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A highly diastereoselective method for the synthesis of dihydroepoxybenzofluorenone derivatives from aromatic/vinylic amides and bicyclic alkenes is described. This new transformation proceeds through cobalt-catalyzed C-H activation and intramolecular nucleophilic addition to the amide functional group. Transition-metal-catalyzed C-H activation reactions of secondary amides with alkenes usually lead to [4+2] or [4+1] annulation; to the best of our knowledge, this is the first time that a [3+2] cycloaddition is described in this context. The reaction proceeds under mild conditions and tolerates a wide range of functional groups. Mechanistic studies imply that the C-H bond cleavage may be the rate-limiting step.

Over the last three decades, transition-metal-catalyzed organic transformations have been shown to be extremely important in organic synthesis. However, most of the successful reactions are associated with noble metals, which are generally toxic, expensive, and less abundant. Therefore, we have focused on catalysis using the abundant first-row transition metals, specifically cobalt. In this Account, we demonstrate the potential of cobalt catalysis in organic synthesis as revealed by our research. We have developed many useful catalytic systems using cobalt complexes. Overall, they can be classified into several broad types of reactions, specifically [2 + 2 + 2] and [2 + 2] cycloadditions; enyne reductive coupling; reductive [3 + 2] cycloaddition of alkynes/allenes with enones; reductive coupling of alkyl iodides with alkenes; addition of organoboronic acids to alkynes, alkenes, or aldehydes; carbocyclization of o-iodoaryl ketones/aldehydes with alkynes/electron-deficient alkenes; coupling of thiols with aryl and alkyl halides; enyne coupling; and C-H bond activation. Reactions relying on π components, specifically cycloaddition, reductive coupling, and enyne coupling, mostly afford products with excellent stereo- and regioselectivity and superior atom economy. We believe that these cobalt-catalyzed π-component coupling reactions proceed through five-membered cobaltacyclic intermediates formed by the oxidative cyclometalation of two coordinated π bonds of the substrates to the low-valent cobalt species. The high regio- and stereoselectivity of these reactions are achieved as a result of the electronic and steric effects of the π components. Mostly, electron-withdrawing groups and bulkier groups attached to the π bonds prefer to be placed near the cobalt center of the cobaltacycle. Most of these transformations proceed through low-valent cobalt complexes, which are conveniently generated in situ from air-stable Co(II) salts by Zn- or Mn-mediated reduction. Overall, we have shown these reactions to be excellent substitutes for less desirable noble-metal systems. Recent successes in cobalt-catalyzed C-H activation have especially advanced the applicability of cobalt in this field. In addition to the more common low-valent-cobalt-catalyzed C-H activation reactions, an in situ-formed cobalt(III) five-membered complex with a 1,6-enyne effectively couples with aromatic ketones and esters through ortho C-H activation, opening a new window in this research area. Interestingly, this reaction proceeds under milder reaction conditions with broad substrate scope. Furthermore, many of the reactions we have developed are highly enantioselective, including enantioselective reductive coupling of enones and alkynes, addition of organoboronic acids to aldehydes, and the cyclization of 2-iodobenzoates with aldehydes. Overall, this Account demonstrates the versatility and utility of cobalt catalysis in organic synthesis.

A new method for the synthesis of highly substituted naphthyridine-based polyheteroaromatic compounds in high yields proceeds through rhodium(III)-catalyzed multiple C-H bond cleavage and C-C and C-N bond formation in a one-pot process. Such highly substituted polyheteroaromatic compounds have attracted much attention because of their unique π-conjugation, which make them suitable materials for organic semiconductors and luminescent materials. Furthermore, a possible mechanism, which involves multiple chelation-assisted ortho C-H activation, alkyne insertion, and reductive elimination, is proposed for this transformation.

An efficient C–H activation method for the ortho alkynylation of aromatic N-methoxyamides with hypervalent iodine–alkyne reagent using a ruthenium catalyst is described. The reaction proceeds under mild reaction conditions with broad substrate scope. A possible catalytic cycle involving a ruthenium carboxylate assisted C–H bond cleavage is proposed from the preliminary mechanistic evidence.

The reaction probably proceeds through a Lewis acidic CuII-assisted rearrangement of benzylic azide to N-methylaniline, followed by a [4+2] cycloaddition with alkene.

