Directed C-H functionalizations

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... 

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

This paragraph details carbazole syntheses that involve the formation of new bonds to nitrogen. A direct C-H functionalization/amination of 2-acetaminobiphenyl compounds give carbazoles in one step <05JA14560>. For example, treatment of biphenyl 130 with palladium acetate and copper(II) acetate gave carbazole 131. A short s)mthesis of carbazoles involved the reductive cyclization of 2-nitrobiphenyl compounds mediated by triphenylphosphine... 

The group have also developed an analogous process for direct C-H functionalization of electron rich aromatic rings and cyclization with unactivated alkenes to access substituted benzofuran and dihydrobenzofuran derivatives (Scheme 43) [71]. 

Yu J-Q, Giri R, ChenX (2006) a-chelation-directed C-H functionalizations using Pd(II) and Cu(II) catalysts regioselectivity, stereoselectivity and catalytic turnover. Org Biomol Chem 4 4041 1047... 

Shi and co-workers have developed various types of C—H bond functionalization and C—C bond formation. Recently, they reported a novel transformation to realize ortho-arylation of acetanilides with trialkoxyarylsilanes through direct C—H functionalization (Equation 11.34) [72]. Furthermore, they also demonstrated a novel method for the direct construction of biaryl C—C bonds via Pd(II)-catalyzed cross-coupling of (hetero)arenes and various arylboronic acids [73]. Various aromatic rings show good selectivity, even without directing groups, under mild conditions. 

Water is a week O-nucleophile however, the hydroxide ion as well as alkoxides and phenolates are appropriate O-centered nucleophilic reagents for direct C-H functionalization of ii-deficient arenes and hetarenes [1,2, 10, 11]. 

Finally, the chapter Electrochemical C-H Eunctionalization of Arenes by lluminada Gallardo and Gonzalo Guirado (University of Barcelona, Spain) provide us with an excellent review showing a practical importance of electrochemical methods for the direct C-H functionalization of aromatic and heteroaromatic compounds - a very promising area that has been advanced significantly by these authors. 

Zinc bis(alkanesulfinate) salts, which permit direct C-H functionalization of heteroaienes. Several of these reagents are now eommercially available. ... 

Development and application of new oxidation systems utilizing oxome-talate catalysts, particularly in direct C—H functionalizations of aromatic compounds and in synthesis of morphinandienone alkaloids 12CPB799. 

Figure 2 Four strategies for the direct C—H functionalization of heterocycles.

Ruthenium(II)-Catalyzed Regio- and Stereoselective Hydroarylation of Alkynes via Directed C-H Functionalization... 

Another C—H activation strategy for lactone synthesis involves the ring closure of benzoic acids with dihaloalkanes [111]. Yu and coworkers recently developed a directed C—H functionalization/alkylation approach using Pd catalysts. Direct access to phthalides and 3,4-dihydroisocoumarins was possible using dibromo-methane and 1,2-dichloroethane, respectively (Scheme 2.56). 

In contrast to the alkynylation of acidic C-H bonds which can also be achieved using alkynyliodonium salts, the direct C-H functionalization of aromatic compounds or olefins has never been realized with this class of reagents so far. However, after several unsuccessful attempts using palladium or copper catalysts and alkynyliodonium salts for the alkynylation of heterocycles, Waser and Brand reported in 2009 the first efficient alkynylation of indoles using TIPS-EBX 52 and AuCl as catalyst (Scheme 18) [117]. With indole, selective C3-aIkynylation was obtained. The reaction was tolerant to many functional groups such as bromides, acids, or alcohols. The method was already used in the synthesis of starting materials for Friedel-Crafts reactions of aminocyclopropanes [118] and for hydroamidation to access indole c -enamides [119]. In 2010, Nevado and de Haro demonstrated that alkynylation was also possible using directly terminal propiolic ester derivatives and (diacetoxyiodo)benzene as co-oxidant [120]. 

Scheme 4.10 Rh(lll)-catalyzed ortho-directed C-H functionalization with di-substituted allenylsilanes to give trisubstituted allenylsilanes, as reported by Zeng ef al. [58].

Figure 4.29 A cross-section of results for the Rh(lll) dual catalysis involving oxidative coupling of aldehydes by directed C-H functionalization as reported by Seayad and covirorkers [61].

The three examples detailed above all show remarkable creativity in the use of C—H functionalizations in order to arrive at greener syntheses. Thus, direct C—H functionalization methods are expected to continue to greatly contribute to the mission of green chemistry Low-energy, waste-free, and atom-economic transformations for the synthesis of organic materials and biologically active molecules in the twenty-first century. 

Borylation of the benzylic position of arenes via C—H functionalization has been achieved. Yu has also reported the ability construct C-B bonds via directed C—H functionalization of arylbenzamides catalyzed by Pd(II). Formation of carbon-carbon bonds between arenes and alkyltrifluoroborates, alkylstannanes, and alkyl halides has been reported. The incorporation of amino acid derived... 

The preparation of 1,2-dibenzoic acids catalyzed by Pd(II) can be accomplished via directed C—H carbonylation followed by the in situ hydrolysis of an intermediary cyclic anhydride. Electron-rich substituted benzoic acids performed better overall with respect to yield and rate with the ortAo-directed C—H functionalization occurring more efficiently. Strongly electron-withdrawing groups on the aromatic ring render such substrates difficult with this protocol. 

Potavathri S, Kantak A, DeBoef B (2011) Increasing synthetic efficiency via direct C-H functionalization formal synthesis of an inhibitor of botulinum neurotoxin. Chem Commun. doi 10.1039/clccl0755k... 

The normally less-reactive 8-position of thiophenes is inaccessible via direct C-H functionalization. However, the 8-selectivity is observed with the catalytic system PdCl2/P OCH(CF3)2 3/... 

Lyons, T. W. Sanford, M. S. Palladium-catalyzed ligand-directed C-H functionalization reactions. Chem. Rev. 2010,110, 1147-1169. 

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