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Thesis for Master Degree
Synthesis of homoisoflavonoids isolated from Portulaca oleracea L .
Advisor: Prof. Youngwan Seo
Jae Min Son
Department of Convergence Study on the Ocean Science and Technology
School of Ocean Science and Technology Korea Maritime and Ocean University
February. 2017
Contents
Page List of Tables --- ⅲ List of Figures --- ⅳ List of abbreviations --- ⅴ
Abstract --- ⅵ
1. Introduction --- 1
1.1. Homoisoflavonoids isolated of P. oleracea L. --- 1
1.2. Homoisoflavonoid --- 3
1.3. Synthetic pathway of homoisoflavonoids --- 5
1.3.1 Synthesis of homoisoflavonoids --- 5
1.3.2 Synthesis of chromanone --- 6
1.3.3 Protection of benzaldehyde with hydroxyl group --- 7
1.3.4 Synthesis of 3-benzylidene-4-chromanone --- 8
2. Laboratory instruments and reagents --- 9
2.1 Instruments --- 9
2.2 Reagents --- 10
3. Result and discussion --- 11
3.1 Synthetic study of 4-chrom anone --- 11
3.1.1 Synthetic Pathway A --- 11
3.1.2 Synthetic Pathway B --- 15
3.2. Synthetic study of 2-(ethoxymethoxy)-benzaldehyde --- 17
3.3 Synthetic study of 3-benzylidene-4-chromanone --- 19
4. Experimental section --- 23
4.1 Synthesis of 1-(6-hydroxy-2,3,4-trimethoxyphenyl)ethanone (2b) --- 24
4.2 Synthesis of 5,7-dimethoxy-4H-chromen-4-one (3a) --- 26
4.3. Synthesis of 5,6,7-trimethoxy-4H-chromen-4-one (3b) --- 28
4.4 Synthesis of 5,7-dimethoxy-4-chromanone (4a) --- 30
4.5 Synthesis of 5,6,7-trimethoxy-4-chromanone (4b) --- 32
4.6 Synthesis of 2-(ethoxymethoxy)-benzaldehyde (6) --- 34
4.7 Synthesis of 5,7-dimethoxy-3-(2-ethoxymethoxybenzylidene)-4-chromanone (7a) -- 36
4.8 Synthesis of 5,6,7-trimethoxy-(2-ethoxymethoxybenzylidene)-4-chroman one (7b) --- 38
4.9 Synthesis of 5,7-dimethoxy-3-(2-hydroxybenzylidene)-4-chromanone (8a) - 40 4.10 Synthesis of 5,6,7-trimethoxy-(2-hydroxybenzylidene)-4-chromanone (8b)- 42 4.11 Synthesis of 5,7-dimethoxy-3-(2-hydroxybenzyl)-4-chromanone (9a) ---- 44
4.12 Synthesis of 5,6,7-trimethoxy-3-(2-hydroxybenzyl)-4-chromanone (9b) -- 46
4.13 Synthesis of 5-hydroxy-7-methoxy-3-(2-hydroxybenzyl)-4-chromanone (9c) --- 48
4.14 Synthesis of 5-hydroxy-6,7-dimethoxy-3-(2-hydroxybenzyl)-4-chromanone (9d) --- 50
5. C o n c lu sio n --- 52
References --- 54
Appendix --- 58
Page
Table. 1. Synthesis of alkyl phenyl ethers --- 12
Table. 2. Synthesis of 4-chromanone --- 13
Table. 3. Protection of 2-hydroxybenzaldehyde --- 18
Table. 4. Synthesis of 3-benzylidene-4-chromanone --- 21
Table. 5. Chemical shift of 1-(6-hydroxy-2,3,4-trimethoxyphenyl) ethanone --- 25
Table. 6. Chemical shift of 5,7-dimethoxy-4H-chromen-4-one --- 27
Table. 7. Chemical shift of 5,6,7-trimethoxy-4H-chromen-4-one --- 29
Table. 8. Chemical shift of 5,7-dimethoxy-4-chromanone --- 31
Table. 9. Chemical shift of 5,6,7-trimethoxy-4-chromanone --- 33
Table. 10. Chemical shift of 2-(ethoxymethoxy)benzaldehyde --- 35
Table. 11. Chemical shift of 5,7-dimethoxy-3-(2-ethoxymethoxy benzylidene)-4-chromanone --- 37
Table. 12. Chemical shift of 5,6,7-trimethoxy-3-(2-ethoxymethoxy- benzylidene)-4-chromanone --- 39
Table. 13. Chemical shift of 5,7-dimethoxy-3-(2-hydroxybenzylidene)- 4-chromanone --- 41
Table. 14. Chemical shift of 5,6,7-trimethoxy-3-(2-hydroxybenzylidene) -4-chromanone --- 43
Table. 15. Chemical shift of 5,7-dimethoxy-3-(2-hydroxybenzyl) -4-chromanone --- 45
Table. 16. Chemical shift of 5,6,7-trimethoxy-3-(2-hydroxybenzyl)-4- chromanone --- 47
Table. 17. Chemical shift of 5-hydroxy-7-methoxy-3-(2-hydroxybenzyl) -4-chromanone --- 49
Table. 18. Chemical shift of 5-hydroxy-6,7-dimethoxy-3-(2-hydroxybenzyl)-4- chromanone --- 51
List of Tables
Page
Fig. 1. P. oleracea. L --- 1
Fig. 2. Homoisoflavonoids and chalcone isolated of P. oleracea L --- 1
Fig. 3. Structures of chromone, chromanone, homoisoflavonoid --- 3
Fig. 4. Various structures of Homoisoflavonoid --- 4
Fig. 5. Synthesis pathway of homoisoflavonoid --- 5
Fig. 6. Synthesis pathway of chromanone --- 6
Fig. 7. Protection of 2-hydroxybenzaldehyde --- 7
Fig. 8. Synthesis of 3-benzylidene-4-chromanone --- 8
Fig. 9. synthesis of 5,7-dimethoxy-4-chromanone --- 14
Fig. 10. Synthesis of 5,7-dimethoxy-4-chromanone, 5,6,7-trimethoxy-4-chromanone --- 16
Fig. 11. Mechanism --- 22
Fig. 12. Reagents and conditions --- 23
Fig. 13. 1H and 13C NMR spectrum of compound 2b in CDCl3 --- 58
