Waste-Minimized Mizoroki-Heck Reactions

Figure 4.16 Mechanism for a waste-minimized Mizoroki-Heck reaction starting from carboxylic acids.

This concept was proven to be viable using the example of 4-nitrophenyl esters in the presence of a palladium(II) chloride/lithium chloride/isoquinoline catalyst system, the 4-nitrophenyl esters 3c of various aromatic, heteroaromatic and vinylic carboxylic acids were converted to the corresponding vinyl arenes 5k along with 4-nitrophenol (Figure 4.17). The latter was demonstrated to react with benzoic acid at the same temperature as required for the vinylation step (160 °C) to regenerate the corresponding ester [28], thus demonstrating that at least a two-step waste-minimized Mizoroki-Heck reaction is feasible. 

Aiming to overcome the limitations of the previous protocols, GooKen et al. then extended their own studies using easily available carboxylic esters [29], This indeed paved the way to waste-minimized Mizoroki-Heck reactions, in which any byproduct was efficiently recyclable such that waste formation was limited to carbon monoxide and water (47->48 Scheme 7.10). Subsequently, this technique has proven to be viable for converting various 4-nitrophenyl esters 47 in the presence of a PdCfi-LiCl-isoquinoline catalyst system into styrenes 48. Under Lewis acid catalysis, 4-nitrophenol (49) cleanly reacts with benzoic acid at the same temperature required for the Mizoroki-Heck arylation (49 47), thereby regenerating 4-nitrophenyl ester 47. 

Scheme 7.11 Proposed mechanism for the waste-minimized Mizoroki-Heck reaction of carboxylic esters.

Another interesting strategy to achieve a waste-minimized Mizoroki-Heck reaction was recently reported by Miura et al. (Scheme 7.13) [31]. Using aroyl chlorides 57, the Mizoroki-Heck reaction proceeded well under base-free conditions, liberating only hydrochloric acid and carbon monoxide as byproducts (57 59). However, due to the particularly waste-intensive preparation of acyl chlorides, it remains questionable whether this procedure would be suitable for large-scale alkene arylation. 

Figure 4.1 General reaction scheme for traditional and waste-minimized Mizoroki-Heck...

While all these approaches point to various possible and often elegant solutions to the waste problem of the Mizoroki-Heck reaction, each still has its drawbacks. Thus, in the short term, customized solutions to minimize the waste effluent will be required for specific synthetic applications, until, in the long run, the ideal, generally applicable method is found. This could on the one hand ensue from the development of shape-selective C—H activation catalysts that by themselves are able to define the position of functionalization, to be used in the oxidative arylation of alkenes with either molecular oxygen or hydrogen peroxide... 

Over the course of the past decade, the intermolecular Mizoroki-Heck reaction has witnessed tremendous progress [9,10]. As a comprehensive survey of this area is certainly beyond the scope of this chapter, the decision was taken to include a few important developments, namely the activation of less-reactive aryl chlorides, waste-minimized processes, and novel catalyst systems. 

The Heck-Mizoroki reaction has also been heavily applied in one-pot sequential reaction sequences. The topic of sequential, domino, consecutive, or tandem catalytic reactions is a very timely subject, as at its core is efficiency, economy, and waste minimization in organic synthesis. In 2010 [59], one of us published a review of this topic which explains the current state of play and includes relevant references on the subject. However, the topic is still rather murky in terms of definitions, and this is something that we feel needs urgent attention. The Heck-Mizoroki is a very suitable transformation for inclusion in a sequential catalytic process, given that it leads to the formation of C=C units, a common functionality for further catalytic transformation. 

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