Transition‐Metal‐Free Reductive Hydroxymethylation of Isoquinolines

A transition‐metal‐free reductive hydroxymethylation reaction has been developed, enabling the preparation of tetrahydroisoquinolines bearing C4‐quaternary centers from the corresponding isoquinolines. Deuterium labelling studies and control experiments enable a potential mechanism to be elucidated which features a key Cannizzaro‐type reduction followed by an Evans–Tishchenko reaction. When isoquinolines featuring a proton at the 4‐position are used, a tandem methylation‐hydroxymethylation occurs, leading to the formation of 2 new C?C bonds in one pot.     

Lactamization of sp2 C−H Bonds with CO2: Transition‐Metal‐Free and Redox‐Neutral

The first direct use of carbon dioxide in the lactamization of alkenyl and heteroaryl C?H bonds to synthesize important 2‐quinolinones and polyheterocycles in moderate to excellent yields is reported. Carbon dioxide, a nontoxic, inexpensive, and readily available greenhouse gas, acts as an ideal carbonyl source. Importantly, this transition‐metal‐free and redox‐neutral process is eco‐friendly and desirable for the pharmaceutical industry. Moreover, these reactions feature a broad substrate scope, good functional group tolerance, facile scalability, and easy product derivatization.     

Transition‐Metal‐Free Trifluoromethylthiolation of N‐Heteroarenes

A general and efficient methodology for the direct transition metal free trifluoromethylthiolation of a broad range of biologically relevant N‐heteroarenes is reported employing abundant sodium chloride as the catalyst. This method is operationally simple, exhibits high functional group tolerance, and does not require protecting groups.     

A Transition‐Metal‐Free Synthesis of Multisubstituted Imidazoles

A novel and simple t‐BuOLi/I₂‐mediated synthesis of 1,2,4‐trisubstituted imidazoles was developed without transition‐metal added. The transition‐metal‐free strategy tolerated a range of substrates and provided products in moderate to good yields with 100% regioselectivity.     

A Transition‐Metal‐Free Synthesis of Fluorinated Naphthols

Herein, we describe a transition‐metal‐free protocol for the conversion of simple 2‐allyl‐3‐(trifluoromethyl)phenols into substituted 5‐fluoronaphthalen‐1‐ols. The key events of this reaction include the selective activation of two C?F bonds and formation of an intermediate hexatriene system, which undergoes a 6π electrocyclization, followed by rearomatization. This concept enables the rapid conversion (three steps) of various commercially available 3‐(trifluoromethyl)phenols into novel fluorine‐containing naphthols, which are difficult to prepare by previous methods. The reported sequence was also extended to a one‐pot transformation of 3‐(trifluoromethyl)phenols into 5‐fluoronaphthalen‐1‐ols.     

Transition‐Metal‐Free Defluorosilylation of Fluoroalkenes with Silylboronates

Silylated fluoroalkenes are important synthetic intermediates with complementary reactivity, which play a key role in the construction of natural products, pharmaceuticals, and manmade materials. Converting the normally highly stable fluoroalkenes into silylated fluoroalkenes by selective defluorosilylation is a challenging task. Herein, we report a simple, inexpensive and robust defluorosilylation of a variety of fluoroalkenes with silylboronates in the presence of alkoxy base to directly synthesize various silylated fluoroalkenes. The protocol features mild and safe reaction conditions that avoid a catalyst, a transition metal, a ligand, and high reaction temperature and tolerates a wide scope of fluoroalkene substrates without compromising the efficiency. Density functional theory calculations show that transient silyl anion complex undergoes an S_N2’ or S_N^V substitution, which is responsible for this base‐mediated defluorosilylation.     

Transition‐Metal‐Free Catalytic Reduction of Carbon Dioxide

Metal‐free systems, including frustrated Lewis pairs (FLPs) have been shown to bind CO₂. By reducing the Lewis acidity and basicity of the ambiphilic system, it is possible to generate active catalysts for the deoxygenative hydroboration of carbon dioxide to methanol derivatives with conversion rates comparable to those of transition‐metal‐based catalysts.     

