Urea library reactions

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. 

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... 

For the construction of a pilot library, we chose R and R groups as the diversity points on tetrahydro-p-carboiine alkaloid core skeleton 22. The R position was diversified by urea formation reaction using eight commercially available isocyanates. The R position was diversified through the amide coupling of 12 Fmoc-protected natural and unnatural amino acids for the synthesis of pilot Ubrary (Scheme 5.4). With these building blocks, an array of 96 compounds was synthesized in excellent purities through solid-phase parallel synthesis platform. 

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],... 

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). 

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]. 

Figure 6.12 Polystyrene-bound Schiff base (thio)urea catalysts HTS-optimized in the asymmetric Strecker reaction between N-allyl-protected benzaldimine and TBSCN key results obtained from the different libraries.

The criteria for an efficient work-up are understandably different for discovery processes and cost-effective large-scale processes. The procedure in Scheme 2.8 provides an efficient, practical route to unsymmetrical ureas (e.g., 30). Volatilizing the acetone byproduct drives the reaction to completion and minimizes the formation of the S5mmetri-cal urea b)q)roducts (Gallou et al., 2005). Simply evaporating the free V-methyl p5rroli-dine and solvent afforded the products, with purities acceptable for assembling libraries of compounds. 

Since the experimental conditions for the traditional Biginelli reaction are quite straightforward, small libraries of DHPMs are readily accessible by parallel synthesis. Along these lines the generation of a 140-member single compound DHPM library by combination of 25 aldehydes, 6 ureas/thioureas, and 7 acetoacetates or acetoamides under standard reaction conditions has been reported [123, 124]. More rapid approaches make use of microwave-enhanced solution-phase protocols [88, 89, 125]. Apart from these conventional solution-phase methods, it is also possible to employ polymer-supported reagents to aid in the purification and workup protocol. Polymer-assisted solution-phase chemistry using polymer-supported... 

Two complementary procedures have been developed for alkylation of secondary amines [11] - both of which involve the use an excess of amine to drive the reaction to completion. The remaining amine was removed from the required tertiary amine using a polymer supported isocyanate 5 as a nucleophilic scavenger (under thermodynamic control) (Table 1 entry 2). The use of this amine scavenger has subsequently been applied in the purification of urea-based libraries prepared by solid-phase organic synthesis [12],... 

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