Arylmetal Reagents Research Articles

Nickel-catalyzed electrophiles-controlled enantioselective reductive arylative cyclization and enantiospecific reductive alkylative cyclization of 1,6-enynes.

Transition metal-catalyzed asymmetric cyclization of 1,6-enynes is a powerful tool for the construction of chiral nitrogen-containing heterocycles. Despite notable achievements, these transformations have been largely limited to the use of aryl or alkenyl metal reagents, and stereoselective or stereospecific alkylative cyclization of 1,6-enynes remains unexploited. Herein, we report Ni-catalyzed enantioselective reductive anti-arylative cyclization of 1,6-enynes with aryl iodides, providing enantioenriched six-membered carbo- and heterocycles in good yields with excellent enantioselectivities. Additionally, we have realized Ni-catalyzed enantiospecific reductive cis-alkylative cyclization of 1,6-enynes with alkyl bromides, furnishing chiral five-membered heterocycles with high regioselectivity and stereochemical fidelity. Mechanistic studies reveal that the arylative cyclization of 1,6-enynes is initiated by the oxidative addition of Ni(0) to aryl halides and the alkylative cyclization is triggered by the oxidative addition of Ni(0) to allylic acetates. The utility of this strategy is further demonstrated in the enantioselective synthesis of the antiepileptic drug Brivaracetam.

Design and Synthesis of Tunable Chiral 2,2′‐Bipyridine Ligands: Application to the Enantioselective Nickel‐Catalyzed Reductive Arylation of Aldehydes

AbstractA new class of chiral 2,2′‐bipyridine ligands, SBpy, featuring minimized short‐range steric hindrance and structural tunability was rationally designed and developed, and the effectiveness was demonstrated in the first highly enantioselective Ni‐catalyzed addition of aryl halides to aldehydes. In comparison with known approaches using preformed aryl metallic reagents, this reaction is more step‐economical and functional group tolerant. The reaction mechanism and a model of stereocontrol were proposed based on experimental and computational results.

Design and Synthesis of Tunable Chiral 2,2'-Bipyridine Ligands: Application to the Enantioselective Nickel-Catalyzed Reductive Arylation of Aldehydes.

A new class of chiral 2,2'-bipyridine ligands, SBpy, featuring minimized short-range steric hindrance and structural tunability was rationally designed and developed, and the effectiveness was demonstrated in the first highly enantioselective Ni-catalyzed addition of aryl halides to aldehydes. In comparison with known approaches using preformed aryl metallic reagents, this reaction is more step-economical and functional group tolerant. The reaction mechanism and a model of stereocontrol were proposed based on experimental and computational results.

Nickel-Catalyzed Reductive 2-Pyridination of Aryl Iodides with Difluoromethyl 2-Pyridyl Sulfone

A novel nickel-catalyzed reductive cross-coupling between aryl iodides and difluoromethyl 2-pyridyl sulfone (2-PySO2CF2H) enables C(sp2)-C(sp2) bond formation through selective C(sp2)-S bond cleavage, which demonstrates the new reactivity of 2-PySO2CF2H reagent. This method employs readily available nickel catalyst and sulfones as cross-electrophile coupling partners, providing facile access to biaryls under mild reaction conditions without pregeneration of arylmetal reagents.

Rh‐Catalyzed Reaction of Propargylic Alcohols with Aryl Boronic Acids–Switch from β‐OH Elimination to Protodemetalation

Summary of main observation and conclusionIt is known that Rh‐catalyzed reaction of propargylic alcohols with aryl metallic reagents undergoes SN2’‐type reaction affording allenes via a sequential arylmetalation and β‐OH elimination process. Here we report a Rh/Ag‐cocatalyzed reaction of propargylic alcohols with organoboronic acids affording stereo‐defined (E)‐3‐arylallylic alcohols via arylmetalation and protodemetalation with a high regio‐ and stereoselectivity under very mild conditions. The reaction exhibits a good substrate scope and the compatibility with synthetically useful functional groups with no racemization for optically active propargylic alcohols. Such a reaction may also be extended to homopropargylic alcohols with a remarkable regioselectivity and exclusive E‐stereoselectivity.

Upgrading Cross-Coupling Reactions for Biaryl Syntheses.

