Of benzylic C —H bonds

As shown in the previous two sections, rhodium(n) dimers are superior catalysts for metal carbene C-H insertion reactions. For nitrene C-H insertion reactions, many catalysts found to be effective for carbene transfer are also effective for these reactions. Particularly, Rh2(OAc)4 has demonstrated great effectiveness in the inter- and intramolecular nitrene C-H insertions. The exploration of enantioselective C-H amination using chiral rhodium catalysts has been reported by several groups.225,244,253-255 Hashimoto s dirhodium tetrakis[A-tetrachlorophthaloyl-(A)-/ r/-leuci-nate], Rh2(derived rhodium complex, Rh2(i -BNP)4 48,244 afforded moderate enantiomeric excess for amidation of benzylic C-H bonds with NsN=IPh. 

The tra x-[Ru (0)2(por)] complexes are active stoichiometric oxidants of alkenes and alkylaro-matics under ambient conditions. Unlike cationic macrocyclic dioxoruthenium I) complexes that give substantial C=C bond cleavage products, the oxidation of alkenes by [Ru (0)2(por)] affords epoxides in good yields.Stereoretentive epoxidation of trans- and cw-stilbenes by [Ru (0)2(L)1 (L = TPP and sterically bulky porphyrins) has been observed, whereas the reaction between [Ru (0)2(OEP)] and cix-stilbene gives a mixture of cis- and trani-stilbene oxides. Adamantane and methylcyclohexane are hydroxylated at the tertiary C—H positions. Using [Ru (0)2(i)4-por)], enantioselective epoxidation of alkenes can be achieved with ee up to 77%. In the oxidation of aromatic hydrocarbons such as ethylbenzenes, 2-ethylnaphthalene, indane, and tetrahydronaphthalene by [Ru (0)2(Z>4-por )], enantioselective hydroxylation of benzylic C—H bonds occurs resulting in enantioenriched alcohols with ee up to 76%. ... 

Table 1. Silylations of C-H bonds in aromatic and heteroaromatic compounds and of benzyl C-H bonds 6mol%...

Silylation of benzyl C-H bonds using hydrosilanes can also be performed with the aid of Ru3(CO)12-catalyst (Table 1) [9]. This silylation occurs only at benzylic CH3 groups. Pyridine, pyrazole, and hydrazones function as good directing groups. Benzylamines, oxime ethers, dimethylanilides, and aryl pyridyl ethers have no activity in this silylation. 

The ET mechanism is proposed on the basis of the high value of p = —2.4 obtained from the Hammett plot, as well as the observation of benzyl chloride and chlorotoluene as the main products when the oxidation is carried out in the presence of high concentrations of LiCl [41]. Similarly, activation of benzylic C-H bonds by other strong oxidants such as Mnm or PbIV has been suggested to occur through an initial electron transfer, especially in the case of aromatic substrates with low ionization potentials [42]. However, there have been no reports of complex formation between the metal and the arene prior to ET, and no such reactive complex has been isolated and characterized by X-ray crystallography. 

Iron-containing cytochrome P-450 constitutes the most famous example of a selective C-H bond oxidizer. Although the exact nature of the mechanism remains controversial, the reaction most likely proceeds through radical intermediates [2]. The hydroxylation of activated C-H bonds has also been carried out in the presence of synthetic porphyrin complexes. In these biomimetic processes, ruthenium plays a relatively minor role when compared with iron. Zhang et al. [50], however, recently reported the enantioselective hydroxylation of benzylic C-H bonds using ruthenium complexes supported by a D4-sym-metric porphyrin bearing a crafted chiral cavity. Thus, complex 23 reacts in a stoichiometric manner with ethylbenzene to give phenethyl alcohol with a... 

Scheme 30 Iron(II)-catalyzed oxidative alkylation of benzylic C-H bonds...

