臺灣博碩士論文加值系統

碘的親電性反應以及金屬氧化性反應在有機化學領域中都佔有相當重要的地位，在過去被廣泛應用於各類有機化合物的合成上。本篇論文將發展以碘的親電性或是以金屬氧化性反應合成苯并呋喃吖啶類(benzo[b]furo[4,3,2-mn]acridine)和苯并萘氮雜類(benzo[b]naphtho[2,3-f]azepine)醌類化合物，並對其結果作探討。
本篇論文主要分三個部分，前兩個部分是以碘配合不同鹼合成苯并呋喃吖啶類(benzo[b]furo[4,3,2-mn]acridine)和苯并萘氮雜類(benzo[b]naphtho[2,3-f]azepine)化合物，第三部分為利用金離子作為催化劑合成苯并萘氮雜類(benzo[b]naphtho[2,3-f]azepine)以及五元環化合物。

第一部份:
利用碘分子配合碳酸氫鈉(Sodium bicarbonate)進行親電性環合反應，將2-[(2’-苯乙炔基)苯胺基]-1,4-萘醌化合物83以及2-[(2’-乙炔基)苯胺基]-1,4-萘醌化合物89合成苯并萘氮雜類化合物91和化合物97。


 
第二部份
利用碘分子配合1,4-二氮雜二環[2.2.2]辛烷(1,4-Diazabicyclo[2.2.2]octane, DABCO)進行親電性環合反應，將2-[(2’-苯乙炔基)苯胺基]-1,4-萘醌化合物83合成苯并呋喃吖啶類化合物100，並伴隨副產物非環合碘化化合物101 。



第三部份
利用氯金酸鈉進行氧化性環合反應，將2-[(2’-苯乙炔基)苯胺基]-1,4-萘醌化合物83合成五元環化合物93或是將2-[(2’-苯乙炔基)苯胺基]-1,4-萘醌化合物89合成苯并萘氮雜類化合物115


關鍵字: 萘醌 ; 氮雜 ; 呋喃吖啶 ; 碘 ; 金

SUMMARY
Benzo[b]furo[4,3,2-mn]acridine and benzo[b]naphtho[2,3-f] azepine have been found possess broad biological activities, such as antifungal, antivirus and antitumor. Their skeleton has also been attracted considerable attention in many literature. Electrophilic reaction and metallic oxidative reaction were occupied an important position in organic chemistry. In the past decades, they have been widely used to synthesis of various types of organic compounds. This thesis will be developed two novel and efficient methods for synthesis of Benzo[b]furo[4,3,2-mn]acridine and benzo[b]naphtho[2,3-f] azepine base on electrophilic cyclization and metal oxidation. From the results, these two methods perform well in producing Benzo[b]furo[4,3,2-mn]acridine and benzo[b]naphtho[2,3-f] azepine. However, there were trace of byproduct in some of case.



Keyword: naphthoquinone; azepine; furo-acridine; iodine; gold catalyst

INTRODUCTION

Similar to dibenzoazepine compounds was first prepared in 1899 by the Thiele and Holzinge. However, dibenzoazepine derivatives have been published until fifty years later, most of the derivatives were used in drug-development. Here are reaport some well-known derivatives often come into contact with daily life. Carbamazepine was first synthesized in 1960 by Walter Schindler and it quickly put as first-line topical and systemic anti-epileptic drugs. Although carbamazepine could be effectively controlled for most of the symptoms, there were still some patients do not apply. To improve this situation, Oxcarbazepine replaced by Carbamazepine in 1990. Compare to Carbamazepine, Oxcarbazepine enhanced the tolerability profile, but still caused low sodium concentration in blood. In recent years, there were some new antiepileptic drugs BIA 2-024 and BIA 2-093 have been developed, both of them would avoid to further degradation of toxic metabolites produced by the human body but without loss in their therapeutic potency.

Acridines is raw material used for the production of dyes and some valuable. Due to the planar area of the tricyclic acridine nucleus being ideally suited to intercalation between nucleotide base pair in the helix, hence, acridines have impotant biological and medicinal activities such as antifungal, antivirus and antitumor. Many acridine derivatives such as acriflavine, unmethylated proflavine have been approved for the treatment of skin injuries as a topical antimicrobial effect.

Acridine base used for the long-term anti-bacterial, anti-cancer, anti-tumor drug development. In 2003, Cristian Dittrich mentioned that DACA and RHPS4 for inhibiting the growth of tumor cells were very well. Due to the topoisomerase responsible for cell transcription and replication, the mechanism of these drugs were inhibit to topoisomerase activity. By inhibiting topoisomerase indirectly inhibit the rapid growth of cancer cells is quitely effective.

