Urea library

Dressman BA, Singh U, Kaldor SW. Solid phase synthesis of urea libraries using a diversifiable thiophenoxy carbonyl linker. Tetrahedron Lett 1998 39 3631-3634. 

For this library, we chose to use three types of isocyanates (neutral, electron rich, and electron deficient) to demonstrate the broad utility of the urea-formation reactions. Employing the above strategy and using the split-and-pool approach, we synthesized a 27-membered urea library with purities ranging from 95 to 99%. All the compounds prepared were characterized by 1FI NMR and mass spectroscopy. Acetonitrile can also be used as a substitute for DCM, but lower yields and product purities are generally observed. Attempts to use other protic solvents, such as isopropyl and ethyl alcohol, were unsuccessful. The best results were achieved when a chlorinated solvent (DCM) was used. The structure identity of all products was confirmed by 1FI NMR and MS spectroscopy. Expected molecular ions (M + Na+) were observed for all the products, and in all cases as the base peak. The compounds and yields are listed in Appendix 3.1. 

Scheme 2.33 Urea library generation and purification using polymer-sup-ported systems.

Dressman, B. A. Singh, U. Kaldor, S. W. Solid Phase Synthesis of Urea Libraries Using a Diversifiable Thiophenoxy Carbonyl Linker, Tetrahedron Lett. 1998, 39. 3631. 

The SP reaction scheme for the generation of a urea library is shown in Fig. 6.22. One percent of cross-linked PS resin was reacted with p-nitrobenzoyl chloride, and... 

Figure 6.22 SP automated chemistry assessment for the urea library L6 from Phoxime resin 6.53.

Figure 6.23 Gleneral structure of the SP urea library L6 and selected library individuals.

Scheme 6 Preparation of a single-step urea library 21 utilising a PASP scavenging step...

The virtual library consists of three sublibraries an amide, a sulfonamide, and a urea library. High-throughput parallel synthesis strategies for the subHbraries are given elsewhere [133]. The schematic set-up of the virtual library is shown in Fig. 24. Examples of building blocks are given in Fig. 25. 

The reaction was first tested with these substances as ligands but the organic molecule, in the absence of any added metal ion, proved to be the most enantioselective catalyst (library 1 19% ee vs. less than 13% ee for the best metal catalyst). The effects of selective variations of the amino acid nature and of the salicylidene moiety on the diamine structure were investigated for urea and thiourea derivatives via HTS (library 2 48 urea compounds and... 

With this set of five optimized reaction conditions in hand (Fig. 5.6), the production of a small DHPM library was performed. As a set of structurally diverse representative building blocks, 17 individual CH-acidic carbonyl compounds, 25 aldehydes, and 8 ureas/thioureas were chosen. Combination of all these building blocks would lead to a library of 3400 individual DHPMs. To demonstrate the practicability of the presented concept, a representative subset library of 48 DHPM analogues involving all of the aforementioned building blocks was generated [2],... 

In closely related work, similar solid-phase chemistry was employed by the same research group to prepare biaryl urea compound libraries by microwave-assisted Suzuki couplings followed by cleavage from the resin with amines (Scheme 7.47) [18]. The above described procedure enabled the generation of large biaryl urea compound libraries employing a simple domestic microwave oven. 

Scheme 5. A library of functionalized ureas synthesized using support-bound reagents and scavengers.

Using this methodology, a library of thousands of compounds could be synthesized by using 20 amino acids and a few hundred isocyanates (about 300 are commercially available). As a followup to this 27-membered library, we did a reductive alkylation with aminomethyl MicroTubes first. Then identical procedures were applied all the way through to provide ureas that have four inputs. We had made nine compounds based on this route, and in all cases 85% purity was achieved for each product. 

In summary, we have described an efficient and facile solid-phase synthesis of substituted ureas starting from aminomethyl MicroTubes. The synthesis takes place under mild conditions. Taking into account the commercial availability of primary amines, this strategy can be ideally used for the synthesis of large combinatorial libraries. 

The combinatorial library synthesis of a diverse set of trisubstituted ureas has been described [64]. The synthetic pathway involves the prehminary preparation of various nitrophenylcarbamates from commercially available nitrophenyl chlorofor-mate and a selection of amines allowing for wide scope in the divergence of the final urea products. In a further reaction of the nitrophenylcarbamates with a second amine, the urea was generated. Simultaneous addition of an electrophilic and basic scavenger resin removed all by-products, again allowing rapid isolation of the products in excellent yield and purity (Scheme 2.43). 

Scheme 2.43 Combinatorial library synthesis of trisubstituted ureas.

Scheme 2.58 The automated preparation of urea, amide and sulfonamide libraries.

The Biginelli reaction is a cyclocondensation between ethylacetoacetate, an arylal-dehyde and urea derivatives to obtain dihydropyrimidines. Transfer this reaction to the solid-phase chemistry, allow the preparation of libraries of this kind of products (Scheme 3.18) [288]. 

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