C -H functionalization

Using a somewhat different C-H functionalization approach to benzimidazoles, Punniyamurthy and co-workers have explored the conversion of A -benzyl bisarylhydrazones to 2-aryl-A -benzyl-benzimidazoles. This conversion is optimally achieved using stoichiometric Cu(OTf)2 in toluene at 110 °C. (This transformation was also reported using catalytic Cu(OTf)2 (20 mol%) under an oxygen atmosphere, albeit in lower yield). This reaction likely proceeds via a copper-amidine intermediate analogous to the intermediate accessed by Brasche and Buchwald in their direct intramolecular arylation of iV-aryl amidines. 

9 Alternative Cyclization Approach Toward Benzimidazoles Process 

6 Suggest a mechanism for the following copper-catalyzed crosscycloaddition between two different isocyanides to produce an imidazole as 

8 Propose a mechanism for the palladium-catalyzed multi-component one-step synthesis of imidazoles from imines and acid chlorides.  

9 Alkylation of 4(5)-iodoimidazole with benzyl bromide provides a mixture of the 1-benzyl 4- and 5-idodo-l//-imidazoles. Provide conditions and draw the mechanism for selective conversion to 1-benzyl-4-iodo- l/Z-imidazole.  

Two of the major goals of alkane functionalization have been the selective conversion of methane to methanol and the replacement of strong terminal alkyl C-H bonds with a functional group. These goals have also included the selective functionalization of a single aliphatic or aromatic C-H bond, directed by either a substituent attached to the arene or controlled by the particular steric or electronic properties of the substrate. Thus, many of the principles that have been developed for the functionalization of small molecules with the goal of producing chemical feedstocks have now been adopted for more intricate synthetic applications. 

Functionalization of alkanes under mild conditions catalyzed by coordination complexes is known. For example, much of the cyclohexanol and cyclohexanone used in the synthesis of adipic acid is produced by the oxidation of cyclohexane with a cobalt catalyst. Chapter 18, however, focuses on the t) pes of alkane functionalization that occur by the reactions described 

Second, the strongest C-H bonds are the most desirable to functionalize with metal catalysts. Because radical reactions can be used to functionalize alkanes or alkyl chains at secondary C-H bonds, one target of catalytic alkane functionalization is the development of reactions at terminal C-H bonds. Because these C-H bonds are stronger than secondary and tertiary C-H bonds and because terminal carbons less readily support an accumulation of positive charge than internal carbons, many reactions of unfunctionalized C-H bonds occur less readily at primary C-H bonds than at secondary and tertiary C-H bonds. 

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Fused pyrazole compounds have been prepared from A-alkyl substituted pyrazoles. For example, a palladium-catalyzed/norbornene-mediated sequential coupling reaction involving an aromatic sp2 C-H functionalization as the key step has been described, in which an alkyl-aryl bond and an aryl-heteroaryl bond were formed in one pot <060L2043>. A variety of highly substituted six-membered annulated pyrazoles 59 were synthesized in a one-step process in moderate yields from IV-bromoalkyl pyrazoles 57 and aryl iodides 58. 

Synthetic organic chemistry applications employing alkane C-H functionalizations are now well established. For example, alkanes can be oxidized to alkyl halides and alcohols by the Shilov system employing electrophilic platinum salts. Much of the Pt(ll)/Pt(rv) alkane activation chemistry discussed earlier has been based on Shilov chemistry. The mechanism has been investigated and is thought to involve the formation of a platinum(ll) alkyl complex, possibly via a (T-complex. The Pt(ll) complex is oxidized to Pt(iv) by electron transfer, and nucleophilic attack on the Pt(iv) intermediate yields the alkyl chloride or alcohol as well as regenerates the Pt(n) catalyst. This process is catalytic in Pt(ll), although a stoichiometric Pt(rv) oxidant is often required (Scheme 6).27,27l 2711... 

