal mol1 lower than the latter. Thus, the formation reactions of mixtures of Z-101 and E-102 as products are competitive.

Scheme 17 Pd(0)-catalysed selenoacylation a,b-unsaturated carbonyl compounds.

of

allenes

leading

to

enantioselective entry to a diboron compound 111 (Scheme 18),142,143 which is an attractive key building block for the synthesis of b-hydroxyketones,144 b-aminoketones,145 and 1,2-diols146 with excellent enantioselectivities. The combined experimental and computational study performed by Morken et al.143 suggests that the catalytic cycle proceeds by a mechanism involving rate-determining oxidative addition of the diboron to Pd followed by transfer of both boron groups to the unsaturated substrate (Scheme 18). As expected, this transfer reaction most likely occurs by coordination and insertion of the more accessible terminal alkene of the allene substrate, by a mechanism that directly provides the Z3 p-allyl complex in a stereospecific, concerted fashion. According to these results,

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Scheme 18 Diboration of allenes. For calculations, PMe3 as the ligand for palladium and ethylene glycol as the ligand on boron were used for reducing computational cost.

the insertion step is most likely the enantiomer-determining step of the allene diboration process. This regioselectivity with palladium catalyst using external Lewis basic ligands and with the two boryl groups connecting to the internal CQC bond of allenes is similar to that observed for the platinum catalyst.147 However, the mechanistic study of the Pt(0)-catalysed allene diboration reaction (B3LYP level)148 found a similar pathway to that proposed for the palladiumcatalysed allene silaboration (see Scheme 14), namely involving


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Scheme 19

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Catalytic cycle for the borylation of allenamide.

isomerization from the s-allyl to the p-allyl complex, after ratedetermining insertion of the allene into the Pt–B bond. The catalytic reaction proceeds exothermically. It is found that the internal carbon atom is favoured over the terminal one during the allene insertion into the Pt–B bond which can be ascribed to the stronger electron back-donation and stronger charge transfer in the d–p interaction in the former case than in the latter case. In the last few years attention has been paid to the synthesis of organoboranes from the Cu-catalysed borylcupration of unsaturated hydrocarbons,149 such as with bis-(pinacolato)diboron. However, for the Cu-catalysed borylcupration reaction of multisubstituted allenes, a formidable challenge is controlling the regio- and stereoselectivity. To this end, Ma et al. have recently reported a novel copper-catalysed, highly regio- and stereoselective borylcupration of substituted 2,3-allenamides with bis(pinacolato)diboron producing Z-b-borylated b,g-unsaturated enoamides (119, Scheme 19).150 DFT calculations (B3LYP/ 6-31G(d)/LANL2DZ) suggested that the stability of the possible regioisomeric b-boryl alkenyl complexes, 116 and 117 intermediates, is the main factor which controls the regioselectivity of this borylcupration reaction. The reaction predominantly takes place with the amide-substituted CQC bond (placing the boron connected to the central carbon atom), followed by the formation of the chelate 117, with the insertion of the coordinated allenamide into the Cu–B bond being the rate-limiting step of the process. The calculations agree with the stereoselectivity found, with the formation of the Z-116 isomer kinetically favoured (by 3.8 kcal mol1) over its E-isomer due to the steric interaction between the boryl group and the larger g-substituent of the allenamide. Hoveyda et al. have recently observed that the regioselectivity in the Cu-catalysed boration of monosubstituted allenes can be modulated by the ligand (N-heterocyclic carbenes).151


Thus, whereas diaryl-NHC as a ligand provides 121, dialkylNHC-Cu gives rise to 123. DFT calculations (BP86/6-31G(d,p)/ LANL2DZ) reveal that the Cu–B addition places the NHC-Cu initially at the less hindered site of the monosubstituted allene (Scheme 20). However, the following g-protonation causes preferential formation of the 1,1-disubstituted vinylboron product with catalysts having the larger NHC ligand (diarylNHC). For the smaller ligand (dialkyl-NHC) the conversion of the 120 to isomeric 122, bearing a secondary Cu–C bond, becomes sufficiently favoured. Calculations also reveal that allylcopper 122 is higher in energy and can more swiftly undergo protonation to afford trisubstituted B(pin)-substituted alkenes 123. Ma et al.152 and Oh et al.153 independently reported the highly regio- and stereoselective palladium-catalysed hydroarylation or hydroalkenylation of allenes with organic boronic acids to give tri- or tetrasubstituted alkenes. Yoshida et al. disclosed that the selectivity of the addition of arylboronic acids to allenes can be altered by the choice of the transition metal and base. In contrast to the formation of endo olefins as products in the reactions with a hydroxopalladium complex, exo olefins were the predominant products in the reaction with

Scheme 20

NHC-Cu-catalysed protoboration of monosubstituted allenes.

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Scheme 21 (a) Allene hydroboration by 124. (b) The steric bulk of the 10-TMS group in products of hydroboration reactions of 124 retards the 1,3-boratropic rearrangement transition state.

platinum154 or rhodium complexes.155 The observed E configuration for the double bond in the endo olefins resulted from the attack of the organoboronic acids on the less hinderic side of the allene. Noteworthily, nickel-catalyst promotes quite a different regioselectivity as the aryl groups selectively add to the terminal carbon atom of the allenes.156 However, to our knowledge, a systematic computational analysis to account for these findings has not been performed to date. 3.3.2. Metal-free boration of allenes. Hydroboration of allenes with borane is complicated, forming mixtures of regioisomers and of mono- and dihydroboration products. The reaction can be controlled by using less reactive 9-BBN or catecholborane to give monohydroboration products. The regioselectivities of hydroboration of those reagents with asymmetric allenes are usually very high. The R and S allenes can be resolved by reacting with chiral hydroborating reagents such as dipinanylborane. The mechanism of this reaction has been considered to be similar to that of hydroboration with ethylene and acetylene. Pioneering calculations by Houk et al.157 showed that the activation energy is intermediate between those for ethylene and acetylene. For methyl-allene and ethyl-allene, two modes of addition of borane relative to the substituted group are possible showing a slightly favourable addition of the borane from the anti side to the substituted group at that level of theory (RHF/3-21G). The hydroboration reaction of 1-substituted allenes with dialkylborane reagents such as 9-borabicyclo[3.3.1]nonane (9-BBN), dicyclohexylborane (Chx2BH), and (Ipc)2BH generally affords g-substituted (E)-allylic boranes.158 Wang et al. proposed that the hydroboration of allenylsilanes with 9-BBN and Chx2BH initially gives (Z)-allylic boranes, which then undergo rapid thermodynamically controlled Z to E isomerization via two [1,3]-boratropic shifts.159 Because of this facile equilibration, hydroboration of allenes with common dialkylborane reagents such as 9-BBN, Chx2BH, and (Ipc)2BH generally gives g-substituted (E)-allylic boranes. Roush and co-workers have developed a

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general methodology for generating g-substituted (Z)-allylic boranes via the hydroboration of monosubstituted allenes with 10-TMS-9-borabicyclo[3.3.2]decane (124),160 which is thermally stable against Z to E isomerization.161 Hydroboration of the allenes with 124 followed by addition of an aldehyde to the derived allyboranes provided the syn adducts as major products (Scheme 21a).160 Mechanistic studies of allene hydroboration with 9-BBN and 124, [1,3]-boratropic shift, and aldehyde addition have been performed by DFT calculations. They have revealed that reagent 124 gives unusually stable (Z)-allylic boranes 126 because the 10-TMS group interacts with the p-allyl C–H bonds in the transition state associated with a [1,3]-sigmatropic shift (Scheme 21b). This raises the barrier for rearrangement, thus allowing kinetic control of the allene hydroboration. In contrast, the [1,3]-boratropic shift rearrangement for 9-BBN shows a considerably lower barrier, thus supporting the experimental evidence.162 More recently, the same group has reported that the hydroboration of allenecarboxylate 132 with borane 124 provides stereoselective formation of (Z)-dienolborinate Z-(O)-133 (Scheme 22), which upon treatment with aldehydes provides syn a-vinyl-b-hydroxy esters 134 in good yields with excellent diastereoselectivities (dr 4 40 : 1) and with good to excellent enantioselectivity (73–89% ee). DFT calculations (M06-2X/ 6-31G(d,p)) and NMR evidence support the proposed pathway and confirm that the 10-TMS group provides large kinetic stability to intermediate Z-(O)-133 with 420 kcal mol1 free energy barriers for 1,3- and 1,5-rearrangement pathways.163 Finally, to end this section we briefly cite some recent computational studies on the reaction pathways followed by these boranes in the synthesis of more complex derivatives to account for experimental results. Thus, for instance, it is wellknown that chiral allyl- and crotylboron are useful reagents for the stereoselective conversion of aldehydes into homoallylic alcohols.164 Asymmetric induction is usually controlled by


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Scheme 22

Review Article

Enantioselective synthesis of syn-a-vinyl-b-hydroxy esters.

ligands linked to boron or by using chiral aldehydes, or by both methods. Ariza et al. have established a new stereodivergent approach to 2-vinyl-1,3-diols based on a hydroboration of allene/addition of aldehyde tandem process. To explain the high facial selectivity of the chiral boron reagent, the reaction of a model crotylboron reagent with acetaldehyde was explored by calculations (RHF/6-31G**), which revealed the ability of the more favoured TS to minimize the interactions of the chain of the aldehyde and the substituents at the chiral center of the crotylboron reagent.165 The stereoselective reaction of allenyl boron(pinacolates) with benzaldehydes catalysed by the chiral Brønsted acids (type 138, Scheme 23) gives chiral homopropargylic alcohols (137), which are highly useful intermediates, with broad synthetic utility. Computational studies suggest that the reaction proceeds through a six-membered ring transition state with activation of the pseudo-equatorial boronate oxygen by the acid catalyst.166 The high enantioselectivity obtained with catalyst 138 originates from steric interactions between the methyl groups of the allenylboronate and the bulky catalyst substituents, and the resulting distortion of the catalyst. A recent computational study on the use of 1,1 0 -bi-2-naphthol (BINOL)-derived catalysts for the asymmetric propargylation of ketones167 has accounted for the observed enantioselectivity. Calculations (M062X/LACVP**//B3LYP/6-31G**) show168 that the reaction also proceeds via a closed six-membered transition structure in which the chiral catalyst undergoes an exchange

process with the original cyclic boronate ligand. This leads to a Lewis acid type activation mode, not a Brønsted acid process, which accurately explains the stereochemical outcome. 3.4.

Radical additions to allenes

Early reports on radical additions to 1,2-dienes already pointed to peculiarities of the allene system concerning its reactivity towards intermediates with unpaired electrons.169 It was soon realized that no correlation between polar and steric substituent effects existed. Addition of carbon-,170 tin-,171 nitrogen-,172 phosphorus-,173 sulfur-174 and selenium-centered radicals175 to allenes has been investigated at experimental and theoretical levels (Scheme 24). The reactions of atoms such as halogen (Cl , Br ),176 hydrogen,177 oxygen178 or metal atoms179 with molecules with cumulated p-bonds have also been studied. The principle of least motion requires that addition to Ca or Cg provides a p-type vinyl radical. This intermediate may isomerize to adopt the energetically favoured s-vinyl radical structure (Scheme 24). Addition to the central carbon atom of an allene (i.e., Cb) furnishes a p-type vinylmethyl radical that, upon rotation of the methylene group by 901, acquires the geometry of an allylic p-radical in order to gain full resonance stabilization. A computational analysis (QCISD(T)/6-311+G(d,p)//QCISD(T)/ 6-31+G(d,p)) of the chlorine addition to propadiene indicates that the chlorine atom encounters no detectable energy barrier as it adds either to Ca or to Cb in l to furnish chlorinated radicals 145 or 146 (Scheme 25).176 A comparison between experimental

Scheme 23 Enantioselective propargylation of aldehydes by reaction with allenyl boronic acid pinacol ester catalysed by Brønsted acid. Most of the hydrogen atoms in the depicted transition structure are omitted for clarity.


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Scheme 24 Schematic representation of intermediates in radical additions to allenes.

Scheme 25

Chlorine radical addition to allene.

and computed heats of formation points to a significant thermochemical preference for 2-chloroalkyl radical 145 in this reaction (Scheme 25). The results also revealed that due to the exothermicity of both addition steps, intermediates 145 and 146 are formed with considerable excess energy, thus allowing isomerisations of the primary adducts involving chlorine atom transfer but not hydrogen atom transfer. The addition of hydroxyl radical to allene in the gas phase has been studied experimentally and computationally. The addition by attacking at the central carbon to form an allylic radical showed a relative energy of 54.8 kcal mol1, lower than for the addition at the terminal carbon to give an alkenyl radical (27.5 kcal mol1).180 The former is expected to be favoured on the basis of conjugative stabilization. The radical addition is highly exothermic, and so isomerization of CH2QCOHCH2( ) to the acetonyl radical followed by dissociation to ketene and a methyl radical occurs as expected. Alkyl- and arylsulfanyl radicals, which may be generated upon photolysing thiols or in the presence of an initiator, readily add to cumulated p-bonds.181,182 In most instances, products of mono- and of twofold addition are formed from a thiol and allene. According to the results from computational studies, the HS addition to 1-donor and 1-acceptor-substituted allenes is considerably exothermic.183 With regard to the regioselectivity of sulfanyl radical attack on allenes, the tendency for b-addition increases along the series HS o MeCOS o RS (R = alkyl) o C6H5S . As a well-known rule, selective a-addition to a cumulated p-bond is restricted to reactions with unsubstituted allene,

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regardless of the nature of the radical. Substituents at the allene in general and methyl groups in particular favour b-addition of radicals, which leads to the formation of allylic and therefore stabilized intermediates. Results from computational studies predict that CH3 addition to Cb of the allene occurs along a trajectory that is orthogonally arranged with respect to the axis that aligns the three allenic carbon atoms (in contrast to the tilted approach for addition to Ca).184 A comparison of high-accuracy compound methods, CBS-QB3 and G3B3, and the density theory functionals, MPW1PW91, BB1K, and BMK, has been performed for the radical addition/b-scission of methyl to allene and other unsaturated compounds.185 DFT based values for b-scission rate coefficients deviate significantly from the experimental ones at 300 K, and the DFT methods do not accurately predict the equilibrium coefficient. The DFT methods predict reaction enthalpies that are generally lower by 1.2–3.6 kcal mol1 than the CBS-QB3 and G3B3 values and tend to underestimate the experimental reference values. Reaction of the phenyl radical with allene has been investigated experimentally and theoretically using high level G2M// IRCMax(RCCSD(T)//B3LYP-DFT).186 Phenyl radicals preferably add to the terminal carbon atoms in allene forming 3-phenylpropen-2-yl radicals. At higher temperatures, the H-abstraction channel, forming benzene and the propargyl radical, is predicted to become more important. These predictions are qualitatively similar to the results of the earlier theoretical investigations by Vereecken and Peeters.187 The calculated total rate constants agree with the experimental values within 40%.

