Gareth E. Arnott

Isomerization of Allylbenzenes

ed from in the transition state. This answers the question of both the retention and the inversion of stereochemistry for the simple exchange reaction giving back I (which it should be noted is highly disfavored because k2 ≫ k−1). Retention of configuration would occur by first noting that the potassium ion would also be coordinated to the same face as the abstracted hydrogen atom because it was originally coordinated to the oxygen of the base. A molecule of deuterated alcohol can then approach this same face through coordination to the potassium. Rotation of these ligands around potassium would result in the deuterated alcohol now hydrogen bonded to the allylic anion (IV-top), which following collapse would return the chiral alkene I-d with the same configuration. On the other hand, inversion of stereochemistry would occur via the deuterated solvent approaching from the face of the allylic anion opposite to that hydrogen bonded, and exchange with the alcohol giving (IV-bottom). This could collapse and give chiral alkene I-d with inversion of configuration. The E/Z ratio of 60 for product III-h is also important because this value is extremely high as compared to the equilibrium value of 4.2 for the diastereoisomers, and compares to other systems as well. For example, the isomerization of allylbenzene into 1-propenylbenzene has an E/Z ratio of 44 when using potassium t-butoxide in DMSO. The reason for this higher-than-equilibrium ratio is explained in Scheme 3. Two “conformations” of the chiral alkene I are suitable for deprotonation and will lead to either the E or the Z allylic anions as shown. The rate of “conformational rotation” must be many orders of magnitude greater than the rates for Scheme 2. Proposed Base-Mediated Reaction Mechanism Scheme 3. Interactions Leading to Observed E/Z Ratios Chemical Reviews Review DOI: 10.1021/acs.chemrev.5b00052 Chem. Rev. XXXX, XXX, XXX−XXX E deprotonation (kE and kZ), and thus the E/Z ratio in the product must be related to the kE/kZ ratio. The transition state leading to the Z-allylic anion must thus be higher in energy than the one leading to the E-allylic anion, presumably due to the disfavored 1,3-allylic interactions, which would make charge stabilization through conjugation more difficult. Cram has reported this in more detail, including an analysis of collapse ratios (i.e., ratio of protonation of either carbon on the allylic anion), the stereochemical stability of allylic and vinyl anions, and the kinetic and thermodynamic stabilities of olefinic products formed by protonation of allylic anions. 2.2. Transition Metal-Mediated Mechanisms The mechanisms for the transition metal-mediated isomerizations have in some cases been very carefully determined, while in many they are assumed from one of two generally accepted pathways (Schemes 4 and 5). The first involves a discrete transition metal−hydride active catalyst and the formation of a transition metal−alkyl intermediate, while the second involves the formation and collapse of a η-allyl hydride complex. Each of the mechanisms described below bases its premise on the fact that each step is reversible, and thus the reactions are under thermodynamic control at equilibrium. 2.2.1. Alkyl Mechanism. For this mechanism to occur, the transition metal catalyst must have both an empty 2e− coordination site (e.g., via dissociation of a ligand) and a metal hydride bond that is typically generated in situ under the reaction conditions (see Scheme 4). The catalyst first coordinates to the π-electrons of the alkene followed by an insertion reaction to give either a primary or a secondary metal−alkyl intermediate. The primary metal−alkyl is generally formed faster for many catalysts, but is a mechanistic dead-end returning the starting material through β-hydride elimination and is thus a nonproductive pathway. The secondary metal− alkyl intermediate can however produce either the Eor the Z1-propenylbenzene on β-hydride elimination, which is clearly thermodynamically favored because of the conjugation to the benzene ring. 2.2.2. Allyl Mechanism. The allyl mechanism, however, requires a transition metal capable of having two vacant coordination sites, and, more specifically, no metal−hydride should be present or the alkyl mechanism will take place (see Scheme 5). The first step involves coordination of the πelectrons of the allylbenzene to one of the transition metal’s vacant sites. This is followed by an oxidative addition reaction giving an η-allyl metal−hydride complex, which can collapse to either the starting material or the rearranged and thus more stable alkene. The η-complex may also rearrange to the ηcomplex as part of the reaction pathway. The difference between these two mechanisms can be determined through deuterium labeling with 32 and crossover experiments (Scheme 6). The allyl mechanism is entirely intramolecular and involves an effective 1,3-hydride shift as the only mechanistic