The syntheses of benzyl derivatives from benzylic C—H are well developed. Traditionally, multi-step syntheses had to be used. Furthermore, a stoichiometric amount of base was used and toxic halides were produced. To avoid such problems, various catalytic methods have been developed recently via direct functionalization of benzylic C—H bonds. More recently, our group has reported the FeCl2-catalyzed oxidative activation of benzylic C—H bonds followed by a cross-coupling reaction to form C—C bonds (Equation 11.1) [7]. The reactions selectively cleave benzylic C—H bonds and avoid further oxidation. The present methodology opens a window for iron-catalyzed C—H bond oxidation and C—C bond formation. 

Iron Catalysts Direct amidation of C—H bonds presents an efficient method for C—N bond formation. A combination of simple air-stable FeCl2 and NBS has been successfully used in the amidation of benzylic sp3 C—H bonds (Equation 11.16) [38], The reactions are insensitive to atmospheric moisture and oxygen. Neither a dried solvent nor an inert atmosphere is required. An iron-nitrene intermediate has been proposed [39]. The carbene insertion of benzylic C—H bonds provides the final products. 

Vinod and coworkers were the first to develop a selective procedure for the oxidation of benzylic C-H bonds to the corresponding carbonyl functionalities using a catalytic amount of 2-iodobenzoic acid and Oxone as a stoichiometric oxidant in aqueous acetonitrile under reflux conditions (Scheme 4.52) [83]. The authors hypothesized that the active hypervalent iodine oxidant generated in situ might not be IBX (90) (Scheme 4.47) but, instead, a soluble derivative of IBX (108) that incorporates a peroxysulfate ligand. This intermediate is believed to oxidize a benzylic C-H bond via a single-electron transfer (SET) mechanism [83]. 

Zhang and coworkers have further improved the procedure for catalytic oxidation of benzylic C-H bonds using IBS as a catalyst, which is generated in situ by the oxidation of sodium 2-iodobenzenesulfonate... 

In 2005, Itoh and co-workers developed a new dinucleating ligand L13. Combining L13 with FeCls gave a dinuclear Fe complex. With this catalyst, hydroxylation of benzylic C—H bonds was realized. Among these cases, one example was the asymmetric hydroxylation of tetrahydronaphthalene, affording the desired oxidized product 146 with only 9.9% ee (Scheme 1.57). 

In 1994, Jacobsen and co-workers demonstrated that stereoseleetive oxidation of benzylic C—H bonds is possible utilizing readily available chiral Mn(salen) complexes.They studied the kinetic resolution of 1,2-dihy-dronaphthalene oxide via an asymmetric C—H bond hydroxylation reaction (Scheme 1.59). During the course of experiments on the asymmetric epoxidation of 1,2-dihydronaphthalene with C24, it was observed that the... 

The aimnation of benzylic C—H bonds proceeds in good yields using 1 equiv of amine and alkane in the presence of 2 equiv of the hypervalent iodine reagent. However, insertion in tertiary and secondary C-H bonds requires 5 equiv of substrate to undergo complete conversion (Eq. (5.15)). 

Zhang and coworkers recently reported on the nse of a cobalt (II) tetraphenyl porphyrin complex, Co(TPP), as a catalyst for the intra-molecnlar amination of snUbnyl azides. Their work builds on early studies where Cenini and coworkers used Co(TPP) for the amination of benzylic C—H bonds with aryl azides. Reactions of primary, secondary, and tertiary sulfonyl azides with Co(TPP) in chlorobenzene in the presence of molecular sieves and under an inert atmosphere at SO C gave the desired sultams 296-301 in high yield. The authors noted that tertiary C—H bonds reacted to give higher product yields then than secondary and primary C—H bonds, respectively, in the formation of live-membered heterocyclic ring structures. 

Alkyl ethers are an important subclass of compounds in natural products. The direct constmction of alkyl ethers from C(sp )-H bonds is a challenging but promising access and thus is being actively pursued. Chen et al. first addressed this unsolved difficulty. They developed a Pd(ll)-catalyzed, picolinamide-assisted functionalization of y-C(sp )-H bond with primary, secondary, and even bulky tertiary alcohols (Scheme 1.29) [73]. The perfect compatibility of simple alcohols was one of the most striking features. Furthermore, under the optimized reaction conditions, functionalization of unreactive primary C(sp )-H bond ispreferential even in the presence of secondary C(sp )-H bond. Besides C-O bond coupling, picolinamide-assisted Pd(II)-catalyzed tandem arylation and oxidation of benzylic C-H bond can dexterously construct unsymmetric diaryl ketones [74]. 

