Enantiospecific sp2–sp3 Coupling of ortho‐ and para‐Phenols with Secondary and Tertiary Boronic Esters

The coupling of ortho ‐ and para ‐phenols with secondary and tertiary boronic esters has been explored. In the case of para ‐substituted phenols, after reaction of a dilithio phenolate species with a boronic ester, treatment with Ph₃BiF₂ or Martin's sulfurane gave the coupled product with complete enantiospecificity. The methodology was applied to the synthesis of the broad spectrum antibacterial natural product (−)‐4‐(1,5‐dimethylhex‐4‐enyl)‐2‐methyl phenol. For ortho ‐substituted phenols, initial incorporation of a benzotriazole on the phenol oxygen atom was required. Subsequent ortho ‐lithiation and borylation gave the coupled product, again with complete stereospecificity.     

Synthesis of 4‐halo‐2 (5H)‐furanones and their suzuki‐coupling reactions with organoboronic acids. A general route to 4‐aryl‐2 (5 H) ‐furanones

4‐Halo‐2(5H)‐furanones were prepared by the halolactonization of 2,3‐allenoic acids. The subsequent Suzuki coupling reaction of 4‐halo 2(5H)‐furanones with aryl boronic acids was carried out to produce 4‐aryl‐2(5H)‐furanones in excellent yields.     

Reaction Optimization,Scalability, and Mechanistic Insight on the Catalytic Enantioselective Desymmetrization of 1,1‐Diborylalkanes via Suzuki–Miyaura Cross‐Coupling

A method for enantioselective desymmetrization of 1,1‐diborylalkanes through a stereoselective Pd‐catalyzed Suzuki–Miyaura cross‐coupling has been thoroughly optimized. The most effective ligand was found to be a α,α,α,α‐tetra‐aryl‐1,3‐dioxolane‐4,5‐dimethanol (TADDOL)‐derived phosphoramidite. Results show that in order to achieve high selectivity, a suitable balance between the sterics of the aryl groups and the amino group on the ligand must be achieved. While the base has been known to facilitate transmetallation in cross‐coupling reactions, mechanistic studies on this desymmetrization process reveal that the base, in the presence of KHF₂, likely plays an additional role in the hydrolysis of the pinacol boronates to the corresponding boronic acids. Through an in depth optimization of the chiral ligand and mechanistic studies, it was possible to obtain ee values over 90 % for several aryl bromides and to develop a reliably scalable process (up to one gram of 1,1‐diborylalkane substrate).     

Palladium‐Catalyzed Suzuki–Miyaura Cross‐Coupling of Secondary α‐(Trifluoromethyl)benzyl Tosylates

A palladium‐catalyzed C(sp³)−C(sp²) Suzuki–Miyaura cross‐coupling of aryl boronic acids and α‐(trifluoromethyl)benzyl tosylates is reported. A readily available, air‐stable palladium catalyst was employed to access a wide range of functionalized 1,1‐diaryl‐2,2,2‐trifluoroethanes. Enantioenriched α‐(trifluoromethyl)benzyl tosylates were found to undergo cross‐coupling to give the corresponding enantioenriched cross‐coupled products with an overall inversion in configuration. The crucial role of the CF₃ group in promoting this transformation is demonstrated by comparison with non‐fluorinated derivatives.     

Rhodium‐Catalyzed Addition of Aryl Boronic Acids to 2,2‐Disubstituted Malononitriles

β‐Ketonitriles bearing a quaternary carbon at the 2‐position were prepared through Rh‐catalyzed addition of aryl boronic acids to 2,2‐disubstituted malononitriles. In contrast to the previously described transnitrilative cyanation of aryl boronic acids with dialkylmalononitriles, the present reaction avoids retro‐Thorpe collapse of the intermediate addition product through the use of a milder base. The reaction was amenable to a variety of aryl boronic acids and disubstituted malononitriles, providing a diverse array of β‐ketonitriles. The products could be further derivatized to valuable chiral α,α‐disubstituted‐β‐aminonitriles through addition reactions to the corresponding N ‐tert ‐butanesulfinyl imines.     

