Regioselective Alkylative Carboxylation of Allenamides with Carbon Dioxide and Dialkylzinc Reagents Catalyzed by an N‐Heterocyclic Carbene–Copper Complex

The alkylative carboxylation of allenamide catalyzed by an N‐heterocyclic carbene (NHC)–copper(I) complex [(IPr)CuCl] with CO₂ and dialkylzinc reagents was investigated. The reaction of allenamides with dialkylzinc reagents (1.5 equiv) and CO₂ (1 atm.) proceeded smoothly in the presence of a catalytic quantity of [(IPr)CuCl] to afford (Z)‐α,β‐dehydro‐β‐amino acid esters in good yields. The reaction is regioselective, with the alkyl group introduced onto the less hindered γ‐carbon, and the carboxyl group introduced onto the β‐carbon atom of the allenamides. The first step of the reaction was alkylative zincation of the allenamides to give an alkenylzinc intermediate followed by nucleophilic addition to CO₂. A variety of cyclic and acyclic allenamides were found to be applicable to this transformation. Dialkylzinc reagents bearing β‐hydrogen atoms, such as Et₂Zn or Bu₂Zn, also gave the corresponding alkylative carboxylation products without β‐hydride elimination. The present methodology provides an easy route to alkyl‐substituted α,β‐dehydro‐β‐amino acid ester derivatives under mild reaction conditions with high regio‐ and stereoselectivtiy.     

Carboxylation Reactions with Carbon Dioxide Using N‐Heterocyclic Carbene‐Copper Catalysts

The development of versatile catalyst systems and new transformations for the utilization of carbon dioxide (CO₂) is of great interest and significance. This Personal Account reviews our studies on the exploration of the reactions of CO₂ with various substrates by the use of N‐heterocyclic carbene (NHC)‐copper catalysts. The carboxylation of organoboron compounds gave access to a wide range of carboxylic acids with excellent functional group tolerance. The C?H bond carboxylation with CO₂ emerged as a straightforward protocol for the preparation of a series of aromatic carboxylic esters and butenoates from simple substrates. The hydrosilylation of CO₂ with hydrosilanes provided an efficient method for the synthesis of silyl formate on gram scale. The hydrogenative or alkylative carboxylation of alkynes, ynamides and allenamides yielded useful α,β‐unsaturated carboxylic acids and α,β‐dehydro amino acid esters. The boracarboxylation of alkynes or aldehydes afforded the novel lithium cyclic boralactone or boracarbonate products, respectively. The NHC‐copper catalysts generally featured excellent functional group compatibility, broad substrate scope, high efficiency, and high regio‐ and stereoselectivity. The unique electronic and steric properties of the NHC‐copper units also enabled the isolation and structural characterization of some key intermediates for better understanding of the catalytic reaction mechanisms.     

Cu‐Catalyzed Alkylative Carboxylation of Ynamides with Dialkylzinc Reagents and Carbon Dioxide

Alkylative carboxylation of ynamides with CO₂ and dialkylzinc reagents using a N‐heterocyclic carbene (NHC)–copper catalyst has been developed. A variety of ynamides, both cyclic and acyclic, undergo this transformation under mild conditions to afford the corresponding α,β‐unsaturated carboxylic acids, which contain the α,β‐dehydroamino acid skeleton. The present alkylative carboxylation formally consists of Cu‐catalyzed carbozincation of ynamides with dialkylzinc reagents with the subsequent nucleophilic carboxylation of the resulting alkenylzinc species with CO₂. Dialkylzinc reagents bearing a β‐hydrogen atom such as Et₂Zn and Bu₂Zn still afford the alkylated products despite the potential for β‐hydride elimination. This protocol would be a desirable method for the synthesis of highly substituted α,β‐ dehydroamino acid derivatives due to its high regio‐ and stereoselectivity, simple one‐pot procedure, and its use of CO₂ as a starting material.     

Reductive carboxylation of alkyl halides with CO2 by use of photoinduced SmI2/Sm reduction system

Upon visible-light irradiation, reductive carboxylation of alkyl halides takes place by using a SmI₂/Sm mixed system under atmospheric CO₂ to afford the corresponding carboxylic acids in good to excellent yields.     

