Remote Functionalization by Pd-Catalyzed Isomerization of Alkynyl Alcohols.

In recent years, progress has been made in the development of catalytic methods that allow remote functionalizations based on alkene isomerization. In contrast, protocols based on alkyne isomerization are comparatively rare. Herein, we report a general Pd-catalyzed long-range isomerization of alkynyl alcohols. Starting from aryl-, heteroaryl-, or alkyl-substituted precursors, the optimized system provides access preferentially to the thermodynamically more stable α,ß-unsaturated aldehydes and is compatible with potentially sensitive functional groups. We showed that the migration of both π-components of the carbon-carbon triple bond can be sustained over several methylene units. Computational investigations served to shed light on the key elementary steps responsible for the reactivity and selectivity. These include an unorthodox phosphine-assisted deprotonation rather than a more conventional ß-hydride elimination in the final tautomerization event.

Transition metal-catalyzed alkene isomerization as an enabling technology in tandem, sequential and domino processes.

One-pot reactions elaborated around transition metal-catalyzed isomerization of alkenes not only offer the inherent advantages of atom-, step- and redox-economy but also enable the preparation of value-added products that would be difficult to access by conventional methods. In this Review, we cover seminal and recent examples of tandem, sequential and domino processes, which incorporate the most attractive features of olefin isomerization.

Access to Highly Stereodefined 1,4-cis-Polydienes by a [Ni/Mg] Orthogonal Tandem Catalytic Polymerization.

A [Ni/Mg]-catalyzed orthogonal tandem polymerization has been developed starting from enol phosphates. Initial investigations conducted on branched 1,3-dienes as monomers enabled identification of a Mg-initiated polymerization process leading to 1,4-cis-polydienes. When aryl enol phosphates are used as monomers, the [Ni/Mg]-catalyzed tandem polymerization affords 1,4-cis-polydienes with selectivities up to 99%. Elastomeric or crystalline materials were obtained by simple structural modifications of the monomeric unit. This tandem approach appears as a straightforward and efficient way to enforce diversity and selectivity in diene polymerization while retaining a fair degree of control, just as observed for stepwise systems that are accessible through established time- and manpower-consuming synthetic procedures.

Bioinspired Ether Cyclizations within a π-Basic Capsule Compared to Autocatalysis on π-Acidic Surfaces and Pnictogen-Bonding Catalysts.

While the integration of supramolecular principles in catalysis attracts increasing attention, a direct comparative assessment of the resulting systems catalysts to work out distinct characteristics is often difficult. Herein is reported how the broad responsiveness of ether cyclizations to diverse inputs promises to fill this gap. Cyclizations in the confined, π-basic and Brønsted acidic interior of supramolecular capsules, for instance, are found to excel with speed (exceeding general Brønsted acid and hydrogen-bonding catalysts by far) and selective violations of the Baldwin rules (as extreme as the so far unique pnictogen-bonding catalysts). The complementary cyclization on π-acidic aromatic surfaces remains unique with regard to autocatalysis, which is shown to be chemo- and diastereoselective with regard to product-like co-catalysts but, so far, not enantioselective.

Ni-Catalyzed Regiodivergent and Stereoselective Hydroalkylation of Acyclic Branched Dienes with Unstabilized C(sp3) Nucleophiles.

Two complementary regiodivergent [(P,N)Ni]-catalyzed hydroalkylations of branched dienes are reported. When amides are employed as unstabilized C(sp3) nucleophiles, a highly regioselective 1,4-addition process is favored. The addition products are obtained in high yield and with excellent stereocontrol of the internal olefin. With use of a chiral ligand and imides as carbon nucleophiles, a 3,4-addition protocol was developed, enabling construction of two contiguous tertiary stereocenters in a single step with moderate to high levels of diastereocontrol and excellent enantiocontrol. Both methods operate under mild reaction conditions, display a broad scope, and show excellent functional group tolerance. The synthetic potential of the 3,4-hydroalkylation reaction was established via a series of postcatalytic modifications.

Direct Access to Chiral Secondary Amides by Copper-Catalyzed Borylative Carboxamidation of Vinylarenes with Isocyanates.

A Cu-catalyzed borylative carboxamidation reaction has been developed using vinylarenes and isocyanates. Alkynes, branched 1,3-dienes, and bicyclic alkenes were also found to be competent coupling partners. Using a chiral phosphanamine ligand, an enantioselective variant of this transformation was developed, affording a set of α-chiral amides with unprecedented levels of enantioselectivity. The synthetic utility of the method was demonstrated through a series of representative stereoretentive postcatalytic derivatizations.

