Cross-coupling reactions on solid supports

Chamoin S, Houldsworth S, Kruse CG, Bakker WI, Snieckus V. The Suzuki-Miyaura cross coupling reactions on solid support. Link to solution phase directed ortho metalation. The Leznoff acetal linker approach to biaryl and heterobiaryl aldehydes. Tetrahedron Lett 1998 39 4179-4182. 

R. Duboc, M. Savignac and J. P. Genet, Palladium cross-coupling reactions on solid support using a new silylated linker, J. Organomet. Chem., 2002, 643, 512-515. 

Chamoin, S. Houldsworth, S. Snieckus, V. The Stille Cross Coupling Reactions on Solid Support. Link to Solution Phase Directed ortho Metala-tion. An Ester Linker Approach to Styryl, Biaryl and Heterobiaryl Carboxylic Acids, Tetrahedron Lett. 1998, 39, 4175-4178. 

C.ii. Cleavage with Ensuing Cross-Coupling Reactions on Solid Support... 

N-Arylated heterocycles are an important class of compounds often associated with biological activity. It has been shown that yields and reaction rates in copper(II)-mediated C-N cross coupling reactions on a solid support could be dramatically im-... 

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]. 

One of the first cross-coupling reactions performed on solid supports was the Stille reaction [250] which is a paUadium-catalyzed reaction of a trialkylaryl or trialkylalkenyl stannane with an aromatic iodide, bromide or triflate. In contrast to the process in liquid-phase, the organotin reagent is easily removed from the solid-phase because of the subsequent washing processes. Immobilized aryl halides have been frequently coupled with aryl and alkenylstannanes, whereas stan-nanes attached to the solid support have been used less frequently for the StiUe reaction. An example is the synthesis of a benzodiazepine library by EUman et al. Recently, a Stille cross-couphng reaction has been employed in the synthesis of al-kenyldiarylmethanes (ADAM) series of non-nucleoside HlV-1 Reverse Transcriptase Inhibitors (Scheme 3.14) [251]. 

Applications of Suzuki and Heck cross-coupling reactions were adopted by Gallop and coworkers [131] to prepare diverse biaryl- and styryl-substituted (3-lactams on solid support. The catalyst system, [PdCl2(dppf)]-TEA, was found to be efficient to promote C-C bond formation around a (3-lactam template (Schemes 26 and 27). 

The Suzuki-Miyaura tactic carried out on solid support (Scheme 28) [52] provides routes to small libraries of condensed heterocycles. Thus, Merrifield resin with the LeznofF-linked bromobenzene derivative 78 undergoes cross-coupling under normal solution-phase conditions with boron pinacolate 79 or boronic acid 80, prepared by DoM, to afford phenan-thridines 81 or, via 82 and some manipulation, dibenzopyranones 83 in good yields and with high purities. The Stille solid-support reaction has also been successfully executed [53]. 

Utesch, N. F., Diederich, F. Acetylenic scaffolding on solid support Poly(triacetylene)-derived oligomers by Sonogashira and Cadiot-Chodkiewicz-type cross-coupling reactions. Org. Biomol. Chem. 2003,1, 237-239. 

Franzen, R. (2000) The Suzuki, the Heck, the Stille reactions three versatile methods for introduction of C-C bond on solid support. Can. J. Chem. 78 957-962. Ruhland, B., Bombrun, A. iand Gallop, M.A. (1997) Solid-phase synthesis of 4-arylazetidin-2-ones via Suzuki and Heck cross-coupling reactions. J. Org. Chem. 62 7820-7826. 

A small library of 2,3,5-trisubstituted indoles was obtained by Schultz and coworkers starting from a solid-supported 3-bromo-2-iodoaniline on commercially available PS-TsCl resin (polystyrene sulfonyl chloride Argonaut Technologies). A successive Larock heteroannulation, followed by electrophilic substitution on indole position three and final Suzuki or Sonogashira cross-coupling reactions, gave excellent results for the preparation of an important number of indole derivatives 19 and 20 (Scheme 9 20010L3827). 

Transition-metal-mediated transformations play an important role in combinatorial synthesis on solid supports because they allow C-C bond formation under mild, neutral conditions and tolerate a broad range of functional groups. In particular, the palladium-mediated cross-coupling reactions, more precisely the Mizoroki-Heck, the Suzuki and the Stille reactions received a lot of attention due to their enormous derivatization potential of functional structures [5]. Although Stille coupling was the first to be explored on and... 

