Amide arylation process

Oxazoles are also obtained by the reaction of a-halogenoketones (78) with primary amides (the Bliimlein-Lewy synthesis), and this method is particularly appropriate for oxazoles containing one or more aryl groups as in (79). Formamide may also be used in this process, resulting in a free 2-position in the oxazole, and when a urea derivative (80) is used, 2-aminooxazoles (81) are formed (80ZOR2185, 78IJC(B)1030, 78JIC264). Numerous applications of these procedures are described in Chapter 4.18. 

Tetrasubstituted phosphinous amides of the type R2NPPh2 have been successfully arylated at phosphorus by the action of bromobenzene, in a process catalyzed by NiBr2, to give the aminophosphonium bromides [R2NPPh3] Br [109]. Other representative members of this class form phosphane-borane complexes [62], are aminated at phosphorus by chloramine to yield bis(amino)phos-phonium salts [110] and have been claimed to be protonated at phosphorus by ethereal tetrafluoroboric acid, as determined by NMR analysis [111]. 

The method is not restricted to secondary aryl alcohols and very good results were also obtained for secondary diols [39], a- and S-hydroxyalkylphosphonates [40], 2-hydroxyalkyl sulfones [41], allylic alcohols [42], S-halo alcohols [43], aromatic chlorohydrins [44], functionalized y-hydroxy amides [45], 1,2-diarylethanols [46], and primary amines [47]. Recently, the synthetic potential of this method was expanded by application of an air-stable and recyclable racemization catalyst that is applicable to alcohol DKR at room temperature [48]. The catalyst type is not limited to organometallic ruthenium compounds. Recent report indicates that the in situ racemization of amines with thiyl radicals can also be combined with enzymatic acylation of amines [49]. It is clear that, in the future, other types of catalytic racemization processes will be used together with enzymatic processes. 

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."... 

Several new methods for the synthesis of the oxazole nucleus were published. A new consecutive three-component oxazole synthesis by an amidation-coupling-cycloisomerisation sequence was developed. The synthesis started from propargylamine 92 and acyl chlorides. To extend this process, a four component sequence involving a carbonylative arylation by substitution of one acyl chloride with an aryl iodide and a CO atmosphere was also performed <06CC4817>. 

Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines, lactones, primary amines, pyridines, aldehydes, carboxylic acids, and esters. The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane. In the course of the preparation of a drug candidate, the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds. The reaction was studied using isobutyronitrile and 2-fluoroanisole. The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished h... 

The use of lithium amides to metalate the a-position of the N-substituent of imines generates 2-azaallyl anions, typically stabilized by two or three aryl groups (Scheme 11.2) (48-62), a process pioneered by Kauffmann in 1970 (49). Although these reactive anionic species may be regarded as N-lithiated azomethine ylides if the lithium metal is covalently bonded to the imine nitrogen, they have consistently been discussed as 2-azaallyl anions. Their cyclization reactions are characterized by their enhanced reactivity toward relatively unactivated alkenes such as ethene, styrenes, stilbenes, acenaphtylene, 1,3-butadienes, diphenylacetylene, and related derivatives. Accordingly, these cycloaddition reactions are called anionic [3+2] cycloadditions. Reactions with the electron-poor alkenes are rare (54,57). Such reactivity makes a striking contrast with that of N-metalated azomethine ylides, which will be discussed below (Section 11.1.4). 

An example of the use of DMF as CO source in the Pd-catalyzed aminocarbonylation with microwave irradiation is shown in Scheme 28. Thus, n-bromotoluene was reacted with benzylamine (4 equiv.) in the presence of Pd-dppf catalyst, imidazole, KOBu, and DMF (17equiv.) with microwave irradiation for 20min to give amide 196 in 94% yield (Scheme 28). A proposed mechanism (Scheme 28) has a close similarity to that of the aminocarbonylation of aryl bromide with formamide (see Scheme 22). However, in this process, a large excess (4 equiv.) of benzylamine was used to suppress a possible reaction involving dimethylamine generated in situ from DMF under reaction conditions. 

Yamamoto reported the first boron reagent-based catalytic method that allows direct amide formahon from a free carboxylic acid and amine as the reaction partners [21]. Aryl boronic acid derivahves bearing electron-withdrawing subshtu-ents in the meta and/or para posihons were found to be the catalyst of choice for these kinds of transformations. Tang s work [22] featured the use of a cheap, readily available, non-toxic, and eco-friendly boric acid, B(OH)i, as a highly effective catalyst that proved to be superior to other known catalysts involved in the amidation process. 

The concept of in situ liberation of carbon monoxide would be even more attractive if a metal-free material could serve as the carbon monoxide source. In the ideal carbonylation method, the organic solvent itself could be exploited for controlled generation of carbon monoxide. In 2002, Wan et al. addressed this issue and developed a microwave-promoted carbamoylation process based on the commonly used solvent dimethylformamide (DMF) as the carbon monoxide precursor75. Firstly, it was discovered that aryl dimethyl amides were accessible from the corresponding bromides in the presence of a nucleophilic catalyst, imidazole (Scheme 2.34). Secondly, tertiary benzamides other than dimethylamides were synthesised by addition of 3 equiv of an external amine (Scheme 2.34). 

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