The intermolecular functionalization of benzylic and activated methylene r/>3-C-H bonds represents another burgeoning field in C-H activation chemistry. A recent sp3-benzylic C-H functionalization was disclosed involving an Ir(m)acac analog. Such a reaction is retarded by pyridine addition, indicating that pyridine loss may initiate the C-H functionalization step. An Ir(v) intermediate has been postulated (Equation (30)).12... 

A mechanism for this process has been postulated involving 73-benzylrhodium intermediates (Scheme 9).39 Gold-catalyzed couplings of activated methylene derivatives with olefins have been postulated to proceed via an in situ formed Au(i) intermediate.40 403 Indeed, gold-mediated C-H functionalization processes are becoming very popular (Equation (32)). For other relevant papers on gold chemistry, see Refs 41 and 41a. 

Thermolysis of ruthenium carbene complexes leads to intramolecular r/> -bcnzylic C-H functionalization in the presence of a hydrogen-accepting olefin (Equation (35)).44,44a. 

The copper-mediated stereoselective C-H functionalization of a prochiral benzyl sp1, as well as an r/>-C-H bonds leads to good enantioselectivities (Equation (45)).so... 

Directed. s/ 3-benzylic C-H functionalization can lead to C-Si bond formation with both mono- and bis-silylated compounds obtained (Equations (53) and (54)). 

Directed sp2 -C-H functionalizations enable the catalytic transformation to be controlled by a coordinating group, often leading to ort o-functionalized products. These are extremely popular processes, and a selection of these reactions have been reviewed in Section 10.03.3.2.60 In contrast, non-directed sp2-C-H functionalization processes are invariably less selective but synthetically more desirable since a directing group is not required. Examples of selective non-directed sp2-C-H functionalizations will be presented, where the regioselective outcome of the reaction is usually more difficult to control. 

More mechanistic insight into the C-H functionalization process of arenes is provided by theoretical and experimental studies. Multifluorinated, electron poor, aromatic substrates readily undergo CH activation with coordina-tively unsaturated rhenium complexes, attributed to the stronger C-Re bond in the product, whereas with monofluorinated analogs, the if -complex predominates (Equation (60)).61... 

Gold-catalyzed direct C-H functionalizations enable the formation of polyalkylated arenes under mild conditions. In many cases, branched products are obtained. Two mechanisms are thought to operate with electron-rich arenes, an S si2-type mechanism via Au(lll) leads to the linear product. The branched product is obtained via a Friedel-Craft-type alkylation. A silver salt is often added and is believed to generate a more electrophilic Au(m) species. Often regioselectivities are poor and symmetric arenes are employed. Intramolecular variants as well as Michael additions are also known (Equations (72)-(74)).71,71a,71b... 

An aromatic C-H functionalization involving the m-addition of benzene to internal alkynes is mediated by a bimetallic palladium complex in the presence of catalytic amounts of a borane. The mechanism of process remains to be clarified (Equation (77)).73... 

A remarkable series of CH functionalizations has been described whereby the regiochemical outcome of the reaction is determined by the catalyst employed. Directed and nondirected C-H functionalizations on 2-phenylimi-dazole were observed. This orthogonal approach is excellent for introducing diversity and may have applications in library generation in areas including medicinal chemistry (Scheme 18). 

Following on from stochiometric iridium-based C-H functionalizations, iridium-catalyzed reactions have been developed and can be combined with oxidation chemistry to enable the selective functionalization of aromatics. Moreover, these reactions can be performed under solventless conditions (Equations (91) and (92)). ... 

Non-directed C-H functionalizations of arenes can be mediated by Cp Ir complexes as in the catalytic synthesis of... 

The selective intramolecular arene C-H/olefin coupling reaction (Murai reaction) represents one of the most important discoveries in catalytic C-H functionalization chemistry (Equation (94)). 

Related alkyne couplings yield tricyclic quinolines via a regioselective amination/C-H functionalization pathway (Equations (104) and (105)).98... 

