Nickel-Catalyzed Cross-Coupling of Redox-Active Esters with Boronic Acids

Whilst looking for sp2-sp3 cross coupling conditions I came across this interesting paper (Angew. Chem. Int. Ed. 2016, 55, 9676) from the Baran group titled “Nickel-Catalyzed Cross-Coupling of Redox-Active Esters with Boronic Acids”. This paper expands the use of N-hydroxyphthalimide (NHPI) esters that they had published earlier in the year (J. Am. Chem. Soc. 2016, 138, 2174−2177) in which they coupled aryl zinc reagents with alkyl esters of N-hydroxyphthalimide.

This paper uses this discovery from the Baran laboratory that N-hydroxy-tetrachlorophthalimide (TCNHPI) esters are able to accept an electron from a low-valent metal in a single electron transfer based thermal process. Using moderate temperatures thermal decarboxylative radical formation was achieved and this radical was immediately captured by a transition metal (Ni). This new cross-coupling reaction allows for the facile coupling of activated alkyl carboxylic acids and boronic acids, figure 1.


Baran gives a snapshot into the optimisation of the reaction conditions but explains they were arrived at by extensive experimentation and some of the empirical observations are poorly understood, figure 2.


It was found that DMF was necessary as a co-solvent in 1,4-dioxane for the reaction to proceed in a reasonable yield. Triethylamine was the best base tested and an optimal metal to ligand ratio of 1:1 for the NiCl2 : 4,4′-di-tert-butyl-2,2′-dipyridyl (BBBPY) system was described. Activated TCNHPI esters were used in placed of the previously used NHPI. The activated NHPI esters were more electron rich and incompetent coupling partners under these reaction conditions. All of the reagents for this reaction are commercially available and reasonably priced.

There are over 30 cross-coupling examples given in this paper which cover primary and secondary alkyl carboxylic acids, heteroaromatic boronic acids and show the tolerance for various functional groups. Baran has also shown that this reaction can be telescoped with the in situ generation of the activated ester, figure 3.


The experimental ease of this reaction was demonstrated by using wet solvents and a flask open to the air whilst still achieving a 65% isolated yield. The reaction was also performed on a gram scale with a 61% yield, figure 4.


A mechanism for this reaction has been proposed based on prior mechanistic investigations of Ni-catalysed reactions alkyl halides and Baran’s previous studies using organozinc reagents. Initially Ni complex I undergoes a base and water aided transmetalation with an arylboronic acid to give complex II. Reduction of the activated TCNHPI ester by complex II gives intermediate III which fragments to give the alkyl radical and phthalimide anion. This radical and anion combine with complex IV to yield complex V. The desired product is formed upon reductive elimination along with regenerating the catalytically active species I.


Although the scope of this reaction in very general Baran does highlight a few examples when diminished yields are observed. These include when an ortho-methoxy group is present on a boronic acid or if the activated ester is labile to hydrolytic cleavage.

This short communication describes a very simple and mild reaction that uses cheap and readily available reagents. It is tolerant of a range of functional groups and offers an attractive route to rapidly synthesise an array of compounds using a sp2-sp3 bond formation.

Blog written by Lewis Pennicott




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