4. Cyclization reactions of allenes The cyclization reactions are one of the most popular methods for the formation of carbo- and heterocyclic compounds. Although in most cases alkenes and/or alkynes are involved, the higher reactivity and the opportunities for regio- and stereoselectivity of the allene unit have significantly increased its use in the last few years, mainly in transition metal catalysed processes. 4.1.

Base-induced intramolecular cyclizations

The additions of nucleophiles to carbon–carbon multiple bonds to form heterocycles are of prime importance in synthetic organic chemistry. However, the reactions are applicable only to activated C–C multiple bonds, for instance by metals, or by using strong acid/base promoters. Reactions of bromoallenes have attracted much interest in recent years, because of their cumulated double bonds and high reactivity under metal-catalysis conditions.188 Tanaka et al. reported a computational analysis of the base-promoted intramolecular cyclization and stereochemical course of the amination of chiral bromoallenes (Scheme 26).189 The observed stereoselectivity was supported by the calculations, which suggested that the transition structures for the cis-aziridines are more stable than those for trans-aziridines. These energy differences are ascribed to different factors: the presence of stabilizing hydrogen


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Scheme 28 Scheme 26

bonds, the dipole moment of the transition structures, and steric and electrostatic factors. Furthermore, the calculations predicted that the use of a less polar solvent could improve the cis selectivity in the reaction. A practical three-step synthesis for 5H-pyrrolo[2,1-d][1,2,5]triazepine derivatives has been recently developed starting from pyrrole and hydrazine monohydrate.190 Mechanistic studies on the synthesis of these pyrrolotriazepine derivatives indicated that the allene can be trapped by nucleophilic attack of the nitrogen atom of the initial hydrazine (Scheme 27). Subsequent protonation and H-shift steps lead to formation of the observed triazepines. 2,3-Dihydrothiophenes are useful synthetic precursors for many compounds, so synthetic routes to 2,3-dihydrothiophenes are varied and numerous,191 where base-induced cyclizations play an important role. Under basic conditions, starting substrates usually require the presence of electron withdrawing groups or other functionalities to facilitate condensation chemistry or to directly participate in the cyclization. Despite that, a simple base-induced 5-endo-trig cyclization of benzyl 1-allenyl sulfides (153) occurs

Scheme 27

Base-induced cyclization of benzyl alkynyl sulfides.

Aziridination of bromoallenes.

Formation of pyrrolotriazepine derivatives.


without the need for initial activation or electron withdrawing substituents directly attached to skeletal carbons (although this cyclization mode should not be allowed according to Baldwin’s rules). According to calculations (CAM-B3LYP/6-311+G(d,p)/CPCM), 2,3-dihydro-thiophene 154 can be formed in three steps from allenyl species 153, including base 155, which undergoes a 5-endo-trig cyclization to 156 (Scheme 28).192 4.2. Transition metal catalysed cyclizations of allenes with a nucleophilic functional group Due to the high reactivity of the allene unit, a significant number of transition metal catalysed cycloisomerisations of allenes has been developed. This type of transformation has become nowadays one of the most popular methods for the construction of carbo- and heterocyclic compounds. Besides their mechanistic interests, these reactions also serve as the starting point of new synthetic strategies allowing for the increase of molecular complexity in the context of atom- and step-economy and development of greener reaction conditions. For these reasons, it is not surprising that the number of transition metal-mediated cyclizations involving allenes has considerably increased in the last few years.193 These reactions may follow different mechanistic pathways depending on the nature of the catalyst. In this section, the most significant computational studies on these processes shall be described. 4.2.1. Activation of the allene by an electrophilic metal. The activation of one of the double bonds of the allene by coordination to an electrophilic metal such as Hg(II), Ag(I), Pd(I), Rh(I), Cu(I) or Au(I)/(III) can give rise to a plethora of transformations.194 Thus, a nucleophile can attack intramolecularly the activated allenyl fragment giving rise, after a protodemetallation step, to the cyclized product. Depending on electronic and steric factors, either the proximal or the distal p-bond of the allene can be activated. In addition, for each of these two possibilities an exo or endo nucleophilic attack mode can be envisaged, leading to different regioisomeric products. The regioselectivity of the nucleophilic attack depends on the structure of the substrate and in particular on the length of the tether connecting the allene and

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Scheme 29

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Possible regioisomers in the cyclization of allenes using metal catalysis.

nucleophile moieties (Scheme 29). In most cases, five- or sixmembered rings, formed by attack at the terminal allenic carbon, are favoured. Moreover, chiral allenes can undergo these cyclization reactions in a stereoselective manner with chirality transfer. 4.2.1.1 Hydroalkoxylation of allenes. The first gold(III)-catalysed intramolecular hydroalkoxylations of functionalised a-allenols to the corresponding 2,5-dihydrofurans were reported by Krause in 2001.195 These reactions occur with complete axis-to-centre chirality transfer. This protocol is superior to the previously reported Ag(I)-catalysed process,196 with respect to functional-group tolerance and enhanced reaction rate. Since then, Krause, ¨der, and co-workers have developed a series of Hoffmann-Ro gold-catalysed cyclization reactions of highly functionalized a- or b-hydroxyallenes to afford the corresponding 2,5-dihydrofurans or dihydropyrans, respectively.197 The mechanistic model assumed for the gold-catalysed cycloisomerization of a-hydroxyallenes is depicted in Scheme 30. Thus, coordination of the carbophilic gold catalyst to the allenic double bond distal to the hydroxy group affords the p-complex 158, which undergoes a 5-endo-cyclization to the zwitterionic s-gold species 159. Final protodeauration leads to the dihydrofuran 160 and regenerates the gold catalyst. The cyclization is accelerated in the presence of external proton donors (i.e. water, methanol), hence suggesting that the protodeauration of 159 is the rate-limiting step.

Scheme 30 Mechanistic model assumed for the gold-catalysed cycloisomerization of a-hydroxyallenes.

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However, as noted above, regioselectivity problems are significant (endo-trig versus endo-dig versus exo-dig versus exo-trig cyclization). In order to get more insight into the factors controlling the selectivity of the reaction, Alcaide and co-workers explored the introduction of a wide range of precursors and expanded its application towards the synthesis of useful chemicals.198 The series of calculations reported by this group started with the investigation of the intramolecular cyclizations of b- and g-allenols.199 In this study, they focused on the effect of the metal and substituents on the chemo-, regio- and stereoselectivities. The authors observed that the regioselectivity of the metal-catalysed cyclizations of g-allenols200 derived from 2-azetidinone could be modulated by the nature of the metal (gold versus palladium) and by the status of the hydroxyl group in the g-allenol (i.e., free or protected) (Scheme 31).199a,201 In contrast, Ln-catalysed reaction provided complementary regioselectivity, but following a different reaction mechanism (see Section 4.2.2). The energy values computed for a model compound 165 (B3LYP/6-31G(d)/LANL2DZ/CPCM) clearly revealed a kinetic preference for the formation of the fused-tetrahydrofuran scaffold 167 (by 5.1–8.2 kcal mol1) by initial 5-exo-trig cyclization of the Z1-reactant complex, 166 (Scheme 32). Moreover, the calculations suggest that the stereoselectivity in this heterocyclization is governed by steric effects in the corresponding transition state. Protonolysis of the s-carbon–gold bond would yield the bicycle 169 (type 162) with simultaneous regeneration of the Au(III)-species. This process, which proceeds through a stepwise migration assisted by the catalyst, is predicted to be considerably favoured (by 13.1 kcal mol1) over a direct 1,3-H shift, which hence can be ruled out as operative. Overall, the formal 1,3-H shift is a strongly exothermic process (22.3 kcal mol1), pointing to a somewhat irreversible character of the process. The Pd(II)-catalysed cyclization coupling reaction of g-allenols 170 with allyl halides gave the tetrahydrooxepine-b-lactams 171 (Scheme 33), resulting from a 7-endo oxycyclization. The computed results for the plausible cyclization modes showed the same kinetic preference for the 5-exo-trig cyclization (by 4.7 and 6.3 kcal mol1 for the 6-exo-dig and 7-endo-trig, respectively). However, they suggested a kinetic preference for the allyl coupling event from the seven-membered-ring intermediate relative to other cyclic adducts (by 14.8 kcal mol1 for the five-membered ring),


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Scheme 31 Regioselectivity in the metal-catalysed cyclizations of g-allenols.

Scheme 32

AuCl3-catalysed cyclization of the g-allenol 165. Scheme 33

which appears as a favoured event over the protonolysis of the metal–carbon bond (by 6.3 kcal mol1). These results, along with the greater stability of the coupling product relative to the H-shift adduct, should funnel the reaction toward the observed product. Protection of the a-hydroxyl functionality with a MOM moiety has been shown to induce a different process when AuCl3 is used as catalyst (Scheme 31): g-allenols 161 are transformed into dihydrofurans of type 163 by a chemoselective 5-endo-trig cyclization over the ether protecting group. DFT calculations suggested that the formation of the corresponding gold-dihydrofuran intermediate complex through a chemoselective 5-endo-trig cyclization involving the ether protecting group is both kinetically and thermodynamically favoured over the competitive 5-exo-trig and 7-endo-trig cyclization reactions. The transition structure associated with the 5-endo-trig cyclization,


PdCl2-catalysed cyclization/cross-coupling of the g-allenol 170.

reached with small structural distortion from the reactant complex, allows an effective orbital overlap between the lonepair orbital n of the O atom and p* orbital and charge transference to the electrophilic fragment, which results in a significant stabilization of this saddle point as compared to those for the alternative routes. In contrast, protection of the g-hydroxyl group inhibits the Au(III)-catalysed 5-exo cyclization, with the 7-endo mode being the operative pathway, to yield fused tetrahydrooxepines of type 164 (Scheme 31). The calculations for a precursor model indicated that the 5-exo-trig cyclization transition structure was 5.1 kcal mol1 less stable than the 7-endo cyclization structure due to strong steric interactions between the protecting group and the catalyst. In summary, these results account for the chemo- and regioselectivity of the Au(III)-catalysed cyclization of g-allenols 161 and justify the influence of the structural properties of the a-substituent.

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Scheme 34

Chem Soc Rev

Metal-catalysed formation of tetrahydrooxepines from g-allenols.

The above results for 2-azetidinone-tethered g-allenol precursors revealed an initially kinetically favoured 5-exo-trig cyclization whereas the 7-endo-trig cyclization mode appeared as a less favourable route (activation barrier 6–8 kcal mol1 higher). This is in part due to the ring strain imposed by the b-lactam ring which restrains the tether flexibility and the successful interaction between reactive centers. Therefore, the authors directed their attention to the influence of the nature of the tether and examined the reactivity of g-allenols lacking the b-lactam ring. The preferential regioselectivity to the 7-endo cyclization in this case (Scheme 34) differs markedly from that of the reported Au-mediated oxycyclization of lactamic g-allenols.199a,202 Interestingly, a similar regioselectivity is observed when using [PtCl2(CH2QCH2)]2 as catalyst.203 The computed energy values reveal that the 5-exo-trig cyclization takes place with a higher activation barrier (4.9 kcal mol1) than the 6-exo-dig (2.5 kcal mol1) and the 7-endo-trig cyclization (2.2 kcal mol1). Furthermore, the same trend is systematically shown by the three catalytic systems. This kinetic preference sharply contrasts with that estimated for the precursors bearing a b-lactam ring as a tether due to the strain imposed by the tether in the transition structures. Thus, the b-lactam forces an eclipsed conformation around the dihedral angle O(H)–C–C–C for the transition and intermediate fused structures, whereas for the acyclic precursors the transition state can be reached through a lower energy staggered conformation because of the tether flexibility. This effect reduces drastically the activation barrier for the cycloetherifications and makes the 6-exo-dig and 7-endo-trig cyclizations the kinetically preferred pathways.204 The computed results for the Pt(II)-catalysed heterocyclizations show the same kinetic preference for the 7-endo-trig heterocyclization mode. Moreover, the calculations suggested that the tetrahydrooxepine 178 isomerizes to 179 through a 1,2-hydrogen migration, assisted by a halide ligand, followed by a Pt-catalysed b-hydrogen elimination and a protonolysis step. This isomerization is not observed under AuCl3 catalysis probably due to the fact that gold shows no tendency to undergo b-hydride elimination reactions;205 indeed, gold-hydrides are rare species which are difficult to access.206