pathway. Thus, in a crossover experiment, such as that in Scheme 6, the deuterium should (a) only be found at the 1and 3-positions of the allylic system, that is, 34, and (b) not be incorporated into the second nondeuterated substrate. In the case of the alkyl mechanism, products similar to those of the allyl mechanism may be detected in addition to (a) the nondeuterated substrate showing some deuterium incorporation and (b) the loss of deuterium and incorporation of hydrogen on the deuterated substrate. Furthermore, deuterium incorporation at the 2-position of the allylic system, 35, is also expected because the initial metal−hydride insertion reaction may have poor regioselectivity as already explained in Scheme 2. Of course it should be noted that these two general mechanisms are just that, and the specific reaction pathway for different transition metal catalysts will depend heavily on the transition metal, ligand, solvent, and substrate combinations. More detailed mechanistic data can be obtained from kinetic studies supplemented by state-of-the-art measurements, for example, nanosecond time-resolved IR, NMR, and DFT calculations. These studies have invariably revealed Scheme 4. Alkyl Mechanism M = transition metal; [L]n = bound ligand(s); [L]0 = dissociating ligand or vacant 2e− site. Scheme 5. Allyl Mechanism M = transition metal; [L]n = bound ligand(s); [L]0 = dissociating ligand or vacant 2e− site. Chemical Reviews Review DOI: 10.1021/acs.chemrev.5b00052 Chem. Rev. XXXX, XXX, XXX−XXX F mechanisms more complicated than those presented above, but at the same time generally holding true to them. One major mechanistic departure has been that proposed by Harvey and Lloyd-Jones in which they suggest a binuclear palladium complex being involved in the E/Z isomerization of alkenes. However, it should be noted that this is only applicable in some cases. More important is that the specific mechanisms themselves answer questions related to E/Z selectivity in these transition metal-mediated isomerizations. Simplistically, the reactions can be considered to be under thermodynamic control, and therefore the E/Z ratios will favor the E-isomer. The π-allyl mechanism has been linked, in a general sense, with higher E/Z ratios, but can by no means be used as proof for a particular mechanism. This is because the E/Z selectivity in the reaction is strongly governed not only by the thermodynamic stability of the E isomer (and intermediates leading to the E-isomer), but can be shifted through ligand and or kinetic control to high ratios of either the E or the Z isomers. The sections below detailing the specific examples in the literature will highlight these selectivities. 3. ISOMERIZATION METHODS − GENERAL Perusal of the literature quickly confirms that 2-propenylaryl isomerization reactions have been promoted by mainly two classes of methods, viz., the application of bases (section 4) or transition metal complexes (section 5). In this Review, these sections will thus be discussed separately, in addition to a final section describing miscellaneous allylaryl isomerizations (section 6). In each section, substrates of particular interest will be highlighted, with particular care being taken to convey important experimental data such as yields, the cis/trans ratios obtained, and any other relevant information. 4. BASE-MEDIATED ISOMERIZATIONS In general, base-initiated reactions require at least a stoichiometric amount of base to accomplish the isomerization of an allylbenzene. This method has seen much application in the past literature, and some general information has been collated in book chapters. 4.1. Hydroxide/Alkoxide Ion-Mediated Isomerizations This particular method involves the use of fairly harsh reaction conditions in that it generally comprises heating the substrate in a protic solution (ethanol, methanol, or n-butanol) of sodium or potassium hydroxide (giving rise to a mixture of the hydroxide and corresponding alkoxide under equilibrium conditions). Other examples include the use of hydroxide in DMSO. Of interest is that the KOH/ethylene glycolmediated isomerization of eugenol 5 has actually been incorporated into the curriculum of a teaching laboratory to demonstrate how the kinetics of a reaction can be studied using NMR spectroscopic, GC, and HPLC laboratory techniques. It should also be mentioned here that the importance of the potassium t-butoxide system means that a separate subsection will be dedicated to this method (see section 4.2). In the first section, examples of where hydroxide-mediated isomerization has been applied will be highlighted. This will be followed by methods in which the isomerization approach has been modified, albeit with additives (phase transfer), microwave heating, or different solvent systems. 4.1.1. Hydroxide/Alkoxide Ions in Alcohol (Methanol, Ethanol, n-Butanol) or without Solvent. It should be noted that the use of sodium ethoxide has been rigorously studied, showing that the isomerization of para-substi

