Palladium‐Catalyzed and Hybrid Acids‐Assisted Synthesis of [60]Fulleroazepines in One Pot under Mild Conditions: Annulation of N‐Sulfonyl‐2‐aminobiaryls with [60]Fullerene through Sequential C‐H Bond Activation,C‐C and C‐N Bond Formation

An extraordinarily efficient hybrid acids‐assisted, palladium‐catalyzed and chelating‐group‐assisted C H bond activation of N‐sulfonyl‐2‐aminobiaryls and their annulations with [60]fullerene via sequential C C and C N bond formation at room temperature to afford [60]fulleroazepines is demonstrated. The formation of [60]fulleroazepines is highly regioselective and tolerant to both electron‐withdrawing and electron‐donating groups on the aryl moiety and the reaction gives monofunctionalized fullerenes in good yields (up to 54% isolated yield and 92% based on converted C₆₀).     

Palladium‐Catalyzed Direct Arylations of 1,2‐Azolo[1,5‐a]pyridines using Copper(I) Chloride as a Lewis Acid Activator and the Synthesis of 2,6‐Disubstituted Pyridines

A direct method for the arylation of 1,2‐azolo[1,5‐a]pyridines has been developed. In the process, the fused pyridines react with aryl halides in the presence of the palladium complex Pd(OAc)₂(Phen) as a catalyst and copper(I) chloride (CuCl) as a Lewis acid to form arylated derivatives. While pyrazolo[1,5‐a]pyridines and [1,2,4]triazolo[1,5‐a]pyridines are arylated at ortho‐positions of their pyridine rings using this method, in situ ring‐opening of the formed C‐7 arylated [1,5‐a]pyridine takes place to generate the 2,6‐disubstituted pyridine. Also, upon treatment with lithium diisopropylamide (LDA), C‐7 arylated pyrazolo[1,5‐a]pyridine‐3‐carboxylates react to produce diversely substituted 2,6‐disubstituted pyridines. Finally, a sequential C‐3 arylation was accomplished through a two‐step sequence involving hydrolysis of pyrazolo[1,5‐a]pyridine‐3‐carboxylates followed by the bimetallic Pd/Cu‐catalyzed decarboxylative coupling reaction with aryl bromide.

     

First Copper‐Catalyzed Intramolecular Amidation in Substituted 4‐Iodopyrazoles Leading to the Synthesis of Pyrazolo[4,3‐b]‐ pyridin‐5‐ones

An unprecedented copper‐catalyzed intramolecular amidation of substituted 4‐iodopyrazoles generated either via Baylis–Hillman or Horner–Wadsworth–Emmons chemistry for the synthesis of pyrazolo[4,3‐b]pyridine‐5‐ones is described. In addition, the effect of the stereochemistry of the acrylamide on the cross‐coupling reaction has been investigated and it is demonstrated that only the Z‐isomer is favoured to undergo the intramolecular cyclization.     

Mechanistic Studies on the Palladium‐Catalyzed Direct C‐5 Arylation of Imidazoles: The Fundamental Role of the Azole as a Ligand for Palladium

An in‐depth mechanistic study on the palladium‐catalyzed direct arylation of imidazoles at the C‐5 position is presented. The interactions of triphenylphosphine (PPh₃)‐ligated aryl‐Pd species with 1,2‐dimethyl‐1H‐imidazole (dmim) have been studied in detail. In contrast with previous suggestions, phosphine‐ligated organo‐Pd species are not active and the reaction proceeds through imidazole‐ligated organo‐Pd intermediates. The kinetics of the oxidative addition of aryl halides with dmim‐ligated Pd(0) species have been characterized in a Pd(dba)₂/dmim model system. A thorough study of the equilibria involving novel [ArPd(dmim)₂X] complexes (X=I, OAc) and the unexpected cationic [ArPd(dmim)₃]⁺ is also reported. The ability of these species to effect the C H arylation of dmim at room temperature in the presence of acetate is also demonstrated.

     

Ruthenium‐Catalyzed Oxidative Homo‐Coupling of 2‐Arylpyridines

A ruthenium‐catalyzed oxidative homo‐coupling reaction of 2‐arylpyridines via C H activation was developed. The reaction could tolerate various functional groups on both the aryl and the pyridyl rings to afford a series of dimerized products with iron(III) chloride (FeCl₃) as a stoichiometric oxidant. A tentative mechanism was proposed for this oxidative C H/C H homo‐coupling.     

