Dicarbonyl solid-phase-bound

Today, multi-parallel synthesis lies at the forefront of organic and medicinal chemistry, and plays a major role in lead discovery and lead optimization programs in the pharmaceutical industry. The first solid-phase domino reactions were developed by Tietze and coworkers [6] using a domino Knoevenagel/hetero-Diels-Alder and a domino Knoevenagel/ene protocol. Reaction of solid-phase bound 1,3-dicarbonyl compounds such as 10-22 with aldehydes and enol ethers in the presence of piperidinium acetate led to the 1-oxa-1,3-butadiene 10-23, which underwent an intermolecular hetero-Diels-Alder reaction with the enol ethers to give the resin-bound products 10-24. Solvolysis with NaOMe afforded the desired dihydro-pyranes, 10-25 with over 90 % purity. Ene reactions have also been performed in a similar manner [7]. 

As the first multi-component domino reaction on solid phase the above mentioned domino-Knoevenagel-hetero-Diels-Alder reaction was performed using a 1,3-dicarbonyl compound bound to a modified Merrifield resin.171... 

Despite all of the activity in pyrimidine-based synthesis, only one study has emerged of solid-phase versions of these reactions <2003TL1267, 20030BC1909>. This chemistry was based upon condensation of dicarbonyl compounds with resin-bound pyrimidine-5,6-diamines through a 2-alkylthio link and oxidative cleavage as described in Section 10.18.7.2. The value of alkylthio substituents in the synthesis of complex substituted pterins has also been demonstrated in the synthesis of nucleic acid conjugates <2004OBC3588> (see Section 10.18.12.4). 

A long-established method to prepare pyridazines is the condensation of 1,4-dicarbonyl compounds with hydrazine. For example, Lam and Lee used a solid-phase procedure to synthesize various substituted pyridazines <01CL274>. Sodium benzenesulfinate resin 112 was treated with a-bromoketones to produce resin-bound sulfones 113 in excellent yields. Further treatment with a second portion of a-bromoketone in base gave the immobilized diketones 114. Finally, a library of substituted pyridazines was prepared by condensation of these diketones with hydrazine to obtain the substituted pyridazines 115 which are released from the resin by elimination driven by aromatization. 

Thiophenes are generally obtained by sulfuration of 1,4-dicarbonyl compounds (Paal s)mthesis). The preparation of the highly substituted 2-(4-bromophenyl)-5-(3,4-dimethoxyphenyl)-3,4-dimethylthiophene from the respective 1,4-diketone represents a recent example. This type of reaction can be performed as a solid-phase synthesis with polymer-bound diketones (132) and LR (eq 44). Trifluoroacetic acid releases the thiophene (133) from the solid support. Bismuth triflate in 1,3-dialkylimida-zolium fluoroborate has been utilized as a catalytic ionic liquid system for the synthesis of thiophenes from 1,4-diketones and LR with significantly improved yields. 

Sodium benzenesulfinate resin 43 can also be used to prepare a traceless solid-phase synthesis for 3,4-dihydropyrimidine-2-ones 54 and 55 (Scheme 12.13). This strategy highlighted the sulfinate acidification to yield resin-bound benzenesulfinic acid 52, followed by the condensation of urea or thiourea with aldehydes and sulfinic acid. A one-pot cyclization-dehydration process with 1,3-dicarbonyl compounds or )8-ketoesters (generated in situ by treating the latter reagents with KOH/EtOH) afforded 54, while cyclization with a mixture of pyrrolidine and /8-ketoacid in ethanol followed by the addition of TsOH HaO gave the ester form of 55. When THF was used as a solvent, the free carboxylic acid form of 55 was obtained in comparable yields. 

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