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The above results clearly show that the regiochemistry for g-allenols can be altered by modifying the substrate structure or by using different metal catalysts. Rzepa et al. have also reported similar conclusions at the B3LYP/cc-pVDZ level (cc-pVDZ-pp for the metal).207 Thus, while the reaction of g-allenol proceeded via a 5-exo-trig pathway in the presence of Ag(I), 6-exo-dig cyclisation is kinetically favoured by Sn(II) and Zn(II) catalysts (Scheme 35). The authors stressed later the active role of the ligand/counterion in the reaction pathway and in the stereoselectivity.208 Although metal-catalysed cyclizations on a-allenols usually favour a 5-endo-trig pathway,209,210 Alcaide and co-workers hypothesized that the product selectivity could be impacted by modulating the relative stability of the Z2-complexes generated by p-coordination of the CQC bonds to the metal. Thus, for instance, whereas the a-allenol 186 (R1 = prop-2-enyl, R2 = Me) afforded the expected cycloisomerization adduct, dihydrofuran 189, the phenyl-derivatives (R1 = 2-methylallyl, R2 = Ph, and R1 = 2-bromoallyl, R2 = Ph) afforded the oxetenes 190 as the sole products in good yields (Scheme 36).211 This transformation can be explained invoking an uncommon allene 4-exo-dig cyclization as well as an infrequent b-hydride elimination reaction in gold catalysis.205 Other precursors provided, at room temperature, a mixture of two different products that arises from competitive 4-exo-dig versus 5-endo-trig cyclizations. The computed reaction profiles (PCM-B3LYP/def2-SVP)211 revealed that whereas the 5-endo-trig reaction is thermodynamically favoured when R = Me (by 5.1 kcal mol1), the 4-exo-dig reaction is favoured when R = Ph (by 2.2 kcal mol1). This justifies the formation of oxetenes 190 as the major reaction product when the reaction is conducted under reflux conditions. The calculations also supported that whereas the 5-endo-trig cyclization, loss of HCl and protonolysis sequence (leading to dihydrofurans 189) is favourably followed for methyl-substituted allenols, the 4-exo-dig step followed by loss of HCl, 1,3-Au-migration and b-elimination pathway (leading to oxetenes 190) is preferred for phenylsubstituted allenols. More recently, this group reported an experimental and computational study on the catalytic cycloisomerization of a-enallenols. They investigated the challenging problem of


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Scheme 35

Regiodivergence in metal-catalysed intramolecular cyclisation of g-allenols.

Scheme 36

Divergent oxycyclization reactions of a-allenols under gold catalysis.

transition metal-catalysed chemo-differentiating (alkene versus allene) cycloetherification of enallenols.212 It was found that chemoselectivity control in the O–C functionalization can be achieved through the choice of the catalyst: whereas AuCl3, PdCl2, and [PtCl2(CH2QCH2)]2 exclusively afford dihydrofurans 195 through selective activation of the allenol moiety, FeCl3 gives tetrahydrofurans 198 (or tetrahydropyrans) through selective activation of the alkenol moiety (Scheme 37). DFT calculations (PCM-M06L/def2-SVP level) on the gold-catalysed mechanism213 indicated that the protonolysis of the carbon–gold bond constitutes 1 the bottleneck of the process (DGa for 298 = +17.6 vs. +38.6 kcal mol the cyclized intermediates involving the allene and alkene moieties, respectively), which makes this step unfeasible for the cyclization of alkenol under the reaction conditions (room temperature) and hence on which the chemoselectivity is based. Finally, since the chemoselectivity for enallenols with FeCl3 was found to be similar to that observed in the presence of HCl, further calculations were performed, which suggested a kinetic preference for the formation


of the product by activation of the alkenol moiety, in agreement with the experimental results. Very recently, the first results on the palladium-catalysed cross-coupling reaction of two different allenes (b,g-allendiols and a-allenic esters) to dihydropyrans have been reported. This chemo- and regiocontrolled process occurs in a heterocyclization/ cross-coupling domino sequence that provides access to enantiopure dihydrofurans and 3,6-dihydropyrans bearing a buta-1,3dienyl moiety (202 and 204, Scheme 38). The computational analysis of the reaction mechanisms suggested a kinetic control of the chemo- and regioselective intramolecular heterocyclization. Moreover, the calculations have accounted for the absence of the plausible homo-coupling, other cross-coupling modes or Pd–C protonolysis products.214 The metal-catalysed heterocyclization of allenes bearing other O-functionalities as nucleophiles has been reported as well. Thus, procedures for the cycloisomerization of allenone to furan have been disclosed in the last few years. Chan and

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Scheme 37

Gold-catalysed divergent oxycyclization reaction of enallenols.

Scheme 38

Pd(II)-catalysed heterocyclization/cross-coupling reaction of b,g-allendiols and a-allenic esters.

co-workers have shown excellent conversion of allenones (B98%) into furans using Au-tetraphenylporphyrin chloride ([Au(TPP)]Cl), in contrast with the much lower efficiency and formation of other side products observed when using [Au(salen)]Cl (salen = N,N 0 -ethylenebis(salicylimine)) and AuCl3, respectively.215 A computational study (B3LYP/6-31G*&LANL2DZ) has revealed216 that in the case of the [Au(salen)]+-catalysed reaction, the computed higher activation energies associated with the cyclization and proto-demetallation processes reduce the efficiency of the process. However, [Au(TPP)]+ acts as a highly efficient chemoselective catalyst because the planar aromatic structure of the porphyrin unit stabilizes the corresponding ring closure transition state through symmetric orbital interactions between allenone and the catalyst, thus leading to a lower energy cyclization pathway. Albeit AuCl3 is a good Lewis acid catalyst for the cycloisomerization of allenone, the computations confirm that it leads to C–C bond formation instead, resulting in the dimerization of the allenone hence lowering the yield of furan. This is in agreement with previous experimental results.217 However, suitably substituted allenone molecules can prevent the dimerization effectively. Thus, Gevorgyan et al. have reported the cycloisomerization of

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bromoallenyl ketones, finding that the regiochemistry depends on the oxidation state of the catalyst and on the counterion.218 When a carbophilic Au(I) species (e.g., Et3PAuCl) is used, the cycloisomerization leads to the expected 5-bromofuran 211, whereas the more oxophilic gold(III) chloride preferentially generates the 4-bromofuran 207 (Scheme 39). It was found (CPCM-B3LYP/6-31G*&LANL2DZ level) that both Au(I) and Au(III) catalysts219 activate the distal double bond of the allene to produce cyclic zwitterionic intermediates, which in the latter case undergoes a kinetically favoured 1,2-Br migration. However, for Au(PR3)L (L = Cl, OTf) catalysts, the counterion-assisted H-shift is the major process, indicating that the regioselectivity of the Au-catalysed 1,2-H vs. 1,2-Br migration is ligand dependent. Chlorinated and iodinated allenes exhibit a similar behaviour. Moreover, silyl-, thio-, or selenofurans can be obtained from the corresponding allenes by a 1,2-Si, 1,2-S, or 1,2-Se shift.220 Hashmi and co-workers have reported the study of the Au(I)cycloisomerization of a-allene amides.221,222 This transformation provides 1,3-oxazines by attacking at the central position of the activated allene. A combined 31P NMR spectroscopic and computational study allowed the characterization of the key


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Scheme 39

Regiodivergent Au(III)- and Au(I)-catalysed cycloisomerizations of bromoallenyl ketones to furans.

intermediate s-allyl gold(I) species and the involvement of a SE 0 -type protodeauration step. The same regioselectivity has been recently reported by Alcaide et al. in the gold-catalysed oxycyclization reactions of allenic carbamates to 1,3-oxazinan-2-ones 216 or to 1,3-oxazin2-ones 220 (Scheme 40).223 The computational results (PCMM06/def2-SVP//B3LYP/def2-SVP level) concluded that the initial 6-endo is kinetically favoured over the 6-exo oxyauration, whereas the latter is thermodynamically favoured. Hence, a thermal isomerization of the less stable 6-endo-dig adduct to the 6-exo-dig product could be speculated. Allenic esters are also an important group of precursors able to form a wide variety of products by intramolecular oxycyclization onto the allene moiety. Thus, a good number of catalysed transformations have been reported for this versatile family. Hammond and Liu described the intramolecular cyclization of allenoates224 with cationic gold(I) and succeeded in isolating room temperature stable vinyl gold(I) lactones 225 under very mild conditions.225 In view of the computed HOMOs and NBO

Scheme 40

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charge densities (Scheme 41) of selected allenoates, it was suggested that those species bearing an aryl-substituent at the g-position are much less nucleophilic226 than alkyl-substituted allenoates, which account for the observed limitations of reactivity. From intermediates 225, the gold catalyst is usually regenerated by a fast protodemetalation step. However, the C–Au bond can also be broken by other electrophiles.227,228 Further DFT calculations (B3LYP/cc-pVDZ) on the hydrolysis of these intermediates revealed a correlation between the reaction rate of the nucleophilic attack and their electronic properties (LUMO energy and p orbital coefficients).229 The allenic esters can be easily formed from propargylic esters by 1,3-carboxylate migration as intermediates under metal-catalysis,60,230,231 and can experience further transformations under simple one-pot conditions.232 This versatile entry to allenes for subsequent transformations has been frequently described experimentally and analysed by theoretical computations. Thus, Gevorgyan et al. reported the gold(III)-catalysed cycloisomerization

Divergent gold-catalysed oxycyclization reactions of allenic carbamates.


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Scheme 41 Computed (B3LYP/6-311G* level) natural bond orbital (NBO) charge densities of selected allenoates.

of propargylic ketoacetates to highly substituted furans under mild conditions.233 A theoretical study (PCM-BHandHLYP/ 6-31G(d,p)&SDD for Au) on precursors bearing different propargylic substituents (Me- vs. Ph-) has been recently described, suggesting that the rate-limiting step depends on the nature of the substituent.234 Nevado and co-workers reported the gold-induced rearrangement of 3-cyclopropylpropargylic carboxylates 226 which provides 5-(E)-alkylidene cyclopentenyl acetates 231 in a highly stereocontrolled manner (Scheme 42).235 The selection of substituents at the cyclopropyl ring provided the handle to favour the cyclopentannulation over the formation of a-ylidene-b-diketones following acetate fission, firstly reported by Zhang et al.236 DFT calculations support the intermediacy of gold-stabilized ‘‘nonclassical carbocationic’’ species and revealed the intrinsic stereospecific nature of these processes. The calculations suggest the easy formation of the expected allene structure 228 where the gold atom is coordinated to the distal allenic double bond for secondary propargylic acetates. The cyclization from 230 to produce 231 involves two adjacent transition states without any discrete intermediate in the reaction profile. The first

Scheme 42

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transition state (higher in energy) leads to a species TSB that can be described as a gold-stabilized nonclassical carbocation. Furthermore, the calculations show that the geometry of the alkylidene olefin is produced under kinetic control, as the alternative diastereomeric transition states confirmed. For the tertiary acetates, the steric hindrance caused by the presence of two methyl groups at the propargylic position makes the mechanisms along the 1,3-migration and the 1,2-migration paths competitive. Using the formation of allenes from propargyl acetates under gold-catalysis, Fensterbank, Malacria and co-workers developed a new synthesis of polycyclic compounds from propargyl acetates and vinyl allenes which involves three different reaction steps: [3,3]-rearrangement, 2-aura-Nazarov reaction, and electrophilic cyclopropanation. The mechanistic rationale, supported by DFT computations, involves, after isomerization of propargyl acetates to 3-acetoxy 1,2,4-trienes, the initial coordination of gold to the allene to give the substrate for the 2-aura-Nazarov as a mixture of diastereomers (233 and 234, Scheme 43). The acetoxy 2-aura-Nazarov cyclization leads to a gold-carbenoid 235 which undergoes a concerted electrophilic cyclopropanation to stereoselectively afford compound 236 (computed activation barrier of 10.2 kcal mol1). Migration of the gold fragment to the acetoxy group is barrierless, and the sequence is completed by decomplexation from 237 to recycle the catalyst.237 The structure of these gold-activated allene complexes has been debated, and their consideration as allyl cations (pentadienyl cations for vinylallenes), bent allenes or other resonance forms has been proposed (see Section 2). Additional computational studies revealed the structural factors affecting the mechanistic dichotomies found in these ene vinylallenes (Scheme 44). The coordination of gold to vinyl allenes may give rise to two types of reactive complexes 239 and 243, which will enter into competition to follow a [4+2] cyclization or an electrocyclic reaction (and hence, cyclopropanation to 247 or b-hydride elimination to 248), respectively.238

Gold-catalysed rearrangement and cyclopentannulation of 3-cyclopropyl propargylic carboxylates 226.

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Scheme 43 Gold-catalysed aura-Nazarov and cyclopropanation reactions of ene acetoxy-vinylallenes (energy differences relative to 234 are shown in kcal mol1).

Scheme 44 Competing 2-aura-Nazarov/cyclopropanation and [4+2]-cycloaddition reactions in the gold-catalysed transformations of ene acetoxyvinylallenes (energy differences relative to 243 are shown in kcal mol1).

