Indol-resin

Contrary to an alkoxy benzene scaffold, secondary amides were generated via novel aldehyde linker 43 based upon an indole scaffold (Scheme 15) [52]. The indole resin was prepared from indole-3-carboxy-aldehyde in two steps and reacted with amines under reductive conditions to generate resin-bound secondary amines. Treatment of the resin with... 

Estep KG, Neipp CE, Stramiello LM, Stephens A, Mavis D, Allen MP. Indole resin A versatile new support for the solid-phase synthesis of organic molecules. J Org Chem 1998 63 5300-5301. 

The first example of microwave-promoted solid-phase methodology in heterocyclic chemistry was the arylation of thiophene and indole via Suzuki couplings on TentaGel S RAM resin, as demonstrated by Hallberg and coworkers in 1996, before temperature- and pressure-controlled microwave instruments were even available [189]. Three years later Schotten and coworkers presented analogous but aqueous Suzuki couplings of 5-bromo-thiophene anchored to PEG soluble support via a carboxylic function at its C-2 position [116]. Unfortunately, this work was performed in a do-... 

AT-acetyltryptamines could be obtained via microwave-assisted transition-metal-catalyzed reactions on resin bound 3-[2-(acetylamino)ethyl]-2-iodo-lH-indole-5-carboxamide. While acceptable reaction conditions for the application of microwave irradiation have been identified for Stille heteroaryla-tion reactions, the related Suzuki protocol on the same substrate gave poor results, since at a constant power of 60 W, no full conversion (50-60%) of resin-bound 3-[2-(acetylamino)ethyl]-2-iodo-lH-indole-5-carboxamide could be obtained even when two consecutive cross-coupling reaction cycles (involving complete removal of reagents and by-products by washing off the resin) were used (Scheme 36). Also under conventional heating at 110 °C, and otherwise identical conditions, the Suzuki reactions proved to be difficult since two cross-coupling reaction cycles of 24 h had to be used to achieve full conversion. 

The intramolecular Heck reaction of polymer bound aryl halides such as 84 affords indole analogs 85 after cleavage of the final product from the resin with TFA <96TL4189>, Other notable uses of the Heck cyclization include a synthesis of an antimigraine agent <96TL4289>, and thia-tryptophans <96T14975>. 

However, thermolysis of the phosphonium salts (X=+PPh3) leads directly to the indolic products without need of acid catalyst or PPh3, and thus may not proceed via a normal Wittig pathway. Alternatively, Hughes has effected a solid-phase version of this reaction employing a polymer-hound phosphonium salt and potassium tert-butoxide as base <96TL7595>. In this case, the phosphine oxide by-product remains bound to the polymer resin. 

In another application, the group of Berteina-Raboin demonstrated the solid-supported synthesis of the indole core of melatonin analogues under microwave irradiation (Scheme 7.6) [26]. A benzoic acid derivative was coupled to Rink amide resin by... 

Bis(indolyl)nitroethanes are obtained readily in 7-10 min in high yields (70-86%) on fine TLC-grade silica gel (5-40 pm) by Michael reaction of 3-(2 -nitrovinyl) indole with indoles. The same reaction reported requires 8-14 h for completion at room temperature [77]. Several functionalized resins have been prepared from Merrifield resin via a MW-assisted procedure that utilized mixed solvent system to facilitate the swelling of resins and coupling with microwaves [78], These resins can function as solid supports or polymeric scavengers in solid phase synthesis. 

Ketcha and Wilson reported the solid-phase version of the classic Nenitzescu indole synthesis in a process involving initial acetoacetylation of ArgoPore-NH2 resin with diketene to afford a polymer bound acetoacetamide <00TL6253>. Formation of the corresponding enaminone 102 via condensation with primary amines in the presence of trimethylorthoformate followed by addition of 1,4-benzoquinones 103 leads to formation of polymer bound 5-hydroxyindole-3-carboxamides 104 which could be cleaved from the resin using TFA yielding the indoles 105. 

Another Suzuki coupling reaction was described by Zhang et al., to produce arylindoles 116a and b, using solid-phase synthesis [76]. The synthesis was achieved by palladium-mediated coupling/intramolecular indole cycli-zation of resin-bound 2-trimethylsilylindole 117, Scheme 29. 

