Control over the Chemoselectivity of Pd‐Catalyzed Cyclization Reactions of (2‐Iodoanilino)carbonyl Compounds

The factors that control the chemoselectivity of palladium‐catalyzed cyclization reactions of (2‐iodoanilino)carbonyl compounds have been explored by an extensive experimental computational (DFT) study. It was found that the selectivity of the process, that is, the formation of fused six‐ versus five‐membered rings, can be controlled by the proper selection of the initial reactant, reaction conditions, and additives. Thus, esters or amides produce ketones by a nucleophilic addition process, whereas the addition of PhO^? ions leads to the formation of indolines by an α‐arylation reaction. In contrast, the corresponding ketone reactants yield a mixture of both reaction products, the ratio of which depends on the base used, in the presence of phenol. The outcome of the processes can be explained by the formation of a common four‐membered palladacycle intermediate from which the competitive nucleophilic addition and α‐arylation reactions occur. The remarkable effect of phenol in the process, which makes the α‐arylation reaction easier, favored the formation of enol complexes, which are stabilized by an intramolecular hydrogen bond between the hydroxy group of the enol moiety and the oxygen atom of the phenoxy ligand. Moreover, the chemoselectivy of the process can be also controlled by the addition of bidendate ligands that lead to the almost exclusive formation of indoles at expenses of the corresponding alcohols.     

Metal‐Catalyzed Cyclization Reactions of 2,3,4‐Trien‐1‐ols: A Joint Experimental–Computational Study

Controlled preparation of tri‐ and tetrasubstituted furans, as well as carbazoles has been achieved through chemo‐ and regioselective metal‐catalyzed cyclization reactions of cumulenic alcohols. The gold‐ and palladium‐catalyzed cycloisomerization reactions of cumulenols, including indole‐tethered 2,3,4‐trien‐1‐ols, to trisubstituted furans was effective, due to a 5‐endo‐dig oxycyclization by attack of the hydroxy group onto the central cumulene double bond. In contrast, palladium‐catalyzed heterocyclization/coupling reactions with 3‐bromoprop‐1‐enes furnished tetrasubstituted furans. Also studied was the palladium‐catalyzed cyclization/coupling sequence involving protected indole‐tethered 2,3,4‐trien‐1‐ols and 3‐bromoprop‐1‐enes that exclusively generated trisubstituted carbazole derivatives. These results could be explained through a selective 6‐endo‐dig cumulenic hydroarylation, followed by aromatization. DFT calculations were carried out to understand this difference in reactivity.     

Enantioselective Organocatalytic Construction of Spiroindane Derivatives by Intramolecular Friedel–Crafts‐Type 1,4‐Addition

The highly enantioselective organocatalytic construction of spiroindanes containing an all‐carbon quaternary stereocenter by intramolecular Friedel–Crafts‐type 1,4‐addition is described. The reaction was catalyzed by a cinchonidine‐based primary amine and accelerated by water and p‐bromophenol. A variety of spiro compounds containing quaternary stereocenters were obtained with excellent enantioselectivity (up to 95 % ee). The reaction was applied to the asymmetric formal synthesis of the spirocyclic natural products (?)‐cannabispirenones A and B.     

Mechanistic Insights into Palladium‐Catalyzed Silylation of Aryl Iodides with Hydrosilanes through a DFT Study

The catalytic cycles of palladium‐catalyzed silylation of aryl iodides, which are initiated by oxidative addition of hydrosilane or aryl iodide through three different mechanisms characterized by intermediates R₃Si−Pd^II−H (Cycle A), Ar−Pd^II−I (Cycle B), and Pd^IV (Cycle C), have been explored in detail by hybrid DFT. Calculations suggest that the chemical selectivity and reactivity of the reaction depend on the ligation state of the catalyst and specific reaction conditions, including feeding order of substrates and the presence of base. For less bulky biligated catalyst, Cycle C is energetically favored over Cycle A, through which the silylation process is slightly favored over the reduction process. Interestingly, for bulky monoligated catalyst, Cycle B is energetically more favored over generally accepted Cycle A, in which the silylation channel is slightly disfavored in comparison to that of the reduction channel. Moreover, the inclusion of base in this channel allows the silylated product become dominant. These findings offer a good explanation for the complex experimental observations. Designing a reaction process that allows the oxidative addition of palladium(0) complex to aryl iodide to occur prior to that with hydrosilane is thus suggested to improve the reactivity and chemoselectivity for the silylated product by encouraging the catalytic cycle to proceed through Cycles B (monoligated Pd⁰ catalyst) or C (biligated Pd⁰ catalyst), instead of Cycle A.     