Ligand Control in Enantioselective Desymmetrization of Bicyclic Hydrazines: Rhodium(I)‐Catalyzed Ring‐Opening versus Hydroarylation

The efficient desymmetrization of 2,3‐bicyclic hydrazines with boronic acids through rhodium‐catalyzed ring‐opening or reductive arylation is described. Excellent levels of enantioselectivity are achieved in ring‐opening with ortho‐substituted boronic acids, using Josiphos‐type ligands. Alternatively, reductive arylation occurs selectively with electron‐poor Josiphos and Walphos ligands. A C H activation/1,4‐migration mechanism was established through deuterium transfer experiments.     

Palladium‐Catalyzed Direct Arylations of 1,2,3‐Triazoles with Aryl Chlorides using Conventional Heating

Generally applicable, palladium‐catalyzed direct arylations of 1,2,3‐triazoles with aryl chlorides were accomplished through conventional heating at reaction temperatures of 105–120 °C. Thereby, intra‐ and intermolecular C H bond functionalizations were achieved with a variety of differently substituted chlorides as electrophiles, bearing numerous valuable functional groups.     

Synthesis of Methylene‐Bridge Polyarenes through Palladium‐Catalyzed Activation of Benzylic Carbon‐Hydrogen Bond

In the presence of palladium(II) acetate [Pd(OAc)₂] and an N‐heterocyclic carbene (NHC) ligand, fluorene derivatives can be generated in good to excellent yields from 2‐halo‐2′‐methylbiaryls through the benzylic C H bond activation (14 examples; 81–97% yields). The scope and limitations of this protocol have been examined. A wide range of functional groups, such as alkyl, alkoxy, ester, nitrile, and others, is able to tolerate the reaction conditions herein. The cyclization of an isotope‐labelled biphenyl gave the corresponding product with a primary kinetic isotope effect (k_H/k_D=4.8:1), which indicates that the rate‐determining step of this reaction is the activation of the benzylic C H bond. Moreover, indenofluorenes were also accessed in excellent results from terphenyls (3 examples; 91–92% yields). The cascade reaction of 2,6‐dichloro‐2′‐methylbiphenyl with diphenylacetylene produced 8,9‐diphenyl‐4H‐cyclopenta[def]phenanthrene in 60% yield through the activation of an aryl and a benzylic C H bond.     

Heterogeneous Palladium Catalysts Applied to the Synthesis of 2‐ and 2,3‐Functionalised Indoles

Heterogeneous palladium catalysts ([Pd(NH₃)₄]²⁺/NaY and [Pd]/SBA‐15) were applied to the synthesis of 2‐functionalised indoles, giving generally high conversions and selectivities (>89% yield) using only 1 mol % [Pd]‐catalyst under standard reaction conditions (polar solvent, 80 °C). For the synthesis of 2,3‐functionalised indoles by cross‐coupling arylation, the [Pd]/SBA‐15 catalyst was found to be particularly interesting, producing the expected compound with =35% yield after 12 days of reaction, which is comparable to the homogeneous catalyst, Pd(OAc)₂ (=48% yield). In the course of the study, the dual reactivity of the indole nucleus was demonstrated: aryl bromides gave clean C C coupling while aryl iodides led to a clean C N coupling.     

Iron‐Catalyzed C?C Bond Cleavage and C?N Bond Formation

A novel approach for C N bond formation was developed by iron‐catalyzed C C bond cleavage. Anilines and sulfonamides reacted smoothly with 2‐substituted 1,3‐diphenylpropane‐1,3‐diones to afford N‐alkylation products, in which the 1,3‐dicarbonyl group acts as a leaving group in the presence of an iron catalyst. The reversible C C bond cleavage plays a driving force to give the thermodynamically stable products. The method is complementary to the previous methods for C N bond formation.     

Lewis Acid‐Catalyzed [3+4] Annulation of 2‐(Heteroaryl)‐ cyclopropane‐1,1‐dicarboxylates with Cyclopentadiene

A novel Lewis acid‐catalyzed [3+4] annulation of 2‐(heteroaryl)cyclopropane‐1,1‐dicarboxylates with cyclopentadiene is reported. This reaction proceeds via an electrophilic attack of the Lewis acid‐activated donor‐acceptor cyclopropane onto cyclopentadiene followed by Friedel–Crafts intramolecular alkylation of the heteroarene substituent. This is the first general example of reactions of donor‐acceptor cyclopropanes wherein the donor substituent serves as a nucleophile. The described annulation represents a convenient approach to bicyclo[3.2.1]octa‐2,6‐dienes with heteroarenes annulated to C(2)‐C(3) bond. Its efficiency was demonstrated for a series of furyl, thienyl, pyrrolyl, benzofuryl, benzothienyl, and indolyl substituted cyclopropanes. Additionally, in the case of 2‐(5‐methyl‐2‐furyl)cyclopropane‐1,1‐diester we observed the predominant formation of product of the [3+4] annulation or the tetracyclic 5,8‐methanocyclopenta[a]azulene derivative, depending on the reaction conditions.     