Computations predict that the 2-aura-Nazarov reaction is rather insensitive to the length of the tether, but it is favoured for tetrasubstituted allenes. The stability of the gold-activated allene that reacts via [4+2]-cycloaddition also depends upon the substitution pattern and increases for R2 = Me. Upon formation of the gold-stabilized allyl cation, the cyclopropanation is the preferred pathway, whereas the b-hydride elimination is even slower with R2 = Me.238 Other competing reactions were discovered upon activation of ene vinylallenes with gold catalysts.238 The structures 253 and 256 are also available from the same cyclopentenylidene intermediates 251 and their occurrence depends upon the ring size (Scheme 45). Ring expansion by 1,2-rearrangement of the


carbenium ion to 253 is favoured with small rings (n = 1 or 2), as also reported by Toste and co-workers.239 With larger rings (n = 4 or 5), ring fusion by unusual 1,3-C–H insertion to give 256 is observed. Lastly, with a six-membered ring (n = 3), a proton transfer gives rise to a spiro-cyclopentadiene 255. DFT computations for the ring fusion and ring expansion agree well with the experimental findings. For model systems using Au(PMe3)+ as an activator, the barrier energy associated with the ring fusion increases from 16.4 to 29.6 kcal mol1 whereas that corresponding to ring expansions decreases from 26.0 to 11.9 kcal mol1 as the ring size decreases. For large systems (n = 3), the activation energies are similarly high (above 22 kcal mol1) thus allowing the alternative protodeauration to occur.

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Scheme 45

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Competing reactions of acetoxy-vinylallenes upon gold(I) activation.

4.2.1.2 Hydroamination and hydrosulfuration of allenes. The N–H addition to allenes has received limited attention, although this transformation produces valuable intermediates.240 In 2004, Morita and Krause241 reported the first intramolecular endo-selective hydroamination of allenes. With gold(III) chloride, various a-aminoallenes were converted to the corresponding 3-pyrrolines with high levels of chirality transfer. By using gold(I) chloride, the reaction time decreases to several hours at room temperature. A computational investigation by Liu et al.,242 focused on the determination of the catalytically active oxidation state of the metal (Au(I) vs. Au(III)) and on the role of the corresponding counterion, has been recently reported (Scheme 46). As it was found for the hydralkoxylation of a-allenols, the Au(I) and Au(III) catalysts activate the distal double bond of allene, which undergoes an intramolecular nucleophilic attack by the nitrogen atom to produce a cyclic zwitterionic intermediate.

Scheme 46 PR3AuSbF6-catalysed cycloisomerization of a-aminoallenes to 3-pyrrolines.

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Then, it leads to the 3-pyrroline via a 1,3-proton migration, followed by demetallation. The H migrations are key steps, and are significantly affected by the oxidation state of the gold catalyst, counterion and ligands. The calculations showed that AuCl is more reactive than AuCl3; however, the Au(III)-catalysed reaction does not involve gold oxidation state change from Au(III) to Au(I) in the catalytic cycle. Furthermore, a second a-aminoallene molecule can play a very efficient bifunctional catalytic role assisting in the H-shift process of both Au(I)- and Au(III)-catalysed reactions. According to the theoretical results, SbF6 could assist the H-shift, as a weak base, which confirms the impact of the counterion on AuPPh3Clcatalysed cycloisomerization reactions. As noted above, the transition metal-catalysed nucleophilic additions usually proceed through an outer-sphere mechanism, that is, anti-addition to the metal-coordinated CQC bond complexes. However, a few alternative inner-sphere mechanisms243 have been proposed, in which the coordination of the nucleophile to the metal is followed by insertion of a C–C multiple bond into the M–Nu bond, including Au-catalysed hydrofunctionalization reactions.244 These reactions are characterized by syn-stereochemical pathways from an outer-sphere mechanism. Based on previous observations on the goldcatalysed enantioselective hydroamination of allenes,245,246 Kang et al. envisaged that nonbonding interactions between the nucleophile and gold in the initial reaction complex could be the origin of the observed enantioselectivity, in addition to the effect of the counterion described by Liu and co-workers242 and the plausible involvement of aurophilic Au Au interactions in the chiral bis(gold)–phosphine complexes (Scheme 47).247 The results revealed that the reaction pathway towards the S isomer is thermodynamically and kinetically favoured, in agreement with the experimentally observed enantioselectivity. Krause et al. reported the first gold-catalysed C–S bond formation of a-thioallenes to give 2,5-dihydrothiophenes with complete axis-to-center chirality transfer.248 However, it is


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Scheme 47 Gold(I)-catalysed enantioselective hydroamination of allenes with [(R)-xylylbinap(AuOPNB)2]. The transition structures for the heterocyclization step for two pathways in the syn-addition mechanism are shown (computed at B3LYP/6-31G(d)&SDD). TS (S) is 2.3 kcal mol1 more stable than TS (R).

well-known that organosulfur compounds such as thiols, sulfides, and disulfides strongly coordinate to transition metals, particularly to gold,249 so the use of gold catalysts would not be expected as promising. The computational study on the mechanism of the AuCl-catalysed reaction of the a-thioallenes to give 2,5-dihydrothiophenes (B3LYP/6-31G*&SDD for Au) performed by Ando revealed an analogous mechanism to that computed for other a-heteroallenes, where the proton transfer from the sulfur atom to the carbon atom is the rate-limiting step. The participating water molecule can act as a bifunctional catalyst, thus reducing the barrier for the H-shift process. Furthermore, the presence of a dichloromethane molecule lowers the activation energies of all the transition structures by means of stabilizing hydrogen bonds.250 4.2.1.3 Carbocyclization of allenes. The metal-catalysed cycloisomerizations and nucleophilic carbocyclizations of allenynes251 are usually mediated by p-alkyne species that form stable allylcation intermediates through an exo or endo attack of the central allene carbon atom on the p-alkyne (according to the so-called Murakami’s model).252,253 The metal-catalysed 1,5- and 1,6-allenyne cyclizations provide a wide variety of cyclic adducts under soft conditions.254 First investigations were made by Fensterbank, Malacria and Marco-Contelles and co-workers, who studied the behaviour of allenyne substrates upon PtCl2 catalysis.255,256 These studies were extended to gold catalysts, cationic Pt(II) complexes and PtCl4.257 These species could efficiently promote the cyclization of 264 (R = H) into the hydrindiene 265 (Scheme 48). Changing to halide-free cationic complexes of gold and platinum resulted in a change of reactivity, as the mixture of Alder-ene isomers 266 was obtained in good yields. Switching from terminal to internal triple bonds allowed the discovery of a third cycloisomerization pathway which produces vinyl allenes 267. This reaction proved to be effective with the chloride salts and cationic halide-free complexes. For Au(I)+, the computational study (B3LYP/LACVP(d,p))


Review Article

suggests a mechanism proceeding through the formation of a stabilized allylic carbocationic intermediate 268/269 by a 6-exodig cyclization. Then, depending on the substrate and catalyst, diverging paths were unveiled. The Alder-ene products 266 were computationally reachable when R = H through a direct 1,5-proton shift. The vinyl allenes 267 are also obtained in a single step by a 1,5-hydride shift (Scheme 48). Moreover, the calculations on the intriguing halide effect suggested a mechanistic path via isomerization of the vinyl metal species 269, followed by elimination of HCl. Then, a 5-endo carboauration reaction followed by protolysis with HCl delivers the final product and restores the catalytic species.257 Toste and Houk reported a similar study on the goldcatalysed cycloisomerization of 1,5- and 1,6-allenynes finding that the catalyst complex [(Ph3PAu)3O]BF4 led to cross-conjugated trienes (Scheme 49). However, their calculations suggested that the reaction proceeds by nucleophilic addition of an allene double bond to a phosphinegold-complexed phosphinegold acetylide to give a gem-diaura-alkene 279 in a 5-exo-dig manner. The catalytic cycle is then terminated through a 1,5 hydrogen shift, protodemetalation, and transfer of the phosphine-gold catalyst to ´ and co-worers100 and another substrate.99 Subsequently Gagne 258 Widenhoefer provided experimental support for a diaurated intermediate259 involved in Au(I)-catalysed intramolecular hydroarylation and hydroalkoxylation of allenes, which acts as an off-cycle catalyst reservoir. Moreover, related dual-activation by gold-catalysts has been recently described by Hashmi and co-workers.260 Interestingly, in the presence of water,261 the reverse process is typically observed, i.e. gold may trigger the nucleophilic attack of alkynes on allenes.262 This unexpected type of reactivity was unearthed within the 1,4- and 1,6-allenyne series. In such cyclizations, water attacks regioselectively at the terminal alkyne carbon, while the internal alkyne carbon attacks the allene. Cyclic ketones are formed with moderate to good levels of diastereoselectivity. The mechanism of this hydrative carbocyclization, partially validated by a theoretical study (B3LYP/LANL2DZ), involves the formation of a p-allene gold complex, a 5-exo attack of the triple bond to form an aryl-stabilized vinyl cation, and the final trapping of the latter species by water (Scheme 50).262 This mechanism leads to a trans double bond as kinetically and thermodynamically preferred over the cis pathway. Electron-rich aromatic rings can act also as nucleophiles, providing access by intramolecular hydroarylation to a variety ¨rstner et al. reported263 the intraof polycyclic systems. Fu molecular formation of polycyclic arenes catalysed by a variety of soft Lewis acids: PtCl2, AuCl3, GaCl3, and InCl3. They observed a well-defined regioselectivity, which strongly depends on the catalyst (Scheme 51). DFT computations264 revealed that the regioselectivity critically depends on subtle structural effects of the reactant complex initially formed by a preferential coordination to the distal p-bond of the allene. The metal complex ligands may involve steric hindrance with the substituent at the internal allene carbon C3, which leads to a slipped Z1-complex (GaCl3-287) with enhanced electrophilicity for the central allene carbon C2 and a selective

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Scheme 48 Mechanistic proposal for the divergent pathways in the transition metal-catalysed cycloisomerization of allenynes.

Scheme 49 Mechanism proposed by Toste and Houk of the ene reaction of phosphine-gold cation coordination to the alkyne of a phosphine-gold acetylide, 278.

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Scheme 50 Au(I)-catalysed hydrative cyclizations of 1,7-allenynes. Energy values are given in kcal mol1.


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Scheme 51 Regioselectivity in the metal-catalysed hydroarylation of allenes. Optimized geometries for the p-reactant complexes are shown (relevant distances are given in Å).

exo-dig-cyclization (288). In contrast, the corresponding Z2 PtCl2reactant complex PtCl2-287, with a trans-halide arrangement, lacks this effect and the reaction is preferentially guided to an unusual 7-endo-trig cyclization (289/290). A computational study (PCM-BP86/SVP&SDD) on the formation of indenes by Au-catalysed intramolecular hydroarylation of allenic esters (formed in situ from propargylic esters and a cationic NHC-gold(I) species) has also been reported by Nolan et al.265 The transformation involves a hydroarylation reaction to produce a kinetically favoured indene, aromatization by ester-mediated H-shift and a subsequent [1,3] O-acyl shift to generate the substituted thermodynamic indene.

Review Article

Very recently, Alcaide, Almendros and co-workers have disclosed a series of metal-catalysed transformations on different aromatic nucleophilic moieties, (indol-2-yl)-a-allenols, which showed divergent patterns of reactivity depending on the indolesubstituents. For unsubstituted precursors, the Pd-catalysed carbocyclization–cross-coupling domino reaction with a-allenic esters266 affords 3-(E-buta-1,3-dienyl) carbazoles through an initial chemo- and regioselective 6-endo-trig carbopalladation, followed by loss of HCl and dehydration, according to DFT calculations.267 Subsequent coupling of the readily formed aryl palladium intermediate with the allenol ester followed by stereoselective trans-b-deacetoxypalladation produces the observed carbazoles. These authors also examined the effect of a substituent (halogen or phenoxy group) at the C3-indole position on the reactivity and found divergent and striking outcome.268 Thus, 3-iodo-(indol-2-yl) allenes 291 afforded 3-iodocarbazoles 292, potentially interesting building blocks for further manipulation,269 involving a rare recycling of the halogen group via the 1,3-halogen shift. This process probably takes place through the intermediacy of an iodonium cation formed by an unprecedented intramolecular iodine cation addition to a metalactivated double bond, as was suggested by a computational study (Scheme 52). Analogously, (indol-3-yl)-a-allenols and allenones were synthesized and submitted to metal-catalysis. The transformations were dependent on the precursor structure, and led to

Scheme 52 Mechanism of the synthesis of 3-iodocarbazoles 292 through carbocyclization/halogen recycling reactions of iodoallenols 291 under Au-catalysis.


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Scheme 53

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Gold-catalysed hydroarylation of allenyl-tethered oxyarenes 297.

oxycyclization or benzannulation products.270 A computational study was performed to clarify these divergences. Alcaide and co-workers have also recently explored the reactivity of (aryl)allene-tethered 2-azetidinones 297, and reported an unprecedented Au-catalysed 9-endo carbocyclization.271 DFT calculations (PCM-M06/def2-SVP//PCM-B3LYP/def2-SVP level) support the 9-endo-carbocyclization as a kinetically, although rate-limiting, and thermodynamically favoured step over the alternative carbocyclization reactions leading to 7- or 8-membered ring intermediates. A subsequent easy and exergonic proton abstraction in 299 by the NTf2 anion and a highly exergonic and fast protonolysis of the s-carbon–gold bond provide the final 9-membered product, 302 (Scheme 53). It is well known that palladium complexes can exhibit two types of catalytic behaviour with allenes272 in the Pd-catalysed intramolecular cyclizations in cascade processes (Fig. 7): (i) the usual electrophilic activation of allenes by coordination to palladium(II) species, similar to late transition metals (p-acid role), and (ii) through the formation of allenylpalladium(II) complexes with nucleophiles.273 The formation of the latter complexes is suggested to occur through an oxidative addition reaction. The number of palladium(II)-catalysed C–C bond-forming reactions under oxidative conditions is steadily increasing in organic synthesis. Most of the palladium-catalysed oxidative processes proceed through a catalytic Pd(II)/Pd(0) cycle,

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Fig. 7 Reactivity modes in the Pd-catalysed intramolecular cyclizations of allenes in cascade processes.

with stoichiometric oxidants to regenerate the catalytically active Pd(II) species from Pd(0).274 Oxidative carbocyclization of allene-substituted 1,3-dienes ¨ckvall group.275 They also has been extensively studied by the Ba reported the computational study (B3LYP/lacvp**&6-31G(d,p)) of palladium(II)-catalysed aerobic carbocyclization of dieneallenes in water,276 on the basis of their previous observations on palladium-catalysed carbohydroxylation of allene-substituted conjugated dienes with water in the presence of p-benzoquinone (BQ) and catalytic amounts of Pd(II).277 Coordination of a carbon–carbon double bond in the endo-(p-allyl)palladium complex, obtained from intramolecular syn-carbopalladation of a 1,3-cyclohexadiene into a Pd-vinyl bond of a vinylpalladium intermediate, is a highly likely intermediate process according to DFT calculations. Coordination of benzoquinone and a double bond in the molecule to Pd creates a


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Scheme 54 Mechanism for palladium-catalysed nucleocyclization of dieneallenes.

