Aqueous Hydroxide as a Base for Palladium-Catalyzed Amination of Aryl Chlorides and Bromides

Abstract

The amination of aryl halides in the presence of inexpensive and air-stable alkali metal hydroxide bases and Pd[P(t-Bu)3]2 as catalyst gave arylamines in high yields. The reactions were conducted with a catalytic amount of cetyltrimethylammonium bromide as phase-transfer agent and either aqueous hydroxide or solid hydroxide in the presence of water. This combination of alkali metal hydroxide base, H2O, and the ammonium salt performed as well as NaO-t-Bu in the amination of p-chlorotoluene with dibutylamine. Hydroxide base was suitable for reactions of a wide range of aryl chlorides and bromides with aliphatic and aromatic amines. Some functional groups that were intolerant of tert-butoxide base, such as esters, enolizable ketones, nitriles, and nitro groups, were tolerated by the combination of hydroxide base, H2O, and cetyltrimethylammonium bromide in toluene solvent.

Palladium‐Catalyzed CN and CO Coupling–A Practical Guide from an Industrial Vantage Point†

“…[7] Recently, Hartwig and Buchwald even reported the use of the most inexpensive bases (KOH, NaOH) in aqueous solution which are active in combination with biphenyl-based systems as well as Hartwigs palladium-dimer complex. [16,64,65] When carbenes are used as ligands, the base also serves as the deprotonating agent for the imdazolium salt precursor, which often requires the use of a strong base. [22,75] LHMDS proved to be especially useful for the coupling of amines with aryl halides containing hydroxy, amide or enolizable keto groups in conjunction with bulky biphenyl-based ligands at least in catalytic amounts.…”

“…[24] Also, the addition of water can even be beneficial as can be seen from the use of aqueous bases in the amination reaction. [16,65,67] Nevertheless, this only holds true for substrates that are not hydrolyzed under basic conditions. Some aminations can even be run in water as the only solvent.…”

“…[69] Conditions rather unusual for traditional ways of organometallic chemistry have been reported, e.g., Hartwigs air stable palladium(I)-(t-Bu 3 )P dimer is used in aqueous media in combination with sodium hydroxide as base. [65] Also allowing for the use of similar bases like potassium hydroxide in water, Buchwalds XPhos-ligand proved to be valuable. [16] Several authors have developed amination reactions using palladium-N-heterocyclic carbene catalysts.…”

“…Mild bases like potassium phosphate [48,66] now represent a cheap alternative to the rather expensive cesium carbonate. [31] The fine tuning of the stronger bases also led to a protocol that allows the use of sodium methoxide [47,64] or even more interesting, sodium hydroxide [16,65] as base. In those cases it was understood that next to the catalyst the right combination of base and solvent plays a very important role in the catalytic activity.…”

Applicability Aspects of Transition Metal‐Catalyzed Aromatic Amination Protocols in Medicinal Chemistry

“…also yield of method A vs. method C1). [22] For an attempted room temperature amination based on the same catalytic system, NaO-t-Pent had to be used in toluene (method D2), as weaker inorganic bases (K 3 PO 4 or Cs 2 CO 3 ) displaying a better compatibility with nitroarenes would have called for elevated reaction temperatures. [17,23] However, in both cases (methods D1 and D2) problems were reported using primary amines other than anilines, and the reactions (entry 1) proceeded accordingly.…”