A Catalytic Dual Isomerization/Allylboration Sequence for the Stereoselective Construction of Congested Secondary Homoallylic Alcohols.

A catalytic sequence for the diastereo- and enantioselective preparation of homoallylic alcohols with an adjacent quaternary (stereo)center is reported. The one-pot process relies on the use of a single (achiral or chiral) iridium complex to catalyze the concomitant isomerization of primary allylic alcohols and homoallylboronates into (chiral) aldehydes and allylboronates, respectively. In the same flask, a chiral Brønsted acid is added next to engage the isomerization products into a stereocontrolled allylboration reaction. Structural variations have been performed on both the allylic alcohols and the homoallylboronates. This mild process affords an array of stereochemically congested and complex chiral secondary homoallylic alcohols in high yield, excellent diastereoselectivity, and usually high enantioselectivity.

Remote Functionalization of α,ß-Unsaturated Carbonyls by Multimetallic Sequential Catalysis.

The remote functionalization of α,ß-unsaturated carbonyls by an array of multimetallic sequential catalytic systems is described. The reactions are triggered by hydrometalation using [Pd-H] or [Ru-H] isomerization catalysts and driven by the formation of thermodynamically more stable 1,2-vinyl arenes. The Pd-catalyzed deconjugative isomerization was combined with a Cu-catalyzed ß-borylation of the transiently generated styrenyl derivatives to deliver a range of products that would not be accessible with the use of a single catalyst. [Pd/Cu] catalytic systems were also identified for the highly enantioselective α-hydroboration and α-hydroamination of the styrenyl intermediates. Difunctionalization simultaneously at the benzylic and homobenzylic positions was achieved by combining the isomerization process with Sharpless asymmetric dihydroxylation (SAD) using [Pd/Os] or [Ru/Os] couples. Starting from a simple α,ß-unsaturated ester, an isomerization/dihydroxylation/lactonization sequence gave access to a naturally occurring γ-butyrolactone in good yield, with excellent diastereo- and enantioselectivity.

Ni-Catalyzed Enantioselective Intermolecular Hydroamination of Branched 1,3-Dienes Using Primary Aliphatic Amines.

A Ni-catalyzed intermolecular enantioselective hydroamination of branched 1,3-dienes is reported. The method is broadly applicable, highly regio-, chemo-, and enantioselective, and provides direct access to valuable chiral allylic amines starting from linear or α-branched aliphatic primary amines or secondary amines. Mechanistic studies have been conducted using 31P NMR spectroscopy for reaction progress monitoring, isotopic labeling experiments (2H), and kinetic analysis. The resting state of the catalyst is a Ni-π-allyl complex, and the outer-sphere nucleophilic attack of H-bonded amine aggregates is proposed to be the rate-determining step. This hypothesis guided the identification of an improved set of reaction conditions for the enantioselective hydroamination of branched 1,3-dienes.

Multicatalytic Stereoselective Synthesis of Highly Substituted Alkenes by Sequential Isomerization/Cross-Coupling Reactions.

Starting from readily available alkenyl methyl ethers, the stereoselective preparation of highly substituted alkenes by two complementary multicatalytic sequential isomerization/cross-coupling sequences is described. Both elementary steps of these sequences are challenging processes when considered independently. A cationic iridium catalyst was identified for the stereoselective isomerization of allyl methyl ethers and was found to be compatible with a nickel catalyst for the subsequent cross-coupling of the in situ generated methyl vinyl ethers with various Grignard reagents. The method is compatible with sensitive functional groups and a multitude of olefinic substitution patterns to deliver products with high control of the newly generated C═C bond. A highly enantioselective variant of this [Ir/Ni] sequence has been established using a chiral iridium precatalyst. A complementary [Pd/Ni] catalytic sequence has been optimized for alkenyl methyl ethers with a remote C═C bond. The final alkenes were isolated with a lower level of stereocontrol. Upon proper choice of the Grignard reagent, we demonstrated that C( sp2)-C( sp2) and C( sp2)-C( sp3) bonds can be constructed with both systems delivering products that would be difficult to access by conventional methods.

Iridium-Catalyzed Selective Isomerization of Primary Allylic Alcohols.

