Luận văn thạc sĩ Kỹ thuật hóa học: Metal-free synthesis of futo (3,2-c) coumarins from 4-hydroxycoumarins and oximes

This novel, efficient and facile reaction swimmingly promoted via molecular iodine catalyst which proceeded to one-pot sequential coupling/cyclization route.. Optimization of reaction co

ĐẠI HỌC QUỐC GIA TP HCM

TRƯỜNG ĐẠI HỌC BÁCH KHOA

-

TRẦN THỊ NGỌC TÚ

METAL-FREE SYNTHESIS OF FURO[3,2-c]COUMARINS FROM 4-HYDROXYCOUMARINS AND OXIMES

Chuyên ngành : KỸ THUẬT HÓA HỌC

Mã số:60520301

LUẬN VĂN THẠC SĨ

TP HỒ CHÍ MINH, tháng 01 năm 2019

CÔNG TRÌNH ĐƯỢC HOÀN THÀNH TẠI TRƯỜNG ĐẠI HỌC BÁCH KHOA – ĐHQG – HCM

Cán bộ hướng dẫn khoa học 1: TS Trương Vũ Thanh

Thành phần Hội đồng đánh giá luận văn thạc sĩ gồm:

(Ghi rõ họ, tên, học hàm, học vị của Hội đồng chấm bảo vệ luận văn thạc sĩ)

ĐẠI HỌC QUỐC GIA TP.HCM

Ngày, tháng, năm sinh: 08/04/1993 Nơi sinh: Tiền Giang

I TÊN ĐỀ TÀI:

Metal-free synthesis of Furo[3,2-c]coumarins from 4-hydroxycoumarins and oximes

II NHIỆM VỤ VÀ NỘI DUNG:

1 Tổng 3 hợp O-acetyloxime và các dẫn xuất của O-acetyloxime

2 Khảo sát hoạt tính xúc tác của I2 lên phản ứng tổng hợp Furo[3,2-c]coumarin từ

4-hydroxycoumarin và O-acetyloxime

3 Tối ưu phản ứng

4 Tổng hợp dẫn xuất của Furo[3,2-c]coumarin từ các dẫn xuất của

4-hydroxycoumarin và O-acetyloxime

III NGÀY GIAO NHIỆM VỤ : 15/01/2018

IV NGÀY HOÀN THÀNH NHIỆM VỤ: 02/12/2018

V CÁN BỘ HƯỚNG DẪN : TS Trương Vũ Thanh

ACKNOWLEDGEMENTS

First and foremost, I would like to thank Dr Truong Vu Thanh for the financial support for this project Dr Truong Vu Thanh also offer me wholehearted guidance on this thesis with his comprehensive knowledge Working with him is an honor and a valuable experience for me

I am also grateful to Mr Ong Duc Toan, who assisted me from the first day when I started my thesis He taught me his own experiences in doing experiments, in operating complicated equipment so that I could do things more smoothly and avoid serious mistakes

In addition, I would like to thank my talented and loyal friends for their encouragement and support during my tough time Their advices made me always have the positive attitude and helped me complete this thesis

Finally, I would like to express my sincere gratitude to my parents Their love, encouragement and continuous support have always been with me in every achievement I get in my life

Ho Chi Minh City, December, 2018

Tran Thi Ngoc Tu

ABSTRACT

A metal-, ligand-, oxidant- and base-free method for the synthesis of

furo[3,2-c]coumarins from commercially available 4-hydroxycoumarin and O-acyl oximes was

successfully developed This novel, efficient and facile reaction swimmingly promoted via molecular iodine catalyst which proceeded to one-pot sequential coupling/cyclization route Additionally, the use of molecular iodine as green catalyst and mesitylene as green solvent contributed to green chemistry and sustainable development

TÓM TẮT

Phương pháp tổng hợp furo[3,2-c]coumarins không sử dụng bazo, chất oxi hóa, và

kim loại đi từ hợp chất có sẵn trên thương mại 4-hydroxycoumarin và hợp chất O-acyl

oximes đã được nghiên cứu và phát triển thành công Trong công trình này, Iốt được

sử dụng như chất xúc tác để tăng hiệu xuất và tốc độ phản ứng theo hướng one-pot sequential coupling/cyclization Bên cạnh đó, việc sử dụng chất xúc tác và dung môi xanh như Iốt và Mesitylene đã đóng góp vào trong sự phát triển bền vững của ngành hoá học hiện đại

