Part I. New useful reagents utilizing 1-benzotriazolyl moiety
Benzotriazol-1-yl diethyl phosphate (BDP) was conveniently prepared in high yield by the reaction of diethyl chlorophosphate with 1-hydroxybenzotriazole. Various amides were obtained in high yields by simple mixing of carboxylic acid, amine, BDP, and triethylamine in various solvents in high yields. The reaction was complete within 20 min in N,N'-dimethylformamide at room temperature and the corresponding amides were obtained in high yields. It was found that practically no racemization was observed using N,N'-dimethylformamide as a solvent during the supersensitive Young test. Furthermore, various peptides were prepared in high yields without racemization using BDP as a peptide coupling agent. Various esters and thioesters were also prepared by simple mixing of carboxylic acid, an alcohol or a thiol, BDP, triethylamine. But BDP was not effective for the β-lactam formation from -amino acid and the success of the reaction might depend critically on the structure of β-amino acids. Similarly, benzotriazol-1-yl diphenyl phosphate and polymer-supported benzotriazol-1-yl diethyl phosphate were prepared under similar conditions to BDP. Those reagents were used for the preparation of amides, or peptides, or β-lactams.
1,1'-(thiocarbonyldioxy)dibenzotriazole was prepared in high yield by the reaction of thiophosgene with 1-trimethylsilyloxybenzotriazole in methylene chloride. It is noteworthy that this reagent violently exploded at 114℃. The reaction of several amines with 1,1'-(thiocarbonyldioxy)dibenzotriazole and triethylamine occurred almost instantly at room temperature to give corresponding isothiocyanates in quantitative yields.
Part II. Synthetic application of amino-azomethine type bases
t-Butyldimethylsilylation; It is found that DBU is very effective and selective in the t-butyldimethyl-silylation of alcohols, under the present reaction conditions, it is expected that DBU forms complex with t-butyldimethylsilyl chloride which subsequently reacted with alcohols to give t-butyldimethylsilyl ethers.
Furthermore, in view of large steric requirements of the complex, it is also expected that high selectivity between primary alcohol and secondary alcohol can be achieved by the use of DBU as a catalyst. Application of 0.2 equiv of DBU in the presence of 1 equiv of triethylamine in several solvents at room temperature within 4 h resulted in clean silylation of primary and secondary alcohols. However, it failed to silylate tertiary alcohols. Furthermore, we have found that the use of TMG as a catalyst is exceedingly effective in the t-butyldimethylsilylation of alcohols.
Benzoylation and tosylation; It is also found that amino-azomethine type bases such as DBU, TMG, 1,8-dizabicyclo[5,4,0]-6-isopropylundec-7-ene and 1,1,3,3,-tetraethyl-4-t-butylguanidine among the bases, 1,8-dizabicyclo [5,4,0]-6-isopropylundec-7-ene and 1,1,3,3,-tetraethyl-4-t-butylguanidine are easily prepared by the known method or application of similar reactions. It is found that the use of catalytic amounts of these bases is efficient and effective in the benzoylation and selective benzoylation of diols under mild conditions. Reaction of phenethanediol with equimolar of benzoic anhydride, triethylamine, and 0.1 equiv of DBU in methylene chloride at room temperature for 24 h gave a mixture of 86:9 of primary and secondary benzoates along with 5% of dibenzoate. Better selectivity was observed in the benzoylation of 1,3-diols. Furthermore, we have studied selective benzoylation with several important carbohydrate derivatives. The selectivity achieved was excellent. For instance, reaction of methyl 4,6-O-benzylidene-α-D-glucopyranoside with benzoic anhydride and triethylamine in the presence of 0.2 equiv of DBU afforded a 65:6 mixture of the 2-O-benzoate and the 3-O-benzoate along with 6% of dibenzoate.
Furthermore, other amino-azomethine type bases and 1-(benzoyloxy)benzotriazole were effective in the selective benzoylation of diols and carbohydrate derivatives similar to DBU. Among the those, 1-(benzoyloxy)benzotriazole is conveniently prepared in 85% yield by the reaction of benzoyl chloride and 1-hydroxybenzotriazole. Furthermore, in the selective tosylation of carbohydrate derivatives, DBU is more effective catalyst than pyridine.
