베일리스-힐만 부가생성물로부터 질소함유 오각형 헤테로고리 화합물의 합성 = Synthesis of nitrogen-containing five-membered heterocycles from Baylis-Hillman adducts

국문 초록 (Abstract)

본 논문에서는 Baylis-Hillman adducts로부터 질소함유 오각형 헤테로고리 화합물의 합성에 관하여 연구하였다. 질소를 함유한 화학종을 Baylis-Hillman adducts의 일차 위치 (primary position)에 도입한 후 형성된 중간체의 다양한 화학적 변환을 통하여 다음과 같은 헤테로고리 화합물들을 합성할 수 있었다.
첫째로 우리는 Baylis-Hillman adducts를 출발물질로 하여 2-benzylidene-7a-alkyltetrahydropyrrolizine-3,5-dione 유도체를 다음과 같은 일련의 단계를 거쳐 합성하였다. 먼저 Baylis-Hillman adducts의 일차 위치 (primary position)에 nitroalkane을 도입한 다음, 연속해서 Michael addition과 reductive cyclization 그리고 최종적으로 lactam고리 형성을 통하여 최종 생성물인 2-benzylidene-7a-alkyltetrahydropyrrolizine-3,5-dione 유도체를 얻을 수 있다.
다중 치환된 pyrrole 유도체는 phenacyl bromide와 aza-Baylis-Hillman adducts 또는 rearranged aza-Baylis-Hillman adducts의 반응을 통하여 합성하였다. 즉, aza-Baylis-Hillman adducts와 phenacyl bromide의 N-alkylation 후, 연속적인 Michael addition과 p-toluenesulfinic acid의 제거, oxidative aromatization 과정을 거쳐 합성할 수 있었다.
변형된 Baylis-Hillman adducts의 radical cyclization을 통해서 N-tosyl-3,3-disubstituted-4-vinylpyrrolidine 유도체를 합성하였다. 여기에서 이용된 출발물질은 Baylis-Hillman adducts의 일차 위치 (primary position)에 tosylamide를 도입한 다음 1,4-dibromo-2-butene과의 alkylation을 통해 합성하였다.
마지막으로 indole 골격을 함유한 Baylis-Hillman adducts로부터 Pd-mediated arylation을 통해 7H-benzo[3,4]azepino[1,2-a]indole-6-carbox-ylic acid 유도체를 합성하였다. 즉, Baylis-Hillman acetate와 indole의 반응 (KOH/DMF/0 ℃)을 통하여 형성된 출발물질을 Pd-mediated arylation의 반응 (Pd(OAc)2/TBAB/K2CO3/DMF/100 ℃)을 시키면 비교적 괜찮은 수율로 7H-benzo[3,4]azepino[1,2-a]indole-6-carboxylic acid 유도체를 합성할 수 있었다.
이와 같이 본 논문에서는 Baylis-Hillman adducts로부터 2-benzylidene-7a-alkyltetrahydropyrrolizine-3,5-dione 유도체와 다중 치환된 pyrrole 유도체, 그리고 N-tosyl-3,3-disubstituted-4-vinylpyrrolidine 유도체의 효과적인 합성법에 대하여 연구하였다.

다국어 초록 (Multilingual Abstract)

