Synthesis of Secondary and Tertiary Alkyl Boronic Esters by gem‐Carboborylation: Carbonyl Compounds as Bis(electrophile) Equivalents

An unprecedent gem‐carboborylation of aldehydes and ketones provides access to various secondary and tertiary alkyl boronic esters. The addition of B₂pin₂ to a carbonyl compound generates α‐oxyl‐substituted alkyl boron species. Organolithium and Grignard reagents are then applied as C nucleophiles for the 1,2‐metalate rearrangement process. The organolithium reagents can also be generated by C?H lithiation or halogen/lithium exchange. The use of chiral ligands led to the generation of chiral alkyl boronic esters in enantioenriched form, demonstrating that the enantioselectivity of this transformation is catalyst‐controlled.     

Decarboxylative Conjunctive Cross‐coupling of Vinyl Boronic Esters using Metallaphotoredox Catalysis

The synthesis of complex alkyl boronic esters through conjunctive cross‐coupling of vinyl boronic esters with carboxylic acids and aryl iodides is described. The reaction proceeds under mild metallaphotoredox conditions and involves an unprecedented decarboxylative radical addition/cross‐coupling cascade of vinyl boronic esters. Excellent functional‐group tolerance is displayed, and application of a range of carboxylic acids, including secondary α‐amino acids, and aryl iodides provides efficient access to highly functionalized alkyl boronic esters. The decarboxylative conjunctive cross‐coupling was also applied to the synthesis of sedum alkaloids.     

Synthesis of Aryldifluoroamides by Copper‐Catalyzed Cross‐Coupling

A copper‐catalyzed coupling of aryl, heteroaryl, and vinyl iodides with α‐silyldifluoroamides is reported. The reaction forms α,α‐difluoro‐α‐aryl amides from electron‐rich, electron‐poor, and sterically hindered aryl iodides in high yield and tolerates a variety of functional groups. The aryldifluoroamide products can be transformed further to provide access to a diverse array of difluoroalkylarenes, including compounds of potential biological interest.     

Photoinduced Copper‐Catalyzed Coupling of Terminal Alkynes and Alkyl Iodides

We have developed a photoinduced copper‐catalyzed alkylation of terminal alkynes with primary, secondary, or tertiary alkyl iodides as electrophiles. The reaction has a broad substrate scope and can be successfully performed in the presence of ester, nitrile, aryl halide, ketone, sulfonamide, epoxide, alcohol, and amide functional groups. The alkylation is promoted by blue light (λ≈450 nm) and proceeds at room temperature in the absence of any additional metal catalysts. The use of a terpyridine ligand is essential for the success of the reaction and is shown to prevent photoinduced copper‐catalyzed polymerization of the starting materials.     

Asymmetric Synthesis of Secondary and Tertiary Boronic Esters

Non‐racemic chiral boronic esters are recognised as immensely valuable building blocks in modern organic synthesis. Their stereospecific transformation into a variety of functional groups—from amines and halides to arenes and alkynes—along with their air and moisture stability, has established them as an important target for asymmetric synthesis. Efforts towards the stereoselective synthesis of secondary and tertiary alkyl boronic esters have spanned over five decades and are underpinned by a wealth of reactivity platforms, drawing on the unique and varied reactivity of boron. This Review summarizes strategies for the asymmetric synthesis of alkyl boronic esters, from the seminal hydroboration methods of H. C. Brown to the current state of the art.     

Rational Design of an Iron‐Based Catalyst for Suzuki–Miyaura Cross‐Couplings Involving Heteroaromatic Boronic Esters and Tertiary Alkyl Electrophiles

Suzuki–Miyaura cross‐coupling reactions between a variety of alkyl halides and unactivated aryl boronic esters using a rationally designed iron‐based catalyst supported by β‐diketiminate ligands are described. High catalyst activity resulted in a broad substrate scope that included tertiary alkyl halides and heteroaromatic boronic esters. Mechanistic experiments revealed that the iron‐based catalyst benefited from the propensity for β‐diketiminate ligands to support low‐coordinate and highly reducing iron amide intermediates, which are very efficient for effecting the transmetalation step required for the Suzuki–Miyaura cross‐coupling reaction.     

Nickel‐Catalyzed Cross‐Coupling of Redox‐Active Esters with Boronic Acids

A transformation analogous in simplicity and functional group tolerance to the venerable Suzuki cross‐coupling between alkyl‐carboxylic acids and boronic acids is described. This Ni‐catalyzed reaction relies upon the activation of alkyl carboxylic acids as their redox‐active ester derivatives, specifically N‐hydroxy‐tetrachlorophthalimide (TCNHPI), and proceeds in a practical and scalable fashion. The inexpensive nature of the reaction components (NiCl₂?6 H₂O—$9.5 mol^?1, Et₃N) coupled to the virtually unlimited commercial catalog of available starting materials bodes well for its rapid adoption.     

Convenient Preparation of Cycloalkenyl Boronic Acid Pinacol Esters

A practical method for the preparation of cycloalkenyl boronic acid pinacol esters is described. These important synthetic intermediates are typically made using more expensive methods like transition metal-catalyzed borylation of alkenyl halides or triflates. In this work, they are obtained from the simple corresponding cycloalkanones, which are subjected to Shapiro reaction conditions followed by trapping with a borate ester. The requisite products are obtained in very good to excellent yields, and the reactions can be scaled up to multigram amounts. By providing a simple alternative to common methods that make use of expensive transition-metal catalysts and formation of sensitive intermediates, this convenient method will be useful for the synthesis of ring-containing partners for Suzuki–Miyaura cross-coupling and other reactions employing boronic esters as substrates.     