LỜI CAM ĐOAN

Em xin cam đoan đề tài: “Phương pháp tổng hợp Furo[3,2-c]coumarins không sử dụng kim loại từ hợp chất 4-hydroxycoumarin và oximes” là một công trình nghiên cứu độc lập dưới sự hướng dẫn của giáo viên hướng dẫn: TS.Trương Vũ Thanh Ngoài ra không có bất cứ sự sao chép của người khác Đề tài, nội dung báo cáo nghiên cứu là sản phẩm mà em đã nỗ lực nghiên cứu trong quá trình học tập và làm nghiên cứu Các số liệu, kết quả trình bày trong báo cáo là hoàn toàn trung thực, em xin chịu hoàn toàn trách nhiệm, kỷ luật của bộ môn và nhà trường đề ra nếu như có vấn đề xảy ra.”

CONTENTS

LIST OF FIGURES iv

LIST OF SCHEMES v

LIST OF TABLES vii

LIST OF ABBREVIATIONS viii

CHAPTER 1 LITERATURE REVIEW 1

1.1 Introduction 1

1.2 The synthesis of furo[3,2-c]coumarins 1

1.2.1 Previous methods for the synthesis of furocoumarin scaffold 1

1.2.2 Previous methods for the synthesis of heterocycles from Oximes 12

1.3 Our approach 15

CHAPTER 2 EXPERIMENTAL SECTION 16

2.1 Material and instrumentation 16

2.2 Procedure for preparation of O-acyl oximes 17

2.3 Procedure for synthesis of furo[3,2-c]coumarins 21

2.4 GC yield determination 23

2.5 Isolated yield determination 25

CHAPTER 3 OPTIMIZATION, RESULT AND DISCUSSION 26

3.1 Optimization of reaction conditions 26

3.1.1 Effect of different types of solvents on the reaction yield 26

3.1.2 Effect of types of catalysts on the reaction yield 27

3.1.3 Effect of reaction environment on the reaction yield 28

3.1.4 Effect of temperature on the reaction yield 29

3.1.7 Effect of solvent volume on the reaction yield 32

3.1.8 Effect of time on the reaction yield 33

3.2 Reaction scope 34

3.3 Reaction Mechanism 38

3.4 Identification of products 39

CHAPTER 4 CONCLUSION 49

REFERENCES 50

APPENDICS 58

LIST OF FIGURES

Figure 1-1 Biologically active compounds that have a furocoumarin moiety 1

Figure 2-1 Synthesis ketoxime derivatives 18

Figure 2-2 Synthesis ketoxime esters 20

Figure 2-3 Procedure of furo[3,2-c]coumarin framework 22

Figure 2-4 Calibration curve of furo[3,2-c]coumarin 24

Figure 3-1 Effect of different solvent on the reaction yield 26

Figure 3-2 Effect of various types of catalyst on the reaction yield 28

Figure 3-3 Effect of reaction environment on the reaction yield 29

Figure 3-4 Effect of temperature on the reaction yield 30

Figure 3-5 Effect of catalyst equivalent on the reaction yield 31

Figure 3-6 Effect of molar ratio of reactants on the reaction yield 32

Figure 3-7 Effect of solvent volume on the reaction yield 33

Figure 3-8 Effect of reaction time on the reaction yield 34 Figure 3-9 ORTEP representation of the asymmetric unit of phenyl-4H-furo[3,2-c]coumarin displayed with 50% probability Atom colors: O, red; C, grey; H, white 40

LIST OF SCHEMES

Scheme 1-1 One-pot synthesis of furocoumarins through cascade addition–

cyclization–oxidation 2

Scheme 1-2 New strategy for synthesis of 4H-furo[3,2-c]chromen-4-one 3

Scheme 1-3 One-pot synthesis of furocoumarins via sequential Pd/Cu-catalyzed alkynylation and intramolecular hydroalkoxylation 4

Scheme 1-4 Synthesis of 3-bromo-4-hydroxycoumarins and their derivatives 5

Scheme 1-5 Synthesis of furo[3,2-c]coumarin derivatives using visible-light promoted radical alkyne insertion with bromocoumarins 5

Scheme 1-6 Synthesis of furocoumarins via cascade palladium catalyzed oxidative alkoxylation of 4-oxohydrocoumarinsand alkenes 7

Scheme 1-7 FeCl3/ZnI2-Catalyzed regioselective synthesis of angularly fused furans 8 Scheme 1-8 Synthesis of substituted furo[3,2‑c]chromen-4-ones via four component reaction 9

Scheme 1-9 Synthesis of functionalized furo[3,2-c]coumarins via a one-pot oxidative pseudo three-component reaction in poly(ethylene glycol) 10

