Boronic acid coupling partner

The neurotoxic quaterpyridine natural product nemertelline was successfully synthesized by S. Rault et al. using a Suzuki cross-coupiing as the key step. The boronic acid coupling partner, required for the Suzuki reaction, was prepared by first subjecting 3-amino-2-chloropyridine to the conditions of the Sandmeyer reaction followed by a lithium-halogen exchange and trapping the lithiopyridine derivative with triisopropylborate. 

The original cross-coupling reactions of aryl and vinyl halides with boronic acid coupling partners have been extensively developed since their inception. Over the past few years several interesting adaptions have expanded the scope of the original coupling protocol, below are just a few recent examples of systems that have harnessed the Suzuki-Miyaura protocol to access enantio-enriched coupling products. 

The boronic acid 2 is first converted to an activated species 8 containing a tetravalent boron center by reaction with a base. Halides or triflates (OTf = trilluoromethanesulfonate) are used as coupling partners R-X for the boronic acids. In many cases the rate-limiting step is the oxidative addition. With respect to the leaving group X, the rate decreases in the order ... 

The widespread use of aryl boronic acids or aryl boronates in various metal-catalysed C-C bond-forming reactions has created a substantial demand for these versatile nncleophiles. A general procedure for the preparation of these compounds, based on a NHC/Pd catalysed coupling, has been reported by Fiirtsner and co-workers nsing aryl chlorides and the tetraalkoxy diboron derivative 27 as conpling partners. Very good yields were obtained in several cases especially when electron poor aryls were employed [169]. Milder reaction conditions can be achieved when diazonium salts are used instead of chlorides [170] (Scheme 6.51). 

Recently, interest in copper-catalyzed carbon-heteroatom bond-forming reactions has shifted to the use of boronic acids as reactive coupling partners [133], One example of carbon-sulfur bond formation is displayed in Scheme 6.65. Lengar and Kappe have reported that, in contrast to the palladium(0)/copper(l)-mediated process described in Scheme 6.55, which leads to carbon-carbon bond formation, reaction of the same starting materials in the presence of 1 equivalent of copper(II) acetate and 2 equivalents of phenanthroline ligand furnishes the corresponding carbon-sulfur cross-coupled product [113]. Whereas the reaction at room temperature needed 4 days to reach completion, microwave irradiation at 85 °C for 45 min in 1,2-dichloroethane provided a 72% isolated yield of the product. 

Thiazoleboronic acids are not trivial to make. Attempts to prepare 2-thiazoleboronic acid were unsuccessful [21], As a consequence, halothiazoles are chosen as the electrophilic coupling partners in the Suzuki reactions with other boronic acids. For instance, 2,5-di-(2-thienyl)thiazole (28) was installed by the union of 2,5-dibromothiazole and easily accessible 2-thiopheneboronic acid [21], Unfortunately, the yield was poor and analogous reactions of 2,5-dibromothiazole with 3-thiopheneboronic acid and 2-selenopheneboronic acid both failed. 

Both 6-alkanesulfanyl- and 6-alkanesulfonylpurines proved competent coupling partners in the palladium-catalyzed Suzuki reaction with boronic acids when an imidazolium carbene ligand was used <20050L1149>. The sulfones were found to be significantly more reactive (60 °C, THF) than the thioethers (90 °C, toluene) (Scheme 44). 

The Suzuki coupling of aryl halides was also extended to tosylates recently. Benzothiazole 5-tosylate reacted with m-xylene-2-boronic acid (6.13.) to give the coupled product in 94% yield using palladium acetate and a stericly congested biphenyl based phosphine ligand as catalyst.17 Another class of less commonly utilised cross-coupling partners are methyltio derivatives. In the presence of a copper salt, which activates the carbon-sulphur bond, 2-methyltio-benzotiazol coupled readily with a series of arylboronic acids.18... 

In the alternate approach arylboronic acids were coupled with A-aryhhio-succinimides. In the process the aryl group of the boronic acid replaces the succinimide moiety in the coupling partner. In the example presented (6.85.) the 2-thiothiophene derivative was converted to 2-(4 -fluorophenylthio)-thiophene in 76% yield. The procedure was successfully extended to benzothiazoles too.115... 

A highly stereoselective synthesis of retinol via a Cm + C6 route was depicted by De Lera et al. [52]. A Suzuki reaction of a C14 alkenyliodide with a Cg alkenylboronic acid afforded retinol in 83% yield, with retention of the geometries of the coupling partners. The alkenyliodide was obtained by a zirconium-mediated methylalumination and a subsequent Al/I exchange by slow addition of ICN. Coupling with the C6 boronic acid (12 hrs to reach completion), afforded retinol in 83% yield [53], Fig. (21). 

The synthesis of llZ-retinal required the boronic-partner, which was prepared from 2-butyn-l-ol by addition of the tributylstannyl cuprate (83%), followed by protection of the alcohol with tBuMe2SiCl (TBDMSC1) (93%). The tributylstannyl group was substituted with boronic acid in three steps lithiation, quenching alkenyllithium with triisopropyl boronate and hydrolysis to the boronic acid. The Suzuki coupling of the C 6 tetraene with the boronic compound was carried out in THF at room temperature, in the presence of a catalytic amount of... 

Trisphaeridine, [8]. The synthesis [9] of trisphaeridine (17) (Scheme 4) involved the known aryl boronic acid 18 and the sterically unencumbered o-bromophenylcaibamate 19 as coupling partners in the Suzuki reaction. The biaryl 20, thus obtained in customary good yield, underwent a Bischler-Napieralsky cyclisation with phosphorus oxychloride to afford the chlorophenanthridine 21. The latter on catalytic dechlorination furnished 17. 

The Suzuki Coupling, which is the palladium-catalysed cross coupling between organoboronic acid and halides. Recent catalyst and methods developments have broadened the possible applications enormously, so that the scope of the reaction partners is not restricted to aryls, but includes alkyls, alkenyls and alkynyls. Potassium trifluoroborates and organoboranes or boronate esters may be used in place of boronic acids. Some pseudohalides (for example triflates) may also be used as coupling partners. 

Coupling of aromatic heterocycles goes well. The 2-position of a pyridine is very electrophilic and not at all nucleophilic (Chapter 43) but couplings at this position are fine with either the halide or the boronic acid in that position. Clearly, it is a mistake to see either of these substituents as contributing a nucleophilic carbon . It is better to see the reaction as a coupling of two equal partners and the two substituents (halide and boronic acid) as a control element to ensure cross-coupling and prevent dimerization. In the second example potassium te t-butoxide was crucial as weaker and less hindered bases gave poor yields. 

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