Organic Reactions in Ionic Liquids: A New Method for the Synthesis of Alkyl Aryl Sulfones by Alkylation of Sodium Arenesulfinates with Unactivated Alkyl Chlorides

Abstract

A new method is reported for the synthesis of alkyl aryl sulfones by alkylation of sodium arenesulfinates with unactivated alkyl chlorides using ionic liquid based on 1‐butyl‐3‐methylimidazolium tetrafluoroborate (BmimBF₄) mixed with water (2:1) as reaction media. The ionic liquid can be reused and the procedure gives the sulfones in moderate yields.     

Generation and Reactivity of Amidyl Radicals: Manganese‐Mediated Atom‐Transfer Reaction

A simple and efficient protocol to generate amidyl radicals from amine functionalities through a manganese‐mediated atom‐transfer reaction has been developed. This approach employs an earth‐abundant and inexpensive manganese complex, Mn₂(CO)₁₀, as the catalyst and visible light as the energy input. Using this strategy, site‐selective chlorination of unactivated C(sp³)?H bonds of aliphatic amines and intramolecular/intermolecular chloroaminations of unactivated alkenes were readily realized under mild reaction conditions, thus providing efficient access to a range of synthetically valuable alkyl chlorides, chlorinated pyrrolidines, and vicinal chloroamine derivatives. These practical reactions exhibit a broad substrate scope and tolerate a wide array of functional groups, and complex molecules including various marketed drug derivatives.     

Computational Insight into Nickel‐Catalyzed Carbon–Carbon versus Carbon–Boron Coupling Reactions of Primary,Secondary, and Tertiary Alkyl Bromides

The nickel‐catalyzed alkyl–alkyl cross‐coupling (C?C bond formation) and borylation (C?B bond formation) of unactivated alkyl halides reported in the literature show completely opposite reactivity orders in the reactions of primary, secondary, and tertiary alkyl bromides. The proposed Ni^I/Ni^III catalytic cycles for these two types of bond‐formation reactions were studied computationally by means of DFT calculations at the B3LYP level. These calculations indicate that the rate‐determining step for alkyl–alkyl cross‐coupling is the reductive elimination step, whereas for borylation the rate is determined mainly by the atom‐transfer step. In borylation reactions, the boryl ligand involved has an empty p orbital, which strongly facilitates the reductive elimination step. The inability of unactivated tertiary alkyl halides to undergo alkyl–alkyl cross‐coupling is mainly due to the moderately high reductive elimination barrier.     

Copper‐Catalyzed Carbotrifluoromethylation of Unactivated Alkenes Driven by Trifluoromethylation of Alkyl Radicals

We report herein an unprecedented protocol for radical carbotrifluoromethylation of unactivated alkenes. With Cu(OTf)₂ as the catalyst, the reaction of unactivated alkenes, TMSCF₃ and activated alkyl chlorides at room temperature provides the corresponding carbotrifluoromethylation products in satisfactory yields. Directed by trifluoromethylation of alkyl radicals, the method exhibits an excellent regioselectivity that is opposite to those driven by CF₃ radical addition.     

Nickel-catalyzed,ring-forming aromatic C–H alkylations with unactivated alkyl halides

The development of a nickel-catalyzed C–H alkylation of aromatic substrates with unactivated alkyl halides is described. This carbocyclization facilitates the synthesis of diverse fused ring systems from simple aromatic substrates and is an attractive alternative to traditional polar or radical-mediated ring formations. The present system uses unactivated primary and secondary alkyl bromides and chlorides, while avoiding the use of precious palladium catalysts and more reactive alkyl halides commonly used in related C–H alkylations.     

Efficient Synthesis of Unsymmetrical Heteroaryl Ethers by a Transition Metal‐Free C?O Cross‐Coupling Reaction of Activated and Unactivated Heteroaryl Chlorides with Alcohols and Phenols

By optimizing the reaction conditions via a careful screening of the bases and solvents, we developed an efficient transition metal‐free method for C? O cross‐coupling of activated and unactivated heteroaryl chlorides with primary and secondary alcohols and phenols, providing a simple, efficient, and practical method for synthesis of the useful unsymmetrical heteroaryl alkyl and heteroaryl aryl ethers.     

Ketone formation via mild nickel-catalyzed reductive coupling of alkyl halides with aryl acid chlorides

The present work highlights unprecedented Ni-catalyzed reductive coupling of unactivated alkyl iodides with aryl acid chlorides to efficiently generate alkyl aryl ketones under mild conditions.     

