Intramolecular C -N coupling

In 2008, Zhao and coworkers have reported a general and highly efficient method for the synthesis of 4-alkyliden-2-azetidinones via copper-catalyzed intramolecular C-N coupling of 3-bromobut-3-enamides [241]. Under Cu(I) catalysis... 

In 2013, Chen and co-workers reported a streamlined approach for the s5mthesis of tetrahydroquinolines (THQs) via the sequential functionalization of remote C-H bonds [53]. Starting from readily available aryl iodide and aliphatic amine precursors, this strategy involved a three-step sequence including palladium-catalyzed y-C(sp )-H arylation, followed by a previously optimized metal-free e-C(sp )-H iodination reaction [54] and a more classical Cu-catalyzed intramolecular C-N coupling. To test the efficacy of this novel procedure, the authors applied it to the total synthesis of the antimalarial alkaloid (+)-angustureine (Scheme 7) [55]. N-Alkylpicolinamide 28 was easily accessible from commercially available (S)-(+)-3-... 

More recently, a simple and efficient reaction for the synthesis of steroid/nonsteroid fused benzo[fe][l,4]thiazepines and 2-aiylsubstituted benzo[Z)][l,4]thiazepines was developed. using Pd(OAc)2 as the catalyst in DMF solvent with heating, a wide variety of steroidal/nonsteroidal p-bromovinyl aldehydes and 2-aminothiophenols undergo this reaction to give good yields of benzo[Z>][l,4]thiazepine derivatives (Scheme 4.17). A palladium catalyst was explored in benzoxazocine synthesis via intramolecular C-N coupling as well. ... 

Jiang et al. also reported a one-pot synthesis of 5,12-dihydroindolo[2,l-b]quin-azolines [56], N-(2-bromobenzyl)-2-iodoani-line and malononitrile were adopted as the raw materials to afford the desired compound through copper-catalyzed intramolecular C-N coupling reaction (Scheme 13.15). 

Scheme 3.8 Visible-light-mediated intramolecular C-N coupling [38]...

The Batey group found that both Pd(PPh3)4 and Cul/l,10-Phen could promote the intramolecular C-N coupling of guanidines 52, providing 2-aminobenzi-midazoles 53 with 22-98% yields (Scheme 18) [48]. The copper catalytic system was found superior to the palladium catalytic system in terms of yields and regioselectivity. 

Intramolecular C-N bond coupling in arylazides via C-H bond activation catalyzed by [Ir(COD)(OMe)]2 was recently reported [131]. The intermediate iridium nitrenoid complex (50) formed after the extrusion of dinitrogen is proposed as a reactive species, which can cleave the benzylic C-H bond to yield indoline derivatives (31). 

The intramolecular C-N bond forming reactions proved to be more straightforward than their intermolecular counterparts [138]. The desired couplings often could be achieved using (Ph3P)4Pd as catalyst to form 5-, 6-, and 7-mem-bered nitrogen heterocycles, Eq. (171). 

Aryl iodides could also be used in the intramolecular C-N bond coupling. Notably, cyclization could be achieved using triethylamine as base and solvent at room temperature in good yield with the iodide substrate, Eq. (176) [138]. 

Cyclohexadienones of the type IV (n = 0, 1, 2)29 are formed from 2,2 -bi-phenyldiols, 2,2 -methylenebisphenols or 2,2 -ethylenebisphenols via intramolecular C-0 coupling. 5, 7, 3 , 5 -Tetra-tert-butylspiro [2,3-dihydrobenzofuran-2,P-cyclohexa-3 , 5 -diene-2 -one] (IV, R1 = R2 = tert-Bu, n = 1) is stable. The similar compound IV (R1 = tert-Bu, R2 = Me, n = 1), prepared from the technically important antioxidant 2,2 -methylenebis (4-methyl-6-tert-butylphenol) by oxidation with sodium hypochlorite30 is oily and crystallizes in the form of Diels-Alder addition compound V. 

Some syntheses and reactions of benzotriazoles were reported. Copper-catalyzed C-N coupling of 2-iodoaryltriazines 163 with sodium azide and intramolecular addition of nitrene to N=N bonds afforded N-aryl-2H-benzotriazoles 164 (14CEJ1825). Photo-initiated benzyne-based [3 + 2] cycloaddition of triazene benzoic acid 165 afforded N-substituted-lH-benzotriazoles 166 (140L2003). An efficient synthetic... 

A number of interesting one-pot or two-pot sequences of Pdarylation processes [14]. For example, a two flask sequence of Negishi coupling followed by intramolecular C—N bond formation has been employed for the synthesis of substituted indolines (Eq. (1.4)) [14a]. Lautens has recently described an elegant one-flask sequence of intermolecular C H bond functionalization followed by intramolecular N-arylation for the preparation of substituted indolines [14b]. As shown below (Eq. (1.5)), the Pd-catalyzed coupling of 2-iodotoluene with 2-bromopropylamine 5 in the presence of norbornene provided indoline 6 in 55% yield. 

Scheme 13.91 Intramolecular C-N cross-coupling to access indoline scaffolds [137].

Scheme 13.93 Synthesis of aminobenzimidazoles by intramolecular C-N cross-coupling [139].

An efficient and simple tandem protocol for the synthesis of 1,2,3-triazole-fused imidazo-[l,2-a]pyridines was reported in 2013. The reactions followed a copper-catalyzed tandem azide-allq ne cycloaddition (CuAAC), Ullmann-type C-N coupling, and intramolecular direct arylation sequence and showed high generality and functional group tolerance. Good yields (59-77%) of 1,2,3-triazole-fused imidazo[l,2-a]pyridines were produced in a single step (Scheme 3.7). 

In 2009, a simple and practical copper-catalyzed method for the synthesis of 1,2,4-benzothiadiazine 1,1-dioxide derivatives was developed. " The reaction proceeded via cascade reactions of substituted 2-halobenzenesulfo-namides with amidines, and the corresponding products were formed in good yields (Scheme 3.75). The reaction was proposed to start with C-N coupling then intramolecular transamination to release ammonia and provide the final product. Later on, a procedure for the synthesis of the same products via intramolecular cyclization of o-bromoarylsulfonylated amidines was developed as well. ... 

Another reaction in water via intramolecular Ullmann type C-N coupling reaction has been developed by Huang et al. [78]. The catalyst in this case is a recyclable, environmentally benign heterogeneous CuI/PSP (polystyrene-supported pyrrole-2-carbohydrazide) utilized for the synthesis of imidazo[l,2-a]quinoxaline (Scheme 54). 

Scheme 7.23 Copper-catalyzed tandem azidealkyne cycloaddition (CuAAC), UUmann-type C-N coupling, and intramolecular direct arylationin...

Routes involving intramolecular C—N bond formation have proved to dominate this area. A number of researchers have reported the cycUzation of appropriately substituted arylhydrazones, as illustrated by Scheme 24.16. Intramolecular coupling of bromo-substituted arylhydrazone 35 using a palladium catalyst derived from biden-tate ligand 36 delivers l//-indazole 37 in good yield [76]. The scope of such a transformation was expanded when it was shown that arylhydrazines such as 38 could also be used. In this case, in situ aromatization occurs following intramolecular N-arylation to yield the desired heterocycle [77]. 

The authors proposed a mechanistic pathway where first the Sjv2 type ring opening of the chiral aziridines 322 by C-nucleophile 324 at benzylic position generates the corresponding bromo amines 325, which undergoes Pd-catalyzed intramolecular C—N bond coupling to produce the tetrahydroquinolines 323 (Scheme 40.71). 

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