Amide arylation coupling

Cross coupling between an aryl halide and an activated alkyl halide, catalysed by the nickel system, is achieved by controlling the rate of addition of the alkyl halide to the reaction mixture. When the aryl halide is present in excess, it reacts preferentially with the Ni(o) intermediate whereas the Ni(l) intermediate reacts more rapidly with an activated alkyl halide. Thus continuous slow addition of the alkyl halide to the electrochemical cell already charged with the aryl halide ensures that the alkyl-aryl coupled compound becomes the major product. Activated alkyl halides include benzyl chloride, a-chloroketones, a-chloroesters and amides, a-chloro-nitriles and vinyl chlorides [202, 203, 204], Asymmetric induction during the coupling step occurs with over 90 % distereomeric excess from reactions with amides such as 62, derived from enantiomerically pure (-)-ephedrine, even when 62 is a mixture of diastereoisomcrs prepared from a racemic a-chloroacid. Metiha-nolysis of the amide product affords the chiral ester 63 and chiral ephedrine is recoverable [205]. 

In addition to the aforementioned oxidative methods for effecting the aryl coupling required for the creation of the quaternary carbon center, photochemi-cally induced cyclizations have proved to be of modest utility. As an example, irradiation of the bromo amides 307 (160) and 308 (161) afforded the corresponding tetracyclic lactams 309 and 310, albeit in rather low yield. The lactam 309 had previously been converted to ( )-galanthamine (291) together with a small amount of ( )-epigalanthamine (301) by reduction with LiAlH4 (162). 

The photochemically induced aryl-aryl coupling reaction of the diphenolic amide 28 was used as the key step in the synthesis of crassifolazonine (2). In this case, in addition to small amounts of the reduced derivative 29, indoline 30 was obtained as the result of N-attack (Scheme 6). Cyclization took place exclusively at the position para to the hydroxyl group to give a low yield of 31, which was transformed by the usual two-step procedure to crassifolazonine (2) (15). 

Furthermore, 6-phenanthridinones 41 and their heterocyclic analogs 42-46 could be obtained in modest to excellent yields via a sequence of Pd-catalyzed aryl-aryl and N-aryl coupling from iodoarenes, ortho-substituted by electron-releasing substituents and amides of o-bromoarene-and heteroarenecarboxylic acids (Scheme 16) [73]. 

Earlier, a one-pot procedure based on consecutive Pd-catalyzed aryl-aryl coupling followed by N-C bond formation had been described for the synthesis of phenanthridones and their thiophene analogs <2004OL4759>. The starting materials were 2-iodotoluene and 3-bromothiophene-2-carboxamides or 3-bromobenzo[3]thiophene-2-carboxamides (Equations 40 and 41). The conditions were rather critical in order to prevent the nucleophilic amide group from coordinating with the palladium, tri-2-furylphosphine had to be added to the reaction mixture. Norbornene serves to form a palladacycle which then reacts with the bromoamide. 

Intramolecular anodic coupling of diaryl amides is a synthetically interesting reaction that may be applied to the synthesis of alkaloidal structures [210]. However, this aryl coupling is initiated by the oxidation of an aromatic ring (aryl ether or phenol) and not by oxidation of the nitrogen. Therefore, it is not discussed further in this chapter. 

Recently, a related reaction protocol was developed with an amino acid as ligand379. In this protocol various amides were coupled with aryl iodides in the presence of Cul (5 mol%), amino acid (glycine, cystine, cysteine, lysine, arginine, tr-alaninc, /3-alanine) (20 mol%) as ligand and K3PO4 as base in dioxane at 100 °C (Figure 23). 

Finally, a tandem jV-arylation/Heck coupling has also been developed for indole synthesis. Vinologous amide 11 couples with aryldibromide 10 to... 