REACTION OF α-BENZENESULFONYLPHENYLACETIC ACID WITH ALKYL HALIDES. DECARBOXYLATIVE ALKYLATION VS. DECARBOXYLATIVE PROTONATION

The reaction of α-benzenesulfonylphenylacetic acid with some alkyl halides, using as base NaH in DMSO, leads to decarboxylative protonation to give benzylphenylsulfone. Decarboxylative alkylation occurs only when CO₂ is expelled by flushing with nitrogen. The mechanism of the decarboxylative protonation is investigated.     

Site-Selective,Remote sp3 C−H Carboxylation Enabled by the Merger of Photoredox and Nickel Catalysis

A photoinduced carboxylation of alkyl halides with CO₂ at remote sp³ C−H sites enabled by the merger of photoredox and Ni catalysis is described. This protocol features a predictable reactivity and site selectivity that can be modulated by the ligand backbone. Preliminary studies reinforce a rationale based on a dynamic displacement of the catalyst throughout the alkyl side chain.     

A mild and variable synthesis of α-ketoesters

The ZnCl₂ promoted addition of 1,2-diethoxy-1,2-disilyloxyethylene 1 with electrophiles such as aldehydes, ketones, α,β-unsaturated ketones or tertiary alkyl halides allows for a simple synthesis of α-ketoesters.     

Gold(I)-Catalyzed [8+2]-Cycloaddition of 8-Aryl-8-azaheptafulvenes with Allenamides and Ynamides: Regioselective Synthesis of Dihydrocycloheptapyrrole Derivatives

Gold(I)-catalyzed higher-order [8+2] cycloadditions of 8-aryl-8-azaheptafulvenes 1 with allenamides 2 and ynamides 3 were studied. 1,8-Dihydrocycloheptapyrroles 4 were achieved by a regioselective [8+2] cycloaddition of azaheptafulvenes 1 and allenamides 2 in the presence of (2,4-ditBuC₆H₃O)₃PAuNTf₂ as catalyst. Besides, ynamides 3 and 8-aryl-8-azaheptafulvenes 1 , undergo a regioselective [8+2] cycloaddition, to give 2-amido-1,4-dihydrocycloheptapyrroles 7 in the presence of JohnPhosAuNTf₂ as catalyst. Both reactions take place with good yields and with a variety of substituents. A plausible mechanism hypothesis suggests a nucleophilic attack of the 8-azaheptafulvene to the gold activated electron rich allene or alkyne moieties of the allenamide and ynamide, respectively.     

Experimental and Computational Insights into Carbon Dioxide Fixation by RZnOH Species

Organozinc hydroxides, RZnOH, possessing the proton‐reactive alkylzinc group and the CO₂‐reactive Zn?OH group, represent an intriguing group of organometallic precursors for the synthesis of novel zinc carbonates. Comprehensive experimental and computational investigations on 1) solution and solid‐state behavior of tBuZnOH ( 1 ) species in the presence of Lewis bases, namely, THF and 4‐methylpyridine; 2) step‐by‐step sequence of the reaction between 1 and CO₂; and 3) the effect of a donor ligand and/or an excess of tBu₂Zn as an external proton acceptor on the reaction course are reported. DFT calculations for the insertion of carbon dioxide into the dinuclear alkylzinc hydroxide 1 ₂ are fully consistent with ¹H NMR spectroscopy studies and indicate that this process is a multistep reaction, in which the insertion of CO₂ seems to be the rate‐determining step. Moreover, DFT studies show that the mechanism of the rearrangement between key intermediates, that is, the primary alkylzinc bicarbonate with a proximal position of hydrogen and the secondary alkylzinc bicarbonate with a distal position of hydrogen, most likely proceeds through internal rotation of the dinuclear bicarbonate.     