Catalytic Enantioselective Arylboration of Alkenylarenes

A method for the catalytic enantioselective arylboration of alkenylarenes is disclosed. The reaction leads to the formation of 1,1‐diarylalkanes that also incorporate an additional pinacol boronic ester which can be easily transformed to a variety of groups. The products are formed with excellent diastereoselectivities and enantioselectivities.     

Synthesis of New 2,4‐Diaryl‐6‐methyl‐5‐nitropyrimidines as Antibacterial and Antioxidant Agents

A new series of 2,4‐diaryl‐6‐methyl‐5‐nitropyrimidines ( 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i ) were synthesized in good yields by Suzuki–Miyaura coupling of 2,4‐dichloro‐6‐methyl‐5‐nitropyrimidine ( 3 ) with various aryl boronic esters ( 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i ) in the presence of 1,1′‐ bis(diphenylphosphino)ferrocene dichloropalladium(II) (Pd(dppf)₂Cl₂). Further, antibacterial and antioxidant properties were screened for the title compounds 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i . Most of the compounds possessed significant activity against Gram‐positive bacteria Staphylococcus aureus and Bacillus subtilis and Gram‐negative bacteria Escherichia coli and Klebsiella pneumoniae. The antioxidant activity of the title compounds showed significant antioxidant activity when compared with vitamin C.     

Synthesis of Functionalized o‐, m‐, and p‐Terphenyl Derivatives by Consecutive Cross‐Coupling Reactions of Triazene‐Substituted Arylboronic Esters

Triazene‐substituted arylboronic esters were prepared readily from the corresponding aryl magnesium derivatives and shown to function as a new class of donor–acceptor‐substituted coupling reagents. The selective functionalization of these aromatic derivatives led to a wide variety of terphenyl derivatives in which the original bifunctional unit (often further substituted with another functional group) formed the central aromatic ring. The functionalized terphenyl derivatives were formed in two efficient cross‐coupling steps from the triazene‐substituted boronic esters: Suzuki cross‐coupling with an aryl halide was followed by BF₃?OEt₂‐induced palladium‐catalyzed coupling of the diazonium salt generated in situ from the triazene with an arylboronic acid.     

Nickel‐Catalyzed Electrochemical Reductive Relay Cross‐Coupling of Alkyl Halides to Aryl Halides

A highly regioselective Ni‐catalyzed electrochemical reductive relay cross‐coupling between an aryl halide and an alkyl halide has been developed in an undivided cell. Various functional groups are tolerated under these mild reaction conditions, which provides an alternative approach for the synthesis of 1,1‐diarylalkanes.     

2‐(6‐Bromopyridin‐3‐yl)‐4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolane and (6‐bromopyridin‐3‐yl)boronic acid,new bifunctional building blocks for combinatorial chemistry

The first comparative study between two new heterocyclic boron derivatives, viz. a (6‐bromo­pyridin‐3‐yl)­boronic ester, C₁₁H₁₅BBrNO₂, and (6‐bromo­pyridin‐3‐yl)­boronic acid, C₅H₅BBrNO₂, shows a small but not significant difference in their C—B bond lengths, which cannot explain the experimentally observed difference in their stabilities. The crystal packing of the boronic ester consists principally of van der Waals interactions, while the boronic acid mol­ecules interact in their crystal through hydrogen bonds.     

