4-Bromo-3-fmoc-aminophenyl ether attached to 4-hydroxymethylphenoxyacetic acid linker on PEG-resin (85) was suspended in 20 % piperidine in DMF and vortexed for 30 min. The resin was washed sequentially with DMF and DCM and treated with the acid chloride (5 equiv.) together with pyridine (7 equiv.) in DCM for 32 h.The resin 86 was washed sequentially with DMF, /-PrOH, and DCM and then slurried in DMF A solution of lithium ben-zyloxazolidinone (15 equiv.) inTHF was added to the reaction mixture. The reaction was vortexed at rt for 1 h followed by addition of the allylic halide (30 equiv.). After 6 h of vor-texing, the alkylation procedure was repeated.The resin 87 was rinsed sequentially with DMF, /'-PrOH, and DCM. Then Pd(Ph3)4 (0.5 equiv.), PPh3 (2 equiv.), NEt3 (13 equiv.), and DMA were added to the derivatized resin.The reaction tube was evacuated, sealed under N2, and heated at 85-90° C for 5 h.This procedure was repeated.The resin was then rinsed with DMF, and with a solution of Et2NCS2Na-3 H20 in DMF (0.2 M).The resin was washed sequentially with DMF, /'-PrOH, and DCM. Cleavage with 95 % (v:v)TFA in H20 for 3 h provided the indole analogs 88. An analytically pure sample is obtained by flash chromatography.
The quinazoline moiety is present in a variety of biologically active compounds known to interact with G-protein-coupled receptors and enzymes [111-115]. Quinazolines are often used as tyrosine kinase inhibitors . In general, the quinazoline template is synthesized starting from polymer-bound anthranilic acids. After diversity generation, the template is normally cleaved by a cyclative release mechanism; this cleavage is directed by either amide or carbamate cyclization. In one reported example, the quinazoline synthesis by N-acylation of anthranilic acid derivatives with the chloroformate of hydroxymethylpolystyrene proceeds via coupling of the free acid group with a primary amine, followed by subsequent release by heating in DMF [116,117],
Syntheses based on a non-cyclative release mechanism have also been reported. Dialkyl quinazolinones were synthesized from an anthranilate immobilized on solid support through a ((4-hydroxymethyl)phenoxy)acetic acid, as depicted in Scheme 24. Although the carboxylic acid to be immobilized was not available commercially, it was readily obtained from 5-hy-droxyanthranilate via a three-step synthesis. Urea formation was either achieved by removal of the Fmoc group and subsequent addition of isocyanate, or by reaction of the anthranilate with 4-nitrophenylchloroformate, to afford a reactive carbamate that gave the urea upon reaction with a primary amine. Subsequent cyclization was achieved by treatment with ethano-lic KOH. Treatment of the product obtained (91) with lithium oxazolidinone followed by addition of an activated alkylating agent, e.g. alkyl iodides, benzylic or allylic bromides, provided di-alkyl quinazolines. Ultimately, the title products were detached from the support using 95 % TFA. Quinazolines bearing alkyl, alkenyl, haloaryl, alkylaryl and heteroaryl substituents on both nitrogen atoms were prepared from isocyanates or primary amines and alkyl halides. The syntheses proceeded in high overall yields (82-95 %; 15 examples) .
Was this article helpful?