Synthesis sequential library

The issue of parallel versus sequential synthesis using multimode or monomode cavities, respectively, deserves special comment. While the parallel set-up allows for a considerably higher throughput achievable in the relatively short timeframe of a microwave-enhanced chemical reaction, the individual control over each reaction vessel in terms of reaction temperature/pressure is limited. In the parallel mode, all reaction vessels are exposed to the same irradiation conditions. In order to ensure similar temperatures in each vessel, the same volume of the identical solvent should be used in each reaction vessel because of the dielectric properties involved [86]. As an alternative to parallel processing, the automated sequential synthesis of libraries can be a viable strategy if small focused libraries (20-200 compounds) need to be prepared. Irradiating each individual reaction vessel separately gives better control over the reaction parameters and allows for the rapid optimization of reaction conditions. For the preparation of relatively small libraries, where delicate chemistries are to be performed, the sequential format may be preferable. This is discussed in more detail in Chapter 5. 

Direct structure determination methods, where positives are characterized directly via off-bead or on-bead identification of their chemical structure, will be described in detail in this section. Indirect methods that determine the structure of positives from the library architecture will be covered later they use either deconvolutive methods (Section 7.3), where the iterative synthesis of library pools with decreasing complexity via sequential determination of the best monomers leads to the identification of a positive structure, or encoding methods (Section 7.4), where, during the library synthesis, the structure of each component is coupled to a tag that can be read from a single bead after the library screening. 

More advanced MW exploitation involves use of a monomode MW reactor equipped with a robotics interface that can be used for automated sequential library synthesis. The Biginelli reaction performed using this procedure employs a diverse set of starting compounds to prepare a 48-compound library of 26 [65], AcOH-EtOH was used as solvent and a catalytic amount of Yb(OTf)3 was added. When the unattended automation capabilities of the MW synthesizer are used a library of this size can be synthesized in 12 h. 

According to SciFinder, over 2700 multicomponent reactions were published just in the 2005-2010 period. They are particularly useful for parallel synthesis of libraries of compounds, the concept briefly discussed in the next chapter. Multicomponent reactions might be amenable to a retrosynthetic approach if sequential disconnection of more bonds can be completed in the synthetic direction from recognizable building blocks reacting in the expected order. 

By combining several click reactions, click chemistry allows for the rapid synthesis of useful new compounds of high complexity and combinatorial libraries. The 2-type reaction of the azide ion with a variety of epoxides to give azido alcohols has been exploited extensively in click chemistry. First of all, azido alcohols can be converted into amino alcohols upon reduction.70 On the other hand, aliphatic azides are quite stable toward a number of other standard organic synthesis conditions (orthogonality), but readily undergo 1,3-dipolar cycloaddition with alkynes. An example of the sequential reactions of... 

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],... 

When the peptide synthesis was complete, the phosphines were deprotected by sequential treatment with MeOTf and HMPT (Scheme 36.9). Addition of the rhodium precursor then created the catalyst library, which was screened, on the pin in the enantioselective hydrogenation of methyl-2-acetamidoacrylate (see Scheme 36.10). Unfortunately, this beautiful concept was poorly rewarded with rather low enantioselectivities. 

The advantages of functional polymers are best realized when used in two situations— multistep sequential reactions and automated parallel combinatorial synthesis to produce libraries of compounds. In both situations there is a large savings in the time and expense of carrying out the many chemical reactions and their corresponding handling and purification steps. 

A 48-membered library of 2-arylbenzoxazoles has been prepared by the condensation of substituted 2-aminophenols with a series of acid chlorides. The reactions proceeded in the absence of a base in sealed tubes in an automated microwave instrument, which used sequential rather than parallel reaction processing. Comparisons to the conventional thermal conditions demonstrated the importance of the high temperatures and pressures achieved under microwave heating, which ensured that the reactions proceeded efficiently (Scheme 3.16)26. An analogous synthesis ofbenzoxazolesby the cyclocondensation reaction of 2-aminophenols with S-methylisothioamide hydroiodides on silica gel, under microwave irradiation, has also been reported (Scheme 3.16)27. 

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