9‐Ethyl‐1,4‐dimethyl‐6‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐yl)‐9H‐carbazole and 6‐bromo‐9‐ethyl‐1,4‐dimethyl‐9H‐carbazole

The title carbazolyl boronic ester, C₂₂H₂₈BNO₂, (I), is a building block for the synthesis of new carbazole derivatives of potential utility as pharmaceutically active compounds. The crystal structure of (I) and of the title bromocarbazole compound, C₁₆H₁₆BrN, (II), the synthetic precursor of (I), were solved and analysed with the aim of understanding the lack of reactivity of (I) under Suzuki cross‐coupling reaction conditions. In both structures, the methyl groups are coplanar with the carbazole ring system, and the ethyl group lies out of the carbazole plane. The dioxaborolane ring of boronic ester (I) adopts a half‐chair conformation but lies approximately in a planar orientation with respect of the carbazole ring system, whereas the Br atom of (II) is coplanar with the carbazole plane. In (I), the carbazole–boronic ester C—B bond length is 1.5435 (14) Å, which is somewhat shorter than the usual value of 1.57 Å.     

Chelation‐Assisted Cross‐Coupling of Anilines through In Situ Activation as Diazonium Salts with Boronic Acids under Ligand‐, Base‐, and Salt‐Free Conditions

We describe the coupling of anilines with aryl boronic acids, under ligand‐, base‐, and salt‐free conditions at room temperature. This new reaction proceeds through the formation of an aryl palladium alkoxo complex, which allows the transmetalation step with aryl boronic acids without any external base. Importantly, this sustainable procedure generates only environmentally friendly byproducts such as tBuOH, H₂O, N₂, and B(OH)₃. The reaction mechanism has been deeply investigated through experimental and theoretical studies.     

Reductive Cross‐Coupling of Conjugated Arylalkenes and Aryl Bromides with Hydrosilanes by Cooperative Palladium/Copper Catalysis

A method for the reductive cross‐coupling of conjugated arylalkenes and aryl bromides with hydrosilanes by cooperative palladium/copper catalysis was developed, thus resulting in the highly regioselective formation of various 1,1‐diarylalkanes, including a biologically active molecule. Under the applied reaction conditions, high levels of functional‐group tolerance were observed, and the reductive cross‐coupling of internal alkynes with aryl bromides afforded trisubstituted alkenes.     

Palladium‐Catalyzed Enantioselective Synthesis of 2‐Aryl Cyclohex‐2‐enone Atropisomers: Platform Molecules for the Divergent Synthesis of Axially Chiral Biaryl Compounds

The palladium‐catalyzed asymmetric synthesis of enone‐based atropisomers from 2‐iodo‐3‐methylcyclohex‐2‐enones and aryl boronic acid is reported. BoPhoz‐type phosphine–aminophosphine ligands showed superior enantioselectivity over other ligands. These cyclohexenone‐based atropisomers are useful compounds for further elaboration. The divergent synthesis of biaryl atropisomers with different ortho substituents was demonstrated.     

Palladium‐Catalyzed Reductive Coupling Reaction of Terminal Alkynes with Aryl Iodides Utilizing Hafnocene Difluoride as a Hafnium Hydride Precursor Leading to trans‐Alkenes

Herein, we describe a reductive cross‐coupling of alkynes and aryl iodides by using a novel catalytic system composed of a catalytic amount of palladium dichloride and a promoter precursor, hafnocene difluoride (Cp₂HfF₂, Cp=cyclopentadienyl anion), in the presence of a mild reducing reagent, a hydrosilane, leading to a one‐pot preparation of trans‐alkenes. In this process, a series of coupling reactions efficiently proceeds through the following three steps: (i) an initial formation of hafnocene hydride from hafnocene difluoride and the hydrosilane, (ii) a subsequent hydrohafnation toward alkynes, and (iii) a final transmetalation of the alkenyl hafnium species to a palladium complex. This reductive coupling could be chemoselectively applied to the preparation of trans‐alkenes with various functional groups, such as an alkyl group, a halogen, an ester, a nitro group, a heterocycle, a boronic ester, and an internal alkyne.     

