Synthesis of Unsymmetrical 3,5ￚDiaryl Pyridones via SiteￚSelective Suzuki- Miyaura CrossￚCoupling Reaction

Abstract

2-Pyridone moiety is valuable in affording diverse bioactive natural products and medicinal compounds. Among the 2-pyridone derivatives, unsymmetrical 3,5-diaryl pyridone serve as synthons for compound with partial seizures activity. Thus, many different synthetic methods were have been developed in providing 2-pyridone up until now. Herein, the regioselective Suzuki-Miyaura cross coupling reaction was demonstrated with 3,5-dibromo pyridine utilizing silyl protecting group such as di-tertbutylisobutylsilyl (BIBS) group. Because of its bulkiness structure, this method suggested the regioselectivity in pyridine moiety through steric effect. Furthermore, ditert-butylisobutylsilyl (BIBS) group can removed easily for obtaining 2-pyridone derivatives. Therefore, regioselective Suzuki-Miyaura cross-coupling reactions was investigated for the synthesis of unsymmetrical 3,5-diaryl pyridine derivatives employing 3,5-dibromo-2-di-tert-butylisobutylsiloxy pyridines with phenylboronic acids and pinacol phenylboronate. Furthermore, one-pot synthesis of unsymmetrical 3,5- diaryl pyridines and the 3,5-diaryl pyridone have been investigated.;2-pyridone은 다양한 치료제, 약물 및 약학 화합물에서 중요한 전구체로 여겨지고 있다. 특히, unsymmetrical 3,5-diaryl pyridine 은 약학분야에서 Perampanel 과 같은 예시의 약학 화합물로 응용되어지고 있다. 그러므로 이 중요한 물질을 합성하기 위해 많은 연구가 보고되어져 왔다. 하지만 지금까지 보고된 연구에서는 unsymmetrical 한 합성을 위해 chemoselectivve Suzuki-Miyaura cross coupling 반응과 많은 step 그리고 긴 시간이 필요했다. 따라서 step 을 줄이기 위해 unsymmetrical 한 3,5diaryl pyridone 을 위한 새로운 합성 방법이 필요해졌다. 이 논문은 3,5-dibromo-2-hydroxypyridine 에 di-tert-butylisobutylsilyl(BIBS)라는 큰 protecting group 을 이용하여 steric effect 를 통한 regioselective Suzuki-Miyaura cross coupling 반응을 시도하였다. 또한, unsymmetrical 한 3,5- diaryl-2-di-tert-butylisobutylsilyloxypyridine derivatives 를 boronic acid 와 Pinacol boronate 를 이용해 높은 수율과 선택성을 가지는 새로운 효과적인 방법을 제시하였다. 특히, 위의 방법을 통해 효과적인 One Pot 반응과 deprotection 반응을 통해 unsymmetrical 한 3,5-diaryl-2-pyridone 합성을 효과적인 수율로 얻었다.