Electrophile-Induced Dearomatizing Spirocyclization of N-Arylisonicotinamides: A Route to Spirocyclic Piperidines

Treatment of N-arylisonicotinamides with trifluoromethanesulfonic anhydride triggers intramolecular nucleophilic attack of the aryl ring on the 4-position of the pyridinium intermediate. The products are spirocyclic dihydropyridines which can be converted to valuable spirocyclic piperidines related to biologically active molecules such as MK-677.

An asymmetric ortholithiation approach to inherently chiral calix[4]arenes.

A general asymmetric synthesis of inherently chiral calix[4]arenes is described: using a chiral oxazoline derived from L-valine, an ortholithiation strategy is employed to give inherently chiral calix[4]arenes with high (93%) enantiomeric excesses. A crystal structure of a phosphine oxide intermediate has been obtained, unambiguously assigning the major diastereomer in the reaction; a mechanism explaining this result is proposed.

Synthesis of Inherently Chiral Calix[4]arenes: Stereocontrol through Ligand Choice

Employing a chiral oxazoline as an ortholithiation directing group allows the synthesis of inherently chiral calix[4]arenes suitable for elaboration into planar chiral molecules. An important finding has been that the diastereoselectivity of the reaction can be tuned by the choice of additive. These results have bearing on the elucidation of the general mechanism of oxazoline-directed ortholithiation.

Manipulating the diastereoselectivity of ortholithiation in planar chiral ferrocenes.

The sense of asymmetric ortholithiation directed by a chiral oxazoline may be inverted simply by the choice of achiral ligand. Comparison of results with a number of ferrocenyl oxazoline derivatives suggests that lithiation takes place by coordination to the oxazoline nitrogen irrespective of the ligand used.

Inherently Chiral Calixarenes: Synthesis and Applications

This article looks at the chemistry surrounding the concept of inherently chiral calixarenes (ICCs), whose synthesis and application have only recently being realised. One challenge in the area of ICC chemistry is the sheer breadth and scope for installing different aspects of inherent chirality. The aim of this article is not to cover every known method, but rather to give the reader an overview of the main themes that have emerged in this area, including more recent additions to the literature. This overview will also touch on the very limited reports on the applications of ICCs which give a glimpse into the potential these compounds may have in future studies.

Inherently chiral calix[4]arenes via oxazoline directed ortholithiation: synthesis and probe of chiral space.

Summary The diastereoselective oxazoline-directed lithiation of calix[4]arenes is reported with diastereoselective ratios of greater than 100:1 in some instances. Notably, it has been found that the opposite diastereomer can be accessed via this approach merely through the choice of an alkyllithium reagent. The inherently chiral oxazoline calix[4]arenes have also been preliminarily examined as ligands in the palladium-catalyzed Tsuji–Trost allylation reaction, returning results comparable to their planar chiral ferrocene counterparts pointing towards future application of these types of compounds.

Transient chirality in a distal-substituted resorcinarene metal complex.

A novel distal bidentate S/S resorcinarene ligand has been synthesised and a bis-mu-chloro-bridged palladium(II) complex obtained. The solid state structure for this complex represents the first crystal structure evidence for a bispalladium-mu-chloro-bridged complex bound to thioether ligands. Furthermore, solution NMR studies revealed conformational changes in the flexible resorcinarene ligand and discreet transient chirality around the sulfur centres.

Selective derivatisation of resorcinarene ethers via an ortholithiation approach

The development of an ortholithiation approach to distal-functionalised resorcinarenes is described, greatly simplifying the current strategies available.

Synthesis of α,ω-heterotelechelic PVP for bioconjugation, via a one-pot orthogonal end-group modification procedure

A simple one pot orthogonal procedure for synthesizing α-aldehyde, ω-thiol heterotelechelic poly(N-vinylpyrrolidone) (PVP) is introduced. Firstly we designed a xanthate chain transfer agent with an acetal protected aldehyde functionality in the leaving group, then we synthesized α-acetal ω-xanthate end-functional PVP, via a RAFT-mediated polymerization. The end-groups were modified via a facile, modular protocol, by first aminolysing the ω-xanthate end-groups to form thiols, using an excess of a primary amine, and subsequently acidifying the reaction medium to simultaneously convert excess primary amine to its (non-interfering) quaternary ammonium salt form, as well as effect the acid-catalysed deprotection of the acetal into an aldehyde functionality, to access the α-aldehyde, ω-thiol-PVP. Finally, we demonstrated the utility of these end-groups by performing conjugations with model small molecules. This study establishes a facile procedure for accessing different and bio-relevant end-functional groups with a biocompatible vinyl polymer, suitable for making drug delivery vehicles.