C—H bonds adjacent to heteroatoms

Examples of catalytic formation of C-C bonds from sp C-H bonds are even more scarce than from sp C-H bonds and, in general, are limited to C-H bonds adjacent to heteroatoms. A remarkable iridium-catalyzed example was reported by the group of Lin [116] the intermolecular oxidative coupling of methyl ethers with TBE to form olefin complexes in the presence of (P Pr3)2lrH5 (29). In their proposed mechanism, the reactive 14e species 38 undergoes oxidative addition of the methyl C-H bond in methyl ethers followed by olefin insertion to generate the intermediate 39. p-hydride elimination affords 35, which can isomerize to products 36 and 37 (Scheme 10). The reaction proceeds under mild condition (50°C) but suffers from poor selectivity as well as low yield (TON of 12 after 24 h). 

It is abundantly clear from the preceding discussion that dihalocyclopropanes are versatile intermediates in organic synthesis. Although a wealth of chemistry has already been uncovered, prospects remain bright for interesting developments in the future. Areas such as the application of dihalocyclopropanes in heterocyclic synthesis via carbene insertion into C—H bonds adjacent to heteroatoms, reactions of dihalocyclopropanes with organometallics and the synthetic applications of metallated derivatives deserve further exploration. The chemistry of difluoro-, diiodo- and mixed dihalo-cyclopropanes can be expected to attract some attention. Finally, other heteroatom-substituted cyclopropanes derived ftom dihalocyclopropanes will also invoke further investigation. 

Scheme 13.8 Iron-catalysed direct functionalisation of C-H bonds adjacent to heteroatoms.

With sp C-H bonds adjacent to heteroatoms such as nitrogen, an sp -sp C-C bond can also be formed by CDC reaction. In 2009, the group of Kami described the direct functionalization of methylamines (2.5 equiv.) with various heterocycles (1 equiv.) in the presence of FeClz 4H2O (10 mol%), with pyridine-iV-oxide (2 equiv.) as the oxidant and two additives [KI (0.2 equiv.) and 2,2 -Bipyridine (bipy) (O.l equiv.)] at 130 °C for 24 h (Scheme 4.19). ... 

Carbon atoms of C-H bonds adjacent to heteroatoms can be employed in C-C bond forming reactions with 1,3-dicaibonyl compounds (Scheme 4-255). Nonacarbonyl-diiron is applied in catalytic amounts in the presence of di-tert-butyl peroxide (DTBP) to afford alkylated 1,3-dicarbonyl compounds in moderate to good yields. When a mixture of two diastereoisomers is obtained in 1 1 to 2 1 ratios. ... 

Alkylation of sp3 C-H bonds adjacent to a heteroatom such as nitrogen and oxygen is possible. The early works using tungsten or iridium complexes involved the reaction of dimethylamine with 1-pentene (Equation (29)) and the alkylation of a C-H bond adjacent to oxygen with / r/-butylethylene.34,34a,34b... 

The alkylation of the sp3 C-H bonds adjacent to a heteroatom becomes more practical when the chelation assistance exists in the reaction system. The ruthenium-catalyzed alkylation of the sp3, C-H bond occurs in the reaction of benzyl(3-methylpyridin-2-yl)amine with 1-hexene (Equation (30)).35 The coordination of the pyridine nitrogen to the ruthenium complex assists the C-H bond cleavage. The ruthenium-catalyzed alkylation is much improved by use of 2-propanol as a solvent 36 The reaction of 2-(2-pyrrolidyl)pyridine with ethene affords the double alkylation product (Equation (31)). 

The direct activation and transformation of a C-H bond adjacent to a carbonyl group into a C-Het bond can take place via a variety of mechanisms, depending on the organocatalyst applied. When secondary amines are used as the catalyst, the first step is the formation of an enamine intermediate, as presented in the mechanism as outlined in Scheme 2.25. The enamine is formed by reaction of the carbonyl compound with the amine, leading to an iminium intermediate, which is then converted to the enamine intermediate by cleavage of the C-H bond. This enamine has a nucleophilic carbon atom which reacts with the electrophilic heteroatom, leading to formation of the new C-Het bond. The optically active product and the chiral amine are released after hydrolysis. 

Catalytic C-C bond formation via sp- C-H bond cleavage represents the ultimate reaction in organic synthesis. A relatively ideal catalytic reaction system involves the use of sp3 C-H bonds adjacent to a heteroatom such as nitrogen and oxygen atoms. Recently, Jim et al. [69] succeeded in the Ru3(CO)12-catalyzed alkylation of an sp3 C-H bond a to the nitrogen atom in benzyl-(3-methyl-2-pyridinyl)amine by means of chelation assistance (Eq. 43). In this case, the coordination of the pyridine nitrogen to the ruthenium complex followed by C-H... 

The direct functionalization of sp C-H bonds in alkanes is an extremely difficult process [69[, and only a limited number of studies have been reported. A much more practical - but still challenging - process is the functionalization of sp C-H bonds adjacent to a heteroatom [70-73]. Murahashi reported the impressing example of an alkyl group exchange reaction and hydrolysis reaction of tertiary amines... 

Direct oxidative activation of sp3 C—H bonds adjacent to a heteroatom is an ideal synthetic route to heteroatom-containing derivatives. Recently, our group has developed an efficient method for the alkylation of 1,3-dicarbonyl compounds using Fe2(CO)9 as a catalyst (Equation 11.2) [8]. The scope of this transformation is fairly broad and various heteroatom-containing compounds have been shown as effective alkylation reagents. Kinetic isotopic effect (KIE) experiments have shown that the reaction has a kH/kD value of 5.4 0.1, which supports a rate-determining C—H bond cleavage step for the overall transformation. 