Abell utilized a Suzuki cross-coupling reaction on resin 153. Subsequent acid treatment effected cyclization to indole 154, which was readily cleaved with amines and alcohols to form potential libraries of amides and esters, respectively [162],... 

The cyclization of IV-allyl-o-haloanilines was adapted to the solid phase for both indoles [332, 333] and oxindoles [334]. For example, as illustrated below, a library of l-acyl-3-aIkyl-6-hydroxyindoles is readily assembled from acid chlorides, allylic bromides, and 4-bromo-3-nitroanisole [332], Zhang and Maryanoff used the Rink amide resin to prepare Af-benzylindole-3-acetamides and related indoles via Heck cyclization [333], and Balasubramanian employed this technology to the synthesis of oxindoles via the palladium cyclization of o-iodo-N-acryloylanilines [334], This latter cyclization route to oxindoles is presented later in this section. 

The Larock indole synthesis was adapted to the solid phase both for the synthesis of 1,2,3-trisubstituted indole-5-carboxamides [396] and, as illustrated, for the "traceless" synthesis of 2,3-disubstituted indoles 308 [397], As seen earlier, the trimethylsilyl group is fastened to C-2 with complete regioselectivity. The TMS group is cleaved under the resin cleavage conditions. The original Larock conditions were not particularly successful. 

An intramolecular Heck cyclization strategy was developed for the construction of indole and benzofuran rings on solid support [82], enabling rapid generation of small-molecular libraries by simultaneous parallel or combinatorial synthesis. Sn2 displacement of resin-bound y-bromocrotonyl amide 97 with o-iodophenol 96 afforded the cyclization precursor 98. A subsequent intramolecular Heck reaction using Jeffery s ligand-free conditions furnished, after double bond tautomerization, the resin-bound benzofurans, which were then cleaved with 30% TFA in CH2CI2 to deliver the desired benzofuran derivatives 99 in excellent yields and purity. 

Wang et al. investigated the catalytic behavior of cation exchange resin supported lanthanide(III) salts of the general structure (31) (Scheme 4.15), prepared from Dowex, Amberlite, Amberlyst and other resins [99]. It turned out that Am-berlyst XN-1010 and Amberlyst 15 complexed best with lanthanides(III). Thus, among others, electrophilic substitution of indole with hexanal and Mukayiama-type aldol reaction of benzaldehyde with ketene silyl acetal proceeded in excellent yields under catalytic conditions (Scheme 4.16). 

For resin-bound carbamates (18-21), indole linker was the most acid-labile linker for this class of compounds. Rink linker ranked second. Resin (20) was cleaved with 0.5% TFA in 20 min. Resin (21) was cleaved with 1% TFA in 2 min. Resins (18) and (19) required higher concentration of TFA. Resin (18) was cleaved with 1% TFA in 5 h. Alternatively, resin (19) was cleaved with 1% TFA in 12 h and with 5% TFA in only 16 min (not shown). 

For resin-bound ureas (22-25), Indole and Rink linkers, generally ranked 1 and 2 in cleavage kinetics, were still the most acid-labile linker for this class of compounds. Resins (24) and (25) were cleaved with 0.5% TFA in 2 and 23 min, respectively. Resins (22) and (23) were cleaved with 1% TFA in more than 10 h. The order of cleavage rates is similar to carbamate compounds. 

Resin-bound sulfonamides (30-33) were easily cleaved by 1% TFA in 3 min or by 0.5% TFA in 2-7 h. Indole linker was still the most labile linker in this class of compounds. 

TFA). Among various linkers studied in this work, the indole linker [21] was found to be the most suitable linker in terms of cleavage kinetics and actual cost. Rink linker was the second best in term of kinetics. The rate of cleavage of various functional groups linked to the above-mentioned resins was as follows sul-fonamide>carbamate urea>amide. Results from this study demonstrated that optimization of cleavage conditions often led to more suitable conditions and safer release of precious compounds synthesized on a solid support. 

Scheme 2. The indole core structure is present in natural products and drugs, like for example Indomethacine and can therefore be considered as a privileged structure. A resin-capture-release strategy to synthesize an indole based compound library has been developed by Waldmann and co-workers.

A solid phase library synthesis method based on the Fischer indole synthesis was developed (Scheme A resin-capture-release method... 

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