Microwave-assisted library synthesis

In an attempt to define the exact amount of timesavings associated with the use of microwave-assisted library synthesis, our group devised a method by which the actual control thermal reactions would be performed side-by-side with the microwave reactions by two independent researchers. Furthermore, it was decided that the two scientists would not share experimental results or methodologies so as to not affect each other s research. This series of experiments was labeled the Contest 15. 

An additional interest in the appUcations of microwave-assisted organic synthesis is related to the possibility of having more rapid access to large libraries of diverse small molecules and heterocycUc compounds... 

In a 1998 publication, the concept of microwave-assisted parallel synthesis in plate format was introduced for the first time. Using the three-component Hantzsch pyridine synthesis as a model reaction, libraries of substituted pyridines were pre-... 

The integration of microwave heating and fluorous technologies has generated a powerful solution to address both the reaction and separation issues in parallel and combinatorial synthesis. With the further development of multimode microwave reactors for plate reactions and F-SPE for plate-to-plate separations, microwave-assisted fluorous synthesis will play an even more important role in compound library synthesis. 

Single mode microwave-assisted combinatorial synthesis of biologically interesting quinoxalinones has been described by Tung and Sun [106]. It enabled chiral libraries of quinoxalinones to be assembled by use of SNAr reactions, reduction, and concomitant cyclization under the action of microwave irradiation. 

Combs P, Takvorian AG (2004) Microwave-assisted organic synthesis using minivials to optimize and expedite the synthesis of diverse purine libraries. J Comb Chem 6 171-174... 

Mmray JK, Gellman SH (2005) Microwave-assisted parallel synthesis of a 14-helical p-peptide library. J Comb Chem 8 58-65... 

The rapid synthesis of heteroaromatic Hantzsch pyridines can be achieved by aromatization of the corresponding 1,4-DHP derivative under microwave-assisted conditions [51]. However, the domino synthesis of these derivatives has been reported in a domestic microwave oven [58,59] using bentonite clay and ammoniiun nitrate, the latter serving as both the source of ammonia and the oxidant, hi spite of some contradictory findings [51,58,59], this approach has been employed in the automated high-throughput parallel synthesis of pyridine libraries in a 96-well plate [59]. In each well, a mixture of an aldehyde, ethyl acetoacetate and a second 1,3-dicarbonyl compound was irradiated for 5 min in the presence of bentonite/ammonium nitrate. For some reactions, depending upon the specific 1,3-dicarbonyl compound used. 

The Ugi reaction is the four-component condensation of an amine, aldehyde or ketone, carboxylic acid and isocyanide to give an o -acylamino amide [22-24], Although this process has the potential to introduce considerable diversity, the products themselves are not heterocycles but through appropriate choice of substrates, latent functionality in one of the precursors can intercept either an intermediate or further derivatize the acylamino amide Ugi product through post-modification. Thus variants of the Ugi reaction have been investigated under microwave-assisted conditions for the synthesis of diverse heterocyclic libraries [16,19-24],... 

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. 

Scheme 32 Microwave-assisted synthesis of a [3-1-2] cycloaddition library...

As for the solid support, several polymer-supported amines were tested (Fig. 2). For either the pyrazole and isoxazole synthesis, the best results were given by aniline-functionalized cellulose, which has also the advantage of a relatively low cost. For the 2-aminopyrimidine library, polystyrene-based piperazine and piperidine gave products with a much higher purity compared with other secondary non-cyclic or primary amines, hi both cases, the resins could be reused for up to four times before degradation in their behavior was observed. This reusability could be further enhanced (up to 10 cycles for cellulose-based aniline) when the microwave-assisted protocols were used. 

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-... 

Microwave-assisted reactions allow rapid product generation in high yield under uniform conditions. Therefore, they should be ideally suited for parallel synthesis applications. The first example of parallel reactions carried out under microwave irradiation conditions involved the nucleophilic substitution of an alkyl iodide with 60 diverse piperidine or piperazine derivatives (Scheme 4.22) [76]. Reactions were carried out in a multimode microwave reactor in individual sealed polypropylene vials using acetonitrile as solvent. Screening of the resulting 2-aminothiazole library in a herpes simplex virus-1 (HSV-1) assay led to three confirmed hits, demonstrating the potential of this method for rapid lead optimization. 

As a suitable model reaction to highlight the steps necessary to successfully translate thermal conditions to microwave conditions, and to outline the general workflow associated with any microwave-assisted reaction sequence, in this section we describe the complete protocol from reaction optimization through to the production of an automated library by sequential microwave-assisted synthesis for the case of the Biginelli three-component dihydropyrimidine condensation (Scheme 5.1) [2, 3],... 

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