Enantiospecific Trifluoromethyl‐Radical‐Induced Three‐Component Coupling of Boronic Esters with Furans

In the presence of trifluoromethylsulfonium reagents, boronate complexes derived from 2‐lithio furan and non‐racemic secondary and tertiary alkyl or aryl boronic esters undergo deborylative three‐component coupling to give the corresponding 2,5‐disubstituted furans with excellent levels of enantiospecificity. The process proceeds via the reaction of boronate complexes with a trifluoromethyl radical, which triggers 1,2‐metallate rearrangement upon single‐electron oxidation. Alternative electrophiles can also be used in place of trifluoromethylsulfonium reagents to effect similar three‐component coupling reactions.     

Synthesis of 2‐Aryl‐ and 2‐Heteroaryl‐3,5‐dimethoxy‐1,4‐benzoquinones Involving Pd‐Catalyzed Cross‐Coupling of (2,3,4,6‐Tetramethoxyphenyl)boronic Acid

A series of 2‐aryl‐ and 2‐heteroaryl‐substituted 3,5‐dimethoxy‐1,4‐benzoquinones (compounds 27 – 36 ) have been synthesized by cross‐coupling of (2,3,4,6‐tetramethoxyphenyl)boronic acid ( 2 ) with aromatic bromides or iodides in the presence of [Pd⁰(Ph₃)₄] and Na₂CO₃, followed by AgO‐promoted oxidation of the resulting biaryl compounds 17 – 26 .     

Facile Synthesis and Palladium‐Catalyzed Cross‐Coupling Reactions of 2,3‐Bis(pinacolatoboryl)‐1,3‐butadiene

Treatment of 1,1‐bis(pinacolatoboryl)ethene with an excess of 1‐bromo‐1‐lithioethene gave 2,3‐bis(pinacolatoboryl)‐1,3‐butadiene in high yield. Palladium‐catalyzed cross‐coupling of the resulting diborylbutadiene with aryl iodides took place smoothly in the presence of a catalytic amount of Pd(OAc)₂/PPh₃ and aqueous KOH to give 2,3‐diaryl‐1,3‐butadienes in good yields. The coupling reaction with commercially available 4‐acetoxyphenylmethyl chloride under the same conditions followed by hydrolysis of the acetyl groups gave anolignan B in a one‐pot manner. A variety of [3]‐ to [6]dendralenes were synthesized by palladium‐catalyzed coupling of the diene or 1,1‐bis(pinacolato)borylethene with alkenyl or dienyl halides, respectively, in good yields.     

Cyclization vs. Elimination Reactions of 5‐Aryl‐5‐hydroxy 1,3‐Diones: One‐Pot Synthesis of 2‐Aryl‐2,3‐dihydro‐4H‐pyran‐4‐ones

2‐Aryl‐2,3‐dihydro‐4H‐pyran‐4‐ones were prepared in one step by cyclocondensation of 1,3‐diketone dianions with aldehydes. The use of HCl (10%) for the aqueous workup proved to be very important to avoid elimination reactions of the 5‐aryl‐5‐hydroxy 1,3‐diones formed as intermediates. The TiCl₄‐mediated cyclization of a 2‐aryl‐2,3‐dihydro‐4H‐pyran‐4‐one with 1,3‐silyloxybuta‐1,3‐diene resulted in cleavage of the pyranone moiety and formation of a highly functionalized benzene derivative.     

Pd‐Catalyzed Enantioselective Ring Opening/Cross‐Coupling and Cyclopropanation of Cyclobutanones

A palladium‐catalyzed enantioselective sequential ring‐opening/cross‐coupling of cyclobutanones is disclosed that provides chiral indanones bearing C3‐quaternary stereocenters. The reaction process involves palladium‐catalyzed nucleophilic addition of cyclobutanones and aryl halides, enantioselective β‐carbon elimination, and intermolecular trapping of a transient σ‐alkylpalladium complex with boronic acids. Alternatively, an intramolecular cyclopropanation is realized through C?H bond functionalization in the absence of external coupling reagents, affording chiral cyclopropane‐fused‐indanones in good yields and enantioselectivity.