Metal catalysts such as bismuth triflate (Bi(OTf)3) and iron chloride hexa-hydrate (FeCl3 6H2O) have been shown to catalyse Ritter reaetions by Barrett and Cossy respeetively. Barrett used 20 mol% Bi(OTf)3 in the synthesis of A(-fe/t-butyl amides by coupling a range of alkyl and aryl nitriles with ferf-BuOH or tert-butyl aeetate (terf-BuOAc). Although Cossy used lower catalyst loadings of a cheaper metal, higher temperatures of 150 °C were... 

Abstract This review covers the recent recyclable protocols for the C-N bond forming reactions between aromatic, heterocyclic and aliphatic amines such as imidazoles, benzimidazoles, benzylamines, piperidine, pyrrole, imides, anilines, hexyl, cyclohexyl amines, and amides as coupling partners with aryl iodides, bromides, chlorides, and arylboronic acids employing copper-mediated systems. The physical properties and characterization of the catalysts and their use in organic synthesis will be outlined. Most importantly, these recyclable versions developed by many groups in the recent years are potential candidates for commercial exploitation. The effect of additives, solvents, temperature, base, the nature of aryl halides on reactivity, and recycle studies of the heterogeneous catalysts are included in this... 

The terminal diyne 320 is prepared by coupling of the zinc acetylide 318 with /rfln.s-l-iodo-2-chloroethylenc (319), followed by elimination of HCI with sodium amide[231]. Similarly, terminal di- and triynes are prepared by using cw-l,2-dichloroethylene[232]. The 1-alkenyl or l-aryl-2-(perefluoroalkyl) acetylene 321 is prepared by the reaction of a zinc acetylide with halides[233]. 

The last method for the preparation of 2-quinolones described in this chapter relies on a intramolecular Heck cyclization starting from heteroaryl-amides (Table 2) [57]. These are synthesized either from commercially available pyrrole- and thiophene-2-carboxylic acids (a, Table 2) or thiophene-and furan-3-carboxylic acids (b, Table 2) in three steps. The Heck cyclization is conventionally performed with W,Ar-dimethylacetamide (DMA) as solvent, KOAc as base and Pd(PPh3)4 as catalyst for 24 h at 120 °C resulting in the coupled products in 56-89% yields. As discussed in Sect. 3.4, transition metal-catalyzed reactions often benefit from microwave irradiation [58-61], and so is the case also for this intramolecular reaction. In fact, derivatives with an aryl iodide were successfully coupled by conventional methods, whereas the heteroarylbromides 18 and 19, shown in Table 2, could only be coupled in satisfying yields by using MAOS (Table 2). 

In contrast to the borylation of alkane C-H bonds, the coupling of aryl halides with amines was based on a literature precedent from another group published about a decade before our initial studies. Kosugi, Kameyama and Migita published the coupling of aryl halides with tin amides." Mechanistic studies we conducted on this process led us to the perhaps obvious realization that the reaction" could be conducted with amines and a silylamide base instead of tin amides (equation 4)." Surveys of bases with similar p a values led Janis Louie to conduct reactions with alkoxide bases. Similar studies were conducted at nearly the same time by Steve Buchwald and coworkers."... 

Amides of phosphorous acid (e.g., P(NMe2)3 and the bicyclic compound (L16)) are useful ligands for cross-coupling of arylboronic acids with aryl bromides and chlorides (system Pd(OAc)2/2L, Cs2C03, toluene, 80 °C), the bicyclic amide being markedly more effective than simple acyclic ones.421 Amides of phosphinous acids are also excellent bidentate ligands with PN coordination mode ((L6), Section 9.6.3.4.2). 

The intermolecular coupling of lactams and acyclic amides has also been reported. Reactions of carbamates with aryl halides occurred in the presence of catalysts ligated by P(/-Bu)3.78 Both carbamates and amides coupled with aryl halides in the presence of a catalyst bearing Xantphos.90 In addition, the coupling of lactams with aryl halides has been successful. A combination of Pd(OAc)2 and DPPF first formed A-aryl lactams in good yields from 7-lactams, but the arylation of amides was improved significantly by the use of Xantphos (Equations (20) and (21)).90 91 The reaction of aryl halides with vinyligous amides has also been reported 92... 

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