The process is found to form the desired carboxylic acids with complete (E) selectivity except for substrate (XV), where an E/Z mixture is identified.

A concise approach to the synthesis of oxindoles and phenanthridones from anilides is described. In the presence of catalytic amount of Pd(OAc) 2 , 2-iodoacetates and 2-iodobenzoates can be used to functionalize ortho C–H bond of anilides, which subsequently undergo intramolecular cyclization to give the products. A possible reaction mechanism that involves a Pd II /Pd IV catalytic cycle is proposed with the support of detailed mechanistic studies.

A highly diastereoselective method for the synthesis of dihydroepoxybenzofluorenone derivatives from aromatic/vinylic amides and bicyclic alkenes is described. This new transformation proceeds through cobalt-catalyzed C-H activation and intramolecular nucleophilic addition to the amide functional group. Transition-metal-catalyzed C-H activation reactions of secondary amides with alkenes usually lead to [4+2] or [4+1] annulation; to the best of our knowledge, this is the first time that a [3+2] cycloaddition is described in this context. The reaction proceeds under mild conditions and tolerates a wide range of functional groups. Mechanistic studies imply that the C-H bond cleavage may be the rate-limiting step.

We describe a highly step and atom economical cobalt-catalyzed cyclization of 1,6-enynes with aldehydes to synthesize functionalized pyrrolidines and dihydrofurans with high chemo- and stereoselectivity. The catalytic reaction plausibly proceeds via the cobaltacycle intermediate generated from the reaction of enyne substrate with cobalt catalyst, followed by switchable C—H functionalization of weakly coordinating aldehydes depending on the electronic nature of the ligand.

A one-pot reaction of substituted benzaldehydes with alkyne-amines by a Rh-catalyzed C-H activation and annulation to afford various natural and unnatural protoberberine alkaloids is reported. This reaction provides a convenient route for the generation of a compound library of protoberberine salts, which recently have attracted great attention because of their diverse biological activities. In addition, pyridinium salt derivatives can also be formed in good yields from α,β-unsaturated aldehydes and amino-alkynes. This reaction proceeds with excellent regioselectivity and good functional group compatibility under mild reaction conditions by using O2 as the oxidant.

Four cobalt-catalyzed oxidative annulation reactions of nitrogen-containing arenes with alkynes proceeds by C-H activation, thus leading to biologically useful quaternary ammonium salts, including pyridoisoquinolinium, cinnolinium, isoquinolinium, and quinolizinium salts, in high yields. The results are comparable to those reactions catalyzed by rhodium and ruthenium complexes. The transformation of the salts into various N-heterocycles has also been demonstrated.

A novel copper promoted synthesis of substituted quinolines from various benzylic azides and internal alkynes has been demonstrated. The reaction features a broad substrate scope, high product yields and excellent regioselectivity. In contrast to the known two-step process of acid promoted [4 + 2] cycloaddition reaction and oxidation, the present methodology allows the synthesis of quinolines in a single step under neutral reaction conditions and can be applied to the synthesis of biologically active 6-chloro-2,3-dimethyl-4-phenylquinoline (antiparasitic agent) and 3,4-diphenylquinolin-2(1H)-one (p38αMAP kinase inhibitor). A plausible reaction mechanism involves rearrangement of benzylic azide to N-arylimine (Schmidt reaction) followed by intermolecular [4 + 2] cycloaddition with internal alkynes.

Cationic N-heterocycles are an important class of organic compounds largely present in natural and bioactive molecules. They are widely used as fluorescent dyes for biological studies, as well as in spectroscopic and microscopic methods. These compounds are key intermediates in many natural and pharmaceutical syntheses. They are also a potential candidate for organic light-emitting diodes (OLEDs). Because of these useful applications, the development of new methods for the synthesis of cationic N-heterocycles has received a lot of attention. In particular, many C-H activation methodologies that realize high step- and atom-economies toward these compounds have been developed. In this review, recent advancements in the synthesis and applications of cationic N-heterocycles through C-H activation reactions are summarized. The new C-H activation reactions described in this review are preferred over their classical analogs.

A novel method for the synthesis of functionalized vinyl arenes by reaction of N-methoxybenzamides or N-phenoxyacetamide (XIV) with vinylstannanes via C—H activation is described.

