Boronic acid supports

Figure1.44 Boronic acid supports for diol compounds.

Crude chloroform-methanol-water (30 60 8, v/v) extracts of immunostainedTLC bands were analyzed without further purification by nanoelectrospray low-energy mass spectrometry. The authors showed that this effective PLC/MS-joined procedure offers a wide range of applications for any carbohydrate-binding agents such as bacterial toxins, plant lectins, and others. Phenyl-boronic acid (PBA) immobilized on stationary support phases can be put to similar applications. This technology, named boronate affinity chromatography (BAC), consists of a chemical reaction of 1,2- and 1,3-diols with the bonded-phase PBA to form a stable... 

Recently, iodobenzoates anchored onto an ionic liquid support (6.4) were coupled to various aryl boronic acids (6.5) in aqueous media using Pd(OAc)2 as the catalyst at 80°C to give the coupled product 6.6 (Scheme 6.3). Compounds 6.6 were purified simply by washing the reaction mixture with ether, which removed the unreacted starting materials and the side product 6.7 without the need of chromatography. Compounds 6.6 were then cleaved from the ionic liquid support... 

Several microwave-assisted protocols for soluble polymer-supported syntheses have been described. Among the first examples of so-called liquid-phase synthesis were aqueous Suzuki couplings. Schotten and coworkers presented the use of polyethylene glycol (PEG)-bound aryl halides and sulfonates in these palladium-catalyzed cross-couplings [70]. The authors demonstrated that no additional phase-transfer catalyst (PTC) is needed when the PEG-bound electrophiles are coupled with appropriate aryl boronic acids. The polymer-bound substrates were coupled with 1.2 equivalents of the boronic acids in water under short-term microwave irradiation in sealed vessels in a domestic microwave oven (Scheme 7.62). Work-up involved precipitation of the polymer-bound biaryl from a suitable organic solvent with diethyl ether. Water and insoluble impurities need to be removed prior to precipitation in order to achieve high recoveries of the products. 

In a more recent study, Wang and coworkers have discussed microwave-assisted Suzuki couplings employing a reusable polymer-supported palladium complex [141]. The supported catalyst was prepared from commercial Merrifield polystyrene resin under ultrasound Bonification. In a typical procedure for biaryl synthesis, 1 mmol of the requisite aryl bromide together with 1.1 equivalents of the phenyl-boronic acid, 2.5 equivalents of potassium carbonate, and 10 mg of the polystyrene-... 

The same authors performed a microwave assisted Stille reaction on the Rink amide (RAM) Tentagel polymer-tethered 4-iodobenzoic acid [5 b]. Successful palladium-catalyzed coupling of heteroaryl boronic acid with anchored 4-iodobenzoic acid enabled both >99% conversion of the starting material within 3.8 min (45 W) and a minimal decomposition of the solid support. The coupling reactions were realized in a mixture of polar solvents (H20-EtOH-DME, 2.5 1.5 6). 

Several microwave-assisted procedures have been described for soluble polymer-supported syntheses. Polyethylene glycol) (PEG)-supported aryl bromides have been shown to undergo rapid palladium(0)-catalyzed Suzuki couplings with aryl boronic acids in water (Scheme 12.16) [63], The reaction proceeded without organic cosolvent... 

The palladium-catalyzed coupling of boronic acids with aryl and alkenyl halides, the Suzuki reaction, is one of the most efficient C-C cross-coupling processes used in reactions on polymeric supports. These coupling reactions requires only gentle heating to 60-80 °C and the boronic acids used are nontoxic and stable towards air and water. The mild reaction conditions have made this reaction a powerful and widely used tool in the organic synthesis. When the Suzuki reaction is transferred to a solid support, the boronic add can be immobilized or used as a liquid reactant Carboni and Carreaux recently reported the preparation of the macroporous support that can be employed to efficiently immobilize and transform functionalized arylboronic adds (Scheme 3.12) [107, 246, 247]. 

Scheme 3.12 Solid supported boronic acids (144) as reagents for Suzuki couplings [107],...

Evaluation of this support for organic chemistry included peptide chemistry (synthesis of Fmoc-Val-Phe-Ala-OH) and a Suzuki coupling of immobilized 4-iodoben-zoic acid with 4-methylbenzene boronic acid coupled under standard conditions. 