This Account presents the development of the iridium-catalyzed isomerization of primary allylic alcohols in our laboratory over the past 8 years. Our initial interest was driven by the long-standing challenge associated with the development of a general catalyst even for the nonasymmetric version of this seemingly simple chemical transformation. The added value of the aldehyde products and the possibility to rapidly generate molecular complexity from readily accessible allylic alcohols upon a redox-economical isomerization reaction were additional sources of motivation. Certainly influenced by the success story of the related isomerization of allylic amines, most catalysts developed for the selective isomerization of allylic alcohols were focused on rhodium as a transition metal of choice. Our approach has been based on the commonly accepted precept that hydrogenation and isomerization are often competing processes, with the latter being usually suppressed in favor of the former. The cationic iridium complexes [(Cy3P)(pyridine)Ir(cod)]X developed by Crabtree (X = PF6) and Pfaltz (X = BArF) are usually considered as the most versatile catalysts for the hydrogenation of allylic alcohols. Using molecular hydrogen to generate controlled amounts of the active form of these complexes but performing the reaction in the absence of molecular hydrogen enabled deviation from the typical hydrogenation manifold and favored exclusively the isomerization of allylic alcohols into aldehydes. Isotopic labeling and crossover experiments revealed the intermolecular nature of the process. Systematic variation of the ligand on the iridium center allowed us to identify the structural features beneficial for catalytic activity. Subsequently, three generations of chiral catalysts have been investigated and enabled us to reach excellent levels of enantioselectivity for a wide range of 3,3-disubstituted aryl/alkyl and alkyl/alkyl primary allylic alcohols leading to ß-chiral aldehydes. The combination of the isomerization reaction with enamine catalysis in a sequential process gave access to α,ß-chiral aldehydes in high diastereomeric ratio and excellent enantioselectivity. Catalyst-controlled diastereoselective isomerization of stereochemically complex steroid scaffolds has been achieved, giving access indifferently to derivatives with the natural and unnatural C20 configuration, a long-standing challenge in the field. Structural diversification at close proximity of the reactive site and within the polycyclic domain served to further demonstrate the generality and the potential of the method. Models based on quadrant diagrams enabled rationalization of the high levels of enantio- and diastereocontrol obtained in the isomerization of allylic alcohols.

Palladium-Catalyzed Long-Range Deconjugative Isomerization of Highly Substituted α,ß-Unsaturated Carbonyl Compounds.

The long-range deconjugative isomerization of a broad range of α,ß-unsaturated amides, esters, and ketones by an in situ generated palladium hydride catalyst is described. This redox-economical process is triggered by a hydrometalation event and is thermodynamically driven by the refunctionalization of a primary or a secondary alcohol into an aldehyde or a ketone. Di-, tri-, and tetrasubstituted carbon-carbon double bonds react with similar efficiency; the system is tolerant toward a variety of functional groups, and olefin migration can be sustained over 30 carbon atoms. The refunctionalized products are usually isolated in good to excellent yield. Mechanistic investigations are in support of a chain-walking process consisting of repeated migratory insertions and ß-H eliminations. The bidirectionality of the isomerization reaction was established by isotopic labeling experiments using a substrate with a double bond isolated from both terminal functions. The palladium hydride was also found to be directly involved in the product-forming tautomerization step. The ambiphilic character of the in situ generated [Pd-H] was demonstrated using isomeric trisubstituted α,ß-unsaturated esters. Finally, the high levels of enantioselectivity obtained in the isomerization of a small set of α-substituted α,ß-unsaturated ketones augur well for the successful development of an enantioselective version of this unconventional isomerization.

Palladium-Catalyzed Enantioselective Intermolecular Carboetherification of Dihydrofurans.

A novel enantioselective Pd-catalyzed intermolecular carboetherification of dihydrofurans is reported. The in situ generation of chiral bis-phosphine mono-oxide ligands is crucial, and a general catalytic system has been identified based on this approach. It provides access to a variety of fused tetrahydrofurobenzofurans in consistently high yield and enantiomeric excess.

Catalyst-Directed Diastereoselective Isomerization of Allylic Alcohols for the Stereoselective Construction of C(20) in Steroid Side Chains: Scope and Topological Diversification.

