An efficient preparation of 2-alkyl-oxazoles from 2-iodooxazoles

Abstract

a b s t r a c tAn efficient synthesis toward 2-alkyl substituted oxazoles has been achieved through Suzuki cross-coupling reaction. Treatment of various alkyl iodides with 9-MeO-BBN, followed by in situ palladium-catalyzed carbon-carbon formation with 2-iodooxazoles obtained the 2-alkyl substituted oxazoles in good to excellent yields. Regioselective C2-alkylation on 2,4-di-iodooxazole under the same reaction conditions was firstly disclosed.Ó 2013 Elsevier Ltd. All rights reserved.Oxazoles are widely distributed in natural products, and many of them possess significant biological activities including antifungal, cytotoxic, and anthelmintic properties.1 Oxazoles have also been utilized as important building blocks in organic syntheses and drug developments. 2,3 The potent biological activity and the prevalence of oxazoles in natural products and drug candidates have stimulated intensive interests in the synthesis of these heterocycles.2b,2d-gAs an important structural motif, 2-alkyl substituted oxazole ring has been found in many oxazole-containing natural products, including the phenoxan, 1g noricumazoles, 4 hennoxazoles, 1f and leiodolides A & B.1d Conventional synthesis of 2-alkyl oxazoles was conducted in multistep reaction, 2f,5 and to the best of our knowledge, direct alkylation at the C2 position is challenging and has very limited success to date. 6 Due to the structural significance in drug development, it has a strong demanding to explore new synthetic methodologies to access this highly functionalized heterocycles in a straightforward and efficient way. Herein, we wish to report our result for the synthesis of 2-alkyl-oxazole via Suzuki-Miyaura cross-coupling reaction between 2-iodooxazoles and alkylboronates.In our efforts toward the total synthesis of leiodolides (Fig. 1), showing potential cytotoxicity against HCT-116 human colon carcinoma cells, 1d we have recently reported the stereoselective synthesis of the C22-C31 fragment of leiodolide A employing a diastereoselective Seebach alkylation and a Brown's P2-Ni catalyzed cis-alkyne semihydrogenation in the presence of a vinyl iodide. 7 To build fragments C1-C17 of leiodolide A, we eagerly required a method for the facile assembly of this densely functionalized 2-alkyl-substitution oxazole derivative, exemption from multistep construction of the oxazole ring. The exploration started from a direct alkylation on oxazole C-2 position through C-2 lithiation and a subsequent quenching with an electrophile, using ethyl oxazole-4-carboxylate (3) and iodomethane (4) as the testing system. Treatment of 3 with lithium base (LiHMDS or t-BuLi) in anhydrous THF, with or without 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), resulted in the recovery of major starting materials. In order to exclude the electron-withdrawing effect of carboxylate at C4-position, TBS group protected substrate 4-(tert-butyl-dimethylsilyloxy)methyloxazole (5) was applied, unfortunately, no desired product was observed. Attempted C-2 alkylation on oxazole through lithium-h...

Chemical and electrochemical synthesis of cobalt hydroxides: selective phase transformation and application to distinct electrocatalytic reactions

“…Recently, cobalt(II) hydroxide (Co(OH) 2 ) and cobalt(III) oxyhydroxide (CoOOH) have attracted signicant interest as alternative electrocatalysts for the OER because of their activity and stability in alkaline solutions. 10,[19][20][21][22][23] Because the catalytic activity of these cobalt hydroxides depends on the crystal structure and intercalated ions, detailed structural analysis is essential for the elucidation of reaction sites. Co(OH) 2 has two polymorphs: a and b-crystal structures.…”