Carbonylations involving catalytic amounts of Pd(n) and substoichiometric Cu(n) have been developed for the synthesis of lactams. This Wacker-type process is assumed to proceed via C-H functionalization involving a palladacycle intermediate such a hypothesis is backed by the high degree of regioselectivity attained, when using a bis-chelating substrate (Equation (114)).104... 

C-H functionalizations of benzimidazoles have been described and are thought to involve an Rh(m) hydride. Hydrochloride salts of bulky electron-rich phosphines were found to be useful additives (Equations (115) and (116)). 

A rhodium-catalyzed intramolecular C-H functionalization has been employed for the synthesis of bicyclic imidazoles. The alkene acts as an anchor to the metal, directing the C-H functionalization process, which involves the formation of an Rh(l) carbene intermediate (Equation (118)).107... 

Palladium-catalyzed room-temperature >rtfe>-alkenylations of anilides have been recently reported, employing benzoquinone as a stoichiometric oxidant. A kinetic isotope effect kn/koof 3 points to a slow C-H functionalization step. Electron-rich acetanilides react faster whereas anilines are unreactive (Equation (138)).120... 

Merry-go-round processes involving multiple C-H functionalizations and carbometallations have been described. In the example depicted, a rhodium hydride continues to be formed until steric factors prevail. The 2-norbornene moiety acts as a directing group (Equation (148)).125... 

A palladium-mediated Stille-C-H functionalization process was recently disclosed. Deuteration of the fused arene led to 92% D-incorporation in the vinylsilane product, suggesting a Pd-migration process (Equation (159)).133... 

A cascade reaction involving multiple C-H functionalizations has been employed for the formation of bicyclic heterocycles with palladium catalysis (Equation (160)).134... 

Intramolecular C-H arylations have been described and are mediated by a variety of palladium complexes, affording a host of heterocyclic products. Carbazoles can be synthesized by a sequential amination/C-H functionalization process (Equation (161)). 

The above reaction is complementary to a related heterocyclization process, which may proceed by a C-H functionalization of the aryl group (Equation (162)).136... 

A palladium-catalyzed aerobic oxidative annulation of indoles, in the presence of ethyl nicotinate, has been disclosed.137,13711 The stereochemical outcome of this reaction indicates that an initial C-H functionalization at C(2) of the indole, followed by yvv/-carbopa 11 adation and ry -/ -H-elimination, operates (Equation (163)).137 This process has also been employed for the synthesis of benzofuran analogs.1373... 

Double C-H functionalizations involving biphenyl couplings can be mediated by other transition metal complexes (e.g., VOf . Ru02/TFA, Fe(m), TTFA (TI2O3/TFA)), or by light. An early review highlighted this chemistry (Equations (170) and (171)).141... 

Similar intramolecular hydroarylations of alkynes and alkenes, which obviate the need for a halide or triflate group on the aryl ring, are now well established. Sames group screened over 60 potential catalysts and over 200 reaction conditions, and found that Ru(m) complexes and a silver salt were optimal. This process appears to tolerate steric hindrance and halogen substrates on the arene (Equations (175)—(177)). The reaction is thought to involve alkene-Ru coordination and an electrophilic pathway rather than a formal C-H activation of the arene followed by alkene hydrometallation, and advocates the necessary cautious approach to labeling this reaction as a C-H functionalization... 

A titanium-mediated amination followed by a directed rhodium-catalyzed C-H functionalization of an olefinic C-H leads to heterocycles (Equation (184)).149... 

A stoichiometric double C-H functionalization mediated by an iridium ketene complex leads to l,4-dien-3-ones,... 

Chemists are exploiting catalytic C-H functionalization methodology for the synthesis of natural products or molecules of increasing complexity often with high degrees of regio-, chemo- and stereoselectivies. 

A copper-catalyzed one-pot three-component atom-economical C-H functionalization process was used to form enantioenriched propargylamines. This protocol was also employed for the synthesis of the alkaloid (A)-(+)-coniine (Equation (196)).159 159a... 

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