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oxidative

carbo-

highly reactive cationic p-allyl complex, which is readily attacked by water (Scheme 54). The insertion of allenes into a Pd–C bond in the synthesis of azepines has been also recently studied by DFT methods.278 According to these calculations, the insertion of the coordinated ligand takes place through a pathway where an intermediate alkylvinyl complex 308 is involved (Scheme 55). This mechanism is similar to that proposed by Lin et al. for the insertion reactions of allenes in palladium aryl complexes [PdI(Ph)(PPh3)]2 and [PdI(Ph)(dppe)].279 4.2.2. Activation of the nucleophile and insertion into the allene. The intramolecular cyclization of the allene moiety can also proceed through an activation of the nucleophile by insertion of some metal centers (Pd(0), Y(III), La(III) or Sm(III))

Scheme 55

into a nucleophile-hydrogen bond. Then, one p-bond of the allene inserts intramolecularly into the nucleophile–metal bond. Depending on the regioselectivity of this insertion, different intermediates can be formed, which after reductive elimination yield the pertinent products. Tobisch has reported a series of computational studies on the intramolecular heterocyclization of allenes catalysed by organolanthanide complexes (see below). These species are established as highly active catalysts in this type of processes.280 Lanthanides have predominantly one stable oxidation state (Ln3+), thereby excluding conventional oxidative addition/reductive elimination steps. These reactions likely proceed through a classical insertive mechanism,281 where the unsaturated CQC unit becomes activated towards nucleophilic attack by the electropositive lanthanide centre. Thus, the pathway comprises C–heteroatom ring closure through migratory CQC insertion into the Ln–heteroatom s-bond and subsequent Ln–C heterocycle protonolysis. This mechanistic proposal (Scheme 56) is supported by both experimental280 and computational evidence.282 In this sense, for the organolanthanide-catalysed intramolecular hydroamination of g- and d-aminoallenes,283 Tobisch concluded that the pathway involves a kinetically rapid substrate association and dissociation equilibrium, facile and reversible intramolecular allenic CQC insertion into the lanthanide-s-bond, and turnover-limiting protonation of the azacycle’s tether functionality, with the amine–amidoallene– lanthanide adduct complex representing the catalyst’s resting state.284 However, the generally accepted mechanism (previously proposed by Marks on the basis of kinetic studies)280 would take place through a slow insertion into the unsaturated moiety, followed by rapid substrate protonolysis, namely, the CQC bond insertion being the turnover-limiting step.285 In a later paper by Alcaide and co-workers,199 aimed at describing the hydroalkoxylation of g-allenols catalysed by different metal complexes and the metal-dependent regioselectivity, further mechanistic insights were reported. Thus, the calculations supported the Marks’s proposal and suggested that the cyclization

Insertion of allenes into a Pd–C bond.


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Scheme 56 Mechanistic proposal for the heterocyclization of allenes catalysed by organolanthanide complexes.

event is sensitive to electronic and steric factors in the alkoxycyclization, but the protonolysis process is even more dependent on steric effects as a result of the substituents on more compact and congested intermediate structures. This would account for the different mechanistic schemes postulated by Marks and Tobisch.286,287 Alternatively, the single step non-insertive cyclization with concurrent amino-proton delivery onto the allene unit, proposed by Scott,288 has also been considered by computational studies. The calculations suggested that this route shows a substantial barrier but it would prevail if the lanthanide center was effectively protected against CQC bond approach, whilst ensuring a high polarity of the Ln–N s-bond together with a sufficiently acidic amino proton.289 The titanium- and zirconium-catalysed intramolecular hydroamination reactions of aminoallenes have been also disclosed.

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Cationic group 4 metal precatalysts are likely to follow a different route employing a metal-amido active species,290 as was proposed by Marks for organolanthanides.280 A computational survey of aminoallene hydroamination by a cationic zirconocene-amido species revealed a smooth energy profile, which is consistent with the observed activity and selectivity.291 A mechanism through the initial protonolytic activation of the precatalyst 316 (Cp2ZrMe+) to afford the cationic amidoallene-Zr active catalyst complex 317 was suggested (Scheme 57). Subsequent ring closure proceeds through addition of an allenic CQC linkage across the Zr–N bond, which requires the dissociation of the substrate. Proton transfer affords first cycloamineamido-Zr compounds, and subsequently the cycloamine products (319 and 321) which are readily released by the incoming substrate with regeneration of the amidoallene-Zr active catalyst species. Formation of the azacycle-Zr intermediate through intramolecular CQC insertion into the Zr–N s-bond is predicted to be turnover-limiting. In contrast, a metal–imido compound represents the active catalyst species for neutral catalysts.292,293 A computational study reveals that initially the precatalyst [Cp2ZrMe2] is transformed into a bis(amido)–Zr compound in the presence of the aminoallene. This complex undergoes a reversible, ratedetermining a-elimination to form an imidoallene–Zr compound, which possesses a chelating imidoallene functionality. This catalytically active species is rapidly transformed into aza-zircona– cyclobutane intermediates through the addition of the allenic CQC linkage across the ZrQN bond. Subsequent protonolysis of the metallacycle moiety by the aminoallene substrate followed by proton transfer from the Zr–NHR moiety onto the azacycle yields the cycloamine product.294 A different study has compared the reaction channels for [Cp2Zr(NHR)2] and [Cp2ZrQNR] complexes as the reactive species.295 Although it was concluded that a [2+2] cycloaddition mechanism seems to be operative, an alternative Zr–N s-bond insertion mechanism may be viable for other unsaturated precursors.296

Scheme 57 Intramolecular hydroamination/cyclisation of aminoallenes to afford functionalised five- and six-membered azacycles, mediated by neutral group 4 metal compounds.

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5. Cycloaddition reactions involving allenes Cycloaddition reactions are one of the most powerful tools for the convergent synthesis of a variety of carbo- and heterocycles from simple precursors.297 Allenes are particularly useful in cycloaddition reactions as they can function as one-, two- or even three-carbon synthons in these transformations. In this section, we shall describe computational studies aimed at deeper understanding of the reaction mechanisms of different types of cycloaddition reactions involving allenes. 5.1.

[2+2]-Cycloadditions

The [2+2]-cycloaddition reaction involving allenes constitutes a valuable synthetic tool toward the preparation of cyclobutane derivatives. The usefulness of this transformation, which is compatible with a great variety of functional groups, has been demonstrated in the preparation of complex molecules and natural products.298 During the last several decades, there has been an intense debate associated with the mechanism of [2+2]-cycloaddition reactions because the [p2s + p2s] transformation is a forbidden process according to the orbital symmetry principles developed by Woodward and Hoffmann.299 Despite that, the alternative [p2s + p2a] mechanism is allowed although it involves significant restrictions on the geometry of the approach for the two components. The great importance of this cycloaddition reaction has led to an impressive number of experimental and computational studies focused on elucidating the reaction mechanism associated with this ‘‘relatively simple’’ transformation.298 In most cases, the occurrence of discrete diradical or ionic intermediates has been suggested for both thermal and photoinitiated [2+2] reactions. For instance, Johnson and Skraba have reported very recently that the thermal dimerization reaction of allene to produce 1,2-dimethylenecyclobutane proceeds through diradical intermediates rather than a concerted [p2s + p2a] mechanism.300 As the synthetic applications and associated reaction mechanisms of [2+2] cycloaddition reactions involving allenes have been thoroughly reviewed quite recently,298 herein we shall only describe recent significant studies focused on intramolecular transformations. With the help of DFT calculations and experiments, Brummond, Tantillo and co-workers have provided insight into the reaction mechanism and regioselectivity of thermally induced intramolecular [2+2] cycloaddition of allene–ynes.301 Despite its demonstrated usefulness in synthesis,302 this type of cycloaddition has been scarcely explored in comparison with the cycloaddition involving allene and double bonds.298 Thus, the alternative reaction pathways depicted in Scheme 58 have been explored. They include the concerted pathway through transition state TS322–323 and two different stepwise transformations via diradicals 324 or 325, which differ in the order in which the two new s-bonds are formed. It was found that the stepwise diradical pathway where one radical center is stabilized by allylic delocalization (as in Scheme 58, top) is favoured over the alternative reaction pathways. The first C–C bond forming process constitutes the rate-determining step for


Scheme 58

[2+2]-Cycloaddition of allene–ynes.

the [2+2]-cycloaddition of the parent hepta-1,2-dien-6-yne (activation barrier of ca. 35 kcal mol1). Although this value is high, it can be surmounted under the experimental conditions (typically 250 1C under microwave heating).301,302a Schmittel and co-workers have reported similar results in the thermal cyclisations of related enyne–allenes. Thus, by means of DFT calculations at the (BS)-uB3LYP/6-31G(d) level, it was found that the exothermic formation of tricyclic species 328 from the initial allene–yne 326 occurs stepwise through the diradical intermediate 327 (Scheme 59). In the first step of the process, the C2–C6 bond is formed via the transition state TS326–327 (activation barrier of 20.0 kcal mol1), while the final product 327 is formed from diradical 326 via the transition structure TS327–328 (activation barrier of 19.9 kcal mol1), which is associated with the formation of the C1–C7 bond. The alternative concerted [2+2] reaction pathway is not competitive in view of the required much higher activation energy (computed activation barrier of 49.0 kcal mol1) via the saddle point TS326–328. A related intramolecular [2+2]-cycloaddition reaction of 5-allenyl-1-ynes catalysed by Mo(CO)6 (10 mol%) was reported by Shen and Hammond (Scheme 60a).303 This process forms cyclobutenes 330 in moderate to good yields (up to 85%) with no traces of the corresponding [3.2.0] exocyclic difluoromethylene regioisomer or the possible [2+2+1] Pauson–Khand derived product. The competence between the different envisaged reaction pathways, i.e. regioselectivity of the [2+2] cycloaddition reaction and preference over the [2+2+1] process, has been recently investigated at the DFT level by Meng and Li using the model reaction depicted in Scheme 60b.304 In agreement with the experimental findings, the formal [2+2]-cycloaddition leading to 332 was found to be kinetically favoured. This reaction begins with the initial coordination of the Mo(CO)4 fragment to the alkyne and to the distal double bond of the allene moiety which produces complex 333. This species is then transformed into metallacycle 334 through transition state TS333–334, a saddle point associated with the C–C oxidative cyclization (activation barrier of 20.3 kcal mol1). Finally, reductive elimination rather than CO insertion (which would lead to the [2+2+1]-product) occurs through TS334–335 with a low activation barrier of only 10.5 kcal mol1. This step forms

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Scheme 59

[2+2]-Cycloaddition reaction transforming allene–yne 326 into 328.

Scheme 60

Mo(CO)6 catalysed [2+2]-cycloaddition of allene–ynes 329.

the experimentally observed product 332 (or 330) regenerating the active catalyst (Scheme 61). A quite similar reaction mechanism has been suggested by ãs and co-workers in the rutheniumEsteruelas, Mascaren catalysed [2+2] intramolecular cycloaddition of allenenes (Scheme 62).305 This process, which is fully diastereoselective and occurs under mild reaction conditions, provides a practical entry to a variety of bicyclic[3.2.0]heptane skeletons featuring cyclobutane rings. Importantly, other cycloadducts, such as the potentially competitive [4+2] product 338, were not detected.

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Scheme 61 Computationally proposed mechanism for the Mo(CO)6 catalysed [2+2]-cycloaddition of allene–ynes 329 depicted in Scheme 60a.

In this case, DFT calculations suggest that the catalytic cycle is initiated by the unsaturated species RuCl2(PiPr3) which arises from the dissociation of molecular hydrogen and one triisopropylphosphine ligand from the ruthenium precursor (Scheme 63). Coordination of the conjugated diolefin unit and the internal allenic double bond of the initial substrate 339 to the metal center generates complex 340, which evolves into the ruthenabicycle 341


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Scheme 62

Ruthenium-catalysed [2+2] intramolecular cycloaddition of allenenes 336.

