Activation of C sp —H Bonds

Iridium PCP-Catalyzed Activation of C(sp )—H Bonds in Unfunctionalized Alkanes... 

Abstract The transition-metal-catalyzed activation of C(sp )-H bonds has emerged as powerful strategy to create bonds and introduce functional groups in a direct fashion. This review focuses on recent applications of C(sp )-H bond functionalization strategies to the synthesis of biologically active and natural compounds. 

The first example of Ru-mediated activation of C(sp )-H bonds of indenyl-functionalised NHCs was reported in 2009. ° Reaction between free carbene IndCH2CH2lmR (Ind = indenyl, Im = imidazol-2-ylidene, R = Mes/Dipp) and Ru3(CO)i2 in refluxing benzene led to four distinguishable multinuclear Ru-NHC C-H activated products. Each product was characterised using NMR and IR spectroscopy, combustion analysis and ultimately X-ray crystallography. The authors propose that the C-H activated products form via a cyclometalated triruthenium intermediate, in which an indenyl proton (Ha) is susceptible to further activation to deliver the dinuclear r] -coordinated indenyl complex, followed by elimination of H2, CO and a Ru(CO)4 unit (Fig. 43A). Alternatively, a side-chain proton (Hb) and vinylic proton (Ho) may be activated to afford the trinuclear r], ri -coordinated complex, with concomitant loss of H2 (Fig. 43B). 

Pincer-ligated metal complexes have displayed extraordinarily rich chemistry and have found widespread use in catalysis. Pincer complexes of numerous transition metals have been synthesized, but the most well-studied probably involve Ru, Rh, Ir, and Pd [1-7], Our group has largely focused on pincer-iridium complexes, which have shown a strong tendency toward the activation of C-H bonds. These complexes have been found to effect the oxidative addition of a variety of C-H bonds including those with sp - and sp-hybridized carbon [8-10], Most notable, however, has been the activation of C(sp )-H bonds, leading to alkane dehydrogenation [6, 7],... 

The use of the same iron salt FeClj in combination with tert-butylhydro-peroxide enables the efficient activation of C(sp )—H bonds in the a-position in MAf-dialkylaniUnes and generates a C—P bond in the product. A variety of functional groups on the snbstrate compounds are tolerated to yield acylic or cyclic a-aminophosphonates. 

Heteroatom-directed C(sp )-H bond fimctionalizalion with stoichiometric transition metals was first disclosed in 1984 [1]. In 2002, Sames and coworkers developed an efficient route to constmct the teleocidin B4 core via the activation of C(sp )-H bond to prepare two diastereomeric paUadacycle key intermediates [2]. As a follow-up work, Ru3(CO)i2-catalyzed arylation of various C(sp )-H bonds with arylboronate esters using pyridine, pyrimidine, and amidine as directing groups was reported (Scheme 1.1) [3]. The use of ketones as solvent was necessary for a successfid arylation, mainly due to the trapping effect of the ruthenium hydride species. Despite of its efficiency, this transformation needs elevated temperatures (150 °C). Further, pyridine-directed a-C(sp )-H arylation of piperidines with arylboronate esters was developed with alcohols as solvent [4]. 

Other types of oxidative processes include the activation of saturated CH bonds. Such processes are especially interesting, from the practical point of view of processing the hydrocarbons from oil refining, and because such processes can occur in living organisms, and thus are definitely catalyzed by transition-metal complexes in aqueous environments. Among recent work on the development of model systems for such a purpose is the following. Water-soluble Ru(lll)-EDTA complexes are usable for activation of C(sp H bonds, e.g. in the oxidation of adamantane to a mixture of 1- and 2-adaman-tanols and adamantanone [184]. 

Comparing to C(sp )-H, the activation of C(sp )-H bonds was not difficult. Buchwald developed a method in which the combination of an amide and an unactivated arene [19], under palladium catalysis (Pd(OAc)2), can be used to efficiently produce a series of carbazoles with the aid of a directing functional group. The derivatives of carbazoles have important photophysical and biological... 

The aforementioned methods to construct benzofurans are all achieved by activation of C(sp )-H bond. In 2012, based on the alkynoxy-directed synthesis of 2-methylidene-2H -chromene derivatives [28], Hiyama and coworkers developed a palladium-catalyzed hydrobenzylation of ortho-tolyl alkynyl ethers to construct 2-methylidene-2,3-dihydrobenzofurans via the activation of benzylic C(sp )-H bond [34]. 

