Palladium-Catalyzed Coupling of Ammonia and Hydroxide with Aryl Halides: The Direct Synthesis of Primary Anilines and Phenols

Link: http://www3.interscience.wiley.com/cgi-bin/abstract/114179535/ABSTRACT

From Prof. Michael C. Willis at University of Oxford, UK

This is a recent highlights in ACIEE EarlyView detailing the recent developments in direct coupling technology of amino (NH2) and hydroxyl (OH) with aryl halides to form aniline and phenol. The methodologies were recently reported by the two research groups, namely the Hartwig group and the Buchwald group. The methodologies developed were both based on Pd-catalyst.

In the background of these couplings, the challenges exist in the formation of aniline directly from ammonia and phenol directly from water. The challenges in using ammonia directly for the formation of aniline are:

- ammonia is an excellent ligand for many metals and will often bind to the metal in preference to the ligands needed to form active catalyst systems

- the stability of amido–metal complexes also makes the key reductive elimination, leading to C-N bond formation, a difficult process

- if a successful amination with ammonia could be achieved, the product of the reaction, a primary amine such as 1 (see below), is very likely to be an excellent coupling partner itself, leading to the formation of di- and triaryl amines

The challenges in using water as a direct coupling partner for phenol formation are also similar.

Recently, the Hartwig group has shown that selective coupling reactions between aryl halides and ammonia can be achieved if catalysts incorporating the bulky ferrocene-based ligand A are employed (Scheme 2). For example, the reaction between unhindered aryl bromide 3 and ammonia (80 psi) at 90 C using 1 mol% of [APdCl2] and the strong base NaOt-Bu delivered aniline 4 in 86% yield. Importantly, only a few percent of the diaryl amine was observed (17:1 ratio of mono-/dicoupled material).

The Hartwig group has shown that solid lithium amide can also be conveniently used in these coupling reactions, although the selectivity for mono- over diarylation was sometimes lower in these modified reactions but still synthetically useful. The selectivity ranges from 8:1 to >50:1, with the more hindered aryl halide substrates being most selective.

The major factor in the success of these reactions is the hindered, tightly bound chelated intermediates generated from the use of the sterically demanding diphosphine ligand.

The Buchwald group has developed a series of bulky electron-rich monophosphines that generate efficient catalysts for the coupling reactions between aryl halides and phenols. They have very recently shown that these ligands are effective for the coupling of potassium hydroxide with aryl halides. For example, the use of a catalyst featuring the sterically demanding biphenyl ligand B allowed the conversion of aryl bromide 5 to phenol 6 in 96%yield after 6 h (Scheme 3).The reactions were conducted in 1:1 water/dioxane at 100 C. As the second example in Scheme 3 illustrates, the process was amenable to aryl chloride substrates. The latter example featured the bulkier ligand C, which was found to generate more stable catalysts and thus allow lower catalyst loadings. The reductive elimination step of the mechanism, responsible for C-O bond formation, was identified as the key step of the process. By matching the ligand, either B or C, with the substrate under investigation, the authors were able to effectively convert a wide range of aryl bromides and chlorides to their corresponding phenol derivatives.

Although the ability to halt both the ammonia and hydroxide coupling reactions at the monoarylation stage was one of the chief difficulties to be overcome,the capacity to utilize these monoarylation products directly in controlled and synthetically useful second transformations presents many exciting possibilities for reaction development.

Both groups have already seized this opportunity. The Hartwig group has demonstrated that the use of dibromobiphenyl substrate 7 allows the direct formation of carbazole 8 in 64% yield by way of a tandem amination process (Scheme 4).

The Buchwald group has developed a tandem process based on an initial hydroxide coupling, followed by the alkylation with an alkyl halide. In the overall transformation an aryl halide is converted to an alkyl aryl ether. For example (Scheme 4), reaction of aryl halide 9 with potassium hydroxide leads to phenoxide intermediate 10. Introduction of a secondary alkyl halide in combination with the phase-transfer catalyst cetyltrimethylammonium bromide, then provides alkyl aryl ether 11 in an overall yield of 84%. This new approach to alkyl aryl ether synthesis avoids the problem of unwanted beta-hydride elimination often encountered with secondary alcohols in palladium-catalyzed etherification reactions of aryl halides.

A second cascade sequence based on an initial hydroxide coupling was also developed. Coupling of potassium hydroxide with (2-chloroaryl) alkynes delivered phenol intermediates that cyclized under the reaction conditions to generate benzofuran products.

The methodology for a direct coupling of aryl halides with H2S may be on the way(?).