Mechanism of the Pd‐catalyzed Decarboxylative Allylation of α‐Imino Esters: Decarboxylation via Free Carboxylate Ion

The Pd‐catalyzed decarboxylative allylation of α‐(diphenylmethylene)imino esters ( 1 ) or allyl diphenylglycinate imines ( 2 ) is an efficient method to construct new C(sp³)? C(sp³) bonds. The detailed mechanism of this reaction was studied by theoretical calculations [ONIOM(B3LYP/LANL2DZ+p:PM6)] combined with experimental observations. The overall catalytic cycle was found to consist of three steps: oxidative addition, decarboxylation, and reductive allylation. The oxidative addition of 1 to [(dba)Pd(PPh₃)₂] (dba=dibenzylideneacetone) produces an allylpalladium cation and a carboxylate anion with a low activation barrier of +9.1 kcal mol^?1. The following rate‐determining decarboxylation proceeds via a solvent‐exposed α‐imino carboxylate anion rather than an O‐ligated allylpalladium carboxylate with an activation barrier of +22.7 kcal mol^?1. The 2‐azaallyl anion generated by this decarboxylation attacks the face of the allyl ligand opposite to the Pd center in an outer‐sphere process to produce major product 3 , with a lower activation barrier than that of the minor product 4 . A positive linear Hammett correlation [ρ=1.10 for the PPh₃ ligand] with the observed regioselectivity ( 3 versus 4 ) supports an outer‐sphere pathway for the allylation step. When Pd combined with the bis(diphenylphosphino)butane (dppb) ligand is employed as a catalyst, the decarboxylation still proceeds via the free carboxylate anion without direct assistance of the cationic Pd center. Consistent with experimental observations, electron‐withdrawing substituents on 2 were calculated to have lower activation barriers for decarboxylation and, thus, accelerate the overall reaction rates.     

DFT Study on the Recovery of Hoveyda–Grubbs‐Type Catalyst Precursors in Enyne and Diene Ring‐Closing Metathesis

DFT (B3LYP‐D) calculations have been used to better understand the origin of the recovered Hoveyda–Grubbs derivative catalysts after ring‐closing diene or enyne metathesis reactions. For that, we have considered the activation process of five different Hoveyda–Grubbs precursors in the reaction with models of usual diene and enyne reactants as well as the potential precursor regeneration through the release/return mechanism. The results show that, regardless of the nature of the initial precursor, the activation process needs to overcome relatively high energy barriers, which is in agreement with a relatively slow process. The precursor regeneration process is in all cases exergonic and it presents low energy barriers, particularly when compared to those of the activation process. This indicates that the precursor regeneration should always be feasible, unlike the moderate recoveries sometimes observed experimentally, which suggests that other competitive processes that hinder recovery should take place. Indeed, calculations presented in this work show that the reactions between the more abundant olefinic products and the active carbenes usually require lower energy barriers than those that regenerate the initial precatalyst, which could prevent precursor regeneration. On the other hand, varying the precursor concentration with time obtained from the computed energy barriers shows that, under the reaction conditions, the precursor activation is incomplete, thereby suggesting that the origin of the recovered catalyst probably arises from incomplete precursor activation.     

A Versatile Synthesis of β‐Lactam‐Fused Oxacycles through the Palladium‐Catalyzed Chemo‐, Regio‐, and Diastereoselective Cyclization of Allenic Diols

Chemo‐, regio‐ and stereocontrolled palladium‐catalyzed preparations of enantiopure morpholines, oxocines, and dioxonines have been developed starting from 2‐azetidinone‐tethered γ,δ‐, δ,ε‐, and ε,ζ‐allendiols. The palladium‐catalyzed cyclizative coupling reaction of γ,δ‐allendiols 2 with allyl bromide or lithium bromide was effective as 8‐endo cyclization by attack of the primary hydroxy group to the terminal allene carbon to afford enantiopure functionalized oxocines; whereas the palladium‐catalyzed cyclizative coupling reaction of 2‐azetidinone‐tethered ε,ζ‐allendiols 4 furnished dioxonines 16 through a totally chemo‐ and regioselective 9‐endo oxycyclization. By contrast, the palladium‐catalyzed cyclizative coupling reaction of 2‐azetidinone‐tethered δ,ε‐allendiols 3 with aryl and alkenyl halides exclusively generated six‐membered‐ring compounds 14 a and 15 a . These results could be explained through a 6‐exo cyclization by chemo‐ and regiospecific attack of the secondary hydroxy group to the internal allene carbon. Chemo‐ and regiocontrol issues are mainly influenced by the length of the tether rather than by the nature of the metal catalysts and substituents. This reactivity can be rationalized by means of density functional theory calculations.     