Oxidation; 1-Methylimidazolium chlorochromate(MIC) was conveniently prepared by the addition of 1-methylimidazole into chromium trioxide of 6M aqueous hydrochloric acid solution in 86% yield as bright yellow crystalline solids. MIC is very useful for the oxidation of alcohols and oxidative cleavage of oximes and N,N'-dimethylhydrazones under mild conditions, and it will complement other similar oxidizing agents.
Part I. 1-벤조트리아졸릴기를 이용한 새로운 시약에 관한 연구
벤조트리아졸-릴-디에틸 포스페이트 ( BDP ) 는 1-벤조트리아졸과 디에틸 크로로포스페이트와의 반응으로 만들어지며, BDP를 이용하여 여러 아미드를 상온에서 DMF 용매하에서 카르복실산, 아민 BDP와 트리에틸아민을 간단히 섞어 높은 수율로 20분 이내에 만들어진다. 또한 단백질 합성에서 중요한 라세미화를 측정하기위한 young test 에 이어 DMF 용매에서 좋은 결과를 얻었다. 더불어 BDP를 이용하여 단백질 합성, 에서터 또는 티오에스터들도 간단히 섞어 쉽게 얻을 수 있으나 β-락탐은 구조에 따라 여러 결과가 나왔다.
비슷한 시약으로 벤조트리아졸-1-릴 디폐닐 포스페이트와 폴리머로 지지된 BDP도 BDP와 비슷한 방법으로 만들었다. 이들을 이용하여 아미드 또는 단백질 또는 β-락탐 합성에 이용하였다.
1,1’-(티오카르보닐디옥시)지벤조트라아졸은 티오포스겐과 1-트리메틸실릴=옥시벤조트리아졸과 반응하여 얻었다. 위 시약은 엷은 노란 고체이며 특히 114℃에서 격렬히 폭발한다. 그리고 트리에틸아민하에서 여러 아민들과 반응하여 높은 수율로 이소티오시안화물이 만들어진다.
Part II. 아미노-아조메틴 형태를 갖는 염기들의 합성에 응용
3차부틸디메틸실릴화반응; DBU를 이용하여 효과적이고 선택적으로 알콜의 3차부틸디메틸화반응에 이용하였다. 이는 DBU가 3차부틸디메틸실릴 염화물과 착물을 형성한 다음 알콜과 반응하여 실릴 에테르가 된다. 또한 형성된 큰 입체 장애를 이용하여 촉매로 사용하여 1차와 2차 알콜과의 높은 선택성을 얻었다.
예로서 여러 용매하에서 0.2당량의 DBU와 트리에틸아민하에서 짧은 시간에 1차 및 2차 알콜이 실릴화되었다. 그러나 3차 알콜의 실릴화 반응은 실패했다.
TMG를 촉매로 이용한 3차부틸디메틸실릴화반응도 좋은 결과를 얻었다.
벤질화 및 토실화반응; DBU,TMG,6-이소프로필-DBU,1,1,3,3,-테트 라에틸-4-3차부틸구아니딘 등 여러 아미노-아조메틴 형태 염기들을 이용하여 효과적이고 선택적인 벤질화반응에 응용하였다.
페닐에탄디올을 0.1당량 DBU를 사용하여 86:9의 비율로 1차 및 2차 벤조화물을 얻었으며 5%의 디벤조화물도 함께 얻었다.
1,3-디올에서는 좀 더 좋은 선택성을 얻었다. 이러한 선택성 벤질화반응을 탄수화물 유도체에도 적용시켜 좋은 결과를 얻었다. 또한 그외 다른 염기및 1(벤조일옥시) 벤조트리아졸을 사용하여 디올 및 탄수화물 유도체의 선택성 벤조화반응에 응용하였다.
또한 DBU를 촉매로 사용하여 알콜의 토실화반응에 사용하였다. 피리딘에 비해 오직 한쪽만 토실화된 화합물만 얻었다.
산화반응; 1-메틸이미다졸리움 크로로크로메이트(MIC)는 6물의 염산과 크롬삼산화물의 수용액에 1메틸이미다졸을 부가하여 만들며 노란 결정체이다. MIC는 여러 알콜들의 산화와 옥심과N,N'-디메틸히드라존들을 순한 조건에서 산화성 절단에 이용하였다.