In recent years, transition-metal-catalyzed directing-groupassisted C H activation has emerged as a sustainable and intriguing protocol for the construction of C C, C N, C O, and C X bonds. In particular, one-pot C C/C N bondforming reactions have been used as key steps for the synthesis of nitrogen-containing natural products and heterocycles in drug discovery. In this context, rhodium catalysts have proven valuable for applications in the step-economical synthesis of complex molecular scaffolds. Although a vast number of rhodium(III)-catalyzed directing-group-assisted C H activation reactions of alkenes and alkynes and nucleophilic addition reactions have been reported, rhodium(III)-catalyzed oxidative C H coupling reactions between arenes or between an arene and an organometallic reagent remain relatively unexplored. Organoboron reagents are stable and powerful reagents for versatile transformations, including the well-known Suzuki–Miyaura coupling. However, very few examples of the use of organoboron reagents as the coupling reagents in palladiumand rhodium(I)-catalyzed C H activation reactions are known. In 2009, Miura and co-workers reported a rhodium(III)-catalyzed oxidative coupling of aryl boronic acids with alkynes to give naphthalenes and anthracenes. We have become interested in the use of N-methoxybenzamides as an important motif for rapid access to phenanthridinone derivatives, which are well-represented in natural products and drugs. Recently, Wang et al. and our research group reported the palladium-catalyzed synthesis of phenanthridinone derivatives from N-methoxybenzamides with iodoarenes and simple arenes, respectively. Although a variety of methods have been documented, a more straightforward alternative method with wide scope under mild conditions is desired for the synthesis of phenanthridinones. Our continuing efforts in metal-catalyzed C H bond activation and cyclization reactions prompted us to explore the reaction of N-methoxybenzamides with aryl boronic acids. Herein we report the Rh-catalyzed regioselective synthesis of phenanthridinones from N-methoxybenzamides and aryl boronic acids through one-pot C C/C N bond formation under mild conditions. To the best of our knowledge, this is the first rhodium-catalyzed dual oxidative C H bond coupling of two aromatic compounds to give a formal [4+2] cyclization product (Scheme 1).

Round and round: An unusual cobalt-catalyzed regio- and enantioselective reductive [3+2] cycloaddition of cyclic enones with alkynes affording bicyclic tertiary alcohols is described. A possible mechanism involving the formation of a cobaltacyclopentene intermediate is proposed.

Many steps make light work: substituted phenanthridinones can be obtained with high regioselectivity and in very good yields by palladium-catalyzed cyclization reactions of N-methoxybenzamides with arenes. The reaction proceeds through multiple oxidative C-H activation and C-C/C-N formation steps in one pot at room temperature, and thus provides a simple method for generating bioactive phenanthridinones.

A novel method for the regio- and stereoselective synthesis of substituted 3-coumaranones from salicylaldehydes and allenes using a rhodium(III) catalyst has been developed. This procedure gives access to new 2-vinyl-substituted 3-coumaranone compounds. The method involves a RhIII-catalyzed aldehyde C–H activation and annulation reactions. Moreover, this RhIII-catalyzed [4 + 1] annulation reaction has been applied to 2-aminobenzaldehydes to afford 2,2-disubstituted 3-indolinones.

The dual annulation of alkyne (VIII) with isolated aldimine (IX) leads to known bioactive tetracyclic derivative (X).

Four cobalt-catalyzed oxidative annulation reactions of nitrogen-containing arenes with alkynes proceeds by C-H activation, thus leading to biologically useful quaternary ammonium salts, including pyridoisoquinolinium, cinnolinium, isoquinolinium, and quinolizinium salts, in high yields. The results are comparable to those reactions catalyzed by rhodium and ruthenium complexes. The transformation of the salts into various N-heterocycles has also been demonstrated.

Transition-metal-catalyzed C - H activation is considered to be an important tool in organic synthesis and has been accepted and widely used by chemists because it is straightforward, cost-effective, and environmentally friendly. A variety of functional groups have been used to direct metal complexes and achieve regioselective C - H activation. Most directing is achieved through the σ-bond coordination of functional groups to the metal catalyst, followed by ortho-selective C - H bond cleavage. However, recent work has demonstrated that π-coordinating functional groups can also assist in guiding metal complexes for site-selective C - H bond activation. This emerging approach significantly expands the scope of C - H activation reactions in organic synthesis. Herein, recent developments in this field are summarized.

