Indole libraries

Transition metal catalysis on solid supports can also be applied to indole formation, as shown by Dai and coworkers [41]. These authors reported a palladium- or copper-catalyzed procedure for the generation of a small indole library (Scheme 7.23), representing the first example of a solid-phase synthesis of 5-arylsulfamoyl-substituted indole derivatives. The most crucial step was the cydization of the key polymer-bound sulfonamide intermediates. Whereas the best results for the copper-mediated cydization were achieved using l-methyl-2-pyrrolidinone (NMP) as solvent, the palladium-catalyzed variant required the use of tetrahydrofuran in order to achieve comparable results. Both procedures afforded the desired indoles in good yields and excellent purities [41]. 

Table 8.3 Direct comparison of thermal and microwave results - indole library...

Kim et al. (294) reported the synthesis of a small, 6-member array of discretes L25 and of a small 27-member pool indole library L26 using a commercially available, polyamide-based dendrimer support (8.107, Fig. 8.50) in which eight amino reaction sites per dendritic unit are present. The synthetic route for the preparation of the indole nuclei is reported in Fig. 8.51. Dendrimer 8.107 was first coupled to the base-labile... 

Figure 8.51 Synthesis and purification of the discrete (L25) and the pool (L26) indole libraries using dendrimer soluble supports.

Transition-metal catalysis on solid supports can also be used for indole formation [43]. A palladium or copper-catalyzed procedure has been described for generation of a small indole library (Scheme 16.21) this is the first example of solid-phase synthesis of 5-arylsulfamoyl substituted indole derivatives. Whereas the best... 

The first reported Au-catalyzed indole synthesis was that of Utimoto and coworkers (Scheme 1, equation 1) [5], Like copper, palladium, and rhodium, gold effects the cycliza-tion of o-alkynylanilines to indoles with ease. This basic electrophilic cyclization was improved upon by MarineUi [6, 7], was adapted to the synthesis of indole libraries [8, 9], was used with supported gold nanoparticles and o-alky-nylnitroarenes under hydrogenation conditions in a one-pot indole synthesis [10], and was employed in total syntheses of the alkaloids (-)-mersicarpine [11] and voacangalactone [12]. There have been an abundance of extensions to the Au-catalyzed cyclization of o-aUcynylanilines to afford 2,3-disubstituted indoles. Arcadi and colleagnes introduced both a,p-enones [13] and 1,3-dicarbonyl compounds... 

Worhkar SA, Neuenswander B, Lushington GH, Larock RC. Highly substituted indole library synthesis by palladium-catalyzed coupling reactions in solution and on a solid support. J. Comb. Chem. 2009 11 875-879. 

Combinatorial chemistry has played an increasing role in drug discovery. Wacker et al. extended the Madelung indole process successfully to solid phase library synthesis for the preparation of 2,3-disubstituted indoles. A number of examples follow in the table. 

More recently, Somfai and coworkers have reported on the efficient coupling of a set of carboxylic acids suitable as potential scaffolds for peptide synthesis to a polymer-bound hydrazide linker [24]. Indole-like scaffolds were selected for this small library synthesis as these structures are found in numerous natural products showing interesting activities. The best results were obtained using 2-(7-aza-l H-benzo-triazol-l-yl)-l,l,3,3-tetramethyluronium hexafluoride (HATU) and N,N-diisopropyl-ethylamine (DIEA) in N,N-dimethylformamide as a solvent. Heating the reaction mixtures at 180 °C for 10 min furnished the desired products in high yields (Scheme 7.4). In this application, no Fmoc protection of the indole nitrogen is required. 

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. 

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. 

This dendritic support (1) was used to generate a library of indole derivatives with three centers of diversity following the Fischer protocol and the split and mix strategy. One example of this sequence is outlined in Scheme 7.1. 

Dialkyltryptaminesfrom 3-Indole-Acetic Acid. Col. Czech. Chem. Com. There are several other methods given with this formula but they are not as good as the one given below. If you do not have a big, complete library, then you may need a translator to understand this and some of the other foreign journals. 

The utility of the privileged structure concept is illustrated by compound library synthesis based on the indole scaffold and the biologically active compounds resulting from that. The indole scaffold is found in natural products, like for example, the neurotransmitter serotonin (5-hydoxytriptamine, 5-HT) and in well-know drugs, like for example, the... 

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... 

Connon and co-workers synthesized a small library of novel axially chiral binaphthyl-derived bis(thio)ureas 152-165 and elucidated the influence of the steric and electronic characteristics of both the chiral backbone and the achiral N-aryl(alkyl) substituents on catalyst efficiency and stereodifferentiation in the FC type additions of indole and N-methylindole to nitroalkenes (Figure 6.50) [315]. 

Our second attempt at using the microwave to accelerate reaction rates was on a library of indoles generated by a McMurray coupling reaction. Heating the reaction mixture at 80°C for 8 h produced poor yields of the desired product (entry 1, Table 8.3). However, when the microwave was utilized the isolated yield was raised to 79% and the reaction was completed in only 5 min. This reaction acceleration allowed for the production of a 300-membered library, which produced compounds of high quality in a significantly reduced time. 

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