Hartwig-Buchwald condition

Very efficient cross coupling reactions of tin derivatives with [4- F]fluorobro-mo and [4- F]fluoroiodobenzenes have been carried out [162, 163] (Scheme 42). Reaction of the appropriate piperazine with [4- F]fluorobro-mobenzene under Hartwig-Buchwald conditions [187] yields [ F]RP 62203 in high specific activity and biologically usable amounts. This method appears superior to the one described previously starting from [ F]fluoronitrobenzene (Scheme 18). 

The Harmata group has also developed a route to enantiomerically pure 2,1-benzothiazines. The process involves the /V-arylation of sulfoximines using the Buchwald-Hartwig reaction conditions, <02MI3 99JOM(576)125> a reaction first reported by Bolm... 

Compound 2 was furthermore employed in the preparation of NH-linked Pc-porphyrin arrays [60]. The reaction between the amino-functionalized porphyrin 8 and 4-iodophthalonitrile using Buchwald-Hartwig amination conditions (Pd(OAc)2/ rac-BINAP (BINAP = 2,2/-bis(diphenylphosphino)-l,l/-binaphthyl) as the catalytic system) in the presence of potassium fe/7-butoxide, delivered the entities connected either at the meso-phenyl group (9 in Fig. 7) or at the /1-pyrrolic position [61]. 

The reaction between vinylogous amides and aryl halides was studied by Edmondson and co-workers in 2000. ° In this report, the first tandem Hartwig-Buchwald-Heck cyclization was described as well and applied to the synthesis of 2,3-disubstituted indole derivatives. The reaction between enaminone and 2-bromobenzaldehyde could lead to a quinoline derivative under their reaction conditions (Scheme 2.12). 

The Heck cyclization proceeds via methylene indolenines (83) (isolable in the presence of Ag salts) and migration of their exocyclic double bond to the internal enamine position under the reaction conditions. A variety of 3-methylindoles (84) is accessible directly from 2-bromoiodobenzenes by a Pd-catalyzed aryl amination (Hartwig-Buchwald reaction)/Heck cyclization cascade [172]. 

Palladium-catalyzed aminations of aryl halides is now a well-documented process [86-88], Heo et al. showed that amino-substituted 2-pyridones 54 and 55 can be prepared in a two-step procedure via a microwave-assisted Buchwald-Hartwig amination reaction of 5- or 6-bromo-2-benzyloxypyri-dines 50 and 51 followed by a hydrogenolysis of the benzyl ether 52 and 53, as outlined in Fig. 9 [89]. The actual microwave-assisted Buchwald-Hartwig coupling was not performed directly at the 2-pyridone scaffold, but instead at the intermediate pyridine. Initially, the reaction was performed at 150 °C for 10 min with Pd2(dba)3 as the palladium source, which provided both the desired amino-pyridines (65% yield) as well as the debrominated pyridine. After improving the conditions, the best temperature and time to use proved... 

The first examples utilising A-heterocyclic carbenes as ligands in the Buchwald-Hartwig amination involved the in situ formation of the catalyst from the corresponding imidazolium salt and a Pd(0) source. Nolan reported IPr-HCl/PdjCdbalj as a catalytic system for the amination of aryl chlorides in excellent yields, using different types of amines, anilines, and also imines or indoles [142,143] (Scheme 6.46). Hartwig showed later that in some cases the reactions could be performed at room temperature and without anhydrous conditions even for aryl chlorides [ 144]. This was later shown for the less challenging bromides and iodides [145,146]. 

The Harmata group also found that certain ort/w-bromocinnamates underwent a Michael addition during the course of the Buchwald-Hartwig reaction. This one-pot process produced the same products as the two step process and with the same, complete stereoselectivity. For example, this was first observed with bromocinnamate 107, where the reaction with (7 )-77b afforded a 53% yield of sulfoximine 108 as well as a 36% yield of benzothiazine 95 under standard coupling conditions (Scheme 27). The cyclization was attributed to a buttressing effect of the ortho-methoxy in bromocinnamate 107. This presumably favored a conformation that placed the methyl group of its sulfoximine functionality near the p-carbon of the a,P-unsaturated ester, thus favoring cyclization. 

