Transition Metal Free C-H Activation and C-C Bond Formation – Is that Really Metal Free?

Transition metal catalysed direct arylation of aromatic C-H bonds is emerging as a valuable and efficient alternative to traditional cross-coupling in the construction of biaryl compounds. Selective functionalization of aromatic C–H bonds is now an important aspect of this rather general field due to the universal existence of aromatic functionalities in nature and the synthetic world. ‘Fenton’ chemistry and Friedel–Crafts reactions are early examples of transformations of aryl C–H bonds to different functionalities.

Many reports have demonstrated that direct arylation of heterocycles, arenes with directing groups, and electron-deficient arenes(1-7). As well a completely unactivated arene, benzene has been directly arylated by a few efficient transition-metal-catalyzed methods (8-12).

In 2003, Leadbeater et.al,. reported a transition metal free Suzuki coupling reaction in water using sodium carbonate as a base(13-14)(Scheme-1). Later, the same group reported the transition metal free sonogashira type reaction (15)(Scheme-2). After that they discovered that the reaction was in fact metal-mediated — by palladium contaminants of as little as 50 ppb that were present in the sodium carbonate base used. In 2009, Buchwald reported that iron catalysed cross coupling reaction has been done by copper catalyst which is an impurity in Iron source(16).

Scheme-1

Scheme-2

In 2008, Daugulis, reported transition-metal-free, base-mediated intramolecular arylation of phenols with aryl halides. The sp2 C-H bond functionalization occurs via a benzyne intermediate. At this point, a phenolate activating group is essential for the arylation(17)(Scheme-3). In the same time, Itami et al. reported a transition metal free direct C-H arylation electron deficient nitrogen heterocycles using haloarenes. As well, they also reported a transition-metal-free systems for the cross coupling reactions of nitrogen heteroaromatics and alkanes (18-19)(Scheme-4). Itami et al. proposed a radical pathway for the sole KOBut promoted direct arylation of electron-deficient nitrogen heterocycles with aryl iodides.

Scheme-3

Scheme-4

Recently, the most notable examples are three ‘transition matal free’ methods for pereparing biaryls by C-H activation. 

Now, these reports getting a lot of attention, and a lot of raised eyebrows. The authors claim that they can couple aryl iodides with  unfunctionalized aromatic compounds with nitrogen bidentate ligands as catalysts - and no transition metals at all - just potassium or sodium t-butoxide as base. Organic chemists will recognize that this is a very unusual reaction indeed, since carbon-carbon bonds between aryl groups are not supposed to be so easy to form. This reaction, in fact, would suggest that a lot of the palladium-catalyzed work is some sort of odd detour to get to a process that happens fairly easily anyway.

The authors suggest that since they're using iodides that a free radical mechanism is operating. Addition of radical scavengers, they say, shuts the reaction down. The fact that they don't get regioisomers, that rules out another possible mechanism through benzyne intermediates.

It is also worth noting a paper from earlier this year reporting the use of an iron catalyst (20) (Scheme-5) — iron acetate combined with 10 mol% bathophenanthroline (4, 7-diphenyl-1, 10-phenanthroline) as a ligand — for the same sorts of couplings. In this case, the researchers actually tried the reaction of iodotoluene and benzene in the absence of the iron salt (but in the presence of the bathophenanthroline) and obtained no product. Could it be that the two ‘transition-metal-free’ methodologies are in fact catalysed by very low levels of iron? This in turn begs the question: What does it take to prove that a transformation is transitionmetal free?

Scheme-5

The authors Liu, W.; as well Sun, C.L.; mentioned that, In order to eliminate the possibility of the presence of trace transition metal elements in the commercially available potassium tert-butoxide that would potentially affect our investigation, they purified the KOBut by sublimation prior to their examination. Almost the same results were obtained between the nonpurified and purified base.

Could trace amounts of transition metal have contaminated the experiment? 'Obviously this is one of the most important factors,' says Lei. 'We have checked the contamination of trace amounts of transition metals by ICP [inductively coupled plasma atomic emission spectroscopy] and excluded the involvement of small amounts of transition metals in this transformation.'

Commenting on the work, Carsten Bolm, an organic synthesis expert from Aachen University in Germany, says, 'To be able to prepare cross-coupling products without the use of transition metals is an important scientific advance. Although at the present stage the substrate scope is by far too limited to make the process synthetically attractive, the findings illustrate that new reaction paths in direct C-H arylations are still to be discovered, and as such this work will be highly stimulating to the community.'

http://www.rsc.org/chemistryworld/News/2010/August/11081002.asp

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