Heteroatom-directed C-H activations

Domino Reactions Involving Heteroatom-Directed C-H Activations... 

Transition-metal-catalyzed (Pd, Rh, and Ru) heteroatom-directed C-H activations have been successfully employed in domino strategies for constructing multiple carbon-carbon/carbon-heteroatom bonds. This area has already been extensively reviewed [46]. Selected recent examples of domino reactions involving heteroatom-directed C-H activations are chosen in this section to highlight this concept. 

Baudoin and coworkers [Ik] published a timely review on arylations that involved C(sp )-H activation. What was pointed out was that many of these transformations take place via heteroatom-directed C-H activation (yetih, you ask what s new). Coordination of the substrate to the catalyst takes place via an appropriate heteroatom, which facilitates the C-H activation taking place (Scheme 4.15). 

Scheme 4.15 Alkyl arylation via Heteroatom-directed C-H activation. (Adapted from Ref. [Ik] from WILEY-VCH Verlag GmbH Co. KGaA, Weinheim.)...

Recently, Sames and co-workers showed an interesting application, in which it was demonstrated that the Shilov chemistry permits heteroatom-directed functionalization of polyfunctional molecules [16]. The amino acid valine (10) was allowed to react in an aqueous solution of the oxidation catalyst PtCU and Cu(ii) chloride as stoichiometric oxidant (Scheme 3). At temperatures >130 °C a catalytic reaction was observed, and a regioselective C-H functionalization delivered the hydroxyvaline lactone 11 as a 3 1 mixture of anti/syn isomers. It was noted that the hydroxylation of amino acid substrates occurred with a regioselectivity different from those for simple aliphatic amines and carboxylic acids. The authors therefore proposed that the amino acid functionalization proceeded through a chelate-directed C-H activation. 

Colby DA, Bergman RG, Elbnan JA (2009) Rhodium-catalyzed C-C bond formation via heteroatom-directed C-H bond activation. Chem Rev 110 624-655... 

Direct C-H activation at abnormal carbene positions was achieved by heteroatom-directed cyclometalation reactions using pyridyl-functionalized azolium salts and [IrCp Cl2]2 (Cp = pentamethylcyclopentadienyl Scheme 3.4). Cyclometalation proceeded well with both triazolium salt 20 and imidazolium salt 22 and yielded iridium complexes 21 and 23 in good yields. Transmetalation from silver was not efficient in either case. The imidazolium precursor underwent activation and oxidation of the exocyclic C2-bound CH3 group, whereas triazolium salt 20 formed a mixture of compounds upon reaction with Ag20, probably due to poor selectivity and competitive coordination of the pyridyl nitrogen. 

Because of the creative minds contributing to the field, the tools of C-H bond transformation available to synthetic chemists are actively expanding [1], Among these, coordination-directed C-H bond-activation has long preserved its appeal, because it enables selective functionalization of a particular C-H bond in the presence of other functional groups. This can be achieved by using a heteroatom (FG = functional group shown in Scheme 1) in the substrate structure to direct the metal complex to the proximity of the specific C-H bond. Even unactivated sp3-centered C-H bonds tend to react in a cyclometalation step with palladium, platinum [2], and ruthenium catalysts [3]. 

A variety of methods are available for the stereochemical construction of these optically active a-heteroatom-substituted carbonyl compounds, and in recent years a large number of new procedures have been developed applying asymmetric catalysis to carbonyl compounds, or their equivalents, as substrates [1]. The trick to these reactions is the direct C-H to C-Het transformation, as outlined in... 

Electrophilic aromatic substitution as a route to differentially substituted products is well established. The often forcing conditions, the incompatibility of this process with acid-sensitive functional groups, and the need for mild and selective syntheses have been the driving forces in the search for new methods of synthesis. A large range of methods has been developed over the past 20 years they include the trimerization of alkynes, the directed orfho-metallation, the benzannellation via metal carbenes, and transition metal-catalyzed carbon-carbon and carbon-heteroatom bond formation. Aromatic C-H activation, while still in its beginning stages, is another area of promise. 

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. 

Through the preceding syntheses, Sames and co-workers demonstrated the potential of the heteroatom-directed C(sp )-H bond activation strategy in total synthesis, which aUows to draw nontraditional discoimections in retrosynthetic... 

Use of other nucleophiles in the presence of an oxidant can install other functionality (Scheme 3.55). While N-halosuccinimides are very effective, other systems, such as iodosobenzene diacetate-halide mixtures, or copper(II) halide salts can be employed. The powerful oxidant oxone can also be used in combination with alcohols, to give ethers (Scheme 3.56). Iodine acetate has been used for C-H activation directed by carboxylic acids (Scheme 3.57). The heteroatom may also be supplied intramolecularly (Scheme 3.58). The use of palladium catalysis can also override the inherent regioselectivity of an arene substrate (Scheme 3.59). 

The extension to catalytic reactions was discovered by Murai in 1993. When an arene bears an acyl or an imino substituent, the heteroatom of this group can direct the alkene or alkyne insertion into the ortho C-H arene bond. These reactions are catalyzed by [Ru(PPh3)3(CO)2] or [Ru(PPh3)3(CO)(H)2], " and represent one of the most practical, well-developed catalytic C-H activations known today. 

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]. 

C-H Activation. Di-tert-butyl(methyl)phosphine is frequently used as a ligand in palladium-catalyzed Ar-H and Het-H arylation reactions. When the reaction is performed on heterocyclic conpounds, the targeted direct functionalization usually occurs at a position adjacent to a heteroatom. The nature of the ligand can have a dramatic influence on the regioselectivity of the arylation process. Although aryl halides are most commonly used... 

C-H Activation. Tri-terf-butylphosphine, combined with palladium acetate, acts as an effective catalytic system for the direct Ar-H arylation of heterocycles. This system has been applied for the functionalization of various five- and six-membered ring heterocycles containing one or more heteroatoms. A base (CS2CO3,... 

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