Fig. 14. 1H and 13C NMR spectrum of compound 3a in CDCl3 --- 59
Fig. 15. 1H and 13C NMR spectrum of compound 3b in CDCl3 --- 60
Fig. 16. 1H and 13C NMR spectrum of compound 4a in CDCl3 ---61
Fig. 17. 1H and 13C NMR spectrum of compound 4b in CDCl3 --- 62
Fig. 18. 1H and 13C NMR spectrum of compound 6 in CDCl3 --- 63
Fig. 19. 1H and 13C NMR spectrum of compound 7a in CDCl3 --- 64
Fig. 20. 1H and 13C NMR spectrum of compound 8a in CDCl3 --- 65
Fig. 21. 1H and 13C NMR spectrum of compound 9a in CDCl3 --- 66
Fig. 22. 1H and 13C NMR spectrum of compound 9b in CDCl3 --- 67
Fig. 23. 1H and 13C NMR spectrum of compound 9c in CDCl3 --- 68
Fig. 24. 1H and 13C NMR spectrum of compound 9d in CDCl3 --- 69
Fig. 25. compounds 2-8 (a,b) --- 70
Fig. 26. compounds 9 (a-d) --- 71
List of Figures
BCl3 : Boron trichloride
BF3Et2O :Boron trifluoride diethyl etherate CDCl3 : deuteated chloroform
CH2Cl2 : dichloromethane (methylene chloride)
13C NMR : carbon 13 nuclear magnetic resonance DMF :N,N-dimethylformamide
EtOAc : ethyl acetate EtOH : ethanol Fig. : figure
1H NMR : proton nuclear magnetic resonance Hz : herz (sec-1)
LiAlH4 :Lithium aluminum hydride MeOH : methanol
t-BuOH : Tert-buthanol TFA : Trifluoroacetic acid TfOH : Triflic acid
THF : Tetrahydrofuran
TLC : thin layer chromatography
Triton B Benzyltrimethylammonium hydroxide
List of abbreviations
쇠비름에서 분리된 homoisoflavonoids의 합성
손 재 민
한국해양대학교 해양과학기술전문대학원 해양과학기술융합학과
요 약
Homoisoflavonoid는 16개의 탄소 골격으로 이루어진 구조이며, 두 개의 phenyl rings와 한 개의 heterocyclic ring로 구성되어 있다. 현재까지 110 가지 이상의 homoisoflavonoids 구조가 천연물로부터 분리 되었으 며, 항암, 항염증, 황반변성, 항바이러스, 항산화, 항 돌연변이, 혈관 보호 등의 다양한 생리 활성이 보고되었다. 최근 쇠비름으로부터 homoisoflavonoid 계열의 새로운 이차대사산물 5종과 homoisoflavonoid 의 전구체인 chalcone 계열의 화합물, 그 밖에 알려진 alkaloids 계열의 화합물 및 terpenoids 화합물이 분리되었다.
본 연구에서는 이중치환 및 삼중치환 된 페놀 유도체로부터 쇠비름에서 분리된 homoisoflavonoids 화합물 중 A-ring에 이중치환 및 삼중치환을 포함하는 4가지 화합물의 효율적인 합성 경로를 탐색하고자 하였다.
Homoisoflavonoids는 대표적으로 두 가지 과정으로 합성이 가능하다.
첫 번 째는 Chromanone 합성을 통해 benzyl aldehyde 와 반응시켜 합성 하는 과정이고, 두 번째는 homoisoflavonoids의 전구체인 dihydrochalcone 형태를 합성하여 B-ring을 형성하는 반응을 통해 합성 하는 과정이다. 두 번째 방법은 chromone 형태의 화합물을 합성하기에는
효과적이지만 다양한 형태의 homoisoflavonoids를 합성할 수 없는 한계 가 있기 때문에 3-benzylidene-4-chromanone 형성하여 isomer 인 E, Z 형을 합성할 수 있을 뿐만 아니라 hydrogenation 다양한 화합물을 얻을 수 있는 첫 번째 과정을 선택하여 실험하였다.
페놀유도체로부터 효율적으로 chromanone을 합성하기 위해서 치환된 페 놀과 Triton B를 촉매로 사용하여 acrylonitrile을 반응시켜 O-alkylation으로 사슬을 연결한 뒤, 고리를 형성하는 방법과 Freidel-Crafts 아실화 반응을 통해 사슬을 연결한 뒤, N,N-Dimethylformamide dimethyl acetal(DMF・DMA)과 반응시켜 고리를 연결한 후, 이중결합을 환원시키는 방법으로 실험을 진행하였다. 두 방 법 중 후자가 비교적 짧은 시간동안 80~90%의 높은 수득률로 chromanone 합성이 가능하여 합성 경로에 적용하였다.
3-Benzylidene-4-chromanone 형태를 합성하기 위해서 chromanone과 benzaldehyde가 사용된다. 본 연구에서는 목표 물질을 합성하기 위해 2-hydroxybenzaldehyde를 사용하였다. 2-Hydroxybenzaldehyde의 hydroxyl 기는 반응성이 높기 때문에 3-benzylidene-4-chromanone 형태를 합성을 저해할 수 있으므로 반응의 효율성을 높이기 위해 반응성이 적은 작용기 인 ethoxymethyl ether로 hydroxyl기를 protection 하였다.
또한 3-benzylidene-4-chromanone 형태를 합성하기 위해서 piperidine 을 촉매로 사용하여 aldol condensation 반응을 통해 합성이 가능하다.
그러나 aldol condensation 반응은 mechanism에 가역적 반응이 많기 때 문에 수득률이 10~20%로 매우 낮다. 반면에 반응을 위한 온도, 용매 및 반응순서를 조절하고, pyrrolidine을 촉매로 사용하였을 경우 Mannich- elimination 반응 과정을 통하여 합성이 가능하며 이 과정의 경우 가역 적 반응이 줄어들기 때문에 수득률이 50~60%로 상대적으로 높아 이 방법 을 응용하여 합성하였다.
위의 여러 합성 경로를 응용하여 5,7-dimethoxy-3-(2-hydroxybenzyl) chroman-4-one과 5,6,7-trimethoxy-3-(2-hydroxybenzyl)chroman-4-one을 합성하였고 각 화합물 A-ring의 ortho 위치에 있는 메톡시기를 demethylation을 통해 hydroxyl로 치환하여 5-hydroxy-7-methoxy-3- (2-hydroxybenzyl)-4-chromanone과 5-hydroxy-6,7-methoxy-3-(2-hydroxybenzyl)-4-chroma none을 효율적으로 합성하고자 하였다.
주제어: Chromanone; Pyrrolidine; Homoisoflavonoids; Portulaca oleracea
1. Introduction
1.1. Homoisoflavonoids isolated of P. oleracea L.
Potulaca oleracea Linne, which is an annual plant belonging to the family of Portulacacea, is widespread on temperate and tropical regions.
It has thinner leaves which are green and yellow, stems flushed red or purple, and roots colored white (Fig. 1).
According to ancient medicine books, P. oleracea L. is effective on hemostasis, enteritis, swelling, skin inflammation, swelling relief and diarrhea. (Lee 1999, Zhang 2009). In addition, it was reported to be effective on anti-inflammatory, anti-bacterial and anti-cancer as bioactives and used by anti-scurvy, antispasmodic, diuretic, insecticide and sedatives (Habtemariam et al. 1993; Lim & Kim 2001 ; Lee et al.