Divergent,Stereospecific Mono‐ and Difluoromethylation of Boronic Esters

There is considerable interest in incorporating fluorine into agrochemicals and pharmaceuticals to improve their biological properties. Whilst a number of methods have been reported for installing CH₂F and CHF₂ groups, they are mainly limited to radical reactions, which are invariably racemic. Herein, we report the divergent, stereospecific reaction of fluoroiodomethyllithium with boronic esters to give α‐fluoro‐boronic esters. These unique intermediates can be readily transformed into the corresponding mono‐ or difluoromethylated compounds through proto‐ or fluorodeboronation, respectively. The use of the highly unstable fluoroiodomethyllithium was key to allowing rapid 1,2‐migration over competing decomposition of the carbanion. DFT calculations informed and supported the experimental findings.     

Palladium‐Catalyzed Aminocarbonylation of N‐Chloroamines with Boronic Acids

Aryl (pseudo)halide‐based (C?X) carbonylation reactions have been extensively studied during the past few decades. From both academic and synthetic points of view, the carbonylative transformation of N?X bonds represents an interesting and attractive area of investigation. In light of this, the first carbonylative cross‐coupling between N‐chloroamines and organoboronic acids has been developed. This new type of aminocarbonylation proceeds at mild temperatures (45–55 °C) with 2 mol % Pd/C (10 wt %) as the ligand‐free catalyst. Not only arylboronic acids, but also alkenyl‐ and alkylboronic acids can be applied as the substrates and bromide and iodide substituents in the substrates are well tolerated. Initial mechanistic investigations have also been performed.     

Visible Light Activation of Boronic Esters Enables Efficient Photoredox C(sp2)–C(sp3) Cross‐Couplings in Flow

We report herein a new method for the photoredox activation of boronic esters. Using these reagents, an efficient and high‐throughput continuous flow process was developed to perform a dual iridium‐ and nickel‐catalyzed C(sp²)–C(sp³) coupling by circumventing solubility issues associated with potassium trifluoroborate salts. Formation of an adduct with a pyridine‐derived Lewis base was found to be essential for the photoredox activation of the boronic esters. Based on these results we were able to develop a further simplified visible light mediated C(sp²)–C(sp³) coupling method using boronic esters and cyano heteroarenes under flow conditions.     

Copper‐Catalyzed Perfluoroalkylthiolation of Alkynes with Perfluoroalkanesulfenamides

Copper‐catalyzed direct perfluoroalkylthiolation of alkynes by using the corresponding perfluoroalkanesulfenamide reagent is reported. The selective mono‐ and bis‐perfluoroalkylthiolation of alkynes can be conducted under very mild conditions (no base, room temperature) in very good to excellent yields. This approach, which uses a low toxicity, inexpensive copper catalyst that incorporates a commercially available ligand, is applied in the absence of any additional base. Preliminary mechanistic investigations shed some light on the nature of the unprecedented reactivity observed.     

Copper‐Catalyzed Carbonylative Coupling of Cycloalkanes and Amides

Carbonylation reactions are a most powerful method for the synthesis of carbonyl‐containing compounds. However, most known carbonylation procedures still require noble‐metal catalysts and the use of activated compounds and good nucleophiles as substrates. Herein, we developed a copper‐catalyzed carbonylative transformation of cycloalkanes and amides. Imides were prepared in good yields by carbonylation of a C(sp³)?H bond of the cycloalkane with the amides acting as weak nucleophiles. Notably, this is the first report of copper‐catalyzed carbonylative C?H activation.     

Enantioselective Copper‐Catalyzed Quinoline Alkynylation

A highly enantioselective copper‐catalyzed alkynylation of quinolinium salts is reported. The reaction employs StackPhos, a newly developed imidazole‐based chiral biaryl P,N ligand, and copper bromide to effect a three‐component reaction between a quinoline, a terminal alkyne, and ethyl chloroformate. Under the reaction conditions, the desired products are delivered in high yields with ee values of up to 98 %. The transformation tolerates a wide range of functional groups with respect to both the alkyne and the quinoline starting materials and the products are easily transformed into useful synthons. Efficient, enantioselective syntheses of the tetrahydroquinoline alkaloids (+)‐galipinine, (+)‐angustureine, and (?)‐cuspareine are reported.     

Copper‐Catalyzed Triboration: Straightforward,Atom‐Economical Synthesis of 1,1,1‐Triborylalkanes from Terminal Alkynes and HBpin

A convenient and efficient one‐step synthesis of 1,1,1‐triborylalkanes was achieved via sequential dehydrogenative borylation and double hydroborations of terminal alkynes with HBpin (HBpin=pinacolborane) catalyzed by inexpensive and readily available Cu(OAc)₂. This process proceeds under mild conditions, furnishing 1,1,1‐tris(boronates) with wide substrate scope, excellent selectivity, and good functional‐group tolerance, and is applicable to gram‐scale synthesis without loss of yield. The 1,1,1‐triborylalkanes can be used in the preparation of α‐vinylboronates and borylated cyclic compounds, which are valuable but previously rare compounds. Different alkyl groups can be introduced stepwise via base‐mediated deborylative alkylation to produce racemic tertiary alkyl boronates, which can be readily transformed into useful tertiary alcohols.     

Copper‐Catalyzed Reduction of Alkyl Triflates and Iodides: An Efficient Method for the Deoxygenation of Primary and Secondary Alcohols

We describe an effective method for catalytic reduction of 1° alkyl sulfonates, and 1° and 2° iodides in the presence of a wide range of functional groups. This Cu‐catalyzed reaction provides a means for the effective deoxygenation of alcohols, as demonstrated by the highly selective reduction of 1° alcohols using a triflation/reduction sequence. A preliminary study of the reaction mechanism suggests that the reduction does not involve free‐radical intermediates.