One representative example in enantioselective alkylation of benzylic C-H bond was disclosed by Gong and co-workers in 2010. Highly enantioselective alkylation of 3-arylmethylindoles with dibenzyl malonate was achieved in the presence of catalytic amounts of chiral copper complex L4 (Scheme 2.31) [169]. This protocol provides an excellent enantioselective route to natural product skeleton of 2,3,4,4a,9,9a-hexahydro-lH-pyrido[2,3-b]indoles. 

In 2013, Chen et al. developed a direct and economical lluorination of benzyUc C-H bond (Scheme 3.27) [78]. Using diaryl ketones as photosensilizers, visible-light-induced fluorination of various benzylic C-H bonds was accomplished with Selectfluor as fluorine source. Selective mono- and difluoiination can be controlled with different photosensitizers. 9-Fluorenone catalyzes the monofluori-nation, while xanthone favors benzylic C-H difluoiination. Also, in the same year, light-induced pyridination of benzylic C-H bond was developed [79]. 

The fluorination of unfimctionalized C—H bonds is a challenging reaction however, it is a highly valuable transformation. To this end, the palladium-catalyzed fluorination of benzyl C—H bonds was developed (Example 7.1) [12]. The chemistry used a common palladium salt to catalyze the process, and A(-fluoropyridinium tetrafluoroborate served as a source of electrophilic fluorine. While only a few substrates were screened in this work, it provided the proof of concept for the approach. Following this report, a host of benzyl C—H fluorination reactions have been reported. Several of these reactions are summarized in Schemes 7.5 through 7.9 and Examples 7.1 through 7.3. 

While the metal-catalyzed fluorination of benzyl C—H bonds has generated a host of valuable compounds, extending this chenustry to saturated hydrocarbons remains a current and significant challenge. To address this issue, a successful approach for the copper-catalyzed fluorination of unfunctionaUzed hydrocarbons has been devised (Example 7.5) [23, 24]. The catalyst for this reaction was an bisimine copper complex, and Selectfluor was used as an electrophilic source of fluorine. The copper complex was essential for the reaction as no fluorination was observed in its absence. A host of cyclic and acyclic saturated hydrocarbons were successfully fluorinated using this approach, and moderate to good yields of the alkyl fluorides were obtained. For substrates such as ethylbenzene and dihydrocoumarin, fluorination of the benzylic position was preferred. 

A process for the fluorination of benzyl C—H bonds would be convenient... 

In 2007, cobalt(II)-tetraphenylporphyrin (TPP) complex was reported to be a competent catalyst for intramolecular amination of benzylic C-H bond through decomposition of sulfonyl azide (Scheme 10.19) [48]. Thus, arylsulfonyl azides... 

More recently, we demonstrated the first alkynylation of benzylic C-H bonds not adjacent to a heteroatom with 1 mol% of a CuOTf-toluene complex in the presence of 1.5 equiv. of DDQ. Various allq nes were successfully coupled with diphenylmethane derivatives (Scheme 1.8). Aromatic allq nes were smoothly converted and the use of electron-rich derivatives resulted in a slightly improved jdeld, rationalized by the nucleophilicity of the substrates. However, aliphatic allq nes [i.e., n-heiq ne) did not give the corresponding CDC product under standard conditions. The mechanism was proposed to proceed via the generation of radical intermediates, which were converted into a benzylic cation in the presence of DDQ through two successive SET steps. The resulting hydroquinone subsequently then abstracted the acidic proton from the allq ne to form the copper acetylide, which added to the benzylic cation to afford the desired product. 

To explore the CDC reaction of benzylic C-H bonds, diphenylmethane vras reacted with benzoylacetone. We found that FeCl2 in combination with TBP (instead of TBHP) is an effective catalyst in this case, giving the corresponding CDC products cleanly in good yields (Scheme 1.32). ... 

---