Transition-metal catalyzed cross-coupling reactions have emerged as a powerful tool for constructing biaryl compounds. Aryl halides and aryl metallic reagents (typically prepared from aryl halides) are used as coupling partners. It would be desirable to replace either aryl halide or aryl metallic reagents used in cross-couplings reactions with more readily available surrogates. Oxidative dehydrogenative cross-coupling between two different "inert" aryl C-H bonds represents an ideal system that would revolutionize cross-coupling chemistry. Furthermore, cross-coupling reactions might be improved by developing new catalytic protocols based on cheap transition-metal catalysts or even transition-metal-free systems to decrease costs and avoid the use of heavy metal and noble transition metals. It would be desirable to promote both catalytic systems and replace either or both coupling partners. We have used different strategies to improve cross-coupling reactions for constructing biaryls, which we categorized into four groups as follows. First, we focused on developing methodologies to be applied to easily produced and naturally abundant arenol-based electrophiles in cross-coupling via C-O activation. We have extended coupling partners to aryl carboxylates and arenols. Direct application of arenes as surrogates for organohalides and organometallic reagents avoids the tedious preparation of these reagents from arenes and considerably reduces the cost of starting materials. We have also explored cross-coupling reactions of arenes with various organometallic reagents, such as arylboronic acids, arylsilanes, and aryl Grignard reagents. Second, we summarize oxidative cross-coupling reactions based on C-H activation with aryl metallic reagents. On the basis of the reactivity patterns of different organometallic reagents, we adapted different catalytic systems to achieve effective cross-coupling reactions. Third, we improved a well-developed cross-coupling between arenes and organohalides through a strategy of replacing one coupling partner and using a new catalytic system. We have applied earth-abundant transition metals, such as Fe, and Co, and even developed transition-metal-free catalytic systems. Finally, our ultimate goal is to construct biaryls by cross dehydrogenative arylation between two different arenes. Owing to the structural similarity of both arenes, in particular two substituted benzenes, the greatest challenges are not only achieving regio- and chemo-selective C-H activation reactions but also matching both the reactivities and selectivities of both substrates to avoid homocouplings of either arene. Through our efforts, we have developed and applied four different strategies by introducing directing groups, controlling electronic and steric properties, and using dual directing strategies. We hope our studies will stimulate interest and new thinking on cross-couplings reactions for building carbon-carbon bonds from readily available and inexpensive chemicals from basic petroleum chemistry and nature.

Synthesis of Aryl C-Glycosides via Iron-Catalyzed Cross Coupling of Halosugars: Stereoselective Anomeric Arylation of Glycosyl Radicals.

We have developed a novel diastereoselective iron-catalyzed cross-coupling reaction of various glycosyl halides with aryl metal reagents for the efficient synthesis of aryl C-glycosides, which are of significant pharmaceutical interest due to their biological activities and resistance toward metabolic degradation. A variety of aryl, heteroaryl, and vinyl metal reagents can be cross-coupled with glycosyl halides in high yields in the presence of a well-defined iron complex, composed of iron(II) chloride and a bulky bisphosphine ligand, TMS-SciOPP. The chemoselective nature of the reaction allows the use of synthetically versatile acetyl-protected glycosyl donors and the incorporation of various functional groups on the aryl moieties, producing a diverse array of aryl C-glycosides, including Canagliflozin, an inhibitor of sodium-glucose cotransporter 2 (SGLT2), and a prevailing diabetes drug. The cross-coupling reaction proceeds via generation and stereoselective trapping of glycosyl radical intermediates, representing a rare example of highly stereoselective carbon-carbon bond formation based on iron catalysis. Radical probe experiments using 3,4,6-tri-O-acetyl-2-O-allyl-α-d-glucopyranosyl bromide (8) and 6-bromo-1-hexene (10) confirm the generation and intermediacy of the corresponding glycosyl radicals. Density functional theory (DFT) calculations reveal that the observed anomeric diastereoselectivity is attributable to the relative stability of the conformers of glycosyl radical intermediates. The present cross-coupling reaction demonstrates the potential of iron-catalyzed stereo- and chemoselective carbon-carbon bond formation in the synthesis of bioactive compounds of certain structural complexity.

Ortho-Quinol Acetate Chemistry: Reactivity toward Aryl-Based Nucleophiles and Applications to the Synthesis of Natural Products.

Two model ortho-quinol acetates were easily prepared by iodane-mediated acetoxylative phenol dearomatization and evaluated for their reactivity toward various aryl-based nucleophiles, i.e., aryl metallic reagents and phenolic derivatives. Novel modes of reactivity, allowing the formation of biaryl linkages, were revealed and here exploited for the synthesis of two natural phenolics.

ChemInform Abstract: Unified Protocol for Cobalt‐Catalyzed Oxidative Assembly of Two Aryl Metal Reagents Using Oxygen as an Oxidant.

The first cobalt-catalyzed oxidative cross-coupling reaction of two aryl metal reagents is described. An equivalent amount of two aryl Grignard or lithium reagents, after mediation by an equivalent amount of simple ClTi(OEt)3, was facilely assembled under the catalysis of 1 mol % of CoCl2/10 mol % of DMPU using oxygen. The cross-couplings between various aryl metal reagents, especially between two structurally similar aryl Grignard reagents, proceeded smoothly and selectively and, thus, provided a highly general and efficient method for the construction of biaryl compounds.