2003).
Chemical composition of P. oleracea L. was reported to be flavonoids, dopamine, courmarin, N-trans feruloyltyramine, alkaloids, terpenes, anthcyanins, glutamic acid, noradrenalin, β-carotene,γ-lenolenic acid and ω-3 fatty acid etc (Awad 1994; Adachi et al. 1983; Sakai et al.
1996; Mizutani et al. 1998; Strak et. al. 2003; Seo et al 2003; Elkahayat et al. 2008; Xiang et al. 2005; Liu et al. 2000; Xin et al 2008. Xing et al. 2008).
Recently, five new homoisoflavnoids and a chalcone, a precursor of homoisoflavonoid, were isolated from P. oleracea L.(Lee et al. 2012;
Yan et al. 2012) (Fig. 2).
Fig. 1. P. oleracea. L It is widely distributed in temperate and tropical regions.
Fig. 2. Homoisoflavonoids and chalcone isolated of P. oleracea L.
Fig. 3 Structures of chromone, chromanone, homoisoflavonoid
1.2 Homoisoflavonoid
Homoisoflavonoid is an oxygen heterocycle which has structure of C6-C3-C6. it has general chemical structure of a 16 carbon skeleton composed of two phenyl ring and heterocyclic ring. That is to say:
benzopyran (chromone or chromanone) and aromatic rings are connected to each other via one carbon (Shaikh et al 2011; Adinolfi et al. 1986).(Fig. 3)
Homoisoflavonoids were isolated from a variety of natural products such as Ophiopogon japonicus, Polygonatum odoratum and P. oleracea L. etc. (Nguyen et al. 2003; Zhou et al. 2015; Lee et al. 2012).
Structures of homoisoflavonoids isolated from these natural products are 3-benzyl-3-hydroxy-4-chromanone, 3-benzyl-4-chromanone, (E)-3-benzylidene-4- chromanone, (Z)-3-benzylidene-4-chromanone and scillascillin (Fig. 4). In general, these compounds are reported to show anticancer, anti-histaminic, antiviral, antimutagenic, antifungal, antioxidant, and anti-inflammatory
Fig. 4 Various structures of Homoisoflavonoid
effects (Biswanath et al. 2009; Desideri et al. 1996; Lee et al 2014;
Qunglia 1999).
In this study, it is aimed to synthesize homoisoflavonoids isolated from P. oleracea L.
Fig. 5 Synthetic pathway of homoisoflavonoids
1.3 Synthetic pathway of homoisoflavonoids
1.3.1 Synthesis of homoisoflavonoid
Homoisoflavonoid is generally possible to synthesize in two ways.
The first one (A route) is to combine chromanone ring with a substituted benzyl aldehyde by Claisen-Schmidt reaction. The second one (B route) is to form B-ring of homoisoflavonoid through a dihydrochalcone derivative (Fig. 5).
In this study, the former was preferred because it enabled us to obtain a variety of homoisoflavonoid derivatives.
Fig. 6 Synthesis pathway of chromanone
1.3.2 Synthesis of chromanone
Generally, chromanone is synthesized sequentially from phenolic compounds. Typically, there are two synthetic pathways.
What synthetic pathway is used depends on the type of starting material used. The first pathway is to form a chromanone ring from 3-phenoxypropanoic acid derivative obtained by O-alkylation of phenol.
The second pathway is to form a ring from o-hydroxyacetophenone derivative obtained by Friedel-Crafts acylation of phenol.
Fig. 7 Protection of 2-hydroxybenzaldehyde
1.3.3 Protection of 2-hydroxybenzaldehyde with hydroxyl group
In this study, 2-hydroxybenzaldehyde was used to synthesize homoisoflavonoid isolated from P. oleracea L. Hydroxy group is very reactive to many reagents. This is a disadvantage in synthesis of homoisoflavonoid. To avoid interference by hydroxy group, the hydroxy group of benzaldehyde was protected with chloromethyl ethyl ether.
Fig. 8 Synthesis of 3-benzylidene-4-chromanone
1.3.4 Synthesis of 3-benzylidene-4-chromanone
3-Benzylidene-4-chromanone can be synthesized by reacting variously substituted chromanone with benzaldehyde in the presence of a base catalyst or an acid catalyst. Aldol-condensation reaction occurs in synthesis process. Because this reaction is reversible, suitable reaction conditions are required to proceed the reaction towards the product.
Several trial or error attempts have been conducted to search for optimal conditions. Through these processes, it was possible to effectively synthesize homoisoflavonoids isolated from P. oleracea L.
2. Laboratory instruments and reagents 2.1 Instruments
This study was conducted using Varian NMR 300 spectrometer (varian Mercury 300, USA) for chemical structure analysis and rotary evaporator (EYELA, JAPAN) for concentration of reaction mixture. Thin layer chromatography (TLC) was performed on TLC silica gel 60 F254 plates.
2.2 Reagents
Reagents used for synthesis are 3,4,5-trimethoxyphenol (Sigma, USA), boron trifluoride diethyl etherate (Sigma, USA), 4′,6′-dimethoxy-2′
-hydroxy acetophenone (TCI, Japan), N,N-dimethylformamide dimethyl acetal (Sigma, USA), lithium aluminum hydride solution 1.0 M in tetrahydrofuran (THF, Sigma, USA), salicylaldehyde (Sigma, USA), chloromethyl ethyl ether (TCI, Japan), N,N-dimethylformamide (Sigma, USA), cesium carbonate (Sigma, USA), 2-hydroxybenzaldehyde, boron trichloride (Sigma, USA) and palladium on activated carbon (Sigma, USA). All solvents to column chromatography were Class 1 reagents and were distilled prior to use. CDCl3 (Cambridge Isotope Laboratories, Inc., USA, deuterium degree 99.8%) was used for NMR measurement.
3. Result and discussion
3.1 Synthetic study of 4-chrom anone
Chromanone synthesis is usually initiated using phenolic compounds as starting materials, and As already mentioned before there are two synthetic pathway, pathway A is to form a chromanone ring from 3-phenoxypropanoic acid derivative obtained by O-alkylation of phenol.
Pathway B is to form a ring from o-hydroxyacetophenone derivative obtained by Friedel-Crafts acylation of phenol (Fig 6). In this study, we will explore how to synthesize homoisoflvonoids from P. oleracea and to increase its yield.
3.1.1 Synthetic Pathway A
The whole process on the pathway A is shown in Table 1. Compounds 1a and 1b were reacted with NaH in DMF solution at 0℃ for 1h, and then reacted at room temperature for 16 h. As a result, 1'a (31%) and 1'b (37%) were obtained, respectively (Table 1, entry 1-2).