Photocatalytic Synthesis of β-Keto Primary Chlorides by Selective Chlorocarbonylation of Olefins

Functionalized primary alkyl chlorides are precursors to a plethora of scaffolds but their access from chemical feedstocks remains challenging. Herein, we report a concise dual Ni/photoredox catalytic protocol for regioselective chlorocarbonylation of unactivated alkenes that enables rapid access to β-keto primary chlorides. The catalytic process features an extensive substrate scope, scalability and functional group tolerance. The Ni/photocatalytic Cl⋅ generation and subsequent cross-coupling is implicated for the process based on the control experiments and DFT study. The synthetic utility of the protocol has been further corroborated through functionalization of complex substrates and modifications of the product.     

Theoretical Study on the Mechanism of Ni‐Catalyzed Alkyl–Alkyl Suzuki Cross‐Coupling

Ni‐catalyzed cross‐coupling of unactivated secondary alkyl halides with alkylboranes provides an efficient way to construct alkyl–alkyl bonds. The mechanism of this reaction with the Ni/ L1 ( L1 =trans‐N,N′‐dimethyl‐1,2‐cyclohexanediamine) system was examined for the first time by using theoretical calculations. The feasible mechanism was found to involve a Ni^I–Ni^III catalytic cycle with three main steps: transmetalation of [Ni^I( L1 )X] (X=Cl, Br) with 9‐borabicyclo[3.3.1]nonane (9‐BBN)R₁ to produce [Ni^I( L1 )(R₁)], oxidative addition of R₂X with [Ni^I( L1 )(R₁)] to produce [Ni^III( L1 )(R₁)(R₂)X] through a radical pathway, and C? C reductive elimination to generate the product and [Ni^I( L1 )X]. The transmetalation step is rate‐determining for both primary and secondary alkyl bromides. KOiBu decreases the activation barrier of the transmetalation step by forming a potassium alkyl boronate salt with alkyl borane. Tertiary alkyl halides are not reactive because the activation barrier of reductive elimination is too high (+34.7 kcal mol^?1). On the other hand, the cross‐coupling of alkyl chlorides can be catalyzed by Ni/ L2 ( L2 =trans‐N,N′‐dimethyl‐1,2‐diphenylethane‐1,2‐diamine) because the activation barrier of transmetalation with L2 is lower than that with L1 . Importantly, the Ni⁰–Ni^II catalytic cycle is not favored in the present systems because reductive elimination from both singlet and triplet [Ni^II( L1 )(R₁)(R₂)] is very difficult.     

Oxidative Alkane C−H Alkoxycarbonylation

Directly utilizing a chemical feedstock to construct valuable compounds is an attractive prospect in organic synthesis. In particular, the combination of C(sp³)?H activation and oxidative carbonylation involving alkanes and CO gas is a promising and efficient method to synthesize carbonyl derivatives. However, due to the high C?H bond dissociation energy and low polarity of unactivated alkanes, the carbonylation of unactivated C(sp³)?H bonds still remains a great challenge. In this work, we introduce a palladium‐catalyzed radical oxidative alkoxycarbonylation of alkanes to prepare numerous alkyl carboxylates. Various alkanes and alcohols were compatible, generating the desired products in up to 94 % yield. Remarkably, ethane, a constituent of natural gas, could be employed as a substrate under the standard reaction conditions. Preliminary mechanistic studies revealed a probable palladium‐catalyzed radical process.     

Oxidative Addition to Palladium(0) Made Easy through Photoexcited‐State Metal Catalysis: Experiment and Computation

Visible‐light induced, palladium catalyzed alkylations of α,β‐unsaturated acids with unactivated alkyl bromides are described. A variety of primary, secondary, and tertiary alkyl bromides are activated by the photoexcited palladium metal catalyst to provide a series of olefins at room temperature under mild reaction conditions. Mechanistic investigations and density functional theory (DFT) studies suggest that a photoinduced inner‐sphere mechanism is operative in which a barrierless, single‐electron transfer oxidative addition of the alkyl halide to Pd⁰ is key for the efficient transformation.     

Cobalt‐Catalyzed Aminocarbonylation of Alkyl Tosylates: Stereospecific Synthesis of Amides

Metal‐catalyzed aminocarbonylation is a standard approach for installing amide functionality in chemical synthesis. Despite broad application of this transformation using aryl or vinyl electrophiles, there are few examples involving unactivated aliphatic substrates. Furthermore, there are no stereocontrolled aminocarbonylations of alkyl electrophiles known. Herein, we report a stereospecific aminocarbonylation of unactivated alkyl tosylates for the synthesis of enantioenriched amides. This cobalt‐catalyzed transformation uses a remarkably broad range of amines and proceeds with excellent stereospecificity and chemoselectivity.     