Scheme 63

Computed reaction pathway for the ruthenium-catalysed [2+2] cycloaddition of allenenes depicted in Scheme 62.

by oxidative cyclometalation through TS340–441 (computed activation barrier of 17.1 kcal mol1). Then, a s-to-p-allyl rearrangement affords complex 342, which finally leads to the observed cyclobutane 343 with concomitant regeneration of the active catalyst. The calculations suggest that the formation of species 342 rather than the final reductive elimination (which proceeds with an activation barrier of only 1.2 kcal mol1) is the rate-determining step of this formal [2+2] cycloaddition reaction. N-Tethered 1,7-bisallenes 344 were explored toward cationic NHC–gold catalysis by Chung, Kang and co-workers.306 The optimized reaction conditions allowed the synthesis of unprecedented 6,7-dimethylene-3-azabicyclo-[3.1.1]heptanes 345 in a formal head-to-head [2+2] cycloaddition reaction (Scheme 64a). Among the several mechanistic scenarios envisioned, DFT calculations suggest that the concerted twisted head-to-head [2+2] cycloaddition is not likely to occur. Instead, a stepwise process, which begins with the coordination of the cationic gold center to one allene of 346 to form 347, is clearly more favoured (Scheme 64b). The activated allene undergoes then a 6-exo attack of the uncomplexed allene internal double bond through transition state TS347–348 to give the long-range gold


stabilized carbocation 348. Final ring closure via TS348–349 produces 349, which after decoordination of the metal complex leads to the observed dimethylenecyclobutyl ring 350 regenerating the active gold catalyst. 5.2.


As many other cycloaddition reactions and sigmatropic rearrangements, [3+2]-cycloadditions may proceed through two main types of mechanisms: (a) the Huisgen-type concerted process via a transition state which is under orbital symmetry control, and (b) the so-called Firestone-stepwise mechanism involving zwitterionic or diradical intermediates. Both types of reaction pathways can also be envisaged for 1,3-dipolar cycloadditions involving allenes. In this subsection, examples of these mechanistic alternatives will be discussed. One of the first computational studies on [3+2]-cycloadditions involving allenes was reported in 1994 by Rastelli and Gandolfi.307 In this paper, the authors analysed the regioselectivity of the 1,3-dipolar cycloaddition reaction between diazomethane and the parent allene 1, which at room temperature affords a mixture of pyrazoniles 351 and 352 in a 93 : 7 ratio (Scheme 65). At the

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Scheme 64

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NHC-gold catalysed formal [2+2]-cycloaddition of bisallenes.

MP4SDTQ/6-31G*//HF/6-31G* level, it was concluded that the process proceeds concertedly and that the observed regioselectivity takes place under kinetic control in view of the higher activation barrier computed for the more synchronous transformation leading to 352. This preliminary study was extended to other allenes (mono- and difluoroallene) and other dipoles (formonitrile oxide) finding a clear correlation between the deformation energies of the allene, i.e. the energy associated with the structural distortion in going from the equilibrium geometry to the geometry adopted in the transition state, and the regioselectivity.308 As it has been shown recently, this distortion energy (also known as strain energy) plays a pivotal role not only in cycloaddition reactions309 but also in other fundamental processes such as nucleophilic substitutions310 and different pericyclic reactions.311 Kavitha and Venuvanalingam have extensively explored the potential energy surface of the reactions of allene with diazomethane, nitrile oxide and nitrone as dipoles (Scheme 66).312 Their calculations indicate that the stepwise reaction pathways are preferred (i.e. lower-lying in energy) over the concerted modes. Particularly, regioisomer 360 is produced through a stepwise reaction mechanism which involves the formation of the so-called gauche diradical intermediate 359 (path 2C) whereas an allylic diradical 355 is suggested to be involved in the formation of regioisomer 356 (path 1C). This is mainly

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ascribed to the cumulenic strain energy as well as to the influence of dipole heteroatoms on the stability of the diradical intermediates. ´pez and Feldman have In a series of related papers, Lo thoroughly investigated the reaction mechanism associated with the thermal conversion of different 5-azidoallenes 361 into bicyclic compounds 364 using a combination of experimental and computational methods.313 It has been suggested that heating (110 1C) of allenic substrates 361 initiates a cascade sequence which proceeds through (i) initial allene/ azide intramolecular [3+2] cycloaddition, (ii) N2 loss from the intermediate triazoline 362 to afford the diyl species 363, and (iii) diyl cyclization through the appended unsaturation to produce the final product 364. In all cases, the cycloaddition reaction has been found to occur concertedly via transition states similar to that depicted in Scheme 67 (TS361–362) with computed activation barriers in the range of 24 to 29 kcal mol1 (at the B3LYP level). A closely related process involving a thermal cascade process ´ˇ was reported by Pota cek and co-workers.314 Thus, symmetric homoallenyl aldazines 366 are transformed into a tetracyclic structure featuring four fused heterocyclic five-membered rings, 368 (Scheme 68). DFT calculations support a double sequential crisscross 1,3-dipolar cycloaddition through the azomethine imine intermediate 367.315 Both consecutive


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Scheme 65

[3+2]-Cycloaddition between allene 1 and diazomethane.

Scheme 66

Concerted and stepwise mechanisms for the [3+2]-cycloaddition of allene 1 and different 1,3-dipoles.

Scheme 67

Proposed cascade sequence for the transformation of 361 into 364 which involves an initial [3+2]-cycloaddition reaction.

cycloaddition reactions occur concertedly through the in-plane aromatic transition states TS366–367 and TS367–368 (computed nucleus independent chemical shift, NICS, values of 14.7 and


18.5 ppm, respectively), thus confirming the pericyclic nature of the transformations. Differently, if conjugation is introduced in 366 through the presence of an olefin system or an oxygen

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Scheme 68

Consecutive [3+2]-cycloadditions forming 368 from 366.

atom in place of the saturated carbon, a pseudopericyclic mechanism occurs instead in view of the low NICS values computed for the corresponding transition states. The reactions of N-heterocyclic carbene-derived 1,3-dipoles with methoxycarbonylallenes were recently reported. Using a combination of experimental and computational methods, the remarkable selectivity of these [3+2] cycloadditions has been established.316 For instance, the reaction of dipole 369 and allene 370 may lead to the formation of cycloadducts 372 and 373 (Scheme 69). DFT calculations suggest that while 373 is formed through a concerted reaction pathway via TS373, a stepwise process involving the zwitterionic intermediate 371 occurs to produce cycloadduct 372. The formation of the latter reaction product is kinetically and thermodynamically favoured in view of the computed lower activation barriers and more

Scheme 69

Chem Soc Rev

exothermic reaction energy, which nicely agrees with the experimentally observed exclusive formation of this type of cycloadducts. In general, it has been found that the regioselectivy of these [3+2]-cycloaddition reactions is strongly governed by the structures of the 1,3-dipoles and, in some cases, also by the reaction temperature. ´ and co-workers reported Very recently, Gornitzka, Escudia that heteroallene 374 can be readily converted into the tricyclic compound 375 when reacted with methyl acetylenedicarboxylate (Scheme 70).317 This process is suggested to proceed via the carbene intermediate 376 through a concerted [3+2]-cycloaddition reaction. Intermediate carbene 376 is then transformed into compound 375 by insertion of the carbenic carbon atom into the C–H bond of an ortho isopropyl group of the Tip (2,4,6-iPr3C6H3) group on the germanium atom.

[3+2]-Cycloaddition between dipole 369 and allene 370.

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Scheme 72

Scheme 70 Formation of tricyclic compound 375 from heteroallene 374 and acetylenedicarboxylate.

This interesting transformation has been computationally studied by analysing the effect of group 14 elements in heteroallenes H2EQCQPH (377, E = C to Pb) in their [3+2]cycloaddition reaction toward acetylene.318 It was found that all processes occur concertedly through Cs-symmetric and in-plane aromatic transition states (NICS values in the range of 10 to 21 ppm) similar to TS377–378 (depicted in Scheme 71). Despite these geometrical and magnetic resemblances, the corresponding reaction barriers drop significantly from E = C (nearly 50 kcal mol1) to E = Si–Pb (ca. 20 kcal mol1). The origin of this differential behaviour is found in the equilibrium geometry of the allene. Thus, the parent heteroallene H2CQCQPH, which possesses a practically linear equilibrium geometry (CQCQP angle of 174.81), must be bent significantly in the transition state (CQCQP angle of 120.81). At variance with this, the heteroallenes with a heavier group 14 element E do already possess a bent equilibrium geometry which better fits into the transition state structure and therefore requires less deformation. As a consequence, the latter compounds undergo a much more facile [3+2]-cycloaddition reaction toward acetylene. In 1995, Lu and co-workers described the phosphine-catalysed [3+2] cycloaddition reaction of allenoates and activated alkenes (Scheme 72).319 Since then, this process has become an important

Scheme 71

Phosphine catalysed [3+2]-cycloaddition of allenoate 379.

synthetic tool toward the construction of five-membered carboand heterocycles, even with high enantioselectivity.320 The great importance of this transformation has attracted the attention of computational chemists in order to elucidate the reaction mechanism of this process. Thus, the proposed mechanism, independently studied by Yu321 and Dunning,322 involves the initial nucleophilic attack of the catalyst phosphine at allenoate 379 to generate a zwitterionic intermediate 381, which acts as a 1,3-dipole and undergoes a [3+2] cycloaddition with activated alkenes to give the phosphorus ylide 382. To complete the catalytic cycle, a formal [1,2]-proton shift assisted by water occurs to produce zwitterion 383 which finally undergoes elimination of the phosphine to yield the Lu [3+2] cycloaddition product 380. The regioselectivity of the [3+2] cycloaddition step has been studied in detail.320b,321a This process is suggested to occur stepwise by the initial attack of the dipole on the activated b-carbon atom of the alkene and subsequent ring closure to form the five-membered cycloadduct. Two possible nucleophilic attacks can be envisaged, i.e. attack from the a- or the g-carbon atom (with respect to the CO2Et moiety) of the initially formed zwitterion 384. The calculations suggest that the regioselectivity of the overall process takes place in the first step of the cycloaddition as the a-attack via TS384–385 is kinetically favoured over the g-attack through transition state TS384–387 (Scheme 73). The computed activation barrier difference DDGa,298 = 1.2 kcal mol1 at the B3LYP/6-31+G* level predicts a 79 : 21 a/g ratio, a value close to the experimental ratio of 85 : 15.319

[3+2]-Cycloaddition between model heteroallenes 377 and acetylene.


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Scheme 73

Regioselectivity of the phosphine catalysed [3+2]-cycloaddition of allenoates.

A similar allene activation to produce a 1,3-dipole can be achieved by reaction with a transition metal. Recently, Iwasawa and co-workers reported an intramolecular [3+2] cycloaddition reaction of silyl 1,2-propadienyl ether and alkenyl ethers to give functionalized cyclopentene derivates.323 The reaction mechanism of this transformation has been investigated by Han and Liu using DFT calculations.324 It was found that the coordination of PtCl2(C2H4) to the distal double bond of the allene leads to the p-complex 388, which rapidly evolves to complex 389 (Scheme 74). The latter zwitterionic complex, which can be viewed as a 1,3-dipole or as an allylic-cation surrogate, undergoes a stepwise [3+2] cycloaddition reaction with enol ethers to produce the cycloadducts experimentally observed. Thus, complex 389 is transformed into zwitterionic intermediate 390 via TS389–390 (activation barrier of 10.5 kcal mol1, at the

Scheme 74

Chem Soc Rev

B3LYP/6-31G(d,p)&LanL2DZ level) followed by ring closure through transition state TS390–391 (activation barrier of 11.1 kcal mol1). The process ends up with a [1,2]-hydrogen shift reaction which forms the final cycloadduct 392 with concomitant regeneration of the catalyst. Intramolecular [3+2]-cycloadditions involving allenes can also be catalysed by gold(I) as recently demonstrated by Liu and co-workers.325 Indeed, the treatment of 1-aryl-1-allene6-enes with [(PPh3)AuCl]/AgSbF6 (5% mol) in CH2Cl2 at room temperature leads to cis-fused dihydrobenzo[a]fluorene derivatives through a formal intramolecular [3+2] cycloaddition reaction. DFT calculations at the B3LYP level suggest that the process occurs stepwise via an initial 6-endo-dig cyclization reaction of the gold(I)-distal coordinated complex 393. This step can give a mixture of cationic cis- and trans-intermediates,

Pt(II)-catalysed [3+2]-cycloaddition.

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Scheme 75

Review Article

Formal gold(I)-catalysed [3+2]-cycloaddition reaction.

as the energy barriers for both cyclization reactions are quite similar (12.4 kcal mol1 and 12.5 kcal mol1, respectively) as well as the relative energy of the intermediates (trans-394 is only 1.6 kcal mol1 more stable than cis-394). Both intermediates can undergo an intramolecular arylation reaction to form the respective cis- or trans-395 adducts (formally the whole process can be considered as a [3+2] cycloaddition reaction). However, the cis-arylation pathway is clearly kinetically favoured over the trans-path, which is in agreement with the exclusive formation of the cis-isomer experimentally observed (Scheme 75). 5.3.

