meta‐C−H Bromination on Purine Bases by Heterogeneous Ruthenium Catalysis

Methods for positionally selective remote C−H functionalizations are in high demand. Herein, we disclose the first heterogeneous ruthenium catalyst for meta ‐selective C−H functionalizations, which enabled remote halogenations with excellent site selectivity and ample scope. The versatile heterogeneous Ru@SiO₂ catalyst was broadly applicable and could be easily recovered and reused, which set the stage for the direct fluorescent labeling of purines. In contrast to palladium, rhodium, iridium, or cobalt complexes, solely the ruthenium catalysis manifold provided access to meta ‐halogenated purine derivatives, illustrating the unique power of ruthenium C−H activation catalysis.     

Programmed Site‐Selective Palladium‐Catalyzed Arylation of Thieno[3,2‐b]thiophene

Mono‐, di‐, tri‐, and tetraarylated thieno[3,2‐b ]thiophenes were synthesized by direct site‐selective Pd‐catalyzed C−H activation reactions with various aryl bromides in the presence of a phosphine‐free Pd(OAc)₂/KOAc catalyst system in N ,N ‐dimethylacetamide (DMAc). The arylation of 2‐arylthieno[3,2‐b ]thiophene took place at the C3 position if the 2‐aryl substituents possessed electron‐withdrawing groups and at the C5 position if they were bulky and possessed electron‐donating groups.     

Rhodium‐Catalyzed meta‐C−H Functionalization of Arenes

Rhodium‐catalyzed ortho ‐C−H functionalization is well known in the literature. Described herein is the Xphos‐supported rhodium catalysis of meta ‐C−H olefination of benzylsulfonic acid and phenyl acetic acid frameworks with the assistance of a para ‐methoxy‐substituted cyano phenol as the directing group. Complete mono‐selectivity is observed for both scaffolds. A wide range of olefins and functional groups attached to arene are tolerated in this protocol.     

Outer‐Sphere 2 e−/2 H+ Transfer Reactions of Ruthenium(II)‐Amine and Ruthenium(IV)‐Amido Complexes

A diverse set of 2 e⁻/2 H⁺ reactions are described that interconvert [Ru^II(bpy)(en*)₂]²⁺ and [Ru^IV(bpy)(en‐H*)₂]²⁺ (bpy=2,2′‐bipyridine, en*=H₂NCMe₂CMe₂NH₂, en*‐H=H₂NCMe₂CMe₂NH⁻), forming or cleaving different O−H, N−H, S−H, and C−H bonds. The reactions involve quinones, hydrazines, thiols, and 1,3‐cyclohexadiene. These proton‐coupled electron transfer reactions occur without substrate binding to the ruthenium center, but instead with precursor complex formation by hydrogen bonding. The free energies of the reactions vary over more than 90 kcal mol⁻¹, but the rates are more dependent on the type of X−H bond involved than the associated ΔG °. There is a kinetic preference for substrates that have the transferring hydrogen atoms in close proximity, such as ortho ‐tetrachlorobenzoquinone over its para ‐isomer and 1,3‐cyclohexadiene over its 1,4‐isomer, perhaps hinting at the potential for concerted 2 e⁻/2 H⁺ transfers.     

Photocatalytic Dehydrogenative Cross‐Coupling of Alkenes with Alcohols or Azoles without External Oxidant

Direct cross‐coupling between alkenes/R‐H or alkenes/RXH is a dream reaction, especially without external oxidants. Inputting energy by photocatalysis and employing a cobalt catalyst as a two‐electron acceptor, a direct C−H/X−H cross‐coupling with H₂ evolution has been achieved for C−O and C−N bond formation. A new radical alkenylation using alkene as the redox compound is presented. A wide range of aliphatic alcohols—even long chain alcohols—are tolerated well in this system, providing a new route to multi‐substituted enol ether derivatives using simple alkenes. Additionally, this protocol can also be used for N ‐vinylazole synthesis. Mechanistic insights reveal that the cobalt catalyst oxidizes the photocatalyst to revive the photocatalytic cycle.     

