C-N Bond Formations

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. 

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 

N-halosuccinimide (NBS or NCS) [42] as the oxidant. The complex TpBr3Cu(NCMe) displays high activity towards nitrene-transfer reactions (Equation 11.17) [43]. Various substrates can be used under the same catalytic conditions. 

Rhodium Catalysts Rhodium catalysts have been widely used in C—N bond formation via the Rh-nitrene intermediates. Du Bois and co-workers have developed various types of Rh-catalyzed intramolecular C—N bond-forming reactions (Equation 11.18) [44] and intermolecular C—N bond-forming reactions (Equation 11.19) [45]. The mechanism of these C—H amidation reactions proceeds via a concerted asynchronous two-electron oxidation pathway. 

Recently, efficient rhodium-catalyzed intermolecular C—H amination reactions have been reported where a sulfonimidamide is used as the nitrene precursor [46]. The functionalizations of various C—H bonds proceed smoothly in this type of intermolecular amidation reaction (Equation 11.20) [47]. When chiral sulfonimida-mides are used, moderate to excellent diastereoselectivities can be achieved. 

The enantioselective aza-Michael [49] reaction of enals has been emerged as one of the most important methodologies for the synthesis of enantiomericaUy pure C-N bonds. These methodologies led to the enantioselective synthesis of N-heterocyclic compounds such as pyrroHdines and piperidines. 

Despite this early success, it was not until 2006 that MacMillan reported the first highly enantioselective intermolecular aza-Michael addition to enals [51]. In this work, MacMillan reported the use of N-sUyloxycarbamates as nucleophiles. The N-O functionality would increase the nucleophilicity at the nitrogen center via the a-effect, while the carbamate functionality would decrease the basicity of the 

Probably inspired by those two reports, Lin reported in 2009 a synthesis of INCB018424 (Janus kinase s inhibitor) based on an enanhoselective aza-Michael reaction with an enal [59]. 

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Oxidative Ring Closure Reactions 4.03.4.1.1 C—N bond formation N—N bond formation C—S bond formation N—S bond formation O—C bond formation O—N bond formation S—S, S—Se and Se—Se bond formation Electrophilic Ring Closures via Acylium Ions and Related Intermediates Ring Closures via Intramolecular Alkylations... 

Synthesis of N-heterocycles with C—N bond formation catalyzed by transition metal catalysts 97SL749. 

Azadienes 89, generated in situ by thermolysis of the corresponding o-aminobenzylalcohols, have been used for the derivatization of [60]-fullerene through C-N bond formation leading to tetrahydropyrido [60]-fullerenes [93]. Theoretical calculations predicted these cycloadditions to be HOMO azadiene-controlled (Equation 2.25). 

Besides sulfonamides, chiral sulfoximines have also been used in C - N bond formation under microwave irradiation [103]. The only heteroaryl chloride used in the study—namely, 2-chloropyridine—gave the desired M-(pyridin-2-yl)sulfoximine at a yield of 43% (Scheme 101). Interestingly,... 

Microwave-assisted intramolecular C - N bond formations have also been studied. Substituted benzimidazoles were easily prepared from the corresponding M-(2-bromophenyl)imidoformamides by Brian et al. (Scheme 102) [ 104]. The protocol involved the use of a combination of Pd2 (dba)3 and PPha in a mixture of DME and water using NaOH as the base at 160 °C. It was apphca-ble for electron poor, neutral and rich as well as sterically hindered amidines. The fastest reactions were obtained with an electron withdrawing substituent... 

Ring Closure Reactions by C-N Bond Formation (Lactamization)... 

Very recently, Dongol and coworker have developed a one-pot synthesis of isoxa-zolidinones starting from O-homoallyl hydroxylamines and aryl halides. After a Heck reaction of the substrates, a subsequent C-N bond formation took place to furnish the target compounds in up to 79% yield [86]. 

AROMATIC C—N BOND FORMATION WITH RELATED SUBSTRATES 378... 

The Harmata group s initial report concerned a one-pot, one-operation procedure <99AG(E)2419> for the synthesis of enantiomerically pure 2,1-benzothiazines via the Buchwald-Hartwig reaction reported by Bolm <98TL5731 OOJOC169> for sulfoximine N-arylation. For example, treatment of ortho-bromobenzaldehyde 78 with enantiomerically pure N-H sulfoximine 77a in the presence of a palladium catalyst and base afforded the benzothiazine 79 in 78% yield (Scheme 22). Both C-N bond formation and condensation occurred during the reaction, a phenomenon that appears general for aldehydes like 78. 

The cyclization of the five-atom component O-acylated amidoximes 204 leads to 1,2,4-oxadiazoles via C-N bond formation as shown in Scheme 30. The requisite O-acylated amidoximes 204 are accessed via the reaction of an amidoxime with an activated carboxylic acid or a carboxylic acid derivative. Often the O-acylated amidoxime 204 is not isolated and the cyclization is either spontaneous or occurs in a one-pot process, and these approaches are dealt with in Section 5.04.9.1.2 as syntheses from a one-atom component and a four-atom component. In this section, only those methods in which the O-acylated amidoxime 204 is isolated and cyclized in a separate step are dealt with. 

C-N Bond Formation through Amination, Pages 695-724, Y. Takemoto and H. Miyabe... 

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