Recently, Hebei and Haag reported on the immobilization of aryl boronic acids (62) on a dendritic polyglycerol support (15) (Fig. 7.8, M =8000 g mol ) (Scheme 7.10) [57]. This commercially available support was directly used and no additional... 

Farrall and Frechet recognized the possibility of forming polymer-bound boronic acids in 1976.66 Supported pnra-benzeneboronic acid groups were generated by direct lithiation of polystyrene, giving a para-lithio intermediate that could be used to generate a host of other resins also (Scheme 27). Conversion to the boronic acid was one of the more successful transformations. The purpose of this transformation was to allow the attachment of sugars to the solid phase via the boronate. 

In a simple strategy to biaryl formation, Han et al.89 showed that silicon-directed ipso-substitution and concomitant cleavage from supports could be used for formation of functionalized biphenyls. For this they used a tethered silyl aryl bromide in a Suzuki cross-coupling reaction, followed by the ipso-substitution/cleavage step (Scheme 39). A variety of boronic acids were coupled in this manner. The only difficulty occurred with electron-deficient nitrophenylboronic acid where the desired product was formed under anhydrous conditions in only 33% yield (the remainder being starting material). Reversion to the more usual conditions of aqueous base-DME (i.e., those used by Frenette and Friesen)70 improved the yield to 82%. 

Sphinx Pharmaceuticals101 patented successful Stille (with a resin-bound organostannane) and Suzuki (with a supported boronic acid) cross-couplings. In the same patent, they also reported a coupling of a phenylacety-lene with a resin-bound bromide wherein Pd(OAc)2 was the catalyst (Scheme 50). 

Nucleophiles other than hydride can be added to support-bound imines to yield amines. These include C,H-acidic compounds, alkynes, electron-rich heterocycles, organometallic compounds, boronic acids, and ketene acetals (Table 10.9). When basic reaction conditions are used, stoichiometric amounts of the imine must be prepared on the support (Entries 1-3, Table 10.9). Alternatively, if the carbon nucleophile is stable under acidic conditions, imines or iminium salts might be generated in situ, as, for instance, in the Mannich reaction. Few examples have been reported of Mannich reactions on insoluble supports, and most of these have been based on alkynes as C-nucleophiles. 

Vinylations and arylations of polystyrene-bound 2-bromofurans have been accomplished by treatment with stannanes [98] or boronic acids [99] in the presence of palladium complexes. Alternatively, 2-furylstannanes can be coupled with support-bound aryl iodides or bromides in the presence of palladium or copper complexes (Entries 5-7, Table 15.8). 

The resulting triazoles can be N-alkylated by treatment with alkyl halides (0.25 mol/L, 30 equiv., DMF, NaOH), but mixtures of the 1-alkylated and 2-alkylated triazoles are obtained [255]. 1,2,4-Triazoles have also been prepared from N-amino-amidines (amidohydrazones Entry 4, Table 15.20), which were prepared from resin-bound thioamides by S-alkylation with methyl triflate followed by treatment with hydrazine [256]. 1,2,4-Tri azoles undergo Michael addition to polystyrene-bound a-acetamido acrylates to yield triazole-derived a-amino acids (Entry 7, Table 15.20). Benzotriazoles have been N-arylated on insoluble supports by treatment with aryl-boronic acids in the presence of catalytic amounts of copper salts (Entry 8, Table... 

Parrish and Buchwald30 performed couplings with a polystyrene-supported biphenyl-phosphine palladium complex between aryl halides and either amines (entry 24) or boronic acids (entry 25). The resin-bound complex is analogous to the corresponding homogeneous compound and is effective for couplings to unactivated aryl halides, including aryl chlorides. The complex is air-stable and retains activity after recovery without apparent loss of palladium. 

Following the same strategy, Landis prepared the l,l -ferrocenyldi-phosphines 53a-c featuring pendant benzoxaborolidine moieties (Scheme 33). 63 Reaction of 2-aminophenol with the ferrocene precursor 51 afforded 52 which was subsequently coupled with various boronic acids to give compounds 53a-c in good yields. Monomeric open structures were supported by 31P NMR spectroscopy and crystallography for 53a. 

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