Isonitrile synthesis, solid-phase

Launay, D., Booth, S., Clemens, I., Merritt, A. and Bradley, M., Solid phase-mediated synthesis of isonitriles, Tetrahedron Lett., 2002, 43, 7201—7203. 

Scheme 7.24 Solid-phase mediated isonitrile synthesis under microwave irradiation.

To address the purification issue, which frequently is a bottle-neck in the fast microwave chemistry, a solid-phase catch and release methodology was utilized in a two-component, two-step synthesis of l-alkyl-4-imidazolecarboxylates [45]. In the first step, a collection of isonitriles 25 was immobilized onto a solid support by the reaction with the commercially available N-mclhyl aminomethylated polystyrene 26. Subsequent treatment with various amines brought about simultaneous derivatization and release of the desired imidazoles 27 back into solution. Significantly, only derivatized material was released from the resin, thus ensuring high purity of the desired product. Both steps of the reaction were substantially accelerated by microwave dielectric heating, resulting in the overall reaction time reduction from 60 hours to 70 minutes (Scheme 18). 

In related work, solid-phase-mediated synthesis of isonitriles from formamides was achieved by using polystyrene-bound sulfonyl chloride as a suitable supported reagent [115]. The sulfonyl chloride resin could be quantitatively regenerated by treatment of the sulfonic acid resin formed with phosphorus pentachloride (PCI5) in N,N-dimethy]formamide at room temperature. 

In an alternative synthesis, a two-step sequence involved an Ugi four-component reaction and an intramolecular nucleophilic aromatic substitution to provide rapid access to biaryl-ether-containing macrocycles in solution phase and solid phase (Figure 11.34). 55 Using isonitriles, aldehydes, amines, and carboxylic acids as inputs for the Ugi reaction, dipeptides 70 were formed. Upon cyclization of 70 with K2CO3 in DMF, macrocycles 71 with four points of diversity were obtained. Moreover, the presence of the nitro group allowed the introduction of further structural variation. In the solid-phase synthesis, the Ugi condensation used isonitriles attached to a Wang resin. 

Direct physicochemical analysis of synthetic affinity ligands is difficult when immobilized to the solid-phase bead (i.e., in situ). Solution-phase synthesis of lead compounds is often performed to allow characterization of the ligand by H-NMR, C-NMR, and mass spectrometry (MS) techniques (6, 10, 12, 14). We describe, herein, the synthesis of the solution-phase modified Ugi ligand, PpL-mimic (amine l-amino-2-naphthol carboxylic acid pentanoic acid isonitrile isopropyl isocyanide aldehyde acetaldehyde) (see Note 13). 

Polymeric reagents bearing an isocyanide group 1654 cannot be prepared easily. A patent application New functionalized polymeric reagents with an isonitrile moiety for solution and solid-phase synthesis details syntheses of such isocyanides 1654 from the corresponding formamides according to an Appel reaction with tiiphenylphos-phane/tetrachloromethane and triethylamine [1228]. 

In a notable exception, Yudin has described the use of amphoteric aldehydes (178) in an Ugi MCR with isonitriles and linear peptides (179) to prepare a series of modified peptidomimetie macrocycles (180) with ring sizes from 9 to 18 atoms (Scheme 11.24). These compounds, via nucleophilic attack on the aziridine, also can be employed as intermediates for further reactions and, hence, provide access to additional structural diversity suitable for library production. Towards this end, the sequence was successfully transferred to an automated mierofluidies platform. The process did not need to be performed under high dilution eonditions (0.2 M). More recently, this approach was applied sueeessfully to the synthesis of bityclic peptidomimetie derivatives, for example 181, in whieh macrocyclization and then disulfide formation were best eondueted in solution after the solid phase MCR to avoid side reaetions. ... 

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