The stereoselective construction of C20 in steroidal derivatives by a highly diastereoselective Ir-catalyzed isomerization of primary allylic alcohols is reported. A key aspect of this strategy is a straightforward access to geometrically pure steroidal enol tosylate and enol triflate intermediates for subsequent high yielding stereoretentive Negishi cross-coupling reactions to allow structural diversity to be introduced. A range of allylic alcohols participates in the diastereoselective isomerization under the optimized reaction conditions. Electron-rich and electron-poor aryl or heteroaryl substituents are particularly well-tolerated, and the stereospecific nature of the reaction provides indifferently access to the natural C20-(R) and unnatural C20-(S) configurations. Alkyl containing substrates are more challenging as they affect regioselectivity of iridium-hydride insertion. A rationale for the high diastereoselectivities observed is proposed for aryl containing precursors. The scope of our method is further highlighted through topological diversification in the side chain and within the polycyclic domain of advanced and complex steroidal architectures. These findings have the potential to greatly simplify access to epimeric structural analogues of important steroid scaffolds for applications in biological, pharmaceutical, and medical sciences.

A general Pd-catalyzed α- and γ-benzylation of aldehydes for the formation of quaternary centers.

A palladium-catalyzed benzylation of α-branched aldehydes has been developed using benzyl methyl carbonates. The method gives access to congested quaternary centers in the vicinity of one of the most sensitive carbonyl functionalities and displays unprecedented generality with respect to both coupling partners. Evidence for the direct involvement of a Pd-η(3)-benzyl intermediate is provided. Extension of this strategy to the γ-benzylation of α,ß-unsaturated aldehydes is further demonstrated.

Scope and mechanism in palladium-catalyzed isomerizations of highly substituted allylic, homoallylic, and alkenyl alcohols.

Herein we report the palladium-catalyzed isomerization of highly substituted allylic alcohols and alkenyl alcohols by means of a single catalytic system. The operationally simple reaction protocol is applicable to a broad range of substrates and displays a wide functional group tolerance, and the products are usually isolated in high chemical yield. Experimental and computational mechanistic investigations provide complementary and converging evidence for a chain-walking process consisting of repeated migratory insertion/ß-H elimination sequences. Interestingly, the catalyst does not dissociate from the substrate in the isomerization of allylic alcohols, whereas it disengages during the isomerization of alkenyl alcohols when additional substituents are present on the alkyl chain.

Highly modular C(1) -symmetric chiral (P,N) ligands with a stereolabile P center: experimental and theoretical studies.

An improved synthesis of a novel class of bidentate (P,N) ligands is presented, the structures of which are characterized by three distinct elements of chirality. The stereoselective installation of the elements of central chirality (at the benzylic carbon and the phosphorus atom) depends on the size of the phosphorus substituent. Thermal inversion of the phosphorus center has been studied experimentally and further correlated by DFT calculations. The potential of these ligands and the role of the phosphorus atom in the asymmetric α-arylation of aldehydes (Pd) and hydrogenation of allylic alcohols (Ir) have also been investigated.

Recent trends in Pd-catalyzed remote functionalization of carbonyl compounds.

Recent advances in the palladium-catalyzed remote functionalization of carbonyl derivatives are highlighted in this review. The structure of the article is based on the three strategies that have emerged in recent years as the most viable tactics to construct C(sp(3))-C, C(sp(3))-N or C(sp(3))-O bonds at a distance of at least three carbon atoms from the carbonyl functionality. The specific aspects of each of these approaches are discussed in detail (reaction conditions, substrate scope and limitations). As the reading progresses, their complementarity should also appear clearly.

Access to Cyclic Borates by Cu-Catalyzed Borylation of Unactivated Vinylcyclopropanes.

We report the copper-catalyzed borylation of unactivated vinylcyclopropanes to form six-membered cyclic borate salts. A copper complex bearing an N-heterocyclic ligand in combination with bis(pinacolato)diboron and LiOtBu catalyzes the ring-opening of the substrate under mild reaction conditions. The protocol can be applied to aryl- and heteroaryl-substituted vinylcyclopropanes and can be conducted on a gram scale. The synthetic utility of the lithium salts of the cyclic borate has been demonstrated through regioselective ring-opening functionalizations.

Ni-Catalyzed Kumada-Corriu Cross-Coupling Reactions of Tertiary Grignard Reagents and Bromostyrenes.

The development of protocols for the construction of congested quaternary centers is highly sought-after. Herein, we report a method for the cross-coupling of C(sp3) tertiary Grignard reagents with C(sp2) styrenyl bromides using readily available nickel precatalysts. We identified conditions that afford the products in practical yield for several combinations of electrophiles and nucleophiles, including sensitive α-magnesiated Grignard reagents. Dependent upon the nature of their substituents, regiodivergency was observed when α-vinyl bromides were employed.