Compound 1'c was synthesized through Oxa-Michael addition reaction.
K2CO3 and t-BuOH was added to compound 1a in acrylonitrile and then refluxed for 8h at 80℃. After additionally adding K2CO3 and refluxing for 36h, 1'c was obtained in 53% yield (Table 1, entry 3).
Alkyl phenyl ethers are usually prepared by O-alkylation of phenols.
most of O-alkylation reactions need reactive electrophiles. In this study methyl-3-bromopropionate was used as electrophile. and Cs2CO3 was
Entry Reactant Base Reagent Solvent Temp.
(℃)
time (h)
Yield (%)
1 1a NaH 3-Bromopropi
onic acid DMF 0-rt 17 31
2 1b NaH 3-Bromopropi
onic acid DMF 0-rt 17 37
3 1a K2CO3
acrylonitrile/
t-BuOH acrylonitrile 80 44 53 4 1a Cs2CO3
Methyl-3-bro
mopropionate CH2Cl2 45 5 0 5 1a Cs2CO3
Methyl-3-bro
mopropionate DMF rt 5 0
6 1a Cs2CO3 Methyl-3-bro
mopropionate DMF rt 48 0
7 1a TritonB acrylonitrile acrylonitrile 80 20 67 8 1b TritonB acrylonitrile acrylonitrile 80 20 0 Table 1. Synthesis of Alkyl phenyl ethers
used as base catalyst. However no O-alkylation reaction occurred.
(table.1, entry 4-6).
Entry Reactant1 Reagent2 Solvent Temp.
(℃)
time (h)
Yield (%)
1 1'c TfOH TFA 0-rt 30 0%
2 1'c HCl HCl 170 4 4c
71%
Table.2 Synthesis of 4-chromanone
Compounds 1'c, 1'd was synthesized through Oxa-Michael addition reaction. Triton B was used instead of K2CO3. As a result, 1'c and 1'd were respectively obtained in 67% and 0% yield (Table 1,entry 7-8).
Through above experiments, we decided to conduct the experiment using the entry 7 method because it gave the highest yield in a short time. And further experiments were conducted to synthesize 5,7-dimethoxy-4-chromanone (Table 2).
Fig. 9. Synthesis of 5,7-dimethoxy-4-chromanone
We tried to synthesize 5,7-dimethoxy-4-chromanone via the TfOH-mediated Friedel–Crafts reaction (Table 2, entry 1). As a result no reaction occurred. So we attempted synthesis using hydrochloric acid at 170℃ for 4 h to obtain 4c (Table2, entry 2) followed by its O-alkylation to give 5,7-dimethoxy-4-chromanone (4a) (Fig. 9).
In pathway A (Fig 6), the best method to synthesize chromanone was to cyclize alkyl phenyl ether with hydrochloric acid after obtaining it using triton B (total yield 50%).
Through the above process, compounds 4a and 4c required for synthesis of homoisoflavonoids from P. oleracea L. were prepared.
3.1.2 Synthetic pathway B
The whole process on the pathway B is shown in the Fig. 10.
Compound 1 was reacted with acetic acid in boron trifluoride diethyl etherate at 85℃ for 7 h, to afford a high yield (93%) of the desired compound 2b by Friedel-Crafts acylation reaction (Dong et al 2016).
Compounds 2a and 2b were treated with N,N-dimethylformamide dimethyl acetal, followed by catalytic hydrogenation of the resulting 4-chromons to afford 4-chromanones. For hydrogenation, compounds 3a and 3b were reduced with LiAlH4 under nitrogen atmosphere at -60℃
for 5 min (Lee et al 2016).
In the above procedure, the total yield was more than 80%. Finally, it was decided to use the Pathway B because the yield was higher than the pathway A.
Fig. 10. Synthesis of 5,7-dimethoxy-chroman-4-one, 5,6,7-triimethoxy-chroman-4-one (ⅰ) BF3Et2O, CH3COOH, 85℃, 7 h, 93%
(ⅱ) N,N-dimethylforamide dimethyl acetal, toluene, 90℃, 20 h, 91%
(ⅲ) LiAlH4 solution 1.0 M in THF, THF, -60℃, 5 min, 95%
3.2. Synthetic study of 2-(ethoxymethoxy)-benzaldehyde
In this study, 2-hydroxybenzaldehyde was used to synthesize homoisoflavonoid isolated from P. oleracea L. Its hydroxy group was
protected as ethoxymethyl ether using chloromethyl ethyl ether as mentioned before. In this process, attempts have been made to find optimal reaction conditions to increase the yield of 2-ethoxymethoxybenzaldehyde.
As shown in Table 3, protection of 2-hydroxbenzaldehyde was performed by reaction of K2CO3, catalytic TBAI, and chloromethyl ethyl ether. This reaction was carried out at 0℃ for 1 hour and then at room temperature overnight. The 81% yield was obtained (Table 3, entry 1).
However, alkylation of phenyl with cesium carbonate instead of potassium carbonate gave 2-ethoxymethoxybenzaldehyde in higher yield than the above procedure. Therefore, this reaction was carried out using Cs2CO3 and chloromethyl ethyl ether (Table 3, entry 2). The reaction conditions are the same as above. As a result, we decided to use entry 2.
Entry Reactant Base Reagent Solvent Temp.
(℃)
time (h)
Yield (%)
1 5 K2CO3
C h l o r o m e t h y l ethyl ether
/ TBAI
Acetone 0-rt 24 81
2 5 Cs2CO3
C h l o r o m e t h y l
ethyl ether DMF 0-rt 24 95
Table.3 Protection of 2-hydroxybenzaldehyde
3.3 Synthetic study of 3-benzylidene-4-chromanone
In the beginning we tried to get the optimal conditions for the aldol condensation. Compounds 4a and 6 were reacted in piperidine at 80℃
for 2h, however the reactants was decomposed under reaction condition (Table 4, entry 1). Therfore, we decided to use a solvent for a stable reaction such as THF and 1,4-dioxane. In this process, the reaction mixture was refluxed increasing up to 110℃ for more extended reaction time using THF as the solvent. However, the yield was low and the reactant was partially destroyed (Table 4, entry 2-5).
1,4-Dioxane was used as the solvent under similar reaction conditions (Table 4, entry 6-9). In this process, the reactant was not destroyed, but the yield was still low. So we tried other base catalysts. Compound 4a was reacted with compound 6 in EtOH in presence of LiOH·H2O at room temperature for 4 h and try to reflux at 80℃ for 4h (Table 4, entry 11-12). However no reaction occurred.
Since all of the above trials were not successful, we decided to use another reaction, not aldol-condensation reaction.
First, we tried Claisen-Schmidt condensation reaction because it was possible to produce α,β-unsaturated ketone by using this reaction.