Asymmetric Cycloisomerization of o‐Alkenyl‐N‐Methylanilines to Indolines by Iridium‐Catalyzed C(sp3)−H Addition to Carbon–Carbon Double Bonds

Highly enantioselective cycloisomerization of N ‐methylanilines, bearing o ‐alkenyl groups, into indolines is established. An iridium catalyst bearing a bidentate chiral diphosphine effectively promotes the intramolecular addition of the C(sp³)−H bond across a carbon–carbon double bond in a highly enantioselective fashion. The reaction gives indolines bearing a quaternary stereogenic carbon center at the 3‐position. The reaction mechanism involves rate‐determining oxidative addition of the N ‐methyl C−H bond, followed by intramolecular carboiridation and subsequent reductive elimination.     

Rhodium‐Catalyzed PIII‐Directed ortho‐C−H Borylation of Arylphosphines

Transition‐metal‐mediated metalation of an aromatic C?H bond that is adjacent to a tertiary phosphine group in arylphosphines via a four‐membered chelate ring was first discovered in 1968. Herein, we overcome a long‐standing problem with the ortho‐C?H activation of arylphosphines in a catalytic fashion. In particular, we developed a rhodium‐catalyzed ortho‐selective C?H borylation of various commercially available arylphosphines with B₂pin₂ through P^III‐chelation‐assisted C?H activation. This discovery is suggestive of a generic platform that could enable the late‐stage modification of readily accessible arylphosphines.     

Aldehyde‐Assisted Ruthenium(II)‐Catalyzed CH Oxygenations

Versatile ruthenium(II) complexes allow for site‐selective C? H oxygenations with weakly‐coordinating aldehydes. The challenging C? H functionalizations proceed with high chemoselectivity by rate‐determining C? H metalation. The new method features an ample substrate scope, which sets the stage for the step‐economical preparation of various bioactive heterocycles.     

Highly para‐Selective C−H Alkylation of Benzene Derivatives with 2,2,2‐Trifluoroethyl α‐Aryl‐α‐Diazoesters

Compared to the most popular directing‐group‐assisted strategy, the “undirected” strategy for C−H bond functionalization represents a more flexible but more challenging approach. Reported herein is a gold‐catalyzed highly site‐selective C(sp²)−H alkylation of unactivated arenes with 2,2,2‐trifluoroethyl α‐aryl‐α‐diazoesters. This protocol demonstrates that high site‐selective C−H bond functionalization can be achieved without the assistance of a directing group. In this transformation, both the gold catalyst and trifluoroethyl group on the ester of the diazo compound play vital roles for achieving the chemo‐ and regioselectivity.     

Bifurcated Nickel‐Catalyzed Functionalizations: Heteroarene C−H Activation with Allenes

A unified strategy for nickel(0)‐catalyzed C−H allylations, alkenylations, and dienylations has been realized through versatile hydroarylations of allenes with ample scope. Thus, an inexpensive nickel catalyst modified with a N ‐heterocyclic carbene ligand enabled the direct transformation of C−H bonds of biologically relevant imidazole and purine derivatives with full control of regio‐ and chemoselectivity.     

4‐Amino‐7‐(2‐de­oxy‐2‐fluoro‐β‐d‐arabinofuranos­yl)‐5‐fluoro‐7H‐pyrrolo[2,3‐d]pyrimidine: a bis‐fluorinated analogue of 2′‐deoxy­tubercidin

The title compound, C₁₁H₁₂F₂N₄O₃, exhibits an anti glycosylic bond conformation, with a torsion angle χ = −117.8 (2)°. The sugar pucker is N‐type (C4′‐exo, between ³T₄ and E₄, with P = 45.3° and τ_m = 41.3°). The conformation around the exocyclic C—C bond is −ap (trans), with a torsion angle γ = −177.46 (15)°. The nucleobases are stacked head‐to‐head. The crystal structure is characterized by a three‐dimensional hydrogen‐bond network involving N—H⋯O, O—H⋯O and O—H⋯N hydrogen bonds.     