Synthesis of nitrogen-containing five-membered heter℃yclic compounds from Baylis-Hillman adducts was studied in this thesis. Introduction of nitrogen atom-containing moiety at the primary position of Baylis-Hillman adducts and the following manipulation of the intermediates gave the desired heter℃yclic compounds.
Various 2-benzylidene-7a-alkyltetrahydropyrrolizine-3,5-diones were synthesized from Baylis-Hillman adducts via the sequential introduction of primary nitroalkane at the primary position of Baylis-Hillman adduct, Michael addition, reductive cyclization, and the following lactam ring construction strategy.
Poly-substituted pyrrole derivatives were synthesized from the reaction of phenacyl bromide and the aza-Baylis-Hillman adducts or their rearranged derivatives. The pyrroles were prepared via the successive N-alkylation, Michael addition, elimination of p-toluenesulfinic acid and oxidative aromatization pr℃essed.
N-Tosyl-3,3-disubstituted-4-vinylpyrrolidine derivatives were synthesized via radical cyclization from the modified Baylis-Hillman adducts. The required starting materials were prepared in moderate yields from the Baylis-Hillman adducts via the sequential introduction of tosylamide at the primary position of the Baylis-Hillman adducts, alkylation with 1,4-dibromo-2-butene.
7H-benzo[3,4]azepino[1,2-a]indole-6-carboxylic acid derivatives were synthesize via the Pd-mediated arylation of indole moiety-containing Baylis-Hillman adducts. The reaction of Baylis-Hillman acetate and indole (KOH/DMF/0 ℃) produced the required starting material, which was transformed to 7H-benzo[3,4]azepino[1,2-a]indole-6-carboxylic acid derivatives under Pd-mediated arylation conditions (Pd(OAc)2/TBAB/K2CO3/ DMF/100 ℃) in moderate yield.
In summary, we examined the synthesis of nitrogen atom-containing five-membered heter℃yclic compounds starting from the Baylis-Hillman adducts. As a result we developed four efficient synthetic pr℃edures for the preparation of 2-benzylidene-7a-alkyltetrahydropyrrolizine- 3,5-diones, poly-substituted pyrrole derivatives, N-tosyl-3,3-disubstituted- 4-vinylpyrrolidine derivatives, and 7H-benzo[3,4]azepino[1,2-a]- indole-6-carboxylic acid derivatives.

목차 (Table of Contents)

• 국문초록 = 1
• Ⅰ. 서론 = 3
• Ⅰ-1. Baylis-Hillman reaction = 3
• Ⅰ-2. Synthesis of nitrogen-containing heterocycles = 13
• Ⅰ-2-1. Synthesis of alkyltetrahydropyrrolizine-3,5-dione derivatives = 13
• Ⅰ-2-2. Synthesis of poly-substituted pyrrole derivatives = 16
• Ⅰ-2-3. Synthesis of pyrrolidine derivatives = 24
• Ⅰ-3. Radical cyclization = 28
• Ⅰ-3-1. Radical cyclization starting from Baylis-Hillman adducts = 28
• Ⅰ-3-2. Radical cyclization involving allyl radical = 36
• Ⅰ-4. Pd-mediated reaction = 38
• Ⅰ-4-1. Intramolecular aryl-indolyl bond formation = 38
• Ⅰ-4-2. Synthesis of 7- or 8-membered ring via Heck reaction = 43
• Ⅰ-4-3. Pd-mediated reaction starting from Baylis-Hillman adducts = 45
• Ⅱ. 결과 및 고찰 = 49
• Ⅱ-1. Baylis-Hillman adducts로부터 2-benzylidene-7a-alkyltetrahydropyrrolizine-3,5-dione 유도체 의 합성 = 49
• Ⅱ-2. Baylis-Hillman adducts로부터 다중 치환된 pyrrole 유도체의 합성 = 56
• Ⅱ-3. Radical cyclization을 통한 N-Tosyl-3,3,4-trisubstituted pyrrolidine 유도체의 합성 = 64
• Ⅱ-4. Indole moiety-containing Baylis-Hillman adducts로부터 Pd-mediated arylation을 통한 7H-Benzo[3,4]azepino[1,2-a]indole-6-carboxylic acid 유도체의 합성 = 72
• Ⅲ. 실험 = 78
• Ⅲ-1. 시약 및 기구 = 78
• Ⅲ-2. 2-Benzylidene-7a-alkyltetrahydropyrrolizine-3,5-dione 유도체의 합성 = 79
• Ⅲ-3. 다중 치환된 pyrrole 유도체의 합성 = 87
• Ⅲ-4. N-tosyl-3,3,4-trisubstituted pyrrolidine 유도체의 합성 = 95
• Ⅲ-5. 7H-benzo[3,4]azepino[1,2-a]indole-6-carboxylic acid 유도체의 합성 = 101
• Ⅳ. 결론 = 108
• Ⅴ. References = 109
• 영문초록 = 119
• Figure = 121
• Curriculum Vitae = 166
• 감사의 글 = 171