Compound 4a in DMSO was added to t-BuOK as a base catalyst. And this reaction mixture was stirred at 0℃ for 3 h, which was not successful.
Next we tried Mannich-elimination sequence. Because it was less reversible reaction than the aldol-condensation reaction (Fig. 11) (Gu et al. 2014).
A mixture of compounds 4a and 6 in CH2Cl2 was reacted with pyrrolidine at room temperature for 2h. And then, this mixture was reacted at 70 ℃ for 3h. As a result, compound 7a was obtained in 65%
yield. Finally, we decide to use entry 16 method.
Therefore, by applying the synthetic methods discussed so far various homoisoflavonoids can be synthesized and various biological activities can be explored.
Entry Reactant Base Solvent Temp.
(℃)
time (h)
Yield (%)
1 4a,6 piperidine x 80 2 0
2 4a,6 piperidine THF 80 4 13
3 4a,6 piperidine THF 80 10 15
4 4a,6 piperidine THF 110 4 27
5 4a,6 piperidine THF 110 10 0
6 4a,6 piperidine 1,4-Dioxane 80 4 11
7 4a,6 piperidine 1,4-Dioxane 80 10 14
8 4a,6 piperidine 1,4-Dioxane 110 4 19
9 4a,6 piperidine 1,4-Dioxane 110 10 21
10 4a,6 LiOH·H2O EtOH rt 4 0
11 4a,6 LiOH·H2O EtOH 80 4 0
12 4a,6 t-BuOK DMSO 0 3 0
13 4a,6 pyrrolidine EtOH 100 4 42
14 4a,6 pyrrolidine EtOH 80 10 35
15 4a,6 pyrrolidine CH2Cl2 rt-40 4 0
16 4a,6 pyrrolidine CH2Cl2 rt-70 4 65
Table.4 Synthesis of 3-benzylidene-4-chromanone
Fig. 11. Mechanism (A) Aldol-condensation
(B) Mannich elimination sequence
Fig. 12. Reagents and conditions (ⅰ) BF3Et2O, CH3COOH, 85℃, 7 h; (ⅱ) N,N-dimethylforamide dimethyl acetal, toluene, 90℃, 20 h; (ⅲ) LiAlH4 solution 1.0 M in THF, THF, -60℃, 5 min; (ⅳ) chloromethyl ehthyl ether, Cs2CO3, DMF, rt, 24 h; (ⅴ) CH2Cl2, pyrrolidine, rt-70℃ 5 h; (ⅵ) 1 N HCl, MeOH, 55℃; (ⅶ) H2, Pd/C (10%), MeOH, rt, 1h; (ⅷ) 1.0 M BCl3 (in CH2Cl2), CH2Cl2, 0℃-rt, 3 h.
4. Experimental section
4.1 Synthesis of 1-(6-hydroxy-2,3,4-trimethoxyphenyl)ethanone (2b)
To a stirred suspension of 3,4,5-trimethoxyphenol (1 g, 5.43 mmol) and BF3Et2O (2.68 mL, 21.72 mmol) was added CH3COOH (1.57 ml, 27.15 mmol). After the reaction mixture was stirred under N2 atmosphere at 85℃ for 5 h, cooled down to room temperature. Ice cold water (50 ml) was added slowly. The mixture was extracted twice with ethyl acetate (100 ml), and washed with water (50 ml). After organic layer was dried over anhydrous Na2SO4, concentrated by using rotary evaporator.
Following this procedure, 1-(6-hydroxy-2,3,4-trimethoxyphenyl)ethanone (931 mg, 93%) was obtained. 1H-NMR (CDCl3, 300 MHz): δ 6.23 (s, 1H), 4.08 (s, 3H), 3.95 (s, 3H), 3.75 (s, 3H), 2.78 (d, 3H), 13C-NMR (75 MHz, CDCl3): δ 198.5, 161.9, 160.7, 155.3, 132.5, 107.3, 95.0, 58.1, 54.8, 28.1
Table.5 Chemical shift of 1-(6-hydroxy-2,3,4-trimethoxyphenyl)ethanone
4.2 Synthesis of 5,7-dimethoxy-4H-chromen-4-one (3a)
4′,6′-dimethoxy-2′-hydroxyacetophenone (1 g, 5.1 mmol) was dissolved in toluene (10 ml) and N,N-dimethylformamide dimethyl acetal (1.36 ml, 10.19 mmol) was added. The mixture was stirred for 20 h at 90 ℃, cooled down to 0 ℃. After Cooled down, c-HCl (1 ml) was added and stirred for 1 h at 50 C. After The mixture was extracted twice with ethyl acetate (100 ml), washed by water (50ml) and dried over anhydrous Na2SO4. The solvent was removed using rotary evaporator and purified by flash column chromatography on silica gel (70% ethyl acetate in n-hexane). Following this procedure, 5,7-dimethoxy-4H-chromen-4-one (913.9 mg, 91%) was obtained. 1H NMR (CDCl3, 300 MHz) δ 7.61 (d, 1H, J = 5.8 Hz), 6.8(dd, 2H, J = 2.4 Hz), 6.0(d, 1H, J = 5.7 Hz), 3.98 (s, 3H), 3.93 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 178.1, 157.1, 155.8, 153.9, 142.8, 127.2, 115.8, 97.6, 95.1, 67.9.
Table.6 Chemical shift of 5,7-dimethoxy-4H-chromen-4-one
4.3. Synthesis of 5,6,7-trimethoxy-4H-chromen-4-one (3b)
1-(6-Hydroxy-2,3,4-trimethoxyphenyl)ethanone was treated by N,N-dimethyl- formamide dimethyl acetal, according to the procedure described above, to give 5,6,7-trimethoxy-4H-chromen-4-one (88%). 1H NMR (CDCl3, 300 MHz) δ 7.64 (d, 1H, J = 6.1 Hz), 6.7 (s, 2H), 6.2 (d, 1H, J = 5.8 Hz), 3.95 (s,3H), 3.93 (s, 3H) 3.90 (s,3H). 13C NMR (75 MHz, CDCl3) δ 182.2, 161.3, 155.8, 152.1, 149.5, 135.1, 115.2, 103.8, 95.7, 56.1, 55.8, 55.2.
Table.7 Chemical shift of 5,6,7-trimethoxy-4H-chromen-4-one
4.4 Synthesis of 5,7-dimethoxy-4-chromanone (4a)
To a stirred solution of 5,7-dimethoxy-4H-chromen-4-one (913.9 mg, 4.43 mmol) in dry THF (10 ml) and a solution of LiAlH4 in dry 1.0 M THF (2.23 ml, 53.16 mmol) was added under N2 atmosphere at -60℃.
