C-H Bonds Adjacent to a Nitrogen Atom

The aerobic CDC of an sp C-H bond with heterocyclic arenes was first reported in 2004 by Tsuchimoto, Shirakawa and co-workers. They found 

CDC Reactions with Molecular Oxygen as the Terminal Oxidant 

In 1997, Backvall and co-workers described the intramolecular oxidative coupling of stabilized carbon nucleophiles with dienes. The carbocycliza-tion catalyzed by Pd(OAc)2 under an atmosphere of ojgrgen afforded the desired products in modest yields because of competing aceto Q lation. In a similar fashion, Yang and co-workers developed an intramolecular oxidative coupling between p-ketoamines and alkenes. Heterocycles were efficiently 

As an alternative to the classical conjugated addition reaction, Pihko and co-workers reported, in 2012, a novel CDC reaction between sp C-H bonds in the p-position of esters and indoles. Soon after, the aerobic methodology was successfully extended to a variety of electron-rich arenes and phenols 

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The carbonylation of the sp3 C-H bond adjacent to a nitrogen atom is also possible by means of chelation-assisted C-H bond activation.121 The carbonylation reaction of A-(2-pyridyl)pyrrolidine occurs at the a-position of the pyrrolidine ring by using [RhCl(cod)]2 as a catalyst and 2-propanol as a solvent. Cyclic amines exhibit a high reactivity (up to 84%) (Equation (93)), while acyclic amines show relatively low reactivity (18%). The use of Ru3(CO)i2 as a catalyst does not result in a carbonylation reaction, but instead the addition of the sp3 C-H bond across the olefin bond to give an alkylation product, as mentioned before (Section 10.05.4). 

An important application of oxidation of a C-H bond adjacent to a nitrogen atom is the selective oxidation of amides. This reaction proceeds in the presence of ferf-BuOOH as the oxidant and Ru(II) salts. Thus in the example of Eq. (36), the a-tert-butylperoxy amide of the isoquinoline was obtained, which is an important synthetic intermediate for natural products [138]. This product can be conveniently reacted with a nucleophile in the presence of a Lewis add. Direct trapping of the iminium ion complex by a nudeophile was achieved in the presence of trimethylsilyl cyanide, giving a-cyanated amines as shown in Eq. (37) [45]. This ruthenium/peracid oxidation reaction provides an alternative to the Strecker reaction for the synthesis of a-amino acid derivatives since they involve the same a-cyano amine intermediates. In this way N-methyl-N-(p-methoxyphenyl) glycine could be prepared from N,N-dimethyl-p-methoxyaniline in 82% yield. 

Chatani, N. et al. 2001. Ru3(CO)i2-catalyzed coupling reaction of sp3 C-H bonds adjacent to a nitrogen atom in aUcylamines with alkenes. Journal of the American Chemical Society, 123 10935 1. 

Copper Catalysts Direct oxidative functionalization of tertiary amines is of importance both enzymatically and synthetically. The combination of CuBr—TBHP has proved to be as an efficient system in the oxidative activation of sp3 C—H bonds adjacent to a nitrogen atom [10]. Various types of cross-dehydrogenative coupling (CDC) reactions have been developed, including compounds with activated methylene groups [11], indoles [12], and terminal alkynes (Scheme 11.2) [13]. Because 1,2,3,4-tetrahydroisoquinoline derivatives are important structure motifs of natural... 

Other Metal Catalysts Murahashi s group has carried out systematic studies on the oxidation of C—H bonds adjacent to a nitrogen atom. An effective... 

Copper Catalysts Copper is an excellent catalyst for nitrogen transfer reactions via copper-nitrene intermediates. Benzylic hydrocarbons are selectively converted to the corresponding sulfonamides [40]. The intermolecular amidation of saturated C—H bonds of cyclic ethers has been reported using TsNH2-PhI(OAc)2 or PhI=NTs as the nitrene source [41]. The copper-catalyzed amidation of unactivated sp3 C—H bonds adjacent to a nitrogen atom has also been achieved using tert-butyl hydroperoxide or... 