Electrooxidative Ruthenium‐Catalyzed C−H/O−H Annulation by Weak O‐Coordination

Electrocatalysis has been identified as a powerful strategy for organometallic catalysis, and yet electrocatalytic C?H activation is restricted to strongly N‐coordinating directing groups. The first example of electrocatalytic C?H activation by weak O‐coordination is presented, in which a versatile ruthenium(II) carboxylate catalyst enables electrooxidative C?H/O?H functionalization for alkyne annulations in the absence of metal oxidants; thereby exploiting sustainable electricity as the sole oxidant. Mechanistic insights provide strong support for a facile organometallic C?H ruthenation and an effective electrochemical reoxidation of the key ruthenium(0) intermediate.     

Lewis Acid–Base Interaction‐Controlled ortho‐Selective C−H Borylation of Aryl Sulfides

An iridium/bipyridine‐catalyzed ortho ‐selective C−H borylation of aryl sulfides was developed. High ortho ‐selectivity was achieved by a Lewis acid–base interaction between a boryl group of the ligand and a sulfur atom of the substrate. This is the first example of a catalytic and regioselective C−H transformation controlled by a Lewis acid–base interaction between a ligand and a substrate. The C−H borylation reaction could be conducted on a gram scale, and with a bioactive molecule as a substrate, demonstrating its applicability to late‐stage regioselective C−H borylation. A bioactive molecule was synthesized from an ortho ‐borylated product by converting the boryl and methylthio groups of the product.     

2′‐De­oxy‐2‐fluoro­tubercidin

In the title compound [systematic name: 7‐(2‐de­oxy‐β‐d ‐erythro‐pentofuranos­yl)‐2‐fluoro‐7H‐pyrrolo[2,3‐d]pyrimidin‐2‐amine], C₁₁H₁₃FN₄O₃, the conformation of the N‐glycosylic bond is between anti and high‐anti [χ = −110.2 (3)°]. The 2′‐deoxy­ribofuranosyl unit adopts the N‐type sugar pucker (₄T³), with P = 40.3° and τ_m = 39.2°. The orientation of the exocyclic C4′—C5′ bond is −ap (trans), with a torsion angle γ = −168.39 (18)°. The nucleobases are arranged head‐to‐head. The crystal structure is stabilized by four inter­molecular hydrogen bonds of types N—H⋯N, N—H⋯O and O—H⋯O.     

Surprisingly Different Reaction Behavior of Alkali and Alkaline Earth Metal Bis(trimethylsilyl)amides toward Bulky N‐(2‐Pyridylethyl)‐N′‐(2,6‐diisopropylphenyl)pivalamidine

N‐(2,6‐Diisopropylphenyl)‐N′‐(2‐pyridylethyl)pivalamidine (Dipp‐N=C(tBu)‐N(H)‐C₂H₄‐Py) ( 1 ), reacts with metalation reagents of lithium, magnesium, calcium, and strontium to give the corresponding pivalamidinates [(tmeda)Li{Dipp‐N=C(tBu)‐N‐C₂H₄‐Py}] ( 6 ), [Mg{Dipp‐N=C(tBu)‐N‐C₂H₄‐Py}₂] ( 3 ), and heteroleptic [{(Me₃Si)₂N}Ae{Dipp‐N=C(tBu)‐N‐C₂H₄‐Py}], with Ae being Ca ( 2 a ) and Sr ( 2 b ). In contrast to this straightforward deprotonation of the amidine units, the reaction of 1 with the bis(trimethylsilyl)amides of sodium or potassium unexpectedly leads to a β‐metalation and an immediate deamidation reaction yielding [(thf)₂Na{Dipp‐N=C(tBu)‐N(H)}] ( 4 a ) or [(thf)₂K{Dipp‐N=C(tBu)‐N(H)}] ( 4 b ), respectively, as well as 2‐vinylpyridine in both cases. The lithium derivative shows a similar reaction behavior to the alkaline earth metal congeners, underlining the diagonal relationship in the periodic table. Protonation of 4 a or the metathesis reaction of 4 b with CaI₂ in tetrahydrofuran yields N‐(2,6‐diisopropylphenyl)pivalamidine (Dipp‐N=C(tBu)‐NH₂) ( 5 ), or [(thf)₄Ca{Dipp‐N=C(tBu)‐N(H)}₂] ( 7 ), respectively. The reaction of AN(SiMe₃)₂ (A=Na, K) with less bulky formamidine Dipp‐N=C(H)‐N(H)‐C₂H₄‐Py ( 8 ) leads to deprotonation of the amidine functionality, and [(thf)Na{Dipp‐N=C(H)‐N‐C₂H₄‐Py}]₂ ( 9 a ) or [(thf)K{Dipp‐N=C(H)‐N‐C₂H₄‐Py}]₂ ( 9 b ), respectively, are isolated as dinuclear complexes. From these experiments it is obvious, that β‐metalation/deamidation of N‐(2‐pyridylethyl)amidines requires bases with soft metal ions and also steric pressure. The isomeric forms of all compounds are verified by single‐crystal X‐ray structure analysis and are maintained in solution.     