After stirring for 5 min, the reaction mixture was extracted with ethyl acetate (100 ml) and washed with water (50 ml) and brine (50 ml), and dried over anhydrous Na2SO4. The crude was concentrated by using rotary evaporator and purified by flash column chromatography on silica gel (40% ethyl acetate in n-hexane) to afford the 5,7-dimethoxychroman-4-one (868.2 mg, 95%). 1H-NMR (CDCl3, 300 MHz): δ 6.04 (s, 2H), 4.45 (t, 2H, J = 6.1 Hz), 3.86 (s, 3H), 3.81 (s, 3H), 2.74 (t, 2H, J = 6.3 Hz). 13C-NMR (75 MHz, CDCl3): δ 189.1, 165.7, 165.2, 162.3, 106.4, 93.3, 92.9, 66.8, 56.1, 55.5, 38.8.
Table.8 Chemical shift of 5,7-dimethoxy-4-chromanone
4.5 Synthesis of 5,6,7-trimethoxy-4-chromanone (4b)
5,6,7-trimethoxy-4H-chromen-4-one was reduced by using a solution of LiAlH4 in dry 1.0 M THF, according to the procedure described above, to give 5,6,7-trimethoxy-4-chromanone (95%). 1H-NMR (CDCl3, 300 MHz): δ 6.24 (s, 2H), 4.45 (t, 2H, J = 6.0 Hz), 3.91 (s, 3H), 3.87 (s, 3H), 3.80 (s, 3H), 2.73 (t, 2H, J = 6.3 Hz). 13C-NMR (75 MHz, CDCl3): δ 189.0, 159.8, 159.1, 154.1, 137.2, 109.5, 96.0, 66.9, 61.6, 61.3, 56.1, 38.8.
Table.9 Chemical shift of 5,6,7-trimethoxy-4-chromanone
4.6 Synthesis of 2-(ethoxymethoxy)-benzaldehyde (6)
To a stirred suspension of salicylaldehyde (2 g, 16.38 mmol) and CS2CO3 (8 g, 24.57 mmol) in N,N-dimethylformamide (DMF, 10 ml) were added chloromethyl ethyl ether (2.28 ml, 24.57 mmol) slowly at 0℃.
After 2 hs of reaction at 0℃, The mixture reacted over night at room temperature. Reaction mixture was extracted twice with ethyl acetate (100 ml), washed with water (50 ml) and brine (10x50 ml). After dried over anhydrous Na2SO4, concentrated by using rotary evaporator and purified by column chromatography (15% ethyl acetate in n-hexane) to yield the 2-(ethoxymethoxy)-benzealdehyde (1.8 g, 90%) as a colorless liquid. 1H-NMR (CDCl3, 300 MHz): δ 10.51(s, 1H), 7.84 (dd, 1H, J = 1.9 Hz), 7.50 (t, 1H, J = 1.1 Hz), 7.23 (d, 1H, J = 8.5 Hz), 7.21 (t, 1H, J = 7.1 Hz), 5.34 (s, 2H), 3.81 (q, 2H, J = 6.8 Hz), 1.26 (t, 3H, J = 4.9 Hz).
13C-NMR (75 MHz, CDCl3): δ 189.6, 159.6, 135.7, 128.1, 125.2, 121.5, 114.9, 93.2, 64.8, 15.2.
Table.10 Chemical shift of 2-(ethoxymethoxy)benzaldehyde
4.7 Synthesis of 5,7-dimethoxy-3-(2-ethoxymethoxybenzylidene)-4-chromanone (7a)
To a stirred suspension of 5,7-dimethoxy-4-chromanone (310 mg, 1.49 mmol) and pyrollidine (0.3 ml, 3.58 mmol) in CH2Cl2 (1 ml) were added 2-(ethoxymethoxy)-benzaldehyde (0.4 ml, 2.24 mmol). After reaction mixture was stirred at room temperature for 2 h and then at 70℃ for 3 h, and concentrated by using rotary evaporator. Reaction mixture was extracted twice with ethyl acetate (100 ml), washed with water (50 ml).
After dried over anhydrous Na2SO4, concentrated by using rotary evaporator. The Pure crude product was isolated to column chromatography on silica gel (25% ethyl acetate in petroleum ether).
Following this procedure, 5,7-dimethoxy-3-(2-ethoxymethoxybenzylidene) -4-chromanone (181 mg, 58%) was obtained. 1H-NMR (CDCl3, 300 MHz):
δ 7.93 (s, 1H), 7.33 (m, 1H), 7.20 (d, 1H, J = 7.9 Hz), 7.04 (m, 2H), 6.11 (dd, 2H, J = 2.4 Hz) 5.24 (s, 2H), 5.11 (s, 2H), 3.91 (s, 3H), 3.83 (s, 3H) 3.75 (q, 2H, J = 7.1 Hz), 1.26 (t, 3H, J = 5.7 Hz). 3C-NMR (75 MHz, CDCl3): δ 179.9, 165.8, 164.9, 163.0, 156.1, 132.5, 132.0, 130.8, 130.4, 124.9, 121.5, 114.9, 107.5, 93.7, 93.6, 68.1, 64.8, 56.5, 55.9, 15.5.
Table.11 Chemical shift of 5,7-dimethoxy-3-(2-ethoxymethoxy benzylidene)-4-chromanone
4.8 Synthesis of 5,6,7-trimethoxy-(2-ethoxymethoxybenzylidene) -4-chromanone (7b)
5,6,7-trimethoxy-4-chromanone and 2-(Ethoxymethoxy)-benzealdehyde was combined by using pyrrolidine, according to the procedure described above, to give 5,6,7-trimethoxy-3-(2-ethoxymethoxy- benzylidene)-4-chromanone (65%). 1H-NMR (CDCl3, 300 MHz): δ 7.95 (s, 1H), 7.30 (m, 1H), 7.22 (d, 1H, J = 7.7 Hz), 7.01 (m, 2H), 6.02 (s, 1H) 5.31 (s, 2H), 5.01 (s, 2H), 3.95 (s, 3H), 3.87 (s, 3H) 3.81 (s, 3H), 3.73 (q, 2H, J = 6.8 Hz), 1.21 (t, 3H, J = 5.5 Hz). 13C-NMR (75 MHz, CDCl3): δ 180.1, 167.8, 166.5, 163.7, 153.1, 134.5, 133.1, 131.0, 129.8, 129.4, 123.2, 119.5, 112.9, 102.5, 95.9, 68.1, 64.8, 56.8, 56.5, 55.9, 11.5.
