Studies on Protecting Group Controlled Regioselective Reactions Employing Batch or Flow Chemistry

Abstract

Six-membered N-heterocycles with an amide group, 2-pyridones are ubiquitous structures found in various bioactive compounds and pharmaceutical drugs. Especially, unsymmetrical 3,5-disubstituted 2-pyridones show antiepileptic, antiallergic, cardiotonic and inotropic activities. Thus, various synthetic methods for the synthesis of unsymmetrical 3,5-disubstituted-2-pyridones have been investigated. Nevertheless, because of their usefulness, new and efficient synthetic strategies have been required. With this consideration in mind, in this thesis, two new synthetic approaches to unsymmetrical 3,5-disubstituted-2-pyridones are reported. First, the regioselctive Suzuki-Miyaura reactions induced by a steric hindrance of 3,5-dibromo-2-(di-tert-butylisobutylsilyl)oxypyridine were studied. The reaction proceeds well under the conditions of 10 mol% of Pd(PPh3)4 and Cs2CO3 in 15:1 toluene/H2O at 100 °C. All reactions furnished the C5 arylated product as a major in yields ranging from 71 to 88% with good to excellent regioselectivity. In addition, to prove the practical convenience a one-pot synthesis of unsymmetrical 3,5-diaryl-2-pyridones was accomplished. Moreover, further functionalization of the remaining bromine group for the synthesis of biologically related unsymmetrical 3,5-disubstituted-2-pyridones was successfully carried out with providing C-C, C-N, C-CN or C-Si bond. Second, the regioselective halogen lithium exchange (HLE) using 3,5-dibromo-2-tosyloxypyridine was investigated. When the reaction was carried out under conventional batch conditions, the regioselectivity was poor providing about 1:1 mixture of 5-bromo-2-tosyloxypyridine and 3-bromo-2-tosyloxypyridine. However, when 3,5-dibromo-2-tosyloxypyridine was treated with n-BuLi under flow conditions with an inner diameter of M1 (Ø = 250 μm) and a flow rate X of 8.0 mL min-1 and a flow rate Y of 2.0 mL min-1 at -40 °C provided only the desired 5-bromo-2-tosyloxy pyridine with excellent selectivity. Furthermore, an integrated-flow microreactor system consisting of two micromixers employing an electrophile for the synthesis of the C3 substituted pyridine was developed. ;본 논문은 많은 천연물과 의약품에서 발견되는 골격인 아마이드 그룹을 포함하는 6각형 N-헤테로 사이클인 2-피리돈 합성을 다루고 있다. 특히, 2-피리돈 유도체 중에서 비대칭 3,5-이중치환 2-피리돈 구조는 심장 질환과 항 알레르기 활성을 갖는 많은 생리 활성 화합물에서 발견되고 있으며 이러한 이유로 현재까지 다양한 비대칭 3,5-이중치환 2-피리돈 합성을 위한 일반적이고 효율적인 합성법의 개발은 상당히 흥미로운 주제로 다루어 지고 있다. 본 논문에서는 일괄 화학과 플로우 화학을 이용하여 비대칭 3,5-이중치환 2-피리돈 유도체 합성을 위한 새로운 두가지 접근법을 제시하고 있다. 첫 번째는 실릴 그룹 중 하나인 다이-터트-뷰틸아이소뷰틸실릴 그룹의 입체 효과를 이용하여 위치 선택적 스즈키-미야우라 커플링 반응을 시도하였다. 두 번째는 토실 그룹의 킬레이트 효과를 극대화할 수 있는 플로우 화학을 활용하여 위치 선택적으로 할로겐/리튬 교환 반응을 이용하여 비대칭 이중치환 피리돈 유도체를 위한 중간체를 합성하였다. 최종적으로 남아있는 브로민 그룹에 다양한 결합 형성 반응을 진행하고 보호기를 제거함으로 최종 타겟 물질인 비대칭 3,5-이중치환 2-피리돈 유도체를 합성할 수 있는 일반적이고 효과적인 방법을 제시하였다.