Mechanistic Origin of Cross‐Coupling Selectivity in Ni‐Catalysed Tishchenko Reactions

Mechanistic studies have been performed for the recently developed, Ni‐catalysed selective cross‐coupling reaction between aryl and alkyl aldehydes. A mono‐carbonyl activation (MCA) mechanism (in which one of the carbonyl groups is activated by oxidative addition) was found to be the most favourable pathway, and the rate‐determining step is oxidative addition. Analysing the origin of the observed cross‐coupling selectivity, we found the most favourable carbonyl activation step requires both coordination of the aryl aldehyde and oxidative addition of the alkyl aldehyde. Therefore, the stronger π‐accepting ability of the aryl aldehyde (relative to alkyl aldehyde) and the ease of oxidative addition of the alkyl aldehyde (relative to aryl aldehyde) are responsible for the cross‐coupling selectivity.     

Efficient Nazarov Cyclization/Wagner–Meerwein Rearrangement Terminated by a CuII‐Promoted Oxidation: Synthesis of 4‐Alkylidene Cyclopentenones

The discovery and elucidation of a new Nazarov cyclization/Wagner–Meerwein rearrangement/oxidation sequence is described that constitutes an efficient strategy for the synthesis of 4‐alkylidene cyclopentenones. DFT computations and EPR experiments were conducted to gain further mechanistic insight into the reaction pathways.     

Palladium‐Catalyzed Cyclopropanation of Alkenyl Silanes by Diazoalkanes: Evidence for a Pd0 Mechanism

Pd ⁰ does the trick! Alkenyl silanes are efficiently cyclopropanated by diazoalkanes at low Pd loadings (see scheme). Clear evidence for the involvement of a Pd⁰ resting state for this reaction is given.

     

On the Mechanism of the Digold(I)–Hydroxide‐Catalysed Hydrophenoxylation of Alkynes

Herein, we present a detailed investigation of the mechanistic aspects of the dual gold‐catalysed hydrophenoxylation of alkynes by both experimental and computational methods. The dissociation of [{Au(NHC)}₂(μ‐OH)][BF₄] is essential to enter the catalytic cycle, and this step is favoured by the presence of bulky, non‐coordinating counter ions. Moreover, in silico studies confirmed that phenol does not only act as a reactant, but also as a co‐catalyst, lowering the energy barriers of several transition states. A gem‐diaurated species might form during the reaction, but this lies deep within a potential energy well, and is likely to be an “off‐cycle” rather than an “in‐cycle” intermediate.     

Mechanism of the Asymmetric Hydrogenation of Exocyclic α,β‐Unsaturated Carbonyl Compounds with an Iridium/BiphPhox Catalyst: NMR and DFT Studies

The mechanism of the asymmetric hydrogenation of exocyclic α,β‐unsaturated carbonyl compounds with the (aS)‐Ir/iPr‐BiphPhox catalyst was studied by NMR experiments and DFT computational analyses. Computed optical yields of the asymmetric hydrogenation proceeding by an iridium(I)/iridium(III) mechanism involving a transition state stabilized through two intramolecular hydrogen bonds are in good accordance with the experimental ee values.     

Double‐Oxygen‐Atom Transfer in Reactions of CemO2m+ (m=2–6) with C2H2

Cerium oxide cluster cations (Ce_mO_n⁺, m=2–16; n=2m, 2m±1 and 2m±2) are prepared by laser ablation and reacted with acetylene (C₂H₂) in a fast‐flow reactor. A time‐of‐flight mass spectrometer is used to detect the cluster distribution before and after the reactions. Reactions of stoichiometric Ce_mO_2m⁺ (m=2–6) with C₂H₂ produce Ce_mO_2m?2⁺ clusters, which indicates a “double‐oxygen‐atom transfer” reaction Ce_mO_2m⁺+C₂H₂→Ce_mO_2m?2⁺+(CHO)₂ (ethanedial). A single‐oxygen‐atom transfer reaction channel is also identified as Ce_mO_2m⁺+C₂H₂→Ce_mO_2m?1⁺+C₂H₂O (at least for m=2 and 3). Density functional theory calculations are performed to study reaction mechanisms of Ce₂O₄⁺+C₂H₂, and the calculated results confirm that both the single‐ and double‐oxygen‐atom transfer channels are thermodynamically and kinetically favourable.     

