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Scheme 9

Procedure for the preparation of tosylimines

To 100 mL of toluene was added 52.4 mmol of the appropriate carboxaldehyde, p-tolue-nesulfonamide (7.47 g, 43.6 mmol) and p-toluenesulfonic acid monohydrate (1 g, 5.27 mmol).The reaction flask was fitted with a Dean-Stark trap and heated to 115° C for 16 h. Upon cooling to rt, the reaction was filtered, and the filtrate concentrated under vacuum. The concentrated filtrate was washed with ether and dried under vacuum to give the corresponding tosylimine.

Procedure: Imidazole synthesis on solid-support

ArgoGel™-MB-CHO resin (0.6 g, 0.246 mmol) was swollen in 1 % (v:v) HOAc in DMF (6 mL).To the reaction tube was added sodium triacetoxyborohydride (417 mg, 1.97 mmol, 8 equiv.).The reaction mixture was treated with the corresponding amino acid methyl ester (1.97 mmol, 8 equiv.), and the capped tube was agitated by shaking at rt for 12 h.The reaction mixture was then filtered and the resin was washed sequentially with DMF (3 x 10 mL), methanol (3 x 10 mL), and DCM (3x10 mL). A portion of the resin was then removed and checked by the dinitrophenylhydrazine test.This test indicates, by the absence of red coloured resin, that the reaction has gone to completion.The resin from the first step (400 mg, 0.164 mmol) was suspended in DCM (2 mL) and treated with DIEA (343 nL, 12 equiv.). The resin was then treated with the appropriate acid chloride (1.64 mmol, 10 equiv.). The reaction was agitated at rt for 12 h.The resin was then washed sequentially with DCM (5 x 10 mL), methanol (3 x 10 mL), and DMF (3 x 10 mL).The resin from step 2 was treated with a degassed solution of potassium hydroxide (92.0 mg, 1.64 mmol, 10 equiv.) in 3 mL of dioxane/water (v:v = 3:1). The reaction mixture was degassed with argon for 10 min, capped, and agitated at rt for 12 h.The resin was then washed sequentially with dioxane

(3x5 mL), water (3x5 mL), methanol (5 x 10 mL), DMF (5 x 10 mL), and DCM (5 x 10 mL). The resin 29 from step 3 (200 mg, 0.082 mmol) was suspended in 2 mL of DCM and treated with EDC (158 mg, 0.82 mmol, 10 equiv.). Subsequently, to the resin was added the appropriate tosylimine (0.82 mmol, 10 equiv.). The reaction was agitated at rt for 12 h.The resin was washed sequentially with DCM (5 x 10 mL), methanol (5 x 10 mL), DCM (5x5 mL), and ether (5 x 10 mL).The washed resin was dried under vacuum for 3 h and weighed.The resin 31 was then suspended in 3 mL of 9:1 (v:v)TFA/H20 for 30 min.The reaction was drained and the procedure repeated as above.The resin was then washed with acetic acid (3x5 mL) at rt. Finally, the resin was placed in a glass tube (13 x 100) and treated with glacial acetic acid (2.5 mL).The reaction was heated to 100° C for 2 h, cooled to rt and the reaction mixture filtered.The resin was washed with acetic acid (2x1 mL) and all the filtrates were collected in preweighed vials and concentrated under vacuum to give the final imidazole 32.

Imidazoles have also been prepared by a three-component or a four-component reaction in a one-pot procedure [51]. The structures of imidazoles obtained after cleavage from the resin with TFA/DCM are depicted in Fig. 1.

HOOC N HO

HOOC N N

Figure 1

The cyclic urea moiety provides structural rigidity as well as hydrogen bonding possibilities similar to that of the imidazoles described above. The corresponding 2-imidazolidones have been prepared on solid phase by tandem aminoacylation of a resin-bound allylic amine with an isocyanate, followed by intramolecular Michael addition [52]. However, due to the scarce data presented on characterized compounds and the brief experimental procedure, the synthesis is not discussed in detail. Likewise, we mention a patent application on cyclic urea derivatives [53],

3.4.7 Pyrazoles and Isoxazoles

Small heterocycles are viewed as an attractive means to display diverse chemical functionality in space through systematic combinatorial rearrangement of substituents.The limited size of the scaffold leaves little residual similarity among the various components of a library, while the substituents have a more prominent impact on the overall characterisics of a compound [9],The relatively low level of upfront structural bias is therefore suited for the design of large libraries for lead finding in multiple targets. To this end, practical combinatorial syntheses of pyrazoles and isoxazoles on solid phase have been envisaged early on. Initially, the isoxazole group was built into the side chains of peptoids. In this strategy isoxazoles were formed through [3+2] cycloaddition reaction of nitrile oxides with alkyne side chains of

N-substituted (oligo)glycines [54], The more versatile role as an actual diversity scaffold was introduced soon thereafter, and a scope and limitation study for a divergent combinatorial pathway, also giving access to pyrazoles, was reported [55], An example is described in Scheme 10 and in the following experimental procedure. In this diversity generation scheme, four sequential reaction steps were validated, including the loading of the support with an acetyl-bearing moiety, a Claisen condensation with esters, an a-alkylation, and a cyclization of a (3-diketone with monosubstituted hydrazines. The a-alkylation is a critical step, but generally works well under the conditions described, i.e. in the presence of TBAF. This reagent shields the oxygen atoms of the (3-dicarbonyl intermediate, thus inhibiting O-alkylation as a side reaction and furthermore increasing the nucleophilicity of the compound. The alkylation yield range is relatively wide, mostly depending on the structure of residues of the diketone intermediate. For this reason, in the construction of a complex library [56], this step was omitted, as it is not a prerequisite for the heterocycle formation. Furthermore, the cyclization kinetics of non-alkylated intermediates of type 35 is more rapid.

Similarly, the condensation of fi-dicarbonyl compounds with hydrazines was used for accessing pyrazolones [57,58], which have a long history of application in the pharmaceutical chemistry.

DMA, 90 °C, 1 h

Scheme 10

5% TFA In DCM cont. flow

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