Ruthenium(II)‐Catalyzed meta C−H Mono‐ and Difluoromethylations by Phosphine/Carboxylate Cooperation

Ruthenium(II)‐catalyzed meta ‐selective C−H (di)fluoromethylation was accomplished by phosphine and carboxylate cooperation. The remote C−H functionalization was characterized by ample substrate scope, thereby setting the stage for meta ‐(di)fluoromethylation through facile C−H cleavage.     

para‐Selective C−H Borylation of (Hetero)Arenes by Cooperative Iridium/Aluminum Catalysis

para ‐Selective C−H borylation of benzamides and pyridines has been achieved by cooperative iridium/aluminum catalysis. A combination of iridium catalysts commonly employed for arene C−H borylation and bulky aluminum‐based Lewis acid catalysts provides an unprecedented strategy for controlling the regioselectivity of C−H borylation to give variously substituted (hetero)arylboronates, which are versatile synthetic intermediates for complex multi‐substituted aromatic compounds.     

Iron‐Catalyzed Oxidative C−C and N−N Coupling of Diarylamines and Synthesis of Spiroacridines

We describe iron‐catalyzed intermolecular oxidative coupling reactions of diarylamines to form substituted 2,2′‐bis(arylamino)biaryl compounds, tetraarylhydrazines, and 5,6‐dihydrobenzo[c ]cinnolines with the same hexadecafluorinated iron–phthalocyanine catalyst. The mild formation of C−C or N−N bonds was controlled by the use of acidic or basic additives. In contrast to most iron‐catalyzed dehydrogenative coupling reactions, ambient air could be used as the sole oxidant. Moreover, iron(III) chloride hexahydrate promoted a one‐pot coupling and subsequent intramolecular dearomative coupling to give 10H ‐spiro[acridine‐9,1′‐cyclohexa‐2′,5′‐dien‐4′‐ones].     

Designing Homogeneous Bromine Redox Catalysis for Selective Aliphatic C−H Bond Functionalization

The potential of homogeneous oxidation catalysis employing bromine has remained largely unexplored. We herein show that the combination of a tetraalkylammonium bromide and meta‐chloroperbenzoic acid offers a unique catalyst system for the convenient and selective oxidation of saturated C(sp³)−H bonds upon photochemical initiation with day light. This approach enables remote, intramolecular, position‐selective C−H amination as demonstrated for 20 different examples. For the first time, an N‐halogenated intermediate was isolated as the active catalyst state in a catalytic Hofmann–Löffler reaction. In addition, an expeditious one‐pot synthesis of N‐sulfonyl oxaziridines from N‐sulfonamides was developed and exemplified for 15 transformations. These pioneering examples provide a change in paradigm for molecular catalysis with bromine.     

Thioamide‐Directed Cobalt(III)‐Catalyzed Selective Amidation of C(sp3)−H Bonds

A mild, oxidant‐free, and selective Cp*Co^III‐catalyzed amidation of thioamides with robust dioxazolone amidating agents via C(sp³)−H bond activation to generate the desired amidated products is reported. The method is efficient and allows for the C−H amidation of a wide range of functionalized thioamides with aryl‐, heteroaryl‐, and alkyl‐substituted dioxazolones under the Cp*Co^III‐catalyzed conditions. The observed regioselectivity towards primary C(sp³)−H activation is supported by computational studies and the cyclometalation is proposed to proceed by means of an external carboxylate‐assisted concerted metalation/deprotonation mechanism. The reported method is a rare example of the use of a directing group other than the commonly used pyridine and quinolone classes for Cp*Co^III‐catalyzed C(sp³)−H functionalization and the first to exploit thioamides.