[4+2] Cycloadditions

The ability of allenes to act as dienophiles in [4+2] cycloadditions has been repeatedly explored by means of computational methods. Thus, earlier molecular orbital calculations involving fluoroallenes and unsubstituted allenes suggested that the process is controlled by the frontier molecular orbitals and occurs concertedly.326 In a systematic study of the reaction between different allenes as dienophiles and furan or cyclopentadiene as diene counterparts (at the AM1 and PM3 semiempirical levels), Manoharan and Venuvanalingam confirmed the concerted nature of the transformation and compared the reactivity of allenes in the process when substituted by halogen atoms (i.e. fluorine and chlorine).327 Interestingly, the ability of allenes to act as dienes when conjugated with alkenes has also been considered. By means of ab initio and DFT methods, the [4+2] Diels–Alder cycloaddition reactions of ethene with 1,3-butadiene, 1,2,4-pentatriene, and 1,2,4,5-hexatetraene have been explored to understand the role of the allene group in this pericyclic reaction (Scheme 76).328 It was found that the addition of an allene group in butadiene decreases the activation barrier and increases the exothermal character of the process. Interestingly, the decrease in the barrier energy is even more marked with the presence of two allenic groups, particularly with regard to the reaction enthalpy, which exhibits an additive effect. The regio- and stereoselectivities of the Diels–Alder reaction of vinylallenes with acrolein have been computationally explored by Wright and Pranata.329,330 Different computational


Scheme 76 [4+2]-Cycloadditions between ethene and 1,3-butadiene, 1,2,4-pentatriene, and 1,2,4,5-hexatetraene.

levels (HF, MP2 and B3LYP) were used to identify the different transition states (endo and exo approaches, s-cis and s-trans conformations of acrolein) for each of the two Diels–Alder cycloaddition reactions (see Scheme 77). It was found that while the endo s-cis transition structure is preferred for the parent reaction between vinylallene 400a and acrolein, the endo s-trans pathway tends to compete with the endo s-cis in the [4+2]-cycloaddition reaction involving the methyl substituted vinylallene 400b. In all cases, concerted (albeit asynchronous) transformations have been located on the potential energy surface. Tolbert, Houk and co-workers have studied the Diels–Alder reaction of strained allenes as dienophiles in a joint experimental-computational (DFT at the B3LYP/6-31G* level) study.331 The computed possible reaction pathways for the reaction of 1,2-cyclohexadiene (404) with 1,3-butadiene and with furan (as well as propadiene with butadiene) indicate that the stepwise pathways, which involve the formation of diradical intermediates, are kinetically favoured over the concerted paths, which occur through extremely asynchronous transition states similar to TS405 (Scheme 78). In addition, no detectable

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Scheme 77

[4+2]-Cycloaddition reactions between vinylallenes 400 and acrolein.

Scheme 78

[4+2]-Cycloaddition between strained allene 404 and butadiene.

diasteroselectivity was observed in the [4+2] cycloaddition reactions involving chiral cyclohexa-1,2-diene compounds (i.e. 1-bornyl and 1-menthyl derivatives), which is fully consistent with the predicted computational preference for the stepwise reaction mechanism. Cid and co-workers have used DFT calculations (B3LYP/ 6-31+G* level) to gain more insight into the mechanism of the Diels–Alder reaction between vinyl ketenimine 408 and buta-2,3-dienoate 409 (Scheme 79a).332 This process produces anilines 410 and 411 upon heating in toluene at 150 1C for 19 h. Using model compounds (Scheme 79b), a competence between the concerted pathway via the asynchronous transition state TS414 and the stepwise mechanism involving diradical 415 has been found in view of the negligible activation barrier difference between both processes (DDEa = 1 kcal mol1). In addition, the formation of diradical 415 has been invoked to justify the observed unexpected 13C-isotope exchange in the final aniline product via a reversible [2+2] cycloaddition reaction. Palenzuela and co-workers have studied the hetero-Diels– Alder reaction of vinyl allenes and aldehydes under Lewis-acid catalysis experimentally333 and also computationally.334 This process exhibits good facial- and regioselectivity and moderate endo/exo selectivity. As expected, DFT calculations indicate that

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the activation barrier of the cycloaddition reaction drops considerably in the presence of BF3 as catalyst (which is bonded to the oxygen atom of the aldehyde carbonyl group).335 Furthermore, the reaction occurs concertedly through highly asynchronous transition states (see Scheme 80) with negligible activation barrier difference between the exo and endo approaches. As a result, a mixture of endo/exo cycloadducts should be obtained, as experimentally observed. Very recently, Houk, Vanderwal and co-workers have studied the reaction mechanism of the intramolecular arene–allene Diels–Alder cycloaddition reaction.336 This process, also known as Himbert cycloaddition,337 permits rapid access to strained polycyclic compounds that offer great potential for the synthesis of complex scaffolds. By means of DFT calculations (B3LYP and M06-2X levels), it has been suggested that the reaction very likely proceeds by a concerted process (via TS419–420) rather than following a stepwise radical pathway (Scheme 81). Although the computed barrier energy for the formation of the diradical intermediate 421 via TS419–421 was quite similar to that involving TS419–420, the subsequent diradical ring closure is the rate-determining step of the process (activation barrier of ca. 38 kcal mol1). This indicates that reversion of the diradical 421 to reactants and subsequent concerted


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Scheme 79 (a) Diels–Alder reaction between buta-2,3-dienoate and vinyl ketenimine 409. (b) Computationally proposed mechanism using model compounds.

Scheme 80

Hetero-Diels–Alder reaction of vinyl allenes and aldehydes under BF3-catalysis.

cycloaddition will be faster than the corresponding ring-closure to the cycloadduct. a-Methylallenoates can also be activated by the Lewis base P(NMe2)3 to afford [4+2] annulated products in their reaction with activated alkenes.338 The mechanism of this transformation has been extensively studied computationally (M05-2X/6-31G* level) focusing on the reaction between allenoate 422 and benzylidenemalononitrile,339 which exclusively affords cyclohexene 427 in the experiment. Interestingly, it was found that instead of a direct [4+2] cyclization (either concerted or stepwise), the reaction proceeds initially through a [3+2] stepwise cycloaddition reaction to produce


compound 424 following the Lu-[3+2] mechanism commented above (see Schemes 72 and 73). Subsequent water-assisted [1,3]hydrogen atom transfer forms 425 which is easily transformed into the six-membered ring compound 426 via TS425–426 (computed activation barrier of only 1.8 kcal mol1). The reaction ends up with the catalyst release through TS426–427 which finally produces the experimentally observed cyclohexene 427 (Scheme 82). ´ group has reported that heteroallene 428 can The Escudie also undergo a [4+2]-cycloaddition reaction when reacting with 2,3-dimethyl-1,3-butadiene as a dienophile (Scheme 83).340 The regioselectivity of the process has been interpreted by

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Scheme 81

Intramolecular arene–allene Diels–Alder cycloaddition reaction.

Scheme 82

Formal [4+2]-cycloaddition reaction between allenoate 422 and benzylidenemalononitrile.

computing the two possible reaction pathways, i.e. involving the CQGe bond or the CQAs bond. Both possible cycloadditions proceed concertedly through TS428–429 and TS428–430, respectively, in a supra-supra facial approach. Despite that, it was found that the formation of cycloadduct 429 is kinetically and thermodynamically favoured over the formation of cycloadduct 430, which was not experimentally observed. [4+2]-Cycloadditions can be also promoted by transition metal catalysts. Indeed, Gandon, Fensterbank, Malacria and co-workers reported that the allenyl acetate species 432, formed from the corresponding propargyl acetates through a gold(I)-catalysed [3,3]-rearrangement, can undergo an intramolecular [4+2] cycloaddition reaction. At the DFT level,

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this transformation was computed in the presence and in the absence of catalyst. It was found that both processes occur concertedly through quite asynchronous six-membered transition states (similar to TS432–433, Scheme 84). A remarkable difference between both types of transition states is that the bond formation at the central carbon atom of the allene is running more ahead in the reaction without metal, whereas in the metal-catalysed process, the bond between the internal carbon atoms of the substrate is more advanced. The energy barriers (enthalpies at 298 K) of the uncatalysed pathway were relatively high, over 23 kcal mol1 regardless of the substituents. As expected, gold-coordination lowers the barrier heights of the [4+2]-cycloaddition by ca. 4 kcal mol1. Other reaction


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Scheme 83

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[4+2]-Cycloaddition reaction between heteroallene 428 and 2,3-dimethyl-1,3-butadiene.

Scheme 84 Gold(I)-catalysed [4+2]-cycloaddition of allenyl acetate derivatives.

pathways different from the [4+2]-reaction (i.e. Nazarov-like cyclization) were also explored in this extensive study.

5.4.


´pez, Mascaren ãs and co-workers reported that Recently, Lo PtCl2 can catalyse the diastereoselective transformation of allene-tethered 1,3-dienes 435 into the synthetically useful bicyclo[5.3.0]decane skeletons 438 (Scheme 85).341 This method provides a straightforward and atom economical entry to a variety of cycloheptene containing polycycles from readily available acyclic allenediene precursors, which tolerate different substituents in both the allene and the diene moieties. Similarly, gold(I) salts containing a s-donor NHC ligand also promote the reaction which can be performed with a greater variety of dienes, including furans.342 Strikingly, the transformation can be carried out with high enantioselectivity when using chiral phosphoramidite-Au(I) catalysts62 thus showing the great synthetic potential of the reaction.


The mechanism of the process has been studied in detail.342,343 It has been suggested that the reaction first involves a p-activation of the allene moiety by the metal catalyst to give rise to a metal–allyl cation intermediate 436 which undergoes a concerted [4+3]-cycloaddition reaction to produce the cycloheptenyl metal–carbene complex 437 (Scheme 85). This transformation occurs through the exo-like transition state TS436–437, which explains the perfect diastereoselectivity of the process towards the formation of trans-fused cycloadducts. A subsequent 1,2-hydrogen shift on complex 437 via TS437–438 yields the final [4C + 3C] adduct and regenerates the catalyst. Interestingly, the use of weak s-donor phosphite ligands (or strong p-acceptor NHC ligands) promotes selectively a ring contraction on carbene 437 through transition state TS437–439 to yield compounds 439 in a formal [4+2]-cycloaddition reaction.342,343 It was found that the stereoelectronic properties of the ligand at gold and the relative strength of the dp to pp interaction in the Au–C bond in the metal–carbene intermediate 437 are decisive to the outcome of the process, i.e. 1,2-H shift versus ring contraction.63

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Scheme 85

Chem Soc Rev

Transition metal catalysed [4+3]-cycloaddition of allene-tethered 1,3-dienes 435 and subsequent reaction pathways.

The intricacies of the [4+3]-cycloaddition step have been studied from a fundamental point of view.344 The above commented pericyclic concerted transition states can be considered as in-plane aromatic species in view of the negative NICS values (ca. 17 ppm) computed at the [3+1] ring critical point of the electron density. Therefore, it was proposed that the six electrons involved in this [p2s + p4s] cycloaddition reaction lie approximately in the molecular plane defined by the carbon atoms involved in the process and give rise to a diatropic ring current which is responsible for the computed diamagnetic shielding at the ring critical point. Moreover, the cycloaddition is highly synchronous in view of the computed high synchronicity values (Sy ca. 0.8). Both parameters (NICS and Sy values) resemble those computed for the [4+3] cycloaddition reaction involving the parent oxyallyl cation,345 thus indicating that both processes are closely related. Finally, the cycloaddition strongly depends on the diene. Indeed, it was found that when furan acts as the diene moiety instead of 1,3-butadiene, the transformation proceeds stepwise through the formation of the s-complex 441 via TS440–441 and subsequent ring closure through TS440–441 forming the [4+3]cycloadduct 442 (Scheme 86).344 This differential behaviour can be ascribed to the higher nucleophilic character of furyl-dienes compared to 1,3-butadiene which increases the net charge transfer towards the electrophilic allyl-moiety. This finding is in line with previous calculations reported by Harmata and Schreiner346 and by Cramer and co-workers,347 who concluded that reactive and strongly electrophilic allylic cations and nucleophilic dienes tend to react via stepwise mechanisms, while less electrophilic cations and less nucleophilic dienes tend to react via concerted processes.

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A related gold-catalysed cycloaddition process involving allenamides and dienes has also been described quite recently.348 Thus, a high regio- and diastereoselective formal [4+2] cycloaddition was found when using AuCl or the cationic gold(I) complex [IPrAuCl]/AgSbF6 (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene) as catalyst. In a number of cases, and depending on the catalyst and diene employed, in addition to the [4+2] cycloadducts of type 443, cyclobutane side products 445 arising from a competitive [2+2] cycloaddition between the allene and one of the CQC double bonds of the diene are also formed (Scheme 87). By means of DFT calculations (B3LYP level), it was found that with [IPrAu]+ and isoprene, the experimental observation of the cyclohexene cycloadduct (Z)-445 can be explained in terms of a concerted [4+2] cycloaddition via the transition state TS445, whereas the formation of the cyclobutane (Z)-446 involves a stepwise cationic process. The mechanistic scenario is more complicated in the presence of AuCl as catalyst: electron-neutral dienes favour a concerted [4+3] cycloaddition followed by a ring contraction event (similar to the pathway described in Scheme 85), whereas electron-rich dienes prefer a stepwise cationic pathway to give the same type of formal [4+2]cycloadducts. 5.5.

Other cycloaddition reactions involving allenes

Allenes can also undergo cheletropic addition of SO2. In fact, de Lera and co-workers experimentally demonstrated that the addition of SO2 to divinylallenes is regio- and stereoselective. With the help of DFT calculations (B3LYP/6-31+G(d,p) level), the diastereofacial differentiation has been ascribed to the


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Scheme 86

Stepwise platinum catalysed [4+3]-cycloaddition reaction involving furyl substituted allenes.

