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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.

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).

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.

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.

An efficient synthesis of quinolizinium salts from 2-vinylpyridines and alkynes via Rh(III) or Ru(II)-catalyzed C–H activation and annulation reaction is described. A possible mechanism involving pyridine assisted vinylic ortho-C–H activation, alkyne insertion and reductive elimination is proposed.

A new rhodium-catalyzed synthesis of biologically active cinnolinium salts from various azobenzenes and alkynes under air is described.

The reductive coupling of an aryl carbonyl group with an activated alkene to give the corresponding γ-hydroxybutyric acid (GHBA) derivative was achieved in the presence of zinc and ammonia. A board scope of GHBA derivatives could be synthesized under ambient conditions by this method. A mechanism involving a Zn-ketyl radical as the key intermediate is proposed.

The synthesis of highly substituted naphthalenes from allylarenes and alkynes is described.

A highly regio- and diastereoselective three-component reductive coupling reaction affording exo-5,6-disubstituted 7-oxanorbornene derivatives in good to excellent yields is reported.

A copper-catalyzed intramolecular oxidative C—H functionalization of 2-aminobenzophenone affords two regioisomeric 6-membered-ring acridones.

The reaction proceeds with high regioselectivity under mild conditions to afford a broad spectrum of substituted title compounds through C—C and C—N coupling.

It all adds up: The 1,4-addition of organoboronic acids to activated alkenes catalyzed by [Co(dppe)Cl(2)] is described. A [3+2]-annulation reaction of ortho-iminoarylboronic acids with acrylates to give various aminoindane carboxylic acid derivatives with cis-stereoselectivity is also demonstrated (see scheme; dppe = 1,2-bis(diphenylphosphino)ethane).

The bridged alcohol systems are synthesized by reductive [3 + 2] cycloaddition of cyclic enones with alkynes in the presence of Co salts.

In the presence of suitable ligands the reaction allows a mild, convenient, and highly selective access to a number of trans-disubstituted alkenes.

The palladium-catalyzed oxidative cyclization of benzophenones (I) leads to desired fluorenones (II) in good yields.

Under optimized conditions, the amidation occurs regioselectively at the ortho-position of the phenyl ring.

An efficient method for the synthesis of substituted isoquinolinium salts from benzaldehydes, amines, and alkynes via ruthenium-catalyzed C–H bond activation and annulation in one pot is described.

A new method for the synthesis of various isochromen-6-ones and phenanthro[1,10-bc]oxepines via a palladium-catalyzed cascade carbocyclization of 2-iodobenzyl-3-phenylpropiolates and 1-iodo-2-(2-(phenylethynyl)benzyloxy)benzenes with arynes is described. The reactions involve interesting biscarbocyclization of alkynes and benzynes and C–H bond activation.

Pd-catalyzed selective ortho-olefination of arenes assisted by an allylic C–C double bond at room temperature using O2 as a terminal oxidant is described. A possible mechanism involving the initial coordination of allylic C═C bond to Pd followed by selective o-C–H bond metalation is proposed.