Amine arylations

Amine arylation.1 This reaction can be effected at 25° with aryllead triacetates in the presence of Cu(OAc)2. Yields are high in reactions of anilines substituted by electron-releasing groups. Only primary linear aliphatic amines are arylated, albeit in poor yield. 

The formation of alkoxo intermediates may be occurring when monophosphines are used, but the stability of the amine complexes favors the deprotonation of coordinated amine. Instead, the alkoxo complexes may be important in catalytic systems involving chelating ligands [51]. Indeed, the DPPF complex [Pd(DPPF)(p-Bu C6H4)(0-f-Bu) reacted with diphenyl amine, aniline, or piperidine, as shown in Eq. (48), to give the product of amine arylation in high yields in each case [51]. Since, no alkali metal is present in this stoichiometric reaction, the palladium amide is formed by a mechanism that cannot involve external deprotonation by alkali metal base. 

Neostigmine (= 3-Dimethyl-carbamoxyphenyl) trimethylammonium] (quaternary amine aryl carbamate) Synthetic - cf. Physostigmine AChE (carbamoylates - forms carbamoyl ester with active site Serine) [cholinergic, myotic, toxic (curare antidote)]... 

Keywords. Amination, Arylation, Catalyst, Ligand, Palladium... 

Additionally, Boger and Panek reported an intramolecular amine arylation mediated by stoichiometric quantities of Pd (0), Eq. (2) [15]. Efforts to render this transformation catalytic in palladium were fruitless, however. The resulting heterocycle was utilized in the total synthesis of lavendamycin. 

Similarly, Hartwig and Louie reported that LiHMDS was also a useful base for such transformations, Eq. (5) [18]. They also reported two different complexes as catalysts [(o-tol)3P]2PdCl2 and [(o-tol)3P]2Pd effectively catalyzed the amine arylation reaction. 

The generally accepted mechanism for the amine arylation is shown in Scheme 1. The catalytic cycle begins with the oxidative addition of the aryl halide (or sulfonate) by Pd (0). The palladium (II) aryl amide can be formed either by direct displacement of the halide (or sulfonate) by the amide or via the intermediacy of a palladium (II) alkoxide [19]. Reductive elimination of the C-N bond results in the formation of the desired arylamine and regeneration of the Pd (0) catalyst [lie,20]. 

Fig. 1. Compounds prepared by the [(o-tol)3P]2PdCl2-catalyzed amine arylation...

Guram has reported similar P,N- and P,0-chelating ligands useful in the amine arylation reaction [47]. For example, the coupling of piperidine with 4-bromobenzophenone proceeds in 98% yield with as little as 0.5 mol% of the palladium catalyst resulting from ligand 5, Eq. (17). 

In 1999, Wolfe and Buchwald reported the synthesis of hindered, electron-rich phosphine 6 and its use in the amine arylation reaction. Use of this new ligand resulted in a catalyst capable of effecting the room temperature reaction between cyclic amines and aryl bromides [42a, 44,48,49]. The catalyst derived from Pd2(dba)3 and 6 couples 3,5-dimethybromobenzene with morpholine in 80% yield while stirring for 20 hours at room temperature, Eq. (18). This new highly active catalyst efficiently arylates a variety of amines with aryl bromides as well as chlorides at room temperature. 

The use of aryl triflates or other sulfonates in the amine arylation reaction is highly desirable from a synthetic standpoint since a large variety of phenols are easily accessed and derivatized. Aryl and vinyl triflates have enjoyed great utility in other Pd-catalyzed transformations such as the Stille [77] and Suzuki [78] couplings, and the Heck [79] reaction. 

During their studies on the synthesis of norastemizol, Senanayake, Tanouxy and co-workers reported that high levels of regioselectivity were observed in the amine arylation such that primary amines reacted in preference to secondary ones [87]. For example, the coupling of 4-aminopiperidine in the presence of the BINAP/Pd-catalyst resulted in reaction at the primary amine functional group, Eq.(72) [34],... 

Nitrogen-containing heterocycles are interesting substrates for the amine arylation reaction since many pharmaceuticals possess such functionality. The arylation of such a species is not always straightforward, however, since their pKas are considerably different from simple amines. In addition, some heterocycles, such as indoles, are able to go unwanted side reactions. 

Several 2 -deoxyadenosine-amine adducts that have been implicated in carcinogenesis were prepared via the Pd-catalyzed amine arylation reaction as reported by Lakshman and co-coworkers [135]. For example, the coupling of the protected 6-bromoadenosine derivative below was achieved in good yield using the 4/Pd-catalyst, Eq. (168). 

More than 15 years ago,Boger reported an intramolecular amine arylation using stoichiometric quantities of palladium. In 1997, the Buchwald group investigated catalytic variants of the cyclization [138]. Initial studies involved the in situ... 

Unlike the intermolecular variants, the intramolecular amine arylation of a-chiral substrates proceeded without racemization when the reaction was performed with the (o-tolljP/Pd-catalyst, Eq. (172) [54]. 

The arylation of aliphatic alcohols is particularly challenging because the competitive /1-hydride elimination side reaction that was problematic in the amine arylation is even more prevalent in the analogous C-O bond forming reactions. Thus, the coupling of tertiary alcohols such as ferf-butanol and aryl halides has seen considerable success, while general methods for the arylation of primary and secondary alcohols have been more elusive. 

In general, primary alkyl halides react better than secondary tertiary halides undergo dehydrohalogenation. High-molecular-weight alkyl halides are slow to react and must be heated with alcoholic ammonia. Anhydrous liquid ammonia fevors the formation of primary amines. Aryl-... 

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