Scheme 87

Gold-catalysed reaction between allenamide 443 and dienes.

approach of the reagent from the less-substituted direction of the allene (anti-approach, Scheme 88) and to the concomitant disrotatory movement of the termini of the vinylallene to afford the sterically more congested 2-alkylidenesulfol-3-ene isomer. Wender, Houk and co-workers have investigated the origins of the experimentally observed differences in the reactivity of alkenes, alkynes and allenes in their [Rh(CO)2Cl]2-catalysed [5+2] cycloaddition reactions with vinylcyclopropanes (Scheme 89).349 It was known that whereas the process is quite efficient for alkynes and allenes, this rhodium-catalyst is relatively inactive toward alkenes.350 The process is suggested to begin with the facile oxidative ring opening of the vinylcyclopropane by the active catalyst, Rh(CO)Cl, to produce intermediate 450 (Scheme 89) which rapidly coordinates with a 2p component (alkene, alkyne or allene). Subsequent insertion into the Rh-allyl bond leads to metallacycle 452 via TS451–452 which evolves to the


final product by a reductive elimination reaction through TS452–453. The computed activation barriers indicate that while the insertion process is similar for all three species (ca. 22 kcal mol1), the reductive elimination is kinetically more difficult for ethylene (activation barrier of 29.3 kcal mol1) than for allene (DGa = 20.0 kcal mol1) or acetylene (DGa = 14.5 kcal mol1). This finding is attributed to the lack of an additional p-system in ethylene able to assist the migratory reductive elimination step. The transition metal (rhodium(I) and molybdenum(0)) catalysed [2+2+1]-cyclocarbonylation of 5-allenyl-1-ynes, which produces bicycle[5.3.0]decanes, has been experimentally351 and computationally (DFT level)352 studied. Similar to related transformations described above (see Section 5.1), the process begins with the initial coordination of the active catalyst to the alkyne and to the proximal or distal double bond of the allene moiety of 455 to produce the corresponding complexes

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Scheme 88 Cheletropic addition of SO2 to divinylallene 447.

Scheme 89

Formal [Rh(CO)2Cl]2-catalysed [5+2] cycloaddition reaction of vinylcyclopropane 449.

456 or 457, respectively (Scheme 90). An oxidative cyclization step (which is the rate-determining step for both reaction pathways) occurs then to form metallacycles 458 or 459 which after CO insertion and reductive elimination lead to the final reaction products 462 or 463. The calculations strongly suggest that geometric constraints imposed by the metal in the transition state are the key controlling factor for the allenic double-bond selectivity. Thus, the transition state structure of rhodium-catalysed oxidative addition (TS457–459 in Scheme 90) has a distorted square planar geometry that affords a lower transition state energy when coordinated to the distal double bond of the allene. In turn, the distorted trigonal bipyramidal geometry of molybdenum in the corresponding transition state imposes conformational constraints upon binding to the distal double bond on the allene and thus leads to the energetically preferred complexation and reaction with the proximal double bond (i.e. the key oxidative addition occurs through the more stable transition state TS456–458). Therefore, the selective reaction of one double bond of the allene over another is mainly controlled by the transition metal and not by the substrate structure.

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The latter process, which leads to the formation of cyclopentenones, can be viewed as a Pauson–Khand reaction involving allenes. This synthetically useful transformation, which significantly increases the molecular complexity in just a single step, was first disclosed in 1971,353 and can be considered as a formal [2+2+1] cycloaddition reaction between an alkene, an alkyne and carbon monoxide to form an a,b-cyclopentenone in the presence of a metal complex.354 Although this reaction was originally mediated by stoichiometric amounts of Co2(CO)8, newer and more active catalytic systems (based on titanium,355 iron,356 rhodium,357 ruthenium,358 iridium,359 nickel,360 zirconium,361 molybdenum,362 tungsten363 and palladium)364 are used nowadays. Cazes et al. have reported the Co-catalysed Pauson–Khand reaction of allenic hydrocarbons.365 Thus, allenes 466 give 4-alkylidenecyclopentenones 467 (Scheme 91) with high regioand stereoselectivities (E/Z 70 : 30), together with the formation of minor amounts of the regioisomeric cyclopentenones 468 and 469. The experimental and computational (PBE/TZP) observations indicated that the process does not follow the usual Magnustype reaction mechanism proposed for this transformation.366 Instead, the involvement of both pseudo-equatorial and


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Scheme 90

Rhodium(I) and molybdenum(0) catalysed [2+2+1]-cyclocarbonylation of 5-allenyl-1-yne 455.

Scheme 91

Co-mediated Pauson–Khand reaction of allenic hydrocarbons 466.

pseudo-axial coordination modes of the allenic hydrocarbons onto one of the cobalt atoms of the initial alkyne–dicobalt complex is suggested, which leads to two isomeric cyclopentenones. Very recent mechanistic studies on the Pauson–Khand reaction of 1,1-disubstituted allenylsilanes mediated by di-iron nonacarbonyl under extraordinarily mild conditions have revealed threemembered iron metallacycles as likely intermediates leading

Scheme 92

to the stereoselective formation of highly functionalized 4-alkylidene-2-cyclopenten-1-ones (Scheme 92).367 This analysis provides further support to that this variant of the Pauson– Khand reaction occurs via an alternative mechanistic pathway which does not involve the initial complexation of the alkyne component. The authors have identified a low energy pathway which begins with the three-membered Fe(0)-complex 470

Mechanistic pathway of the iron-mediated Pauson–Khand reaction of allenylsilanes.


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(Scheme 92), initially formed upon coordination of the allylsilane to Fe(CO)4. Subsequent NMO-mediated decarboxylation followed by addition of alkyne leads to the formation of complex 472 which after an intramolecular insertion reaction followed by insertion of CO produces complex 474. Final reductive elimination affords the experimentally observed cyclopentenone 475. This study concludes that the arrangement of stereochemistry of bound ligands at the transition metal center is crucial for the C–C bond formation.

6. Other pericyclic reactions In this section, several computational studies on pericyclic reactions involving allenes, different from the cycloaddition reactions discussed in the previous sections, shall be described. In a series of reports, Wentrup and co-workers have experimentally and computationally investigated rearrangements in different cumulene derivates including the interconversion of vinylketenes and acylallenes.368 As shown in Scheme 93, this process takes place by means of a 1,3-shift of the substituent R through a common transition structure TS476–477. In general, it was found that the 1,3-shift, which can be considered as a pseudopericyclic reaction, is kinetically facilitated by electronrich migrating groups, especially those having lone pairs on the migrating atoms. This effect has been ascribed to a bonding interaction between the lone pair orbital and the LUMO of the cumulene moiety which greatly stabilizes the corresponding transition state.311d,369 Interestingly, when the group R is –OMe or –NMe2 a retroene type elimination of aldehydes or imines to afford the corresponding vinylketenes occurs instead of the 1,3-shift described above.370 This reaction proceeds through transition state TS478–479 with an activation barrier of 43 (R = OMe) and 40 (R = NMe2) kcal mol1, computed at the G2(MP2/SVP) level of theory (Scheme 94).

Scheme 93

Interconversion of vinylketenes and acylallenes.

Scheme 94

Retro-ene elimination of acylallenes.

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de Lera and co-workers have thoroughly studied the thermal electrocyclic ring closure of vinylallenes to afford alkylidenecyclobutenes.371 This transformation, which is totally regioselective, proceeds via transition states similar to TS480–482 depicted in Scheme 95. Moreover, the process occurs with high torquoselectivity (i.e. leads exclusively to the formation of the E-isomer) when the substituent at C4 is a sterically demanding alkyl group as confirmed by MP2/6-31G* calculations. In addition, the torquoselectivity can be enhanced in those cases where the cyclization reaction involves loss of conjugation (e.g. by placing a formyl group at C2). The same electrocyclic ring closure reaction involving bisallene has been studied by Sakai.372 Interestingly, it was found that, at the CASSCF level, the activation barrier involving the parent vinylallene is 8.5 kcal mol1 higher than that involving bisallene. The de Lera group expanded this process to vinylallenals and their corresponding Schiff base derivatives to produce alkylidene-2H-pyrans and alkylidenepyridines, respectively.373 With the help of DFT calculations, it was concluded that the cyclization reactions are again highly torquoselective, with the formation of the E-alkylidene heterocycles being kinetically favoured (Scheme 96). NICS calculations and charge analyses on the corresponding transition states suggest that the process can be considered as a pseudopericyclic reaction. Therefore, instead of a disrotatory electrocyclization process, the reaction proceeds by a nucleophilic addition of the heteroatom lone pair onto the sp-hybridized carbon atom of allene (Scheme 96). Finally, the cyclization reaction of closely related vinylallene acetals 486 has also been considered.374 This cyclopentannelation reaction, which occurs by the simple addition of acid to 485 at room temperature, involves the electrocyclic ring closure of substituted hydroxypentadienyl carbocations, and therefore can be considered as a variant of the Nazarov cyclization (Scheme 97).375 DFT calculations suggest that the R-outwards rotation is kinetically favoured over the alternative R-inwards rotation, which nicely agrees with the observed experimental reaction products distribution. Cope rearrangements are also possible in processes involving allenes. Indeed, Beauchemin and co-workers have recently reported the thermal hydroamination of monosubstituted allenes with N-alkylhydroxylamines which affords exclusively ketonitrones 491 in moderate to good yields (Scheme 98).376 With the help of DFT calculations (B3LYP/TZVP level), it was found that the reaction involves a Cope-type reaction through five-membered coplanar transition states (similar to TS490 depicted in Scheme 98) which are associated with the amination on the central carbon atom of the allene. Interestingly, the calculations suggest that the exclusive formation of ketonitrones takes place under kinetic control in view of the higher activation barrier computed for the formation of isomer 492 through TS492 (associated with the addition to the terminal p-bond). Very recently, a computational study (B3LYP/LANL2DZ and M05-2X/LANL2DZ) of the gold(I)-catalysed [3,3]-sigmatropic rearrangement of allenyl vinyl ethers 493 has been carried out.377 The results have shown that the product preferentially originates from the higher energy Lewis acid coordination Au(I)– oxygen complex 494 instead of the more stable but less reactive


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Scheme 95

Thermal electrocyclic ring closure of vinylallenes 480.

Scheme 96

Reactivity of vinylallenals and their corresponding Schiff base derivatives 483.

Scheme 97

Cyclopentannelation reaction of vinylallene acetals 480.

Au(I)–allene or Au(I)-vinyl complexes 495 and 496 (Scheme 99). Complexes 488 produce species 492 via a low barrier cationaccelerated oxonia Claisen pathway via aromatic transition states (similar to TS494–497, Scheme 99). In addition, the accelerating effect of electron donors predicted by the computational study is


masked by the unproductive coordination of Au(I) to either the electron rich p-systems or heteroatomic Lewis bases. Decreased reaction rates in the presence of external donor additives provided experimental evidence to this conclusion and illustrated the unproductive role that the stabilization of the starting materials

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Scheme 98

Cope-type hydroamination of allenes.

Scheme 99

Gold(I)-catalysed oxonia-Claisen rearrangement of allenyl vinyl ethers 493.

may play in the Au-catalysed processes. Similar conclusions have been drawn by the authors in the strongly related process involving vinyl ethers possessing triple bonds instead of allenes.378

7. Outlook The tremendous development of Computational Chemistry in the last few decades has provided chemists with a powerful tool to not only rationalize the experimental findings but also to predict new molecular systems and reactions. This review compiled the substantial advances recently made in the study of the bonding situation and rich reactivity of allenes by means of computational methods. The contents herein described clearly illustrate the great ability of Computational Chemistry to understand the wide variety of reactions that allenes can undergo in organic and organometallic chemistry. In addition, Computational Chemistry has also been quite helpful in rationalizing the bonding situation of allenes and related compounds such as carbodiphosphoranes or carbones. It becomes obvious that the synergy between computation and

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experiment that we have tried to show along this review has led to the rapid development experienced by the allene-chemistry. In our opinion, the predictive ability of the state-of-the-art computational methods will contribute enormously to the discovery of novel bonding situations and reactions in allenes which will lead to intensive research of the involved reaction mechanisms from both computational and experimental points of view. Apart from describing representative applications of computational methods in the chemistry of allenes, we hope that the contents of this review motivate researchers to investigate new transformations involving allenes of interest for the wide chemical (experimental and computational) community.

Acknowledgements E.S. thanks the Spanish MINECO for grant CTQ2009-10478. I.F. is grateful for financial support from the Spanish MINECO (CTQ2010–20714-C02–01/BQU and Consolider-Ingenio 2010, CSD2007–00006) and CAM (S2009/PPQ-1634).


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Computational contributions to chemistry, biological chemistry and biophysical chemistry: the 2013 Nobel Prize in Chemistry.

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Mechanistic insights into the gold chemistry of allenes.

Nobel 2013 Chemistry: Methods for computational chemistry.

Foreword: applied computational chemistry.

Applied computational chemistry.

Chemical reaction mechanisms in solution from brute force computational Arrhenius plots.

Computational organic chemistry: bridging theory and experiment in establishing the mechanisms of chemical reactions.

Unstable, metastable, or stable halogen bonding interaction involving negatively charged donors? A statistical and computational chemistry study.

Crossing the Boundaries within Computational Chemistry: From Molecular Dynamics to Cheminformatics and back.

Computational study of the kinetics and mechanisms for the HCO + O3 reaction.

Complex Chemical Reaction Networks from Heuristics-Aided Quantum Chemistry.

Uranium release from sediment to groundwater: influence of water chemistry and insights into release mechanisms.

Early Experiences with Computational Quantum Chemistry.

Prebiotic chemistry: geochemical context and reaction screening.

The atmospheric degradation pathways of BrCH2O2: computational calculation on mechanisms of the reaction with HO2.

Mechanistic Investigation on the Formation of 2-Halo-3-aryl-4(3H)-quinazoliniminium Halides from Heteroenyne-allenes: A Computational Study.

BindingDB in 2015: A public database for medicinal chemistry, computational chemistry and systems pharmacology.

Computational chemistry for graphene-based energy applications: progress and challenges.

International Conference on Theoretical and High-Performance Computational Chemistry.

Spectroscopic and computational investigation of actinium coordination chemistry.

Can substituted allenes be highly efficient leaving groups in catalytic processes? A computational investigation.

Kaempferol and inflammation: From chemistry to medicine.

Complex Reaction Environments and Competing Reaction Mechanisms in Zeolite Catalysis: Insights from Advanced Molecular Dynamics.