Cr(CO)3‐Activated Diels–Alder Reaction on Single‐Wall Carbon Nanotubes: A DFT Investigation

Breaking barriers : In agreement with experimental evidence, it was found by means of high‐level DFT calculations that the Cr(CO)₃ metal fragment considerably reduces the reaction energy barrier—for both the concerted and stepwise reaction mechanisms (see graphic)—of the Diels–Alder reaction of butadiene on (5,5) carbon nanotubes.

     

Density Functional Study of Proline‐Catalyzed Intramolecular Baylis–Hillman Reactions

A rationalization of stereoselectivity : The mechanisms of proline‐catalyzed and imidazole‐co‐catalyzed intramolecular Baylis–Hillman reactions have been studied by using density functional theory methods. The computational data has allowed us to rationalize the experimental outcome, validating some of the mechanistic steps proposed in the literature, as well as to propose new ones that considerably change and improve our understanding of the full reaction path (see scheme).

     

Theoretical Studies on the Asymmetric Baeyer–Villiger Oxidation Reaction of 4‐Phenylcyclohexanone with m‐Chloroperoxobenzoic Acid Catalyzed by Chiral Scandium(III)–N,N′‐Dioxide Complexes

The mechanism and enantioselectivity of the asymmetric Baeyer–Villiger oxidation reaction between 4‐phenylcyclohexanone and m‐chloroperoxobenzoic acid ( m ‐CPBA ) catalyzed by Sc^III–N,N′‐dioxide complexes were investigated theoretically. The calculations indicated that the first step, corresponding to the addition of m ‐CPBA to the carbonyl group of 4‐phenylcyclohexanone, is the rate‐determining step (RDS) for all the pathways studied. The activation barrier of the RDS for the uncatalyzed reaction was predicted to be 189.8 kJ mol^?1. The combination of an Sc^III–N,N′‐dioxide complex and the m ‐CBA molecule can construct a bifunctional catalyst in which the Lewis acidic Sc^III center activates the carbonyl group of 4‐phenylcyclohexanone while m ‐CBA transfers a proton, which lowers the activation barrier of the addition step (RDS) to 86.7 kJ mol^?1. The repulsion between the m‐chlorophenyl group of m ‐CPBA and the 2,4,6‐iPr₃C₆H₂ group of the N,N′‐dioxide ligand, as well as the steric hindrance between the phenyl group of 4‐phenylcyclohexanone and the amino acid skeleton of the N,N′‐dioxide ligand, play important roles in the control of the enantioselectivity.     

Trifluoromethylthiolation of Aryl Iodides and Bromides Enabled by a Bench‐Stable and Easy‐To‐Recover Dinuclear Palladium(I) Catalyst

While palladium catalysis is ubiquitous in modern chemical research, the recovery of the active transition‐metal complex under routine laboratory applications is frequently challenging. Described herein is the concept of alternative cross‐coupling cycles with a more robust (air‐, moisture‐, and thermally‐stable) dinuclear Pd^I complex, thus avoiding the handling of sensitive Pd⁰ species or ligands. Highly efficient C? SCF₃ coupling of a range of aryl iodides and bromides was achieved, and the recovery of the Pd^I complex was accomplished via simple open‐atmosphere column chromatography. Kinetic and computational data support the feasibility of dinuclear Pd^I catalysis. A novel SCF₃‐bridged Pd^I dimer was isolated, characterized by X‐ray crystallography, and verified to be a competent catalytic intermediate.     

Gold(I)‐Catalyzed Dearomative [2+2]‐Cycloaddition of Indoles with Activated Allenes: A Combined Experimental–Computational Study

The gold‐catalyzed synthesis of methylidene 2,3‐cyclobutane‐indoles is documented through a combined experimental/computational investigation. Besides optimizing the racemic synthesis of the tricyclic indole compounds, the enantioselective variant is presented to its full extent. In particular, the scope of the reaction encompasses both aryloxyallenes and allenamides as electrophilic partners providing high yields and excellent stereochemical controls in the desired cycloadducts. The computational (DFT) investigation has fully elucidated the reaction mechanism providing clear evidence for a two‐step reaction. Two parallel reaction pathways explain the regioisomeric products obtained under kinetic and thermodynamic conditions. In both cases, the dearomative C?C bond‐forming event turned out to be the rate‐determining step.