Insertion of CO2 Mediated by a (Xantphos)NiI–Alkyl Species

The incorporation of CO₂ into organometallic and organic molecules represents a sustainable way to prepare carboxylates. The mechanism of reductive carboxylation of alkyl halides has been proposed to proceed through the reduction of Ni^II to Ni^I by either Zn or Mn, followed by CO₂ insertion into Ni^I‐alkyl species. No experimental evidence has been previously established to support the two proposed steps. Demonstrated herein is that the direct reduction of (tBu‐Xantphos)Ni^IIBr₂ by Zn affords Ni^I species. (tBu‐Xantphos)Ni^I‐Me and (tBu‐Xantphos)Ni^I‐Et complexes undergo fast insertion of CO₂ at 22 °C. The substantially faster rate, relative to that of Ni^II complexes, serves as the long‐sought‐after experimental support for the proposed mechanisms of Ni‐catalyzed carboxylation reactions.     

Nickel‐Catalyzed Alkyl–Alkyl Cross‐Couplings of Fluorinated Secondary Electrophiles: A General Approach to the Synthesis of Compounds having a Perfluoroalkyl Substituent

Fluorinated organic molecules are of interest in fields ranging from medicinal chemistry to polymer science. Described herein is a mild, convenient, and versatile method for the synthesis of compounds bearing a perfluoroalkyl group attached to a tertiary carbon atom by using an alkyl–alkyl cross‐coupling. A nickel catalyst derived from NiCl₂?glyme and a pybox ligand achieves the coupling of a wide range of fluorinated alkyl halides with alkylzinc reagents at room temperature. A broad array of functional groups is compatible with the reaction conditions, and highly selective couplings can be achieved on the basis of differing levels of fluorination. A mechanistic investigation has established that the presence of 2,2,6,6‐tetramethyl‐1‐piperidinyloxy (TEMPO) inhibits cross‐coupling under these conditions and that a TEMPO–electrophile adduct can be isolated.     

Diversity in Gold‐Catalyzed Formal Cycloadditions of Ynamides with Azidoalkenes or 2H‐Azirines: [3+2] versus [4+3] Cycloadditions

Gold‐catalyzed cycloadditions of ynamides with azidoalkenes or 2H‐azirines give [3+2] or [4+3] formal cycloadducts of three classes. Cycloadditions of ynamides with 2H‐azirine species afford pyrrole products with two regioselectivities when the C_β‐substituted 2H‐azirine is replaced from an alkyl (or hydrogen) with an ester group. For ynamides substituted with an electron‐rich phenyl group, their reactions with azidoalkenes proceed through novel [4+3] cycloadditions to deliver 1H‐benzo[d]azepine products instead.     

Transition metal promoted carboxylation of unsaturated substrates with carbon dioxide

The use of CO₂ as a C1 building block for the synthesis of useful chemicals is of great significance, and has attracted increasing attention in recent years. The transition metal catalyzed or mediated addition of CO₂ to unsaturated chemical bonds has proved to be a powerful and versatile protocol for the incorporation of CO₂ into various unsaturated organic substrates such as alkynes, alkenes, allenes, aldehydes, and 1,3-dienes. The hydrogenative, alkylative and arylative carboxylation, heterocarboxylation, and carboxylative cyclization with CO₂ have led to efficient and selective formation of various functionalized carboxylic acids and derivatives. This review focuses on recent advances in this area with emphasis on conceptual reaction design.     

Mechanism of the Ir/Pd catalyzed photocarboxylation of aryl halides

The recent Ir/Pd co-catalyzed photo carboxylation of aromatic halides with CO_2 has shown high efficiency and excellent functional group tolerance for preparing aromatic carboxylic acids and esters.With the aid of density functional theory(DFT) calculations,the carboxylation starts with two parallel steps,i.e.,oxidative addition of aromatic halides on Pd~0 and reductive quenching of the photocatalyst Ir(ppy)_2(dtbpy)~+with amine.Thereafter,a successive oxidation of Pd~Ⅱ with the amine radical(generated by the reaction of cationic radical amine and Cs_2 CO_3) and Ir~Ⅱ species occurs to generate Pd~0,from which the carboxylation occurs easily via a coordination,Pd-C insertion step.The release of the carboxylate product then regenerates the catalyst.     

Nickel-mediated carboxylative cyclization of enynes

Nickel-mediated carboxylative cyclization of α,ω-enyne using carbon dioxide was investigated. Oxidative cycloaddition of enynes having an electron withdrawing group on alkene to a zero-valent nickel complex smoothly proceeded to provide nickelacyclopentene intermediates, which regioselectively reacted with CO₂ at the Csp³-nickel bond, giving cyclized carboxylation products in good yields.     