Complex 81 contains two substrate molecules. One of them is metallated, as a consequence of C(sp )-H bond activation of the CH2 group of the vinyl substituent, whereas the other one is coordinated to the osmium atom by the nitrogen atom and the C=C double bond of the alkene. 

Abstract Iron-catalyzed C-H bond activation followed by C-C bond formation has received much attention in recent years, motivated by the environmental and economical merits of iron, as well as the scientific challenge in controlling and understanding the reactivity of iron species. This review describes the utilization of iron as a catalyst for directed C-H bond activation, followed by C-C bond formation. Catalytic activation of C(sp )-H and C(sp -H) bonds, followed by oxidative reaction with nucleophiles, or reaction with electrophiles is described. Reactions of substrates possessing a directing group are mainly discussed, but other substrates are also presented. Carbon-heteroatom bmid formation is also briefly discussed. 

Directed activation of a C(sp )-H bond by an iron complex was much less investigated than the reaction of C(sp )-H bonds. Li reported the phosphine-directed C (sp )-H to form an iron pincer complex (e.g., [80]). Ohki and Tatsumi reported that Cp Fe complexes bearing imidazolium salts undergo cyclometalation through C-H activation or can cleave the C-H bond of a heteroarene [81]. 

The selectivity of C-H activation is a key issue in developing practical C-H functionalization strategies, as most relevant substrates will have multiple C-H bonds that are available for activation. As part of our ongoing collaboration with the Davies group, a series of competition experiments were devised to probe the relative reactivity of C(sp )-H bonds in iV-alkylimines, H-Li s, and phenylpyridine, H-Lg [64]. These substrates all undergo directed C-H activation in the presence of [Cp MCl2]2 and NaOAc to give well-defined cyclometallated species as their chloride adducts (Fig. 7). Stoichiometric reactions with H-L3 in... 

With commercially available boronate esters as aryl coupling partners, the first Pd(ll)-catalyzed P-C(sp )-arylation of simple carboxylic acids was reported (Scheme 1.2) [5]. The reaction presumably relied on the binding of carboxylate directing group to Pd(ll) center, triggering a C-H activation/transmetalation/ reductive elimination sequence. The P-arylated carboxylic acids can be obtained in satisfactory yields. It represents an important step forward in arylation of C(sp )-H bonds. 

An efficient CuS04/Cul-catalyzed aerobic intramolecular dehydrogenative cyclization reaction of A-methyl-Af-phenylhydrazones to cinnolines has been developed by Ge and coworkers through sequential C(sp )-H oxidation, cyclization, and aromatization processes (Scheme 8.107). This transformation is the first example of copper-catalyzed coupling reactions of hydrazones through a C(sp )-H bond functionalization pathway. This transformation starts with the oxidation ofiV-methyl-Af-phenylhydrazones into aldehyde intermediate through the activation of C(sp )-H under CuSO /O, catalytic system [181]. 

Under comparable reaction conditions, no C—H bond activation is observed for adducts of 6-Phbipy and 6-Rbipy. Nevertheless, [Au(N,N,C)Cl] derivatives can be obtained with 6-Phbipy [18] and with 6-tBubipy (tBu = CMe3) [20]. The former is obtained by a transmetallation reaction of the arylmercury(II) derivative with [AuClJ, while activation of a C(sp )—H bond of the tert-butyl substituent is accomplished by reaction of the Au(N)Cl3 adduct 3 (N = 6-tBubipy) with AgBp4 in the presence of excess ligand (Scheme 2.2). 

The first step involves reductive elimination of cyclohexane from a six-coordinate Ir(in) complex (ML3X3 via the CBC method in Section 13.7) to afford a four-coordinate Ir(I) intermediate (ML3X). Like most reductive eliminations, this first step involves a decrease by two in both the oxidation state and coordination number of the metal. The second step results in oxidation from Ir(I) to Ir(III) as benzene oxidatively adds to the iridium center, resulting in activation of a C(sp )—H bond. Like most oxidative additions, this second step involves an increase by two in both the oxidation state and the coordination number of the metal. 

---