Decarboxylative biaryl synthesis

GooBen, L. J., Rodriguez, N., Linder, C. (2008). Decarboxylative biaryl synthesis from aromatic carboxylates and aryl triflates. Journal of the American Chemical Society, 130,15248-15249. 

Scheme 3.5 Palladium-catalyzed decarboxylative biaryl synthesis and its putative mechanism, as described by Liu and coworkers [15],...

Scheme 3.11 Proposed mechanism for the palladium-catalyzed decarboxylative biaryl synthesis, as described by Xie and coworkers [23],...

Scheme 3.18 Decarboxylative biaryl synthesis from aromatic carboxylates and aryltriflates, as described by Goossen and coworkers [33],...

Synthetic highlights The Cu-promoted catalytic decarboxylative, biaryl synthesis of valsartan is an example of biomimetic, aerobic decarboxylation and enables C-C bond formation in aqueous solution. The chiral variant of biaryl synthesis is exemplified by the stereoselective approach to the axially chiral biaryl system present in vancomycin. 

Cu-Promoted Catalytic Decarboxylative Biaryl Synthesis, a Biomimetic Type Aerobic Decarboxylation... 

Scheme 5.3 Synthesis of valsartan, based on decarboxylative biaryl synthesis...

In conclusion, an innovative route to valsartan that comprises decarboxylative biaryl coupling afforded this antihypertensive dmg in approximately 40% overall yield, which compares favourably with aU other reported routes. This approach was the result of meticulous synthetic experimental work. Professor Goosen stated that at the beginning of the project, one of his collaborators had performed close to 2000 test runs for the model reaction... before he observed the desired product in more than trace quantities [42]. The route to the dream reaction was extensively explored by Goosen s group. Fine-tuning of many parameters in the Cu(II)-catalyzed decarboxylative biaryl synthesis was performed [38, 41] and the final results were impressive... 

Our partners at Bayer, by now Lanxess, realized already at this early state of development that the new decarboxylative biaryl synthesis would open up opportunities for the industrial synthesis of high-value pharmaceutical intermediates and were pleased to find that it worked also on kilogram scales [32-34] (Scheme 11). 

The applicability of the decarboxylative biaryl synthesis was rapidly extended to a broad range of aryl electrophiles with the help of new catalyst generations, including not only aryl iodides, bromides, and triflates but also the inexpensive but unreactive aryl chlorides and tosylates [46, 47]. Its preparative utility was demonstrated, e.g., in the synthesis of telmisartan and valsartan [48, 49]. The key factor in these advances was the identification of ligands that strongly activate the palladium catalysts toward oxidative addition steps while not interfering with the decarboxylation activity of the copper cocatalysts (Scheme 14). 

This synthetic plan, which initially involved an efficient asymmetric biaryl synthesis, suffered from two weaknesses, namely in the manipulation of configurationally fragile intermediates and in the epimerization at the biaryl axis during the decarboxylation step. These... 

Goossen LJ, Rodriguez N, Melzer B, Linder C, Deng G, Levy LM (2007) Biaryl synthesis via Pd-catalyzed decarboxylative coupling of aromatic carboxylates with aryl halides. J Am Chem Soc 129 4824-4833... 

Becht, J. M., Le Drian, C., (2008). Biaryl synthesis via decarboxylative Pd-catalyzed reactions of arenecarboxylic acids and diaryliodonium triflates. Organic Letters, 10, 3161-3164. 

The scope and potential economic impact of this decarboxylative biaryl coupling is demonstrated by the synthesis of over 40 biaryls, some of them with substantial industrial relevance. 

Indanones are very useful and versatile intermediates in the synthesis of metallocene catalysts. Scheme 1 has the synthetic scheme originally used for the preparation of 2-alkyl-4-aryl-substituted ansa metallocenes [9-11]. In the first part of this sequence, the biaryl unit is assembled and the missing carbon atoms are introduced as a side chain. The reaction of 2-phenylbenzyl bromide with malonic acid ethyl ester under basic conditions, followed by a decarboxylation, affords the 2-(2-phenylbenzyl)propionic acid. Chlorination and Friedel-Crafts acylation yields the 2-methyl-4-phenylindanone in 93 % yield. From here, only a few standard transformations are required to complete the synthesis, finally yielding the desired metallocene. 

Goossen LJ, Deng G, Levy LM (2006) Synthesis of biaryls via catalytic decarboxylative coupling. Science 313 662-664... 

In a handful of cases, two CCXIH groups have been activated for the synthesis of biaryls. Larrosa and coworkers reported for the first time the decarboxylative homocoupling of aromatic acids mediated by Pd and Ag [62a]. The reaction makes use of Pd(TFA)j as a catalyst and Ag CO as an additive to afford the desired biaryls in 76-95% yields. The only by-products observed were due to the proto-decarboxylation of the aryl carboxylic acid. Both metals are essential for the reaction, and the role of the Ag salt is not only as the terminal oxidant but also as a mediator of the decarboxylation process. The method is subject to some limitations on the substituents on the benzoic acids. Thus, m- and p-nitrobenzoic acids as well as benzoic acids ortho substituted with F, Br, or MeO failed to give decarboxylative homocoupling products. In all cases, protodecarboxylations to the corresponding arenes were the main products observed. The same problem was reported in the protocol developed by Deng and coworkers, where the best results were obtained with PdCl and PPhj in the presence of Ag COj [62b]. 

SCHEME 22.44 (a) Synthesis of biaryl compounds from Pd-catalyzed decarboxylative cross-coupling reaction between aryl carboxylic acids and (b) proposed reaction mechanism. 

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