Generation and Reactivity of Amidyl Radicals: Manganese-Mediated Atom-Transfer Reaction

A simple and efficient protocol to generate amidyl radicals from amine functionalities through a manganese-mediated atom-transfer reaction has been developed. This approach employs an earth-abundant and inexpensive manganese complex, Mn₂(CO)₁₀, as the catalyst and visible light as the energy input. Using this strategy, site-selective chlorination of unactivated C(sp³)−H bonds of aliphatic amines and intramolecular/intermolecular chloroaminations of unactivated alkenes were readily realized under mild reaction conditions, thus providing efficient access to a range of synthetically valuable alkyl chlorides, chlorinated pyrrolidines, and vicinal chloroamine derivatives. These practical reactions exhibit a broad substrate scope and tolerate a wide array of functional groups, and complex molecules including various marketed drug derivatives.     

Copper‐Catalyzed Alkylarylation of Unactivated Alkenes: Synthesis of 3‐Alkyl Indolines from N‐Allyl Anilines and Alkanes

A rare example of C(sp³)?H functionalization of simple alkanes with unactivated alkenes is presented. In the presence of a copper salt and di‐tert‐butyl peroxide (DTBP), N‐allyl anilines underwent exo‐selective alkylation/cyclization cascade with unactivated alkenic bonds as radical acceptors and simple alkanes as radical precursors, providing a direct access to 3‐alkyl indolines. The present protocol features simple operation, broad substrate scope and great exo selectivity.     

Copper‐Catalyzed Decarboxylative Radical Silylation of Redox‐Active Aliphatic Carboxylic Acid Derivatives

A decarboxylative silylation of aliphatic N ‐hydroxyphthalimide (NHPI) esters using Si−B reagents as silicon pronucleophiles is reported. This C(sp³)−Si cross‐coupling is catalyzed by copper(I) and follows a radical mechanism, even with exclusion of light. Both primary and secondary alkyl groups couple effectively, whereas tertiary alkyl groups are probably too sterically hindered. The functional‐group tolerance is generally excellent, and α‐heteroatom‐substituted substrates also participate well. This enables, for example, the synthesis of α‐silylated amines starting from NHPI esters derived from α‐amino acids. The new method extends the still limited number of C(sp³)−Si cross‐couplings of unactivated alkyl electrophiles.     

Zinc‐Catalyzed Borylation of Primary,Secondary and Tertiary Alkyl Halides with Alkoxy Diboron Reagents at Room Temperature

A new catalytic system based on a Zn^II NHC precursor has been developed for the cross‐coupling reaction of alkyl halides with diboron reagents, which represents a novel use of a Group XII catalyst for C? X borylation. This approach gives borylations of unactivated primary, secondary, and tertiary alkyl halides at room temperature to furnish alkyl boronates, with good functional‐group compatibility, under mild conditions. Preliminary mechanistic investigations demonstrated that this borylation reaction seems to involve one‐electron processes.     

Nickel‐Catalyzed Reductive Allylation of Tertiary Alkyl Halides with Allylic Carbonates

The construction of all C(sp³) quaternary centers has been successfully achieved under Ni‐catalyzed cross‐electrophile coupling of allylic carbonates with unactivated tertiary alkyl halides. For allylic carbonates bearing C1 or C3 substituents, the reaction affords excellent regioselectivity through the addition of alkyl groups to the unsubstituted allylic carbon terminus. The allylic alkylation method also exhibits excellent functional‐group compatibility, and delivers the products with high E selectivity.     

Nickel‐Catalyzed C?H Alkylations: Direct Secondary Alkylations and Trifluoroethylations of Arenes

A versatile nickel catalyst allowed for C H alkylations of unactivated arenes with challenging secondary alkyl bromides and chlorides. The high catalytic efficacy also set the stage for direct secondary alkylations of indoles as well as C H trifluoroethylations with ample substrate scope.     

High yielding alkylations of unactivated sp3 and sp2 centres with alkyl-9-BBN reagents using an NHC-based catalyst: Pd-PEPPSI-IPrf

High yielding, room temperature cross couplings of unactivated alkyl bromides and aryl bromides/chlorides with alkyl-9-BBN reagents has been achieved using an NHC-based catalyst (Pd-PEPPSI-IPr) via a general, functional-group tolerant and easily implemented protocol.     

Rh(Ⅰ)-catalyzed borylation of primary alkyl chlorides

Rhodium-catalyzed cross-coupling reactions of unactivated primary alkyl chlorides with diboron reagents have been developed as practical methods for the synthesis of alkylboronic esters. These reactions expand the concept and utility of Rh(I)-catalyzed cross-coupling of aliphatic electrophiles.