Advantage of iodine compared to transition metal, have low toxicity, cheap, and mild reaction condition. Mechanism of iodine is the use of its Lewis acid structure with inorganic base or Lewis base to generated iodocation, iodocation has high activity to chelate double and triple bonds. Under this condition, it tend to addition and cyclization. Common sources of iodocation is from ICl, IOAc, NIS, etc., it also can use of I2 / NaHCO3, I2 / MeCN and I2 / pyridine indirect to produce iodocation.

Gold is a “soft” transition metal that shows high electrophilic affinity for alkynes, arenes, allenes, and even alkenes. It can also act simultaneously as a Lewis acid for the activation of electrophiles. Carbon–gold bonds are labile to protonolysis but undergo β-hydride elimination reactions only with difficulty. Reactions catalyzed by gold generally proceed under mild conditions and can be performed in the presence of water or even in pure water.


 
RESULTS AND DISCUSSION

This thesis is divided into three parts:
(1) The iodocyclization of 2-amino-1,4-naphthoquinones 83, 89 produce benzo[b]naphtho[2,3-f] azepine 91, 97 via iodine with sodium bicarbonate in high yield. Most of case accompany seven-membered ring compound except that substitutent R’is p-methoxyphenyl group. When substitutent R’ is p-methoxyphenyl group, the reaction also produce five-membered ring compound 93. If substitutent R is electro-withdrawing group such as chloro, fluoro, dichloro group, it would made compound deactivity, so that the yield of benzo[b]naphtho[2,3-f] azepine 91 has declined. The point that merits our particular attention, when substitutent R is 2,4-dimethyl group, the impact of steric effect also causes the yield of product 91to fall.

(2) The electrophilic cyclization of 2-amino-1,4-naphthoquinones 83 produce benzo[b]furo[4,3,2-mn]acridine 100 via iodine with 1,4-diazabicyclo[2.2.2]octane(DABCO)
in high yield. However, there were some non-cyclized byproduct 101 in thereac-tion. To our surprise, the reaction previous synthesis nine-membered ring comp-ound, finally close to form product 100 and release iodine in the same time.



(3) The oxdative cyclization of 2-amino-1,4-naphthoquinones 83 produce five-membered ring compound 93 in high yield even if the substituent on the triple bond is alkyl group. However, the yield of benzo[b]naphtho[2,3-f] azepine 115 is not well, the major hurdle for us to overcome is the conversion of reactant 89 is not up to standard.






CONCLUSION

In conclusion, we have successfully developed two novel and efficient methods for synthesis of benzo[b]furo[4,3,2-mn]acridine and benzo[b]naphtho[2,3-f] azepine base on electrophilic cyclization and metal oxidation. To the best of our knowledge, this is not only the first iodocyclization of 2-Amino-1,4-naphthoquinones giving benzo[b]naphtho[2,3-f] azepine but also a electrophilic of 2-Amino-1,4-naphthoquinones giving Benzo[b]furo[4,3,2-mn]acridine. Moreover, an iodine among the products provides an attractive and useful route to introduce new groups for the synthesis of new bioactive products. On the other hand, although, the reaction for synthesis of benzo[b]naphtho[2,3-f] azepine with gold catalyst is not well, it still has greater potential and value to research.

