Buchwald-Hartwig procedure

The reaction conditions are similar to the palladium-catalyzed Buchwald-Hartwig amination (see Chapter 3) with one distinct advantage when the base NaOt-Bu used in the Buchwald-Hartwig procedure is replaced with KOt-Bu, the reaction proceeds without the need for a palladium catalyst. Primary and secondary amines, as well as aromatic and aliphatic amines, undergo the amination smoothly however, only meto-substituted aniUnes can be obtained. 

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... 

However, the Buchwald-Hartwig reaction with NHCs as hgands is not limited to palladium. Nickel has also been successfully employed in this catalytic amination. In situ procedures have been described for the coupling of aryl chlorides [163] and tosylates [164] and, more interestingly, anisoles [165]. The use of well-defined Ni(0) catalysts has also been studied [166] (Scheme 6.49). 

The Harmata group s initial report concerned a one-pot, one-operation procedure <99AG(E)2419> for the synthesis of enantiomerically pure 2,1-benzothiazines via the Buchwald-Hartwig reaction reported by Bolm <98TL5731 OOJOC169> for sulfoximine N-arylation. For example, treatment of ortho-bromobenzaldehyde 78 with enantiomerically pure N-H sulfoximine 77a in the presence of a palladium catalyst and base afforded the benzothiazine 79 in 78% yield (Scheme 22). Both C-N bond formation and condensation occurred during the reaction, a phenomenon that appears general for aldehydes like 78. 

The synthetic potential of palladium-mediated cross-coupling reactions (Heck, Suzuki, Stille, Sonogashira, Buchwald-Hartwig) led to the search for a practical synthesis of p-[ F]fluoroiodo- and p-[ F]fluorobromobenzene. p-[ F]Fluoroio-dobenzene (G, X = iodine) can be obtained in poor yield from p F]fluoride and a trimethylammonium precursor (P7). p-p F]Fluorobromobenzene can be prepared in a more reproducible way from 5-bromo-2-nitrobenzaldehyde (radiochemical yields > 70%). The synthesis involves a two-step procedure radiofluorination (F for NO2 substitution), then a catalysed decarbonylation [190,191]. Also very efficient is the one-step reaction of p F]fluoride with a suitable diaryliodonium salt (P6) giving >70% radiochemical yield [192-194]. 

The dehydrohalogenation approach outlined in Scheme 1 reduces problems of selectivity in the synthesis of carbazoles. The method can be improved further by producing the N-aryl-2-haloaniline starting materials in the same pot as the subsequent carbazole product. This is achieved by Buchwald-Hartwig amination of 2-chloroanilines with aryl bromides [13], An illustrative example of this one-pot procedure is shown in Scheme 4. 

Orr/zc- em-Dihalovinylanilines 278 were also used in another example of a Buchwald-Hartwig-type/Mizoroki-Heck reaction for the synthesis of 2-vinylic indoles 279 (Scheme 8.69). Lautens and coworkers [140] recently illustrated a domino coupUng under Jeffery s condition where the aniline nitrogen undergoes an amination step followed by a Mizoroki-Heck coupling with various alkenes. In this process, electronic factors and steric hindrance of the different substituents had only a small effect on the yield however, in the formation of 3-substituted indoles using this method only very poor yields were obtained. The procedure can also be performed in an intramolecular mode leading to tricycUc compounds such as pyridino and azepino indoles 281 and 282 (Scheme 8.69). 

Typical Buchwald-Hartwig Cross-Coupling Procedure. Synthesis of N,N-Diethyl-N-phenylanthranilamide 1124 Acknowledgments 1124... 

Scheme 2.2 The proposed mechanism for the Buchwald-Hartwig arylation procedure [12e, 14b, 15].

These reductive eliminations tend to have a higher kinetic barrier than for C-H or C-C. In RE of C-X (X = F, OR, NR2), the tt donor X group prefers to locate at the base of the Y in the Y-shaped intermediate mentioned earlier, and thus is remote from the RE partner. Numerous cases of such REs have been reported in recent years, however, notably in connection with the Buchwald-Hartwig coupling procedure to form C-X bonds (Section 9.7 and 14.1). 

The first application of the single-step procedure to the synthesis of azacafix-arenes was laimched by Ito et al., who prepared a series of azacafix[ ]arenes 4a-f with different ring sizes (w = 3 to 8) [16,17]. As shown in Scheme 2, starting from the N-methylation of 3-bromoaniline (2) in 3 steps, the resultant 3-bromo-N-methylaniline (3) was subjected to the Buchwald-Hartwig aryl amination reaction to yield azacaUxarenes 4a-f, which were isolated by medium-pressure liquid chromatography. 

Another application of the single-step procedure tvas made by Miyazaki et al, who utilized the Buchwald-Hartwig aryl amination reaction for the preparation of azacalix[6]pyridine 7d [18], in which all the benzene rings of the above azacalix[6]arene 4d were replaced by pyridine rings (Scheme 3). Azacalix[ ]pyridines 8a-f (n = 3-8) with tolyl groups on the nitrogen bridges... 

The following Experimental Procedures should give a feeling for the scope of the Buchwald-Hartwig reaction. 

The GooBen group developed palladium-catalyzed Buchwald-Hartwig amination reactions of aryl chlorides using a bench-stable, commercially available A -heterocycle-based catalyst (Experimental Procedure below). ... 

The Buchwald-Hartwig reaction ( 5.1) can be combined with an intramolecular cyclization i.e., carbopalladation). In particular, an allene can serve as suitable starter molecules see the Experimental Procedure below. "" Depending on the reaction conditions, either the C-N or the C-C coupling proceeds first. 

Despite the success of the original Hartwig-Buchwald protocol, this procedure was not without its drawbacks. The scope was limited to aryl bromide substrates and secondary amine coupling partners, and the requirement of a strong rert-butoxide or amide base meant that substrates with base-sensitive fimctional groups would not be compatible. While this latter constraint has since been obviated by the discovery that weaker bases such as CS2CO3 can promote the reaction, the extension of the scope has required some sophisticated catalyst development (vide infra). 

A rather unusual procedure has been published for the palladium- and copper-catalyzed synthesis of triarylamines, using an alkaline water-ethanol emulsion stabilized by cetyltrimethylammonium bromide [41]. Anyway, this method overcomes the problem in the synthesis of N-aryl carbazoles (Eq. 14), which are not accessible by the method developed by Hartwig and Buchwald [42],... 

The synthesis of Spiro-DPSP 115 starts with 2,7-dibromospirobifluorene (9), which is iodinated in the 2 and 7 position by the procedure of Merku-shev [35]. After Suzuki couphng [72] of 120 with biphenylboronic acid, the target compound is formed by Hartwig-Buchwald coupling [103] of 121 with diphenylamine (Fig. 43). 

The annus mirahilis of the palladium-catalyzed C—N bond formation was 1995, when Buchwald and Hartwig reported, independently, two milestone events -Buchwald the amination of aryl bromides with different amines using [ P(o-Tol)3 2PdCl2] and NaOt-Bu as base [24], and Hartwig a similar procedure using LHMDS as base (Scheme 3.3) [25]. 

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