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.

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.

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.

Pd-Catalyzed Regioselective Cyclopropanation of 2-Substituted 1,3-Dienes.

A Pd-catalyzed 3,4-regioselective cyclopropanation of 2-substituted 1,3-dienes by decomposition of diazo esters is reported. The vinylcyclopropanes generated are isolated in practical chemical yields with high levels of regioselectivity but low diastereoselectivity. The system operates under mild reaction conditions, is scalable, and tolerates various sensitive functional groups. A series of original postcatalytic derivatizations is presented to highlight the synthetic potential of the catalytic method.

Cu-Catalyzed Enantioselective Protoboration of 2,3-Disubstituted 1,3-Dienes.

A Cu-catalyzed regio- and enantioselective protoboration of 2,3-disubstituted 1,3-dienes is described. The protocol operates under mild conditions and is applicable to symmetrically and unsymmetrically substituted dienes, providing access to homoallylic boronates in consistently high yield, regioselectivity, and enantiomeric ratio. Preliminary investigations point to a complex mechanism.

Assisted Tandem Pd Catalysis Enables Regiodivergent Heck Arylation of Transiently Generated Substituted Enol Ethers.

Two complementary regiodivergent Pd-catalyzed assisted tandem [isomerization/Heck arylation] reactions are reported. They provide access to a broad array of acyclic trisubstituted vinyl ethers starting from readily available alkenyl ethers. In both cases, the isomerization is conducted with a [Pd-H] precatalyst supported by tris-tert-butyl phosphine ligands. When the catalyst is modified by the addition of a chelating bisphosphine ligand (dppp), an organic base (Cy2NMe), sodium acetate, and aryl triflates are used as electrophiles, the α-arylation pathway is promoted preferentially. The ß-arylation pathway is favored for electron-deficient and electron-neutral aryl halides when the catalyst is simply modified by the addition of an excess of an organic base (Et3N) after completion of the isomerization reaction. Electron-rich aryl halides lead to reduced levels of regiocontrol. The moderate stereoselectivity obtained are proposed to reflect the absence of stereocontrol in the isomerization step. Computational analyses suggest that migratory insertion is selectivity-determining for both the arylations. For the ß-selective arylation, an energy decomposition analysis underscored that electronic factors favor α-regioselectivity and steric effects favor ß-regioselectivity. Preliminary investigations show that high levels of stereoselectivity can be achieved for the α-selective arylation by ligand control. Complementarily, reaction conditions for postcatalytic stereo-correction have also been identified for each catalytic system.

Ni-Catalyzed Enantioselective Hydrofunctionalizations of 1,3-Dienes.

Ni-catalyzed enantioselective hydrofunctionalizations of conjugated dienes are particularly demanding reactions to devise because they require not only addressing the inherent challenges associated with the development of an enantioselective transformation but also overcoming all other aspects of selective catalysis (chemoselectivity, regioselectivity, diastereoselectivity, etc.). However, the value-added nature of the chiral allylic and homoallylic derivatives obtained by these methods, the lack of efficient alternatives, and the use of an earth-abundant first-row transition metal have led to renewed interest over the past decade. In this Perspective, we give an overview of the developments in this field, from the original findings (often dating back to the last century) to the most recent contributions. Emphasis is placed on the nature of the hydrofunctionalization agent (C(sp), C(sp2), C(sp3), N, P, or O).

Stereoselective Access to Conjugated and Cross-Conjugated Dienoates by Rh- and Ru-Catalyzed Isomerizations of Vinylcyclopropanes.

Two complementary catalytic protocols for the isomerization of stereoisomeric mixtures of vinylcyclopropanes are described. A commercially available cationic rhodium complex provides access to conjugated dienoates in high yield with excellent stereocontrol. The combination of a bisphosphine ligand and a ruthenium precatalyst affords cross-conjugated dienoates via a formal 1,3-ring opening. The products are obtained with moderate to high stereoselectivity. The ability of each type of dienoate to engage in [4 + 2] cycloaddition reactions has been demonstrated.

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.

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.

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.

[n]Dendralenes as a Platform for Selective Catalysis: Ligand-Controlled Cu-Catalyzed Chemo-, Regio-, and Enantioselective Borylations.

We report the development of two complementary methods for the Cu-catalyzed anti-Markovnikov borylation of one specific olefin in 2-substituted [n]dendralenes (n = 3-6). The first protocol operates with a bisphosphine ligand and occurs with high regio- and chemoselectivity for the terminal double bond, independently of the number of cross-conjugated alkenes. We show that the use of a chiral phosphanamine ligand enables the highly chemo-, regio-, and enantioselective borylation of the alkene cross-conjugated with the terminal olefin in [n]dendralenes.

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.

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.

Ni-Catalyzed Regioselective Hydroalkoxylation of Branched 1,3-Dienes.

A highly regioselective Ni-catalyzed hydroalkoxylation of 1,3-dienes is reported. The use of a (P,N) ligand is essential in achieving high levels of selectivity. The optimized protocol operates under particularly mild conditions, it provides access to a broad range of structurally diverse allylic ethers, and tolerates a number of sensitive functional groups.

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.

Copper-catalyzed enantioselective 1,2-borylation of 1,3-dienes.

A highly enantioselective Cu-catalyzed borylation of 2-substituted 1,3-dienes is reported. The use of a chiral phosphanamine ligand is essential in achieving high chemo-, regio-, diastereo- and enantioselectivity. It provides access to a variety of homoallylic boronates in consistently high yield and enantiomeric excess with 2-aryl and 2-heteroaryl 1,3-dienes as well as sterically demanding 2-alkyl 1,3-dienes. Preliminary investigations based on a non-linear effect study point to a mechanism involving more than one metal center.

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.