Muscone (40) is a sex pheromone of the musk deer and a chemical component of cosmetics. A 12-member library of racemic muscone analogs was synthesized by Nicolaou et al.," who anployed a cyclorelease method on solid support to form the macrocycle scaffold (Figure 11.17). A phosphonate-functionalized resin loaded on encoded SMART microreactors 36 was coupled to olelinic esters 35 to form the p-ketophosphonates 37. Sorting and cross olefin metathesis of 37 with two alkenols followed by oxidation with Dess-Martin reagent gave aldehydes 38. An intramolecular ketophosphonate-aldehyde condensation (Homer-Emmons-Wadsworth reaction) of 38 caused smooth cyclorelease of macrocyclic enones 39. Parallel solution-phase chemistry completed the sequence. 

An enzyme-labile so-called safety catch linker 452 was used successfully in various palladium-catalyzed cross-coupling reactions [592]. The linker 452, which releases a hydroxy or an amino functionality on enzymatic cleavage of its phenylacetamide moiety and subsequent rapid lactam formation, was attached to a soluble POE 6000 (polyethylene oxide) polymer and its free phenylacetic acid moiety was transformed to an m-iodobenzyl ester. The thus immobilized m-iodobenzyl alcohol was Heck-coupled with tert-butyl acrylate, and the coupling product 453 was cleaved off the solid support with penicillin G acylase under very mild conditions (pH 7, 37°C) (Scheme 8.84). 

Cross-coupling reactions are extremely valuable tools for the construction of complex structures also on solid support. The accessibility of appropriate building blocks, in former times the bottleneck of library syntheses, has improved since a wide variety of alkenyl-, aryl-substituted stannanes or boranes can now be purchased from commercial suppliers in a broad variety. 

The chemoselectivity provided by the solid support in the cross-metathesis reaction is evident in ene-ene metathesis reactions, as both olefins are capable of a homodimerization reaction. The Mata laboratory has devoted significant effort toward the understanding and development of cross-metathesis reactions on a solid support. To probe the limits of the reaction, aliphatic, aryl, and acryloyl alkenes 8,11, and 12 were immobilized and reacted with a variety of soluble olefins 13-16 from different classifications based on homodimerization potential (Scheme 6.2). For example, the immobilized acrylate 8 was reacted with several soluble olefins to form the immobilized coupling product 9. Subsequent cleavage with TFA and esterification with diazomethane delivered the esters 10. Other immobilized alkenes explored in the same process were 11 and 12. Among other olefins, they were reacted with the soluble alkenes 13-16. Modest to good yields (shown in parentheses) were obtained, but, most importantly, no dimerization of the immobilized alkenes 8,11, and 12 was observed, and undesired homocoupling products of the alkenes 13-16 in solution were easily washed away in the workup step. 

The authors further explored the chemistry on solid support by decorating the obtained resin-bound 2-aminobenzothiazoles using different palladium-catalyzed cross-coupling reactions (Scheme 8.24). Thus, the reaction product of 3-bromoaniline was subjected to bromine-mediated cyclization in AcOH at rt for 16 h, furnishing a 1 1 mixture of 5- and... 

Due to the substantial amount of literature, even when excluding supported catalysts, only selected articles on the solid phase Suzuki reaction are mentioned here, concentrating on the more recent publications. Apart from the general palladium reviews cited in Sect. 5, some examples of solid phase synthesis can be found in a review of apphcations of the Suzuki-Miyaura cross-coupling reactions in organic synthesis by Kotha in 2002 [114]. 

In contrast, the Stille reaction was one of the first cross-coupling reactions performed on solid support. For the palladium-catalyzed coupling of various aryl, vinyl, or alkynyl stannanes with aryl or alkenyl bromides, iodides, or triflates, the reaction conditions employed were chosen in analogy to the liquid phase procedures and often feature an arsine or trifurylphosphine as an added ligand. Due to the tedious separation of tin and organo tin reagents or by-products in solution phase, this carbon-carbon bondforming reaction is particularly suitable for solid-phase synthesis. ... 

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