Regio- and diastereoselective functionalization of (−)-cytisine

(−)-N-Benzyl cytisine has been stereoselectively substituted in moderate to high yields on its carbon 6 (Csp³ α to the pyridone nitrogen). The reaction involved the in situ trapping of the carbanion formed by reaction of lithium diisopropyl amide (LDA) and its reaction with electrophiles (alkyl, allyl, benzyl halides, non-enolizable aldehydes, and Weinreb amide). In the absence of an electrophile or with its addition after the formation of the carbanion, a dimeric structure was isolated (yield: 42%) resulting from the 1,4-addition of the carbanion on the pyridone ring of another cytisine molecule. Deprotection of the benzyl group (Olofson's reagent) allowed the formation of 6-substituted derivatives of the natural product, cytisine, a potent agonist of nicotinic receptors of subtype α₄β₂.     

Development in the green synthesis of cyclic carbonate from carbon dioxide using ionic liquids

This brief review presents the recent development in the synthesis of cyclic carbonate from carbon dioxide (CO₂) using ionic liquids as catalyst and/or reaction medium. The synthesis of cyclic carbonate includes three aspects: catalytic reaction of CO₂ and epoxide, electrochemical reaction of CO₂ and epoxide, and oxidative carboxylation of olefin. Some ionic liquids are suitable catalysts and/or solvents to the CO₂ fixation to produce cyclic carbonate. The activity of ionic liquid is greatly enhanced by the addition of Lewis acidic compounds of metal halides or metal complexes that have no or low activity by themselves. Using ionic liquids for the electrochemical synthesis of the cyclic carbonate can avoid harmful organic solvents, supporting electrolytes and catalysts, which are necessary for conventional electrochemical reaction systems. Although the ionic liquid is better for the oxidative carboxylation of olefin than the ordinary catalysts reported previously, this reaction system is at a preliminary stage. Using the ionic liquids, the synthesis process will become greener and simpler because of easy product separation and catalyst recycling and unnecessary use of volatile and harmful organic solvents.     

An efficient synthetic method for Z-fluoroalkene dipeptide isosteres: Application to the synthesis of the dipeptide isostere of Sta-Ala

Reaction of γ,γ-difluoro-α,β-enoates having a δ-hydroxyl group with trialkylaluminum (R₃Al) was found to be promoted by CuI·2LiCl and to proceed in SN2′ manner giving rise to the α-alkylated (Z)-γ-fluoro-β,γ-enoates, while reductive defluorination of γ,γ-difluoro-α,β-enoates with Me₂CuLi followed by reaction with alkyl halides provided the corresponding (Z)-α-alkylated products in high yields. The latter reaction was applied to the preparation of the dipeptide (Z)-fluoroalkene isostere of Sta-Ala, which is the central dipeptide unit in Pepstatin, a natural inhibitor of aspartate proteases.     

Electroreductive Cobalt‐Catalyzed Carboxylation: Cross‐Electrophile Electrocoupling with Atmospheric CO2

The chemical use of CO₂ as an inexpensive, nontoxic C1 synthon is of utmost topical interest in the context of carbon capture and utilization (CCU). We present the merger of cobalt catalysis and electrochemical synthesis for mild catalytic carboxylations of allylic chlorides with CO₂. Styrylacetic acid derivatives were obtained with moderate to good yields and good functional group tolerance. The thus‐obtained products are useful as versatile synthons of γ‐arylbutyrolactones. Cyclic voltammetry and in operando kinetic analysis were performed to provide mechanistic insights into the electrocatalytic carboxylation with CO₂.     

A green and highly efficient alkylation of thiols in water

An environmentally benign and efficient process for the preparation of thioethers was developed by simple and practical reactions of alkyl halides and thiols in water in the presence of K₂CO₃ or Et₃N in very high yields. The reaction of aryl, alkyl, aliphatic and hindered thiols with various alkyl halides gave the corresponding products with significant advantages such as high conversions, short reaction time, mild reaction conditions, and low cost, simple workup with good to quantitative yields.