Table.12 Chemical shift of 5,6,7-trimethoxy-3-(2-ethoxymethoxy- benzylidene)-4-chromanone
4.9 Synthesis of 5,7-dimethoxy-3-(2-hydroxybenzylidene)-4-chroman one (8a)
5,7-dimethoxy-3-(2-ethoxymethoxybenzylidene)-4-chromanone (100 mg, 0.29 mmol) was stirred with 1 N HCl (1 ml) in MeOH (2 ml) for 1 h at 55℃. After The mixture was concentrated by using rotary evaporator and extracted by using EtOAc, washed several time with water. The crude was dried over anhydrous Na2SO4. The Pure crude product was isolated to column chromatography on silica gel (50% ethyl acetate in n-hexane) to afford 5,7-dimethoxy-3-(2-hydroxybenzylidene)-4- chromanone (87.9 mg, 88%). 1H-NMR (CDCl3, 300 MHz): δ 7.85 (s, 1H), 7.27 (m, 2H), 7.02 (m, 2H), 6.09 (dd, 2H, J = 2.2 Hz), 5.06 (s, 2H), 5.05 (s, 1H) 3.87 (s, 3H), 3.83 (s, 3H). 13C-NMR (75 MHz, CDCl3): δ 179.7, 163.8, 162.8, 161.0, 156.1, 135.5, 133.2, 129.8, 128.3, 121.5, 113.8, 108.5, 101.5, 93.8, 93.7, 61.1, 56.5, 55.9.
Table.13 Chemical shift of 5,7-dimethoxy-3-(2-hydroxybenzylidene)-4- chromanone
4.10 Synthesis of 5,6,7-trimethoxy-(2-hydroxybenzylidene)-4-chroma none (8b)
Phenyl ring (B-ring) of 5,6,7-trimethoxy-3-(2-ethoxymethoxy- benzylidene)-4-chromanone was deprotected, according to the procedure described above, to give 5,6,7-trimethoxy-3-(2-hydroxybenzylidene) -4-chromanone (88%) by using 1 N HCl in MeOH 1H-NMR (CDCl3, 300 MHz): δ 7.93 (s, 1H), 7.13 (m, 2H), 7.01 (m, 2H), 5.98 (s, 1H), 4.95 (s, 2H) 3.91 (s, 3H), 3.88 (s, 3H), 3.81 (s, 3H). 13C-NMR (75 MHz, CDCl3):
δ 181.1, 165.8, 164.8, 163.7, 157.5, 138.5, 137.1 133.2, 130.8, 128.3, 121.7, 118.2, 113.8, 101.5, 95.8, 59.7, 56.5, 56.2, 55.9.
Table.14 Chemical shift of 5,6,7-trimethoxy-3-(2-hydroxybenzylidene)-4- chromanone
4.11 Synthesis of 5,7-dimethoxy-3-(2-hydroxybenzyl)-4-chromanone (9a)
5,7-dimethoxy-3-(2-hydroxybenzylidene)-4-chromanone (101 mg, 0.28 mmol) and 10% Pd/C (26mg) in anhydrous MeOH solution was stirred under H2 atomosphere for 1 h at room temperature. And Then, the reaction mixture was diluted with ethyl acetate , filtered through Celite filter. These solution was concentrated by using rotary evaporator and purified by column chromatography (50% ethyl acetate in n-hexane) to yield the 5,7-dimethoxy-3-(2-hydroxybenzyl)-4-chromanone (75 mg, 75%). 1H-NMR (CDCl3, 300 MHz): δ 7.10 (td, 1H, J = 6.8, 1.3 Hz), 7.02 (dd, 1H, J = 7.4, 1.2 Hz), 6.81 (dd, 1H, J = 7.7, 1.3 Hz), 6.79 (td, 1H, J
= 7.5, 1.2 Hz), 6.02 (s, 1H), 4.48 (dd, 1H, J = 4.9 Hz) 4.15 (t, 1H, J = 11.2 Hz), 3.85 (s, 3H), 3.80 (s, 3H), 3.05 (m, 3H), 2.76 (m, 1H). 13C-NMR (75 MHz, CDCl3): δ 193.6, 165.2, 162.4, 154.7, 130.8, 128.4, 128.2, 124.8, 120.0, 117.2, 105.1, 93.2, 92.9, 70.2, 66.3, 56.1, 55.6, 26.9.
Table.15 Chemical shift of 5,7-dimethoxy-3-(2-hydroxybenzyl)-4-chroman one
4.12 Synthesis of 5,6,7-trimethoxy-3-(2-hydroxybenzyl)-4-chromanone (9b)
5,6,7-Trimethoxy-3-(2-hydroxybenzylidene)-4-chromanone was hydrogenated according to the procedure described above to give 5,6,7-Trimethoxy-3- (2-hydroxybenzyl)-4-chromanone (74%). 1H-NMR (CDCl3, 300 MHz): δ 7.11 (td, 1H, J = 7.4, 7.7, 1.4 Hz), 7.02 (dd, 1H, J = 7.4 Hz), 6.89 (dd, 1H, J = 7.7, 1.4 Hz), 6.81 (t, 1H, J = 7.4 Hz), 6.22 (s, 1H), 4.50 (dd, 1H, J = 11.1, 3.7 Hz) 4.16 (t, 1H, J = 11.2 Hz), 3.90 (s, 3H), 3.87 (s, 3H), 3.78 (s, 3H), 3.04 (m, 1H), 2.82 (m, 1H). 13C-NMR (75 MHz, CDCl3): δ 193.9, 160.0, 159.9, 154.7, 154.3, 137.3, 130.9, 128.4, 124.7, 120.2, 117.5, 108.5, 108.5, 95.9, 70.4, 61.7, 61.3, 56.2, 47.6, 26.8.
Table.16 Chemical shift of 5,6,7-trimethoxy-3-(2-hydroxybenzyl)-4- chromanone
4.13 Synthesis of 5-hydroxy-7-methoxy-3-(2-hydroxybenzyl)-4-chroman one (9c)
To a stirred suspension 5,7-dimethoxy-3-(2-hydroxybenzyl)-4-chroman one (150 mg, 0.48 mmol) in CH2Cl2 (5 ml) was added BCl3 (1.0 M solution in CH2Cl2, 0.8 ml, 0.96 mmol) for 1 h at 0℃ under N2
atomosphere. After 1 h, stirrring continously this mixture for 2 hs at room temperature. The reaction mixture was poured into ice-cold water and extracted twice with CH2Cl2. Then, washed with brine several time, dried over anhydrous Na2SO4. and concentrated by using rotary evaporator. The compound was purified by flash column chromatography on silica gel (30% ehtyl acetate in hexane) to afford the 5-hydroxy-7-methoxy-3-(2-hydroxybenzyl)-4-chromanone (127.5 mg, 85%). 1H-NMR (CDCl3, 300MHz): δ 7.13 (td, 1H, J = 8.5, 1.7 Hz), 7.05 (dd, 1H, J = 7.4, 1.7 Hz), 6.86 (dd, 1H, J = 8.5, 1.1 Hz), 6.81 (dd, 1H, J
= 7.4, 1.1 Hz), 6.03 (d, 1H, J = 2.2 Hz), 5.95 (d, 1H, J = 2.2 Hz) 5.1(s, 1H), 4.45 (dd, 1H, J = 11.3, 4.8 Hz), 4.17 (dd, 2H, J =11.3, 9.9 Hz), 3.79 (s, 3H), 3.14(m, 1H), 3.08(m, 1H), 2.86(m. 1H). 13C-NMR (75 MHz, CDCl3):
δ 198.9, 168.2, 164.2, 163.0, 154.2, 131.1, 128.5, 124.2, 120.5, 116.9, 102.7, 95, 94.1, 70, 55.8, 45.7, 26.7.