The Heck reaction is a well-established transition-metal catalyzed reaction for coupling alkenes with sp2 alkyl halides to give novel unsaturated compounds. Herein we report an analogous Heck-inspired, simple efficient coupling of sp3 alkyl halides with electron-withdrawing alkenes to form reductive coupling products where saturated esters are obtained. A range of acrylates were coupled with sp3 alkyl halides in the presence of Ni(PPh3)2Cl2 catalyst, Zn metal powder, CH3CN solvent, and water, at 80 °C to form the reductive Heck type saturated ester products in good yields. This strategy was further extended to couple oxabenzonorbornadiene with the alkyl halides resulting in ring opening to give rise to bicyclic alcohol products. The mechanism for both the reactions appears to be the usual oxidative-addition driven alkene insertion reaction where the water appears to act as the protonating agent.

Highly substituted pyridinium salts are synthesized via a multicomponent reaction of vinyl ketones/aldehydes, amines, and alkynes.

ConspectusOver the last three decades, transition-metal-catalyzed organic transformations have been shown to be extremely important in organic synthesis. However, most of the successful reactions are associated with noble metals, which are generally toxic, expensive, and less abundant. Therefore, we have focused on catalysis using the abundant first-row transition metals, specifically cobalt. In this Account, we demonstrate the potential of cobalt catalysis in organic synthesis as revealed by our research.We have developed many useful catalytic systems using cobalt complexes. Overall, they can be classified into several broad types of reactions, specifically [2 + 2 + 2] and [2 + 2] cycloadditions; enyne reductive coupling; reductive [3 + 2] cycloaddition of alkynes/allenes with enones; reductive coupling of alkyl iodides with alkenes; addition of organoboronic acids to alkynes, alkenes, or aldehydes; carbocyclization of o-iodoaryl ketones/aldehydes with alkynes/electron-deficient alkenes; coupling of thio...

An efficient o-arylation of pivalamides by aryl iodides via rhodium(III)-catalyzed C–H activation is demonstrated for the first time. Further, the biaryl products can be converted effectively into biologically active phenanthridine and phenanthridinone derivative.

This efficient reaction which proceeds regioselectively at the sterically more congested C—H bond can be scaled up.

Rh-catalyzed reaction of N-hydroxybenzamidines with an excess of internal alkynes and an excess of Cu(OAc)2 as the oxidant is described to produce polyhetarenes in good yields.

The highly chemo- and stereoselective title reaction furnishes functionalized pyrrolidines and dihydrofurans via cobalt-triggered C-H activation.

[Reaction: see text]. An efficient method for the synthesis of cis-2-alkyl- or allyl-1,2-dihydronaphthalenes via a nickel-catalyzed highly regio- and stereoselective ring-opening addition of alkyl- or allylzirconium reagents to 7-oxabenzonorbornadienes is described. Treatment of 7-oxabenzonorbornadienes 1a-c with various alkylzirconium reagents 2a-j (Cp2ZrClCH2CH2R: R = tert-butyl, n-butyl, n-pentyl, -(CH2)3CH=C(CH3)2, -SiMe3, -CH2SiMe3, -(CH2)3Br, cyclopentyl, cyclohexyl, and benzyl) in the presence of NiBr2(dppe) and Zn powder in dry THF at 50 degrees C afforded the corresponding cis-2-alkyl-1,2-dihydronaphthalene derivatives 3a-m in good yields. In addition, allyl zirconium reagents 4a-c also underwent ring-opening reactions with 1a and 1c to give 5a-d in very good yields. The alkylative ring-opening products from 7-oxabenzonorbornadiene can be further converted to naphthalene derivatives 6a-c, via an acid-mediated dehydration, in good to excellent yields. A possible mechanism for the present catalytic reaction was proposed.

