Solvent-free Library Synthesis

In most of the parallel reactions, solvent is rarely used and the starting materials or reagents are either supported on mineral soHd supports or these supports are 

---

This transformation can also be carried out under solvent-free conditions in a domestic oven using acidic alumina and ammoniiun acetate, with or without a primary amine, to give 2,4,5-trisubstituted or 1,2,4,5-tetrasubstituted imidazoles, respectively (Scheme 15A) [69]. The automated microwave-assisted synthesis of a library of 2,4,5-triarylimidazoles from the corresponding keto-oxime has been carried out by irradiation at 200 ° C in acetic acid in the presence of ammonium acetate (Scheme 15B) [70]. Under these conditions, thermally induced in situ N - O reduction occurs upon microwave irradiation, to give a diverse set of trisubstituted imidazoles in moderate yield. Parallel synthesis of a 24-membered library of substituted 4(5)-sulfanyl-lff-imidazoles 40 has been achieved by adding an alkyl bromide and base to the reaction of a 2-oxo-thioacetamide, aldehyde and ammonium acetate (Scheme 15C) [71]. Under microwave-assisted conditions, library generation time was dramatically re-... 

Fewer procedures have been explored recently for the synthesis of simple six-membered heterocycles by microwave-assisted MCRs. Libraries of 3,5,6-trisubstituted 2-pyridones have been prepared by the rapid solution phase three-component condensation of CH-acidic carbonyl compounds 44, NJ -dimethylformamide dimethyl acetal 45 and methylene active nitriles 47 imder microwave irradiation [77]. In this one-pot, two-step process for the synthesis of simple pyridones, initial condensation between 44 and 45 under solvent-free conditions was facilitated in 5 -10 min at either ambient temperature or 100 ° C by microwave irradiation, depending upon the CH-acidic carbonyl compound 44 used, to give enamine intermediate 46 (Scheme 19). Addition of the nitrile 47 and catalytic piperidine, and irradiation at 100 °C for 5 min, gave a library of 2-pyridones 48 in reasonable overall yield and high individual purities. 

The condensation between enaminones and cyanoacetamide is a well-established method for the synthesis of 2-pyridones (see c, Scheme 2, Sect. 2.1), and the use of malonodinitrile instead of the amide component has also been shown to yield 2-pyridones [39-41]. Recently, Gorobets et al. developed a microwave-assisted modification of this reaction suitable for combinatorial synthesis, as they set out to synthesize a small library of compounds containing a 2-pyridone scaffold substituted at the 3, 5, and 6-positions [42]. The 2-pyridones were prepared by a three-component, two-step reaction where eight different carbonyl building blocks were reacted with N,N-dimethylformamide dimethyl acetal (DMFDMA) to yield enaminones 7 (Fig. 2). The reactions were performed under solvent-free conditions at el-... 

The glass plate was exposed to microwave irradiation, eluted, and viewed by standard TLC visualization procedures to assess the results of the reaction. In this particular example, the synthesis of an arylpiperazine library (Scheme 4.25) was described, but the simplicity and general utility of the approach for the rapid screening of solvent-free microwave reactions may make this a powerful screening and reaction optimization tool. The synthesized compounds were later screened for their antimicrobial activity without their removal from the TLC plate utilizing bioautogra-phical methods [84],... 

A rapid parallel solvent-free synthesis of a representative 28-membered library of phthalimides was achieved utilizing a household microwave oven under highly optimized conditions [35]. Thus, the highest irradiation area inside the household microwave oven was determined to ensure better reproducibility of results (Scheme 12). 

Scheme 12 A rapid parallel solvent-free synthesis of a library of phthalimides...

Heterocyclic chemistry was facilitated by microwave-expedited solvent-free chemistry utilizing mineral supported reagents [65]. The scope now includes parallel synthesis [66]. A representative multi-component condensation to create a library of imidazo[l,2-a]pyridines, imidazo[l,2-a]pyrazines and imidazo[ 1,2-a]pyrimidines is depicted in Scheme 12 [67]. 

Microwave-assisted solvent-free synthesis of a quinoline-3,4-dicarboximide library on inorganic solid supports has recently been reported [103]. Wet clay KIO was shown to be the best medium for the condensation reaction between 2-methylquinoline -3,4-dicarboxylic anhydride and several primary amines. Micro-wave irradiation is essential for rapid and complete formation of imides (Scheme 8.35). 

According to Blackwell [103] the application of microwave irradiation to expedite solid-phase reactions could be the tool that allows combinatorial chemistry to deliver on its promise - providing rapid access to large collections of diverse small molecules. Several different approaches to microwave-assisted solid-phase reactions and library synthesis are now available. These include the use of solid-supported reagents, multi-component coupling reactions, solvent-free parallel library synthesis, and spatially addressable library synthesis on planar solid support. 

Recently this approach has been extended to parallel combinatorial library synthesis. One example is the solvent-free synthesis of a 96-member library of substituted pyridines via a one-step Hantzsch-3CC conducted in 96-weU micro titer filter plates (Scheme 2.3-12). Here the p-ketoester and aldehyde reagents were impregnated onto a 5 1 bentonite clay-ammonium nitrate mixture. Irradiation for 5 min in a domestic MW oven, followed by washing the product off the support into a receiver daughter plate gave substituted-pyridine products in >70% purity overall. 

A similar approach has been used for the synthesis of 3-lH-pyrazolo[3,4-fc]pyridyl-indole ° and 2-aminochromene libraries, the latter being performed solvent free using a clay as a support and base. In addition, a library of over 100 derivatized substituted 2-pyridones (21 x 5 members) has been prepared by the reaction of 1,3-cyclohexane-diones, dimethylformamide dimethylacetal, and various cyanoacetamides (Scheme 4.10). The outcome of the reaction could be controlled to furnish different products by changing the basicity of the medium to involve either the amide or nitrile functionality of the cyanoacetamide substrate during the 2-pyridone ring-formation step. 

Song SJ, Cho SJ, Park DK, Kwon TW, Jenekhe SA (2003) Mierowave enhaneed solvent free synthesis of a library of quinoline derivatives. Tetrahedron Lett 44 255-257... 

KF impregnated on alumina (KF-alumina) has been shown to act as solid heterogeneous base to catalyze various organic reactions. A facile and expedicious solvent-free synthesis of libraries of quinoxalines promoted on KF-alumina surface has been realized from the condensation of a-hydroxy-, a-haloketones, or 1,2-diketones with aryl... 

The purity of compounds in the library is an important factor. Reaction side products (e.g., triphenylphosphine from a Wittig reaction) should be completely removed from a compound in a library. Similarly, compounds should be free of any solvents used in their synthesis. Unfortunately, not all impurities are easily removed. Impurities can sometimes interfere with an assay and lead to inaccurate results.2... 

---