Table.17 Chemical shift of 5-hydroxy-7-methoxy-3-(2-hydroxybenzyl) -4-chromanone
4.14 Synthesis of 5-hydroxy-6,7-dimethoxy-3-(2-hydroxybenzyl)-4-chroman one (9d)
5,6,7-trimethoxy-3-(2-hydroxybenzyl)-4-chromanone was ortho-demethylated by using BCl3 (1.0 M solution in CH2Cl2) according to the procedure described above to give 5-hydroxy-6,7-dimethoxy-3-(2-hydroxybenzyl)-4-chromanone (85%) 1H-NMR (CDCl3, 300 MHz): δ 7.11 (t, 1H, J = 6.9 Hz), 7.05 (dd, 1H, J = 7.7, 1.7 Hz), 6.83 (t, 1H, J = 7.7 Hz), 6.00 (s, 1H), 4.41 (dd, 1H, J =11.3 Hz, 4.4), 4.16 (dd, 1H, J = 11.3, 9.4 Hz ), 3.86 (s, 3H), 3.8 (s, 3H), 3.13 (m, 1H), 2.82 (dd, 1H, J = 6.6 Hz). 13C-NMR (75 MHz, CDCl3):
δ 199.3, 160.9, 158.9, 154.9, 154.1, 131, 130.2, 128.3, 124, 120.4, 116.4, 102.6, 91.3, 70, 60.9, 56.2, 45.5, 27.1.
Table.18 Chemical shift of 5-hydroxy-6,7-dimethoxy-3-(2-hydroxybenzyl)-4-chromanone
5. Conclusion
As various structure of homoisoflavonoids were isolated from natural resources and reported to show various bioactivities such as anticancer, anti-histaminic, antiviral, antimutagenic, antifungal, antioxidant, and anti-inflammatory, there has been increasing much interest in synthetic homoisoflavonoids to have a variety of functional groups (Biswanath et al. 2009; Desideri et al. 1996; Lee et al 2014; Qunglia 1999). Recently, synthetic homoisoflavonoids were reported to have much better antioxidant activities than BHA and BHT widely known as synthetic antioxidant (Rao et al. 2005).
In this study, we tried to find an efficient synthetic method of homoisoflavonoids isolated from P. oleracea L.
4-Chromanone was efficiently synthesized from acetophenone by treating with N,N-dimethylformamide dimethyl acetal, followed by catalytic hydrogenation of the resulting 4-chromenes to afford 4-chromanones (Lee et al. 2016). Through this process, the yield of the di- and tri-substituted 4-chromanone was increased to 90%.
In case of aldol condensation reaction for synthesis of 3-benzyl idene-4-chromanone, combination of 4-chromanone and 2-hydorxybenzaldehyde using piperidine showed very low yield (20%~30%). Therefore, for Mannich-elimination sequence, 2-hydroxybenzaldehyde was protected by using chloromethyl ethyl ether and pyrrolidine was chosen as a basic catalyst. In the result, 2-methoxyethoxybenzyl-4-chromanones were obtained in a relatively high yield (50%~60%), followed by deprotection with hydrochloric acid to
give 2-hydroxybenzyl-4-chromanones. It can be considered as the efficient synthetic method for homoisoflavonoids to have various substituents.
After reduction of 3-benzylidene-4-chromanone by catalytic hydrogenation (Pd/C), BCl3 can be used to selectively demethylate methoxy groups of A ring of 2-hydroxybenzyl-4-chromanones. Through the above process it was possible to effectively synthesize four homoisoflavonoids which were 5,7-dimethoxy-3-(2-hydroxybenzyl)-4- chromanone, 5-hydroxy-7-methoxy-3-(2-hydroxybenzyl)-4-chromanone, 5,6,7-trimethoxy-3-(2-hydroxybenzyl)-4-chromanone and 5-hydroxy-6,7-trimethoxy -3-(2-hydroxybenzyl)-4-chromanone.
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Fig. 13. 1H and 13C NMR spectrum of compound 2b in CDCl3
Appendix
Fig. 14. 1H and 13C NMR spectrum of compound 3a in CDCl3
Fig. 15. 1H and 13C NMR spectrum of compound 3b in CDCl3
Fig. 16. 1H and 13C NMR spectrum of compound 4a in CDCl3
Fig. 17. 1H and 13C NMR spectrum of compound 4b in CDCl3
Fig. 18. 1H and 13C NMR spectrum of compound 6 in CDCl3
Fig. 19. 1H and 13C NMR spectrum of compound 7a in CDCl3
Fig. 20. 1H and 13C NMR spectrum of compound 8a in CDCl3
Fig. 21. 1H and 13C NMR spectrum of compound 9a in CDCl3
Fig. 22. 1H and 13C NMR spectrum of compound 9b in CDCl3
Fig. 23. 1H and 13C NMR spectrum of compound 9c in CDCl3
Fig. 24. 1H and 13C NMR spectrum of compound 9d in CDCl3
Fig. 25. compounds 2-8 (a,b)
Fig. 26. compounds 9 (a-d)
감사의 글
짧았지만 많은 것을 배울 수 있었던 석사 과정 2년을 보내고 이제 졸업논문을 마무리하게 되었습니다. 학부 때부터 지금까지 아낌없이 가르침 주신 서영완 교수님께 우선 감사드립니다. 교수님의 지도와 조언으로 2년의 석사과정이 너 무나도 값진 시간들 이었습니다. 그리고 타 대학 학생임에도 불구하고 많은 조 언과 가르침 주신 공창숙 교수님께도 감사드립니다.
실험실 생활 편하고 즐겁게 할 수 있도록 도와주신 호준이형, 여러 모로 많은 도움 주신 형주누나, 오 박사님, 정임 박사님 지연이 듬직한 후배 준세 그리고 민정이 누나 모두 감사드립니다.
그리고 함께 졸업하는 정우 2년간 고생 많았고 착한 후배 은이 연정이 원희 모두 고맙고 덕분에 석사생활 하는 동안 즐거웠다.
항상 아들 걱정하고 응원해 주신 부모님, 언제나 형 생각해주는 동생에게도 너무나도 감사드립니다. 이제 새롭게 한 발짝 나아가려고 합니다. 그동안에 감사한 부분들, 가르침 받고 조언 받았던 많은 것들을 잊지 않겠습니다.
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