Transition‐Metal‐Free Borylation of Allylic and Propargylic Alcohols

The base‐catalyzed allylic borylation of tertiary allylic alcohols allows the synthesis of 1,1‐disubstituted allyl boronates, in moderate to high yield. The unexpected tandem performance of the Lewis acid–base adduct, [Hbase]⁺[MeO‐B₂pin₂]^? favored the formation of 1,2,3‐triborylated species from the tertiary allylic alcohols and 1‐propargylic cyclohexanol at 90 °C.     

Transition‐Metal‐Free Carbon Isotope Exchange of Phenyl Acetic Acids

A transition‐metal‐free carbon isotope exchange procedure on phenyl acetic acids is described. Utilizing the universal precursor CO₂, this protocol allows the carbon isotope to be inserted into the carboxylic acid position, with no need of precursor synthesis. This procedure enabled the labeling of 15 pharmaceuticals and was compatible with carbon isotopes [¹⁴C] and [¹³C]. A proof of concept with [¹¹C] was also obtained with low molar activity valuable for distribution studies.     

Transition‐Metal‐Free Reaction of Aryltrimethylammonium Iodides with Arylzinc Reagents

Reaction of aryltrimethylammonium iodides with arylzinc chlorides in the absence of a transition‐metal catalyst to form biaryl compounds was performed under mild conditions. The reaction was suitable for a broad scope of substrates and exhibited good compatibility of functional groups. The Mg²⁺ ion was demonstrated to markedly promote the reaction.     

Transition‐Metal‐Free N‐Arylation of Pyrazoles with Diaryliodonium Salts

A new synthetic method was developed for the N‐arylation of pyrazoles using diaryliodonium salts. The transformation does not require any transition‐metal catalyst and provides the desired N‐arylpyrazoles rapidly under mild reaction condition in the presence of aqueous ammonia solution as a mild base without the use of inert atmosphere. The chemoselectivity of unsymmetric diaryliodonium salts was also explored with large number of examples.     

Regioselective Transition‐Metal‐Free Allyl–Allyl Cross‐Couplings

Readily prepared allylic zinc halides undergo S_N2‐type substitutions with allylic bromides in a 1:1 mixture of THF and DMPU providing 1,5‐dienes regioselectively. The allylic zinc species reacts at the most branched end (γ‐position) of the allylic system furnishing exclusively γ,α′‐allyl–allyl cross‐coupling products. Remarkably, the double bond stereochemistry of the allylic halide is maintained during the cross‐coupling process. Also several functional groups (ester, nitrile) are tolerated. This cross‐coupling of allylic zinc reagents can be extended to propargylic and benzylic halides. DFT calculations show the importance of lithium chloride in this substitution.     

Stereoselective Synthesis of Piperidines by Iridium‐Catalyzed Cyclocondensation

An iridium‐catalyzed cyclocondensation of amino alcohols and aldehydes is reported. Intramolecular allylic substitution by an enamine intermediate and subsequent in situ reduction furnishes 3,4‐disubstituted piperidines with high enantiospecificity and good diastereoselectivity. The modular approach and the broad functional group tolerance provide access to diverse piperidine derivatives, which were further functionalized to give a versatile set of products.     

Transition‐Metal‐Free C3 Arylation of Indoles with Aryl Halides

We report an unprecedented transition metal‐free coupling of indoles with aryl halides. The reaction is promoted by KOtBu and is regioselective for C3 over N. The use of degassed solvents devoid of oxygen is necessary for the success of the transformation. Preliminary studies implicate a hybrid mechanism that involves both aryne intermediates and non‐propagative radical processes. Electron transfer is also a distinct possibility. These conclusions were substantiated by EPR data, isotopic labeling studies, and the use of radical scavengers and electron transfer inhibitors.