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.

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