Abstract Selective functionalization of one specific C(sp )-H bond in a complex molecule without the assistance of a directing group represents the state of the art in organic synthesis and will be a dynamic topic in future. In the past decade, many excellent methods have been developed to accomplish this goal with transition-metal catalysts and even under metal-free conditions. In this chapter, we summarize the recent achievements in this realm during the past 5 years, including oxidative functionalization of a-C(sp )-H bonds adjacent to heteroatoms, allylic, benzylic, and unactivated aliphatic C(sp )-H bonds. The total redox-neutral C(sp )-H bond functionalization is also briefly introduced. 

C-H Insertion. Insertion of carbenoid species generated from dimethyl diazomalonate in the presence of Rh into activated C-H bonds proceeds in moderate yields (eq 33). Sometimes undesired insertion into the C-H bond adjacent to the heteroatom complicates the utilization of Ganem epoxide deoxygenation procedure (eq 34). ... 

Two particularly important facets of the lone-pair interaction were discovered by Bohlmann. First, the interaction is not limited to methyl C—H bonds, but most C—H bonds adjacent to lone pairs of electrons demonstrate the effect. Second, there is a distinct stereochemical requirement that all interactions have the lone-pair orbital and the involved C H bond trans diaxial. Two good examples of this latter requirement are the quinolizidine (bicyclic) and yohimbine (pentacyclic) ring systems in which the stereochemistry of the heteroatom ring fusion can be established by the single C—H stretching mode which will be equitorial to the nitrogen lone pair in the cis fused systems and trans diaxial in the trans fused derivatives. 

Rhodium carbenoids, especially the donor/acceptor carbenoids, act as very sterically demanding electrophiles. Hence, based on size alone, the favored order of reactivity of C-H bonds would be 1°>2°>3°, yet carbenoids are also very electrophilic, so they would prefer to react with more electron rich C-H bonds, thus 1°<2°<30. So, in practice, secondary C-H bonds tend to be the most active overall, because they possess the proper balance between these steric and electronic requirements [5], Furthermore, when the C-H bond is adjacent to an electron donating group such as a heteroatom or an aromatic ring, it becomes even further activated towards functionalization. Based upon these few general trends, a surprising level of control of reactivity can be achieved in carbenoid reactions with complex molecules, especially when their reactivity is attenuated with proper substituents on the carbenoid. 

Structural parameters for aromatic five-membered rings are shown in Table 6. All the C-H distances are near 107.5 pm, which is close to the C-H bond in ethylene. With heteroatoms at adjacent ring positions, the C-H groups are displaced from the bisector of the ring angles toward the adjacent heteroatom <1974PMH(6)53>. 

Protons attached to sp carbons are more acidic than protons attached to nonallylic sp carbons. Also, the inductive effect of a heteroatom further increases the acidity of an adjacent sp C-H bond, facilitating a-lithiation. The relative activating effect of heteroatoms is sulfur > oxygen > nitrogen. Thus, treatment of 2-ethoxy-l-(phenylthio)ethylene with t-BuLi results in exclusive lithiation at the phenylthio substituted carbon. ... 

Organometallics react with this sink by addition to the multiple bond (path Ad r). The more covalent, less reactive organometallics, like R2Cd, react very slowly with almost all of these sinks, whereas organomagnesiums, RMgX, and organolithiums react quickly. Complexation of the metal ion to the Y heteroatom catalyzes this reaction. Organometallics react much faster as nucleophiles with polarized multiple bonds than as bases with the adjacent C-H bonds, (carbon-acid, carbon-base proton transfer is slow). C=Y example ... 

The rates span several orders of magnitude, indicating that selectivity should be possible in more elaborate substrates. The least favorable is insertion into the unactivated tertiary position of 2,3-dimethylbutane. The secondary C-H bonds of cyclohexane are intermediate in reactivity, but those adjacent to heteroatoms are much more reactive. The steric bulk of the Boc group slows the rate of insertion of this substrate relative to THF. Finally, the double activation of 1,4-cyclohexadiene makes this the most reactive substrate. By comparison, cyclopropanation of styrene and Si-H insertion into PlyBuSi-H both had relative rates of 24,000, so the majority of the C-H insertion processes are relatively slow by carbenoid standards. Notably, these studies were conducted at ambient temperature, and even greater differences in reactivity, and hence better selectivity, might be expected under milder conditions. 

In sum, the course of heteroatom oxidation appears to be sensitive to the oxidation potential of the heteroatom, the acidity of hydrogens on the adjacent carbon, and steric factors. The bulk of the evidence suggests that oxidation of the nitrogen in amines generally involves electron abstraction followed primarily by A-dealkylation if a labile proton is present, or nitrogen oxidation if it is not. As the nitrogen oxidation potential increases, there is a shift toward direct insertion into the C-H bond, as is thought to occur in the A-dealkylation of amides. 

In the above chemistry, the carbon-heteroatom bonds are generally formed via established palladium-catalyzed coupling, and C—H activation is subsequently responsible for cydization. In prindple, carbon-heteroatom formation itself can also be performed via this oxidative coupling strategy. One version of this transformation was reported by Smitrovich in the reductive cydization of 2-aryl-substituted nitroarenes (Scheme 6.63) [88]. As previously noted, carbon monoxide is postulated to reduce the nitro unit to a nitrene, which can undergo insertion into the adjacent C H bond. 

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