A highly regio- and stereoselective ring-opening addition of alkenylzirconium reagents to bicyclic olefins catalyzed by nickel complexes was described. Treatment of 7-oxa- and 7-azabenzonorbornadienes (1a-e) with various terminal alkenylzirconium reagents 2a-f (Cp(2)ZrClCH=CHR; R = t-Bu, n-Pr, n-Oct, 1-cyclohexenyl, SiMe(3), and Ph) in the presence of Ni(PPh(3))(2)Cl(2) and Zn powder (or a combination of ZnCl(2) and NEt(3)) in dry THF at 50 degrees C afforded the corresponding cis-2-alkenyl-1,2-dihydronaphthalene derivatives 3a-l in moderate to excellent yields. Under similar reaction conditions, internal alkenylzirconium reagents 2g,h (Cp(2)ZrClCR=CHR: R = Et and n-Pr) also undergo ring-opening addition to oxanorbornadienes 1a and 1d to give cis-2-alkenyl-1,2-dihydronaphthalene derivatives 4a-c in good yields. Possible pathways involving the transfer of alkenyl group in the alkenylzirconium reagent to the Ni(II) center followed by migration of the alkenyl group from the Ni(II) center to the carbon-carbon double bond of 7-oxanorbornadiene or the reaction of 7-oxanorbornadiene with Ni(0) to form a Ni(II)-pi-allyl prior to the transfer of the alkenyl group as key steps for the catalytic reaction were proposed and discussed.

In the presence of CoX 2 (PPh 3 ) 2 /3 PPh 3 and zinc metal conjugated alkenes (CH 2 CHCOOR, CH 2 CHCN, CH 2 CHSO 2 Ph and CH 2 CHCONEt 2 ) undergo reductive tail-to-tail dimerization to yield the corresponding saturated linear products. Under similar reaction conditions, vinylarenes (ArCHCH 2 ) give stereoselective head-to-tail dimerization products, trans -1,3-diarylbut-1-ene, in good to excellent yields.

In the presence of Ni(dppe)Br(2) and Zn powder in acetonitrile at 80 degrees C, oxa-bicyclic olefins undergo cyclization with o-iodobenzoate and with beta-iodo-(Z)-propenoates to give the benzocoumarin derivatives in moderate to good yields. This methodology offers a simple efficient way for the synthesis of structurally complicate coumarins in one pot. [reaction: see text]

A new method for the synthesis of substituted 2-acylallylmetal reagents in a highly regio- and stereoselective fashion involving a three-component assembly of allenes, acyl chlorides, and bimetallic reagents (B-B, Si-Si, and Sn-Sn) catalyzed by phosphine-free palladium complexes is described. Treatment of various allenes (CR(2)R(3)=C=CH(2)) with acyl chlorides (R(1)COCl) and bispinacolatodiboron in the presence of PdCl(2)(CH(3)CN)(2) in toluene at 80 degrees C gave 2-acylallylboronates in moderate to good yields. The acylsilation of allenes with acid chlorides and hexamethyldisilane (5) proceeded successfully in the presence of Pd(dba)(2) in CH(3)CN affording the corresponding allylsilanes (CR(2)R(3)=C(COR(1))CH(2)SiMe(3)) in good to moderate yields. Several chloroformates (R(4)OCOCl) also react with 1,1-dimethylallene (2a) and 5 to afford allylsilanes (CR(2)R(3)=C(COOR(4))CH(2)SiMe(3)) in 66-70% yields. Acylstannation of allenes could also be achieved by slow addition of hexabutylditin (10) to the reaction mixture of acyl chloride (or chloroformate) and allene 2a in CH(3)CN in the presence of Pd(dba)(2) at 60 degrees C; the corresponding 2-substituted allylstannanes were isolated in moderate to good yields. The above catalytic reactions are completely regioselective and highly stereoselective. A mechanism is proposed to account for the catalytic reactions and the stereochemistry.

An efficient method for the preparation of various monosubstituted arylallenes, disubstituted allenes and alkenylallenes via palladium-catalyzed coupling of allenylstannanes with aryl iodides or alkenyl iodides is described. The coupling reaction was carried out in the presence of Pd(PPh 3 ) 4 and LiCl using DMF as solvent. The possible role of LiCl in this coupling process is discussed based on the 119 Sn NMR studies.