一、 前言 1
二、 研究背景與動機
第一節 合成苯并萘氮雜類化合物 6
第二節 合成苯并呋喃吖啶類化合物 9
第三節 碘的親電性反應 11
第四節 金(III)催化反應 14
三、 結果與討論
第一章 以碘的親電性反應合成苯并萘氮雜類化合物 17
第一節 2-碘基-苯胺類化合物的合成 19
第二節 2-胺基-二苯乙炔化合物的合成 21
第三節 2-胺基-苯乙炔化合物的合成合成 23
第四節 2-[(2’-苯乙炔基)苯胺基]-1,4-萘醌化合物的合成 26
第五節 2-[(2’-乙炔基)苯胺基]-1,4-萘醌化合物的合成 28
第六節 以碘合成苯并萘氮雜類化合物 31
第二章 以碘的親電性反應合成苯并呋喃吖啶類 38
第一節以碘的合成苯并呋喃吖啶類化合物 39
第三章 以金屬催化反應合成苯并萘氮雜類化合物 47
第一節以銅(II)催化反應合成苯并萘氮雜類化合物 47
第二節以金(III)催化2-[(2’-苯乙炔基)苯胺基]-1,4-萘醌化合物合
成苯并萘氮雜類化合物 50
第三節以金催化2-[(2’-苯乙炔基)苯胺基]-1,4-萘醌化合物合成五元環化合物 55
四、 實驗部分 59
(1) 2-胺基-二苯乙炔化合物71與1,4-萘醌化合物83的加成反應一般反應步驟: 60
(2) 2-[(2’-苯乙炔基)苯胺基]-1,4-萘醌化合物83、89與碘和碳酸氫鈉一般反應步驟: 64
(3) 2-[(2’-苯乙炔基)苯胺基]-1,4-萘醌化合物83 與碘和DABCO反應一般反應步驟: 75
(4) 2-[(2’-苯乙炔基)苯胺基]-1,4-萘醌化合物89a 與其他不同的銅(II)金屬催化劑進行反應一般步驟反應一般步驟: 85
(5) 2-[(2’-苯乙炔基)苯胺基]-1,4-萘醌化合物89a 與氯金酸鈉氧化性反應一般步驟: 86
(6) 2-[(2’-苯乙炔基)苯胺基]-1,4-萘醌化合物83a 與氯金酸鈉氧化性反應一般步驟: 90
參考文獻 93
1H、13CNMR光譜資料 96
表一　苯胺類化合物的碘化反應 19
表二　合成2-胺基-二苯乙炔化合物 21
　　 表三 合成2-胺基-三甲基矽苯乙炔化合物 23
表四 2-胺基-三甲基矽苯乙炔化合物去保護基反應 24
表五 合成2-[(2’-苯乙炔基)苯胺基]-1,4-萘醌化合物 26
表六 合成2-[(2’-乙炔基)苯胺基]-1,4-萘醌化合物 28
表七 合成2-[(2’-三甲基矽乙炔基)苯胺基]-1,4-萘醌化合物 29
表八 2-[(2’-三甲基矽乙炔基)苯胺基]-1,4-萘醌化合物去保護基反 30
　　 表九 2-[2’-(苯乙炔基)苯胺基]-1,4-萘醌化合物親電性反應 31
表十 合成12-苯-苯并萘氮雜類化合物 34
表十一 合成苯并萘氮雜類化合物 37
　　 表十二 2-[(2’-苯乙炔基)苯胺基]-1,4-萘醌化合物83i以碘分子配合不同的路易士鹼的結果探討 40
表十三 2-[(2’-苯乙炔基)苯胺基]-1,4-萘醌化合物83i以碘分子配合DABCO結果探討 41
表十四 合成苯并呋喃吖啶類化合物 43
表十五 鹽類對於合成苯并萘氮雜類化合物112的影響 48
　　 表十六 2-[(2’-乙炔基)苯胺基]-1,4-萘醌化合物的銅催化反應 49
表十七 2-[(2’-乙炔基)苯胺基]-1,4-萘醌化合物的金屬催化反應 51
表十八 以氯金酸鈉催化合成苯并萘氮雜類化合物 53
表十九 以氯化鈰(III)催化合成苯并萘氮雜類化合物 54
表二十 金屬催化2-[(2’-苯乙炔基)苯胺基]-1,4-萘醌化合物合成 55
表二十一 以金(III)催化合成五元環化合物 56
流程一　Diels−Alder反應合成苯并奈氮雜類化合物反應機構 8
　　 流程二　銅(II)催化7-氨基苯酞合成苯并呋喃吖啶類化合物反應機
　　　　　　 構 9
流程三　Multi-component Reactions合成苯并呋喃吖啶類化合物反
　　　　　　 應機構 10
　　 流程四 碘的參鍵環合反應基本步驟 12
　　 流程五 金催化反應的反應機構 15
流程六　2-[(2’-苯乙炔基)苯胺基]-1,4-萘醌化合物逆合成路徑 17
　　 流程七 2-[(2’-乙炔基)苯胺基]-1,4-萘醌化合物逆合成路徑 18
流程八　碘親電性芳香環取代反應的反應機構 20
流程九　2-碘基苯胺類化合物之Sonogashira coupling Reaction反應　
　　　　　　 機構 22
流程十 2-胺基-三甲基矽苯乙炔化合物去保護基反應機構 25
　　 流程十一　2-胺基-二苯乙炔化合物和1,4-萘醌化合物之1,4加成反
　　　　　　　 應機構 27

流程十二　以碘的親電性反應合成12-苯-苯并萘氮雜類化合物和五元環化合物之反應機構 36
流程十三　以碘的親電性反應合成苯并呋喃吖啶類化合物之反應機
　　　　　構 45
流程十四　非環合碘化反應的反應機構 46
流程十五　以金(III)合成苯并萘氮雜類化合物和五元環化合物之反
　　　　　應機構 57

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