Hartwig-Buchwald amination

The Buchwald-Hartwig amination is an exceedingly general method for generating an aromatic amine from an aryl halide or an aryl sulfonates. The key feature of this methodology is the use of catalytic palladium modulated by various electron-rich ligands. Strong bases, such as sodium tert-butoxide, are essential for catalyst turnover. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 40, Springer-Verlag Berlin Heidelberg 2009 

Example 3, Room temperature Buchwald-Hartwig amination  

Buchwald-Hartwig amination, In Name Reactions for Functional Group Transformations-, Li, J. J., Corey, E. J. Eds. Wiley Sons Hoboken, NJ, 2007 pp 564—609. (Review). 

The Burgess reagent [(methoxyearbonylsulfamoyl)triethylammonium hydroxide inner salt], a neutral, white erystalline solid, is effieient at generating olefins from seeondary and tertiary aleohols where the first-order thermolytie Ei (during the elimination takes plaee— flie two groups leave at about the same time and bond to each other concurrently) mechanism prevails. 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 45, Springer International Publishing Switzerland 2014 

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Carbon-carbon bond formation reactions and the CH activation of methane are another example where NHC complexes have been used successfully in catalytic applications. Palladium-catalysed reactions include Heck-type reactions, especially the Mizoroki-Heck reaction itself [171-175], and various cross-coupling reactions [176-182]. They have also been found useful for related reactions like the Sonogashira coupling [183-185] or the Buchwald-Hartwig amination [186-189]. The reactions are similar concerning the first step of the catalytic cycle, the oxidative addition of aryl halides to palladium(O) species. This is facilitated by electron-donating substituents and therefore the development of highly active catalysts has focussed on NHC complexes. 

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... 

Fig. 9 Examples of Buchwald-Hartwig amination of bromo-pyridines and subsequent hydrogenolysis leading to amino-substituted 2-pyridones...

Independently, Antane reported that arylisonipecotic acids were obtained from aryl bromides in a two-step process involving microwave-assisted palladium-catalyzed amination with ethyl isonipecotate followed by ester hydrolysis with KOH (Scheme 91) [96]. Interestingly, toluene, which is the standard solvent for Buchwald-Hartwig aminations under conventional heating, was used as the sole reaction medium, although it is a very weak... 

More challenging are the (hetero)aryl chlorides, since they are cheaper and more widely available than the corresponding bromides and iodides. Maes et al. published the first examples of microwave-assisted Buchwald-Hartwig aminations on (hetero)aryl chlorides in a commimication in 2003 [99]. The substrates 2- and 3-chloropyridine as well as 2-chloroquinoline were smoothly coupled with N-methylaniline and p-toluidine within only 10 min using a catalyst loading of only 1 mol% (Schemes 96 and 97). The diazine... 

The coupling between an aryl halide or triflate and an amine is known as the Buchwald-Hartwig amination [138]. Originally it was described using a tributyltin amine [139,140] and was thus considered to be a coupling reaction. Subsequently, tributyltin amine was replaced by a standard amine and a strong base. It is a reaction of great academic and industrial interest [11]. 

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]. 

Scheme 6 46 Buchwald-Hartwig aminations with in situ-formed catalysts...

Scheme 6.48 AUyl-modified Pd-NHC complexes as improved catalysts in Buchwald-Hartwig aminations...

The Buchwald-Hartwig amination reaction has gained great interest in the last decade in both academic and industrial environments. In the work presented herein, we discuss a very interesting effect in the competitive reaction of two amines (benzophenone hydrazone and n-hexylamine) with 3-bromobenzotrifluoride. 

Scheme 6.61 Buchwald-Hartwig amination reactions of aryl chlorides.

A more recent publication by Weigand and Pelka has disclosed a polymer-bound Buchwald-Hartwig amination [40], Activated, electron-deficient aryl halides were coupled with conventional PS Rink resin under microwave irradiation. Subsequent acidic cleavage afforded the desired aryl amines in moderate to good yields (Scheme 7.22). Commercially available Fmoc-protected Rink amide resin was suspended in 20% piperidine/N,N-dimethylformamide at room temperature for 30 min to achieve deprotection. After washing and drying, the resin was placed in a silylated microwave vessel and suspended in dimethoxyethane (DME)/tert-butanol... 

Scheme 7.22 Palladium-catalyzed Buchwald-Hartwig amination.

A synergistic combination of Pd-catalyzed amination and arylation was the central operation of Sakamoto s synthesis of carbolines [147]. Diarylamine 187 was first installed via the Buchwald-Hartwig amination protocol. Subsequent intramolecular Heck-like arylation of 187 provided a novel route to a-carboline 188. 

Buchwald-Hartwig amination of iodobenzene 92 with 2-benzyloxy-4-methyl-aniline 93 affords the diarylamine 94 in high yield (Scheme 32). In this case the Goldberg coupling gives poor yields. Oxidative cyclization of compound 94 using stoichiometric amounts of palladium(II) acetate in acetic acid under reflux leads to the carbazole 95, which by reductive debenzylation provides... 

The reaction of an orf/io-ester, e.g., HC(OEt)3, with a secondary bisamine in the presence of an anunonium salt yields imidazolidinium salts (Scheme The necessary secondary diamines can be generated by a classical condensation-reduction sequence or by applying the palladium-catalyzed Buchwald-Hartwig amination." The latter reaction offers convenient access to imidazolidinium salts with chiral backbones starting from chiral diamines, a number of which are commercially available. ... 

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 relay compound 1025 required for the synthesis of all of these 7-oxygenated carbazole alkaloids was obtained starting from commercially available 4-bromo-toluene (1023) and m-anisidine (840) in two steps and 72% overall yield. Buchwald-Hartwig amination of 4-bromotoluene (1023) with m-anisidine (840) furnished quantitatively the corresponding diarylamine 1024. Oxidative cyclization of 1024 using catalytic amounts of palladium(ll) acetate afforded 3-methyl-7-methoxycarbazole (1025). Oxidation of 1025 with DDQ led to clauszoline-K (98), which, on cleavage of the methyl ether using boron tribromide, afforded 3-formyl-7-hydroxycarbazole (99) (546) (Scheme 5.149). 

Scheme 7 Scale-up of Pd-catalyzed Buchwald-Hartwig aminations utilizing different microwave instruments...

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. 

Scheme 4. One-pot synthesis of a carbazole via consecutive Buchwald-Hartwig amination and ring-closing reactions ...

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