The Heck-Matsuda Reaction

1 Catalytic Synthesis of (E)-3-(4-Methoxyphenyl)acrylic add Using Palladium Acetate in Water 

4-Methoxyphenyldiazonium tetrafluoroborate (0.054g, 0.5 mmol) is placed in a flask with PdfOAcfj (1.1 mg, 5 pmol, 1 mol%) and water (5 ml) [95]. Acrylic acid (0.054g, 0.75 mmol) is added and the mixture stirred at room 

Analyzed with HPLC to determine yield vs. internal standard 

2 Catalytic Synthesis of 2-Phenyl-1H-lndene Using Copper Chioride 

---

The use of arenediazonium salts as arylating reagents of olefins was first reported by Matsuda in 1977 [18,19]. This reaction has been appropriately coined the Heck-Matsuda reaction (Scheme 1.4a). 

Scheme 1.4 (a) The Heck-Matsuda reaction conditions and (b) accepted mechanism for the Heck-Matsuda reaction [19]. 

Arylations with the Heck-Matsuda Reaction - Recent Developments... 

Alternative solvents have been developed for the Heck-Matsuda reaction. This reaction has recently been performed in neat water by Najera s group [95]. The reaction was carried out using an oxime-derived palladacycle catalyst and palladium acetate using a variety of different diazonium tetrafluoroborates giving styrenes, stllbenes, arylideneketones, and cinnamate esters (Figure 1.26). 

In 2012, Gholinejad reported the Heck-Matsuda reaction (as well as the Suzuki-Miyaura reaction) using palladium nanoparticles [97]. The nanoparticles were supported on agarose beads, and at a loading of 2.6 pmol a variety of aryl ditizonium tetrafluoroborate salts could be coupled with... 

Figure 1.25 A cross-section of key synthetic targets accessed by the Heck-Matsuda reaction in recent years.

The Heck-Matsuda reaction has also been subjected to continuous flow chemistry conditions, as reported by Wirth et al. [100]. The reaction that was studied involved the reaction between an in situ generated diazonium ion and/r-fluorostyrene to give ( )-/ -fluorostilbene (Scheme 1.35) and the device used by this group relied on a segmented flow (liquid-liquid slug flow) to increase reaction rates in microfluidic flow. They used perfluorodecalin as an inert and immiscible liquid spacer. 

Scheme 1.35 The segmented flow process for the Heck-Matsuda reaction developed by Wirth s group...

Another aspect that probably contributed to the limited interest in the Heck-Matsuda reaction in organic synthesis for many years was the absence of its enantioselective version. In 2012, we described the first enantioselective Heck-Matsuda arylation of olefins using the chiral bisoxazoline 1 as the ligand for this transformation. This opened the door for the application of this reaction in more challenging transformations such as the enantioselective arylation of acyclic olefins in good yields with enantiocontrol (Scheme 2). Initial studies were carried out aiming at the desymmetrization of cyclic olefins (2), and arylation of more challenging acyclic olefins (4). 

The general catalytic cycle for the Heck-Matsuda reaction using acyclic olefins starts with the oxidative addition of the Pd(0) catalyst A to the aryldiazonium salt and sequential elimination of nitrogen to produce the cationic palladium species C. This intermediate is very electrophilic and it promptly... 

SCHEME 3 General catalytic cycle for the Heck-Matsuda reaction. 

We reported our first results with the Heck-Matsuda reaction in the late 1990s for the arylation of chiral, nonracemic, endocyclic enecarbamates 9 to produce the aryl pyrroUdines 8. These interesting intermediates were further applied in the total synthesis of several fully substituted A -heterocycles with pharmacologically active compounds such as the antibiotic and hypertensive pyrrolidine alkaloid codonopsinine 6, and the antitrypanosomal Schramm s C-azanucleoside 7 (Scheme 4). ... 

The initial objective in these early studies was the synthesis of the trans-substituted aryl pyrrolidines. Therefore, the Heck-Matsuda reactions were... 

These substrate-directed Heck reactions allowed the synthesis of pharmacologically active compounds in a very straightforward way. For example, compotmd 26 was oxidized with DDQ to provide the natural product yango-nine 27. Additionally, methysticin 28 was obtained in 59% yield (95% based on recovered starting material) directly from the Heck-Matsuda reaction. The chemoselective reduction of the least hindered double bond of 28, using Pd/C as catalyst, provided dehydromethysticine 29 in 95% yield (Scheme 11). 

An interesting observation in this process concerns the influence of the solvent. We used benzonitrile as the solvent, whereas Cacchi s method uses acetonitrile. With benzonitrile electronic factors rule the selectivity, while with acetonitrile the steric aspects seem to predominate. A plausible explanation is based on the difference of polarity between the two solvents as well as their donicity number (a tendency of the solvent to interact with a Lewis acid). As acetonitrile is more polar than the benzonitrile, transition states without the interaction between the palladium and the carbonyl such as 59 and 60 are favored. The opposite phenomenon is expected for the benzonitrile, with its lower donicity. The cationic palladium intermediate is internally solvated by the carbonyl oxygen, thus favoring the cyclic intermediate. With decreased solvation of the cationic palladium, a closer contact of the carbOTiyl moiety to the metal is facilitated (Scheme 17). These data suggest that these parameters explain the key role of the benzonitrile in the Heck-Matsuda reaction. 

To circumvent this steric problem, the Boc group was replaced by a formyl group, which was installed on amine 80 by the in situ generated mixed anhydride 86 (Scheme 22). The newly formed formamide 87 was successfully used for the Heck-Matsuda reaction. This was followed by a reduction of the styrenic double bond by simply adding a balloon of hydrogen to the reaction flask (98% yield over two steps). Next, the A-formyl moiety of 88 was hydrolyzed in concentrated HCl to furnish cinacalcet hydrochloride in quantitative yield. 

SCHEME 23 Overview of the Heck-Matsuda reaction with cyclic olefins. Asterisk in compound 111 indicates the presence of a stereogenic center of unknown absolute configuration. 

The authras specially thank the many past and present members of the research group involved in the development of the Heck-Matsuda reaction whose names appear in the references. The authms also thank the Brazilian funding agencies, in particular to the State... 

---