Nucleophilic arylation with tetraarylphosphonium salts

Organic phosphonium salts have served as important intermediates in synthetic chemistry. But the use of a substituent on the positive phosphorus as a nucleophile to construct C–C bond remains a significant challenge. Here we report an efficient transition-metal-free protocol for the direct nucleophilic arylation of carbonyls and imines with tetraarylphosphonium salts in the presence of caesium carbonate. The aryl nucleophile generated from phosphonium salt shows low basicity and good nucleophilicity, as evidenced by the successful conversion of enolizable aldehydes and ketones. The reaction is not particularly sensitive to water, shows wide substrate scope, and is compatible with a variety of functional groups including cyano and ester groups. Compared with the arylmetallic reagents that are usually moisture sensitive, the phosphonium salts are shelf-stable and can be easily handled.

Cobalt‐Catalyzed Alkenylzincation of Unfunctionalized Alkynes

AbstractWhile transition metal catalyzed addition reactions of arylmetal reagents to unfunctionalized alkynes have been extensively developed in the last decade, analogous reactions using alkenylmetal reagents remain rare regardless of their potential utility for the synthesis of unsymmetrical 1,3‐dienes. Reported herein is the development of a cobalt/diphosphine catalyst which promotes efficient and stereoselective addition of alkenylzinc reagents to unfunctionalized internal alkynes. The resulting dienylzinc species serve as versatile intermediates for further synthetic transformations.

Cobalt-Catalyzed Alkenylzincation of Unfunctionalized Alkynes.

While transition metal catalyzed addition reactions of arylmetal reagents to unfunctionalized alkynes have been extensively developed in the last decade, analogous reactions using alkenylmetal reagents remain rare regardless of their potential utility for the synthesis of unsymmetrical 1,3-dienes. Reported herein is the development of a cobalt/diphosphine catalyst which promotes efficient and stereoselective addition of alkenylzinc reagents to unfunctionalized internal alkynes. The resulting dienylzinc species serve as versatile intermediates for further synthetic transformations.

Unified Protocol for Cobalt-Catalyzed Oxidative Assembly of Two Aryl Metal Reagents Using Oxygen as an Oxidant.

The first cobalt-catalyzed oxidative cross-coupling reaction of two aryl metal reagents is described. An equivalent amount of two aryl Grignard or lithium reagents, after mediation by an equivalent amount of simple ClTi(OEt)3, was facilely assembled under the catalysis of 1 mol % of CoCl2/10 mol % of DMPU using oxygen. The cross-couplings between various aryl metal reagents, especially between two structurally similar aryl Grignard reagents, proceeded smoothly and selectively and, thus, provided a highly general and efficient method for the construction of biaryl compounds.

Iron catalyzed oxidative assembly of N-heteroaryl and aryl metal reagents using oxygen as an oxidant.

An equivalent amount of N-heteroaryl and aryl Grignard or lithium reagents, after mediation by an equivalent of titanate, was facilely coupled to furnish N-heteroaryl-aryl compounds under the catalysis of FeCl3/TMEDA at ambient temperature using oxygen as an oxidant. Most of the common N-heteroaryls were all good candidates, and thus provided a general, green and pratical protocol for the flexible construction of various N-heteroaryl-aryl structures.

ChemInform Abstract: Selective Co/Ti Cooperatively Catalyzed Biaryl Couplings of Aryl Halides with Aryl Metal Reagents.

Various aryl bromides or chlorides, including those bearing a free COOH, OH, CONHR, and SO2NHR group, coupled with aryl magnesium or lithium reagents in the presence of 7.5 mol % CoCl2/15 mol % PBu3 and substoichiometric Ti(OEt)4 (40 mol % to ArM) at room temperature in high yields with high chemo- and regioslectivity. This simple reaction represents the first example of Co/Ti cooperative catalysis which plays a key role in suppressing undesired homocouplings.

Selective Co/Ti Cooperatively Catalyzed Biaryl Couplings of Aryl Halides with Aryl Metal Reagents

Various aryl bromides or chlorides, including those bearing a free COOH, OH, CONHR, and SO2NHR group, coupled with aryl magnesium or lithium reagents in the presence of 7.5 mol % CoCl2/15 mol % PBu3 and substoichiometric Ti(OEt)4 (40 mol % to ArM) at room temperature in high yields with high chemo- and regioslectivity. This simple reaction represents the first example of Co/Ti cooperative catalysis which plays a key role in suppressing undesired homocouplings.

ChemInform Abstract: Cobalt‐Catalyzed Cross‐Coupling Reaction of Arylzinc Reagents with Ethyl Bromodifluoroacetate.

