Buchwald-Hartwig reaction

The Buchwald-Hartwig reaction in its original scope is an organic reaction describing a coupling reaction between an aryl halide and an amine in presence of base and a palladium catalyst forming a new carbon-nitrogen bond.

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The X in the aryl halide (Ar-X) can also be a triflate. The primary or secondary amine substituents can be any organic residue, the metal M in the reactions original scope is palladium and the ligand L can be a wide range of phosphines such as triphenylphosphine. Another regular catalyst ligand combination is tris(dibenzylideneacetone)dipalladium(0). [OrgSynth | author = John P. Wolfe and Stephen L. Buchwald | collvol = 10 | collvolpages = 423 | year = 2004 | prep = v78p0023 | title =Palladium-Catalyzed Amination Of Aryl Halides And Aryl Triflates ] The base can be sodium bis(trimethylsilyl)amide or a tert-butoxide. The reaction is conceptually related to the Stille reaction and the Heck reaction and its scope extends to oxygen nucleophiles like phenols and carbon nucleophiles like malonates. It replaced to an extent the copper catalysed Goldberg reaction.

The first example of a Buchwald - Hartwig amination reaction was realized in Kiev, Ukraine, in 1985, by Professor Lev M. Yagupolskii et al. Polysubstituted activated chloroarenes and anilines underwent a C-N coupling reaction catalyzed by [PdPh2(PPh3)2] I (1 mol%) in moderate yield: [cite journal | title = Poly(nitro- and trifluoromethylsulphonyl)substituted diphenylamines | author = N. B. Kondratenko, A. A. Kolomejcev, B. O. Mogilevskaya, N. M. Varlamova, L. M. Yagupolskii | journal = Zh. Org. Khim. (Rus.) | year = 1986 | volume = 22 | issue = 8 | pages = 1721–1729] This reaction type was developed independently by the groups of Buchwald and Hartwig. The reactants in the original Hartwig 1994 publication were a bromobenzene and a tributyltin amine: [cite journal | title = Palladium-catalyzed formation of carbon-nitrogen bonds. Reaction intermediates and catalyst improvements in the hetero cross-coupling of aryl halides and tin amides | author = Frederic Paul, Joe Patt, John F. Hartwig | journal = J. Am. Chem. Soc. | year = 1994 | volume = 116 | title = 13 | pages = 5969-5970 | doi = 10.1021/ja00092a058]

The Buchwald 1994 reaction looked very similar: [cite journal | title = Palladium-Catalyzed Aromatic Aminations with in situ Generated Aminostannanes | author = Anil S. Guram and Stephen L. Buchwald | journal = J. Am. Chem. Soc. | year = 1994 | volume = 116 | issue = 17 | pages = 7901 - 7902 | doi = 10.1021/ja00096a059]

In the second-generation Buchwald-Hartwig reaction, the aminostannane was replaced by a free amine and a strong base such as lithium bis(trimethylsilyl)amide: [cite journal | title = Palladium-catalyzed synthesis of arylamines from aryl halides. Mechanistic studies lead to coupling in the absence of tin reagents | author = Janis Louie and John F. Hartwig | journal = Tetrahedron Letters | volume = 36 | issue = 21 | pages = 3609-3612 | doi = 10.1016/0040-4039(95)00605-C]

Reaction mechanism

The reaction mechanism for this reaction is outlined below:

The Pd^II catalyst 1 is reduced to the active Pd⁰ species 2 which is stabilized by a ligand L usually a phosphine. The catalytic cycle starts with species 3 lacking one ligand and the aryl halide 4 coordinates to palladium by oxidative addition to intermediate 5 which is in chemical equilibrium with dimeric species 5b. In the next step a halide atom is replaced by the nitrogen atom of the amine 6 to intermediate 7. The strong base 8 is required to abstract the proton from the amine towards 9. This intermediate gives either reductive elimination to the desired aryl amine 10 or undesired β-hydride elimination to the arene compound 11 and the imine 12. In either case the liberated Pd-L species starts a new catalytic cycle.

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One study addressed the choice of solvent for this reaction [cite journal | title = Effect of Solvents on the Product Distribution and Reaction Rate of a Buchwald-Hartwig Amination Reaction | author = Henrik Christensen, Sren Kiil, Kim Dam-Johansen, Ole Nielsen, and Michael B. Sommer | journal = Org. Process Res. Dev. | year = 2006 | volume = 10 | issue = 4 | pages = 762 - 769 | doi = 10.1021/op050226s] and found that with certain reactants aprotic polar solvents such as NMP and DMAC promoted beta-elimination and the reaction was best carried out with aprotic apolar solvents such as "m"-xylene even though this solvent does not dissolve a tert-butoxide base.

References

External links

* "Buchwald-Hartwig Chemistry" Ian Mangion MacMillan Group Meeting July 30, 2002 [http://www.its.caltech.edu/~dmacgrp/grpmtgs/2002/powerpoint-ian-buchhart.pdf#search=%22Buchwald-Hartwig%20amination%22 Link]
* "Buchwald-Hartwig reaction Precious-Metal catalysts from Acros Organics for coupling reactions in organic synthesis" [http://www.acros.com/_Rainbow/pdf/Buchwald_Hartwig.pdf#search=%22Buchwald-Hartwig%20reaction%22 Link]