Palladium‐Catalyzed Aryl Amination Reactions of 6‐Bromo‐ and 6‐Chloropurine Nucleosides

Palladium‐catalyzed C N bond forming reactions of 6‐bromo‐ as well as 6‐chloropurine ribonucleosides and the 2′‐deoxy analogues with arylamines are described. Efficient conversions were observed with palladium(II) acetate/Xantphos/cesium carbonate, in toluene at 100 °C. Reactions of the bromonucleoside derivatives could be conducted at a lowered catalytic loading [5 mol% Pd(OAc)₂/7.5 mol% Xantphos], whereas good product yields were obtained with a higher catalyst load [10 mol% Pd(OAc)₂/15 mol% Xantphos] when the chloro analogue was employed. Among the examples evaluated, silyl protection for the hydroxy groups appears better as compared to acetyl. The methodology has been evaluated via reactions with a variety of arylamines and by synthesis of biologically relevant deoxyadenosine and adenosine dimers. This is the first detailed analysis of aryl amination reactions of 6‐chloropurine nucleosides, and comparison of the two halogenated nucleoside substrates.     

Rhodium(III)‐Catalyzed Synthesis of Indole Derivatives From Pyrimidyl‐Substituted Anilines and Diazo Compounds

An efficient method for the synthesis of indole derivatives from readily available pyrimidyl‐substituted anilines and diazo compounds via rhodium(III)‐catalyzed C H bond activation has been developed. This cyclization reaction displays excellent functional group compatibility and regioselectivity, which overcomes some drawbacks of the classical indole synthetic methods and provides a facile approach for the construction of multi‐substituted indole derivatives. The redox‐neutral intermolecular annulation procedure comprises tandem C H bond activation, cyclization, and condensation steps, releasing water and nitrogen as by‐products.

     

Rhodium‐Catalyzed Direct Oxidative C?H Acylation of 2‐Arylpyridines with Terminal Alkynes: A Synthesis of Pyrido[2,1‐a]isoindoles

A synthesis of pyrido[2,1‐a]isoindoles is reported by the rhodium‐catalyzed direct oxidative C H acylation of 2‐aryl pyridines with terminal alkynes. The desired products were obtained in moderate to excellent yields. This is an efficient and clean method to construct C C/C N bonds in one step. In addition, the effective rhodium(III) catalyst was isolated and characterized by X‐ray crystallography.

     

Palladium‐Catalysed Intramolecular Direct Arylation of 2‐Bromobenzenesulfonic Acid Derivatives

A palladium‐catalysed intramolecular direct arylation of 2‐bromobenzenesulfonic acid derivatives was found to proceed using 1 mol% of palladium acetate as the catalyst. The influence of the substituents on the phenol moiety of 2‐bromobenzenesulfonic acid phenyl esters reveals that electron‐donating substituents favour the reaction while electron‐withdrawing ones are unfavourable. The reactivity of sulfonamides was also studied and, in all cases, a selective activation at sp² C H vs. sp³ C H was observed. A sulfonamide bearing both phenyl and benzyl substituents on nitrogen gave selectively the six‐membered ring product.     

Copper(I)‐Catalyzed Synthesis of Novel 4‐(Trifluoromethyl)‐[1,2,3]triazolo[1,5‐a]quinoxalines via Cascade Reactions of N‐(o‐Haloaryl)alkynylimine with Sodium Azide

Novel tricyclic 4‐(trifluoromethyl)‐[1,2,3]triazolo[1,5‐a]quinoxalines were readily prepared from N‐(o‐haloaryl)alkynylimines and sodium azide via copper(I)‐catalyzed tandem reactions. This synthetic strategy provides an efficient way to access a library of novel heterocyclic compounds that are of interest in drug discovery.     