A novel acid-catalyzed ring expansion of methanofullerenes bearing an alpha-ylidic ester has been investigated. Treatment of dialkyl acetylenedicarboxylate and tricycloalkylphosphine with C(60) led to the isolation of a methanofullerene ylide after passing the reaction mixtures through a basic alumina column. If the reaction mixture was passed through a silica gel column, a cyclopentanofullerene was isolated instead. These new cyclopentanofullerenes consisted of a fused cyclopentanone ring bearing an alpha-hydroxy ester and a phosphonium ylide and were confirmed by their NMR, mass, and X-ray diffraction data. The cyclopentanofullerenes were formed by the ring expansion of the corresponding methanofullerenes in the presence of silica gel. The ring expansion also proceeded by treating methanofullerene with acetic acid in chloroform. On the other hand, the methanofullerenes from RO(2)CCCCO(2)R, PAr(3), and C(60) were stable in silica gel. However, upon heating with acetic acid at 50 degrees C, they underwent ring expansion and dephosphination to give cyclopentenofullerenes. An implicit vinyl cyclopropane ring expansion mechanism was proposed to account for this novel acid-catalyzed rearrangement.

A nickel-catalyzed regio- and stereoselective reductive coupling of oxa- and azabicyclic alkenes with activated alkenes and electron-rich alkynes is described. Thus, 7-oxabenzonorbornadienes underwent reductive coupling with various vinyl ketones such as ethyl, methyl, propyl and alpha-methyl-substituted vinyl ketones, in the presence of a nickel(II) iodide (NiI2), zinc (Zn), and water catalyst system in acetonitrile at 50 degrees C for 14 h to afford 2-alkylnaphthalenes in good to excellent yields. Under similar reaction conditions, 7-azabenzonorbornadiene derivatives provided cis-2-alkyl-1,2-dihydro-naphthalene derivatives in high yields. On the other hand, the nickel(II) iodide, tris(4-fluorophenyl)phoshine [P(4-FC6H4)(3)] and zinc catalyst system successfully catalyzed the reductive coupling reaction of electron-rich alkynes, with 7-aza- and 7-oxabenzonorbornadienes to give cis-2-alkenyl-1,2-dihydronaphthalene derivatives in good to excellent yields. In the reaction, a mild reducing agent (zinc) and simple hydrogen source (water) were used.

A nickel-catalyzed, highly regioselective conjugate addition of boronic acids to dienones to form 1,4-addition products with an all-carbon quaternary center is described.

The highly regioselective synthesis of unprotected indoles involves the reaction of the hydrochloride substrates with diethyl ketone to form hydrazones.

The target compounds can be obtained from the premade imines or imines, generated in situ from anilines and aldehydes, with arenes.

Moreover, the intramolecular reductive coupling of ene-phthalimide (XI) proceeds highly diastereoselective.

Metal-catalyzed annulation reactions to synthesize carbo- and heterocycles have been an attractive field of research for many years. The development of new cyclization reactions utilizing readily available less expensive metal catalyst is one of the important tasks. In this regard, this review summerizes and discusses about nickel- and cobalt-catalyzed [4+2] and [3+2] annulation reactions of ortho-halo substituted imines and alkynes. Nickel complexes under suitable reaction conditions underwent [4+2] annulation to form six-membered isoquinoline (salts) derivatives. However, cobalt complexes afforded aminoindenes via [3+2] annulation reactions. Both reactions proceed through a five membered metallacycle. The regioselective insertion of alkyne containing keto or ester groups into the metallacycle further demonstrates the difference in selectivity of these metal complexes.

The presented oxidative carbonylation of 2-arylphenols proceeds under acid-base free and mild conditions with a variety of substrates.

An efficient method for the synthesis of highly substituted isoquinolines by a Rh(III)-catalyzed hydrazone directed ortho C—H bond activation and annulation without an external oxidant is described.

A convenient, mild, and efficient method for the synthesis of a broad range of substituted isoquinolinium salts from pyridines and alkynes is presented.

The one-pot synthesis of substituted phenanthridinones involves a rhodium-catalyzed dual C—H bond activation and annulation reactions.

Discover nickel! A nickel-catalyzed alkenylative cyclization of 1,6-enynes and alkenyl boronic acids affording substituted pyrrolidines and dihydrofurans is described (see scheme; cod = 1,5-cyclooctadiene, Ts = p-toluene sulfonate). The reaction is highly chemo- and stereoselective. A possible reaction mechanism involving a nickelacyclopentene intermediate is proposed.

2-Aminoaryl methyl ketones undergo intramolecular oxidative C–H amination to give the corresponding substituted isatins under an oxygen atmosphere in the presence of [CuI(bpy)]2.