Abstract Transition metal-catalyzed cross-coupling reactions of arylmetal reagents with ethyl bromodifluoroacetate have been explored. After intensive investigations, we have successfully found that a cobalt-catalyzed cross-coupling reaction (catalytic alkoxycarbonyldifluoromethylation) of arylzinc reagents with ethyl bromodifluoroacetate smoothly proceeded to afford the corresponding ethyl aryldifluoroacetates in moderate to good yields.

Cobalt-catalyzed cross-coupling reaction of arylzinc reagents with ethyl bromodifluoroacetate

Transition metal-catalyzed cross-coupling reactions of arylmetal reagents with ethyl bromodifluoroacetate have been explored. After intensive investigations, we have successfully found that a cobalt-catalyzed cross-coupling reaction (catalytic alkoxycarbonyldifluoromethylation) of arylzinc reagents with ethyl bromodifluoroacetate smoothly proceeded to afford the corresponding ethyl aryldifluoroacetates in moderate to good yields.

ChemInform Abstract: Borylation of Aryl and Alkenyl Carbamates through Ni‐Catalyzed C—O Activation.

In the past several decades, Suzuki–Miyaura coupling has been well developed and has become one of the most useful tools to construct C C bond in both laboratory and industry. As the major coupling partner of Suzuki–Miyaura coupling, aryl boronic acid and its derivatives showed their advantages due to the readily availability, low toxicity and high functional group tolerance. Traditionally, they can be prepared by metal exchange from aryl Grignard reagents or aryl lithium reagents with boronic esters, in which the sensitivity to moisture and functional group incompatibility limits their implementation. Subsequently, new methods were developed through direct borylation starting from aryl haACHTUNGTRENNUNGlides, catalyzed by Pd and other metal complexes and avoiding the use of aryl metallic reagents. Recent advances also showed the power of the direct C H borylation with Rh and Ir catalysis. Herein we reported a novel useful method to produce aryl boronic esters from aryl and vinyl carbamates with diboronic reagents through Ni catalysis. Phenols and carbonyl compounds exist in many forms in the natural and synthetic world. However, only very few examples for the construction of useful aryl boronic derivatives starting from phenol and ketone compounds have been reported. In some examples, aryl sulfonates have been successfully applied to carry out the borACHTUNGTRENNUNGyl ACHTUNGTRENNUNGation.[8] When we were preparing this manuscript, Percec and co-workers first reported Ni-catalyzed borylation starting from aryl mesylates and tosylates. Based on our and others recent investigations on the cleavage of aryl C O bond of aryl carboxACHTUNGTRENNUNGylACHTUNGTRENNUNGates and other derivatives, 9] we envisioned that it might be possible to carry out aryl borylation from arylcarbox ACHTUNGTRENNUNGyl ACHTUNGTRENNUNGates by means of Ni catalysis (Scheme 1).

Borylation of Aryl and Alkenyl Carbamates through Ni‐Catalyzed CO Activation

In the past several decades, Suzuki–Miyaura coupling has been well developed and has become one of the most useful tools to construct C C bond in both laboratory and industry. As the major coupling partner of Suzuki–Miyaura coupling, aryl boronic acid and its derivatives showed their advantages due to the readily availability, low toxicity and high functional group tolerance. Traditionally, they can be prepared by metal exchange from aryl Grignard reagents or aryl lithium reagents with boronic esters, in which the sensitivity to moisture and functional group incompatibility limits their implementation. Subsequently, new methods were developed through direct borylation starting from aryl haACHTUNGTRENNUNGlides, catalyzed by Pd and other metal complexes and avoiding the use of aryl metallic reagents. Recent advances also showed the power of the direct C H borylation with Rh and Ir catalysis. Herein we reported a novel useful method to produce aryl boronic esters from aryl and vinyl carbamates with diboronic reagents through Ni catalysis. Phenols and carbonyl compounds exist in many forms in the natural and synthetic world. However, only very few examples for the construction of useful aryl boronic derivatives starting from phenol and ketone compounds have been reported. In some examples, aryl sulfonates have been successfully applied to carry out the borACHTUNGTRENNUNGyl ACHTUNGTRENNUNGation.[8] When we were preparing this manuscript, Percec and co-workers first reported Ni-catalyzed borylation starting from aryl mesylates and tosylates. Based on our and others recent investigations on the cleavage of aryl C O bond of aryl carboxACHTUNGTRENNUNGylACHTUNGTRENNUNGates and other derivatives, 9] we envisioned that it might be possible to carry out aryl borylation from arylcarbox ACHTUNGTRENNUNGyl ACHTUNGTRENNUNGates by means of Ni catalysis (Scheme 1).