One-pot annulation of 2-naphthol analogs to heterocycles 12COS613. Organocatalytic asymmetric halocyclization (among catalysts are bis-cinchona alkaloids and chiral trisimidazolines) 13H(87)763. Photoredox functionalization of C—H bonds adjacent to a nitrogen atom 12CSR7687. 

Li and Li have reported Cu(I)-catalyzed enantioselective alkynylation of prochiral sp C-H bonds adjacent to a nitrogen atom [58]. In this approach, a combination of CuOTf and pybox (197) in the presence of t-BuOOH results in coupling of N-aryl tetrahydroisoquinolines (209) with terminal alkynes (Scheme 17.42). The desired coupling products (211) were generally isolated in moderate to good yields with moderate enantioselectivities. Although it is not clear if the catalytically active Cu(I) species acts as a Lewis acid in this protocol, the chemistry is, nonetheless, worthy of mention. 

Ru3(CO)i2 catalyzes the addition of an sp C-H bond adjacent to a nitrogen atom of JV-(2-pyridyl)alkylamines to olefins. Substitution of the pyridyl group at the amine nitrogen is crucial to this reaction. Examples are shown in eqs 19 and 20. ... 

Another unusual three-component coupling reaction involving an imine as intermediate has been developed by Ishii who has shown that a C-H bond adjacent to the nitrogen atom of an imine can be activated by an iridium complex. Carbo-metallation reactions of acetylenic compounds may then be achieved, which lead to unsaturated imines 155 (Scheme 8.67) [122]. 

The sp C-H bonds of terminal alkynes are well known to become activated by metal salts in the presence of bases. A variety of research groups have examined the use of terminal alkynes as nucleophiles for the oxidative addition to the C-H bond adjacent to the nitrogen atom of amines. Li and co-workers examined the oxidative coupling of /V,/V-dimethylaniline 26 with 1-alkynes 27 (Scheme 15) [31, 32]. 

In the presence of base, the C—H bond adjacent to the nitrogen atom is involved in the formation of cyclopaUadated intermediate C. In the second stage of the catalytic cycle the alkyl halide oxidatively adds to the Pd center with the generation of a Pd species (D). Reductive elimination followed by norbomene expulsion gives 2-alkyl-N-paUadaindole (F) which upon 1-protonation delivers the final 2-alkylated IH-indole product. 

Initially, carbonylation of unactivated alkanes sp C-H bonds to produce aldehydes has been performed by Tanaka in the presence of rhodium catalyst tmder photochemical irradiation [6]. The Chatani-Kakiuchi-Murai group also performed the rhodium-catalysed monocarbonylation of sp C-H bond adjacent to the nitrogen atom of cyclic amines and directed by a pyridine group in the presence of ethylene to produce a-propanoyl amines [7]. It is only very recently in 2011 that Chatani has... 

A plausible mechanism was proposed in Scheme 7.46. Firstly, hydrogen abstraction from the C-H bond adjacent to the nitrogen atom of DMA through SET could give an imine, which could react with 65 to generate intermediate A. In the... 

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... 

With a strong oxidant [(NH4)2S20g], visible-light-driven Friedel-Crafts amidoalkylation of dialkylamides was reported via oxidation of C(sp )-H bond adjacent to amide nitrogen atom (Scheme 3.10) [43]. Alternatively, Stephenson and co-workers found that mild heating of amides with persulfate salts could also work for the Friedel-Crafts amidoalkylation reaction. 

The most direct evidence that stereoelectronic effects are also important in these reactions follows from the specificity observed in hydrogen atom abstraction from confoiTnatioually constrained compounds. " " C-H bonds adjacent to oxygen" "" or nitrogen" and which subtend a small dihedral angle with a lone pair orbital (<30°) are considerably activated in relation to those where the dihedral angle is or approaches 90 . fhus, the equatorial H in 20 is reported to be 12 times more reactive towards /-butoxy radicals than the axial 11 in 21. 

All the CDC reactions presented in the previous section involve the functionalization of the C—H bond in the a-position of an amine nitrogen atom. However, only few precedents focus on the coupling of a C—H bond adjacent to an... 

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