Hartwig-Buchwald coupling

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... 

Indole systan 168 has been prepared from a ring closure reaction of dihydroisoqui-noline derivative 167 catalysed by a NHC-Pd system (Scheme 5.44) [49], The product 168 was prepared from an intramolecular Buchwald-Hartwig coupling and was used in the total synthesis of rac-mangochinine 169. 

Commensurately with the development of various catalyst systems, the Pd-catalyzed G-O cross-coupling has found a number of synthetic applications. Examples include the syntheses of the protein kinase G (PKC) activator (+)-decursin,104 the natural product heliannuol E,105 a chiral 2-methyl chroman,106 and a series of aryloxy and alkoxy porphyrins.107 The Buchwald-Hartwig coupling has also been utilized in the preparation of a heterocycle library.108 Intramolecular O-arylation has also been achieved in the reactions of enolates with aryl halides leading to benzofur-ans.109,110 Finally, a double cross-coupling between an 0-dibromobenzene and a glycol has also been applied for the preparation of benzodioxanes (Equation (16)).1... 

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... 

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). 

Scheme 6.1. Buchwald-Hartwig coupling chemistry for C-N bond formation.

Chiral imidazolinylidenes with N-aryl substituents have been employed by Grubbs and coworkers in the stereoselective ring closing metathesis of olefins [52]. The introduction of the aryl groups as N-substituents was achieved by a palladium catalyzed Buchwald-Hartwig coupling (Scheme 16) [53]. 

Natural product synthesis and medicinal chemistry exist in a symbiotic relationship with the development of synthesis methodology. Noy-ori s asymmetric hydrogenations, Sharpless olefin oxidations, Grubbs olefin metathesis, Buchwald-Hartwig couplings and Jacobsen s hydrolytic kinetic resolution are illustrious examples with many practical applications. The key to the success of the above-mentioned reactions is that they have provided reliable shortcuts to more traditional synthetic... 

The synthesis of 7-azaindoles is a challenging task and there are few efficient routes to substituted derivatives. In the laboratory of C. Thibault, the concise and efficient synthesis of 4-fluoro-1/-/-pyrrolo[2,3-jb]pyridine was achieved. The fluorination was carried out using the Balz-Schiemann reaction. The aromatic amine precursor was prepared via the Buchwald-Hartwig coupling of the aryl chloride with A/-allylamine followed by deallylation. The diazonium tetrafluoroborate intermediate was generated at 0 C and it decomposed spontaneously in 48% HBF4 solution to afford the desired aromatic fluoride. 

Other Metal Catalysts Palladium catalysts are most widely used for C—N bond formation, particularly in Buchwald-Hartwig coupling reactions [48], Halides or pseudohalides are generally used. Recently, direct aminationof C— H bonds has been developed with palladium catalysts. Pd(0)-catalyzed diamination of terminal olefins at allylic and homoallylic carbons takes place via formal sp3 C—H activation under solvent-free conditions [49]. More recently, an asymmetric version of allylic and homoallylic diamination has been successfully achieved using di-tert-butyldiaziridi-none as the nitrogen source (Equation 11.21) [50]. 

Clausine V (151) was prepared in two steps (Scheme 32) [150]. Buchwald-Hartwig coupling of /n-anisidine (113) with 3-bromoanisole afforded the diaryla-mine 150. Different reaction conditions have been tried for the subsequent palladium(ll)-catalyzed oxidative cychzation to clausine V (151) (Table 3). Application of 0.1 equiv. of palladium(ll) acetate and 0.1 equiv. of copper(ll) acetate in glacial acetic acid under an oxygen atmosphere gave the best result for the catalytic process (49% yield). The turnover number of almost 5 confirmed that the system works in a catalytic mode. However, in this case the best yield (67%) was obtained using stoichiometric amounts of palladium(ll) acetate in air without co-oxidant. 

Fagnou et al. applied the intramolecular arylation to the synthesis of mukonine (201) (Scheme 46) [200]. Buchwald-Hartwig coupling of 2-chloroaniline (199)... 

Dibromobiphenyl 210 and the amine 209 were prepared in five and ten steps, respectively. The double Buchwald-Hartwig coupling of 209 and 210 using 0.2 equiv. of tris(dibenzylideneacetone)dipalladium, 0.6 equiv. of 2-dicyclohexyl-phosphino-2, 4, 6 -triisopropylbiphenyl (X-Phos), and 3 equiv. of sodium ferf-but-oxide in toluene at 130°C in a sealed tube afforded the carbazole 213 in 59% yield (Scheme 50) [206]. Subsequent treatment with scandium(III) triflate resulted in removal of the MOM group, cleavage of the ketal, and subsequent Friedel-Crafts-... 

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