Independent investigations by Maes and coworkers have involved the use of commercially available and air-stable 2-(dicydohexylphosphanyl)biphenyl (ligand B) as a ligand system for the successful and rapid coupling of (hetero)aryl chlorides with amines under microwave Buchwald-Hartwig conditions (0.5-2 mol% palladium catalyst) [129, 130]. Both methods provide very high yields of products within an irradiation time of 10 min. 

The Buchwald-Hartwig aryl animation methodology cited above in this section was engaged by Hartwig and others to synthesize AT-arylindoles 377 [469]. Carbazole can be N-arylated under these same conditions with p-cyanobromobenzene (97% yield). Aryl chlorides also function in this reaction. The power of this animation method is seen by the facile synthesis of tris-carbazole 378 [469c]. 

The double N-arylation of primary amines or ammonia equivalents 592 with 2,2 -biphenylylene ditriflate (591) under Buchwald-Hartwig N-arylation conditions gave the unsymmetrically multi-substituted carbazoles 593. Among the various... 

Lin and Zhang reported the synthesis of l-hydroxy-3-methylcarbazole (23) starting from the nitro derivative 625 (578). This synthesis uses a Buchwald-Hartwig amination for the synthesis of the diphenylamine 628. After protection of the hydroxy group in the nitrophenol 625 as a benzyl ether, the nitro group was reduced to the corresponding amino derivative 627. Amination of 627 with iodobenzene under Buchwald-Hartwig conditions afforded the diarylamine 628. Palladium(ll)-mediated cyclization of 628 led to the carbazole derivative 629, albeit in low... 

The double N-aiylation of the 6-aminocarbazole 1082 with the dibromobiphenyl derivative 1075 under Buchwald-Hartwig N-arylation conditions afforded N-SEM-murrastifoline-A (1083) in 58% yield. Finally, the M-SEM group was removed under acidic conditions to furnish murrastifoline-A (186) in 94% yield (666,667) (Scheme 5.174). 

The palladium catalyzed intramolecular coupling of aryl halides and classical carbanions, sometimes considered a variant of the Buchwald-Hartwig coupling, might also be used for the formation of heterocyclic systems. 7V-(2 -bromophenyl)-propionamides were converted in the presence of the appropriate palladium catalyst and lithium hexamethyldisilazide to oxindoles (3.2.). Under the applied conditions a series of electron deficient and electron rich aniline derivatives, including 2-chloroanilines were transformed successfully.2... 

In certain cases, when the palladium or nickel catalyzed coupling is not efficient or fails completely, an alternate solution is provided by the use of copper based catalyst systems. The 5-iodouracil derivative shown in 7.77. was unreactive towards imidazole using either the Buchwald-Hartwig conditions or the copper(I) triflate promoted the carbon-nitrogen bond formation reported by Buchwald98 These latter conditions, however, were effective in coupling the iodouracil with a series of other amines (7.77.), The optimal catalyst system consisted of copper(I) triflate, phenantroline and dibenzylideneacetone (dba).99... 

Very recently 5- and 8-aminoquinolines have been prepared from the respective aryl bromides by microwave-assisted Buchwald-Hartwig couplings in 10 min at 120°C63. Enhanced yields were observed under microwave conditions as compared to the corresponding classical oil-bath heated reactions (Scheme 2.25). 

The Buchwald-Hartwig reaction was performed under a variety of conditions starting with the model compounds and leading up to target substrate. The results are shown in Table 3. There was a 70 % yield obtained in the reaction of triflate 35 with the cyclic secondary amine morpholine using condition A (entry l),32 however the reaction fails with diphenethylamine (entry 2). Changing the base to sodium tert-butoxide (condition B) or the catalyst to Pd2(dba)3 and ligand (condition C) also resulted in no reaction (entries 3 and 4). 

Table 3. Conditions Applied to the Buchwald-Hartwig Reaction.

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