2‐Aminopyridines as an α‐Bromination Shuttle in a Transition Metal‐Free One‐Pot Synthesis of Imidazo[1,2‐a]pyridines

A wide range of imidazo[1,2‐a]pyridines are accessible from cheap and readily available 2‐aminopyridines and 1,3‐dicarbonyl compounds using a unique CBrCl₃/2‐aminopyridine system for bromination at the α‐carbon. 2‐Aminopyridine is not only the substrate but also acts as a bromination shuttle, transferring the bromine atom from CBrCl₃ to the α‐carbon of the 1,3‐dicarbonyl. The reaction mechanism involves a series of reversible steps, including an addition reaction with cyclic transition state, to form a bromo‐hemiaminal intermediate. Isolated yields of up to 97% were obtained under mild conditions and at short reaction times in this transition metal‐free, one‐pot synthesis.

     

Palladium(II) Complexes of C2‐Bridged Chiral Diphosphines: Application to Enantioselective Carbonyl‐Ene Reactions

(11bR,11′bR)‐4,4′‐(1,2‐Phenylene)bis[4,5‐dihydro‐3H‐dinaphtho[2,1‐c:1′,2′‐e]phosphepin] [abbreviated as (R)‐BINAPHANE], (3R,3′R,4S,4′S,11bS,11′bS)‐4,4′‐bis(1,1‐dimethylethyl)‐4,4′,5,5′‐tetrahydro‐3,3′‐bi‐3H‐dinaphtho[2,1‐c:1′,2′‐e]phosphepin [(S)‐BINAPINE], (1S,1′S,2R,2′R)‐1,1′‐bis(1,1‐dimethylethyl)‐2,2′‐biphospholane [(S,S,R,R)‐TANGPHOS] and (2R,2′R,5R,5′R)‐1,1′‐(1,2‐phenylene)bis[2,5‐bis(1‐methylethyl)phospholane] [(R,R)‐i‐Pr‐DUPHOS] are C₂‐bridged chiral diphosphines that form stable complexes with palladium(II) and platinum(II) containing a five‐membered chelate ring. The Pd(II)‐BINAPHANE catalyst displayed good to excellent enantioselectivities with ee values as high as 99.0% albeit in low yields for the carbonyl‐ene reaction between phenylglyoxal and alkenes. Its Pt(II) counterpart afforded improved yields while retaining satisfactory enantioselectivity. For the carbonyl‐ene reaction between ethyl trifluoropyruvate and alkenes, the Pd(II)‐BINAPHANE catalyst afforded both good yields and extremely high enantioselectivities with ees as high as 99.6%. A comparative study on the Pd(II) catalysts of the four C₂‐bridged chiral diphosphines revealed that Pd(II)‐BINAPHANE afforded the best enantioselectivity. The ee values derived from Pd(II)‐BINAPHANE are much higher than those derived from the other three Pd(II) catalysts. A comparison of the catalyst structures shows that the Pd(II)‐BINAPHANE catalyst is the only one that has two bulky (R)‐binaphthyl groups close to the reaction site. Hence it creates a deep chiral space that can efficiently control the reaction behavior in the carbonyl‐ene reactions resulting in excellent enantioselectivity.     

Sulfonic Acid‐Catalyzed Autoxidative Carbon‐Carbon Coupling Reaction under Elevated Partial Pressure of Oxygen

An aerobic organocatalytic oxidative C C bond formation reaction of benzylic C H bonds with various C‐nucleophiles is described. The coupling reaction proceeds by simply stirring the substrates under elevated partial pressure of oxygen in the presence of a sulfonic acid catalyst at room temperature. Elevation of the pressure enables the reaction of a broad scope of nucleophile substrates otherwise showing poor reactivity at ambient pressure. The benzylic C H bonds of xanthene, acridanes, isochromane and related heterocycles could be functionalized with nucleophiles including ketones, 1,3‐dicarbonyl compounds and aldehydes. Electron‐rich arenes could be utilized as nucleophiles at elevated temperatures. The reactions are believed to proceed via autoxidation of the benzylic C H bonds to the hydroperoxides and subsequent nucleophilic substitution catalyzed by sulfonic acids.     

A Novel Rhodium‐Catalyzed Cascade Cyclization: Direct Synthesis of 3‐Substituted Phthalides from Aldehydes and Aromatic Acids

A novel rhodium(III)‐catalyzed direct functionalization of ortho C H bonds of benzoic acid derivatives and an intramolecular cyclization sequence generates 3‐substituted phthalides in moderate to good yields. This cascade cyclization involves a Grignard‐type arylation of an aldehyde and subsequent intramolecular nucleophilic substitution. No theoretical waste except for water is generated in the reaction.