Scheme 1-10 The Synthesis of furo[3,2-c]coumarins via I2/TBHP-mediate reaction of 4-hydroxycoumarins with terminal alkynes 11

Scheme 1-11 Rhodium(III)-Catalyzed synthesis of isoquinolines from aryl ketone O-acyloxime derivatives and internal alkynes 12

Scheme 1-12 Copper-catalyzed 5-endo-trig cyclization of ketoxime carboxylates: a facile synthesis of 2-arylpyrroles 13

Scheme 1-13 Metal-Free Assembly of Polysubstituted Pyridines from Oximes and Acroleins 13

Scheme 1-14 Transition-Metal-Free N-O Reduction of Oximes: A Modular Synthesis of Fluorinated Pyridines 14

Scheme 1-15 Conversion of Oxime Ethers into 2-Arylbenzofurans 14

Scheme 1-16 Synthesis Furan from Aldehyde and Oxime ethers 14

Scheme 1-17 Metal,ligand, and base-free reaction for the generation of 15

Scheme 3-3 Optimization of reaction condition by changing reaction environment 28Scheme 3-4 Optimization of reaction condition by changing temperature 29Scheme 3-5 Optimization of reaction condition by changing catalyst equivalent 30Scheme 3-6 Optimization of reaction condition by changing molar ratio of reactants 31Scheme 3-7 Optimization of reaction condition by changing volume of mesitylene 32Scheme 3-8 Optimization of reaction condition by changing reaction time 33Scheme 3-9 Control Experiments 38Scheme 3-10 Plausible Mechanism 39Scheme 4-1 Metal-free synthesis of furo[3,2-c]coumarins from oximes and 4-hydroxycoumarins 49

LIST OF TABLES

Table 1-1 Substrate scope exploring different substituted nitrostyrenes, aromatic aldehydes 9Table 2-1 List of chemicals required for the synthesis of furo[3,2-c]coumarins 16Table 2-2:Calibration curve preparation for 3-Phenyl-4H-furo[3,2-c]chromen-4-one 23Table 2-3 Calibration curve of 3-Phenyl-4H-furo[3,2-c]chromen-4-one 24Table 3-1 Scope of furo[3,2-c]coumarin products 35

GC-MS Gas chromatography–mass spectrometry

TEMPO 2,2,6,6-Tetramethyl-1-piperidinyloxy

CHAPTER 1 LITERATURE REVIEW

Coumarins, widely distributed among plant kingdom, play an important role in application for several fields[1-4] such as pharmaceutical, cosmetics, pesticides and fluorescent dyes[5] Among coumarin derivatives, furo[3,2-c]coumarin have drawn considerable attention from organic chemistry owing to their presence in potent biological and pharmacological activities [6-10] including anticancer and anti-HIV properties[11-13], anti-microbials[14], anti-oxidants[15, 16], anti-fungal[17], anti-coagulants and anti-inflammatories[18, 19] Thus, development of new methods for an efficient and selective preparation of furo[3,2-c]coumarin framework is of great interest in organic chemistry

Figure 1-1 Biologically active compounds that have a furocoumarin moiety

1.2.1 Previous methods for the synthesis of furocoumarin scaffold

In the last few decades, plenty of great efforts have been made to develop efficient, practical and selective methodologies for the synthesis of furocoumarin

Notwithstanding a wide range of presently available protocols, one-pot synthesis

of substituted furocoumarins in the presence of transition-metal catalyst has proved to

be one of the most compelling approaches, which only a limited number of reports are currently known[29, 30, 32] One of typically successful examples is one-pot synthesis of furocoumarins through cascade addition–cyclization–oxidation reported by Cheng and

taken into serious consideration Therefore, the accessibility of higher reaction efficiency and straightforward protocol is highly desirable

In 2010, Chen et al came up with a novel and rapid approach of the interesting

class of furocoumarins-4H-furo[3,2-c]chromen-4-ones which could be formed via intramolecular after the corresponding alkynylation of 3-halo-4-hydroxycoumarin by using transition-metal catalyst such as palladium or copper.[34] (Scheme 1-12)

Scheme 1-2 New strategy for synthesis of 4H-furo[3,2-c]chromen-4-one.

Inspired by this strategy, Chen et al succeeded in synthesizing

furocoumarins-4H-furo[3,2-c]chromen-4-ones from 3-bromo-4-acetoxycoumarins and terminal alkynes through one-pot sequential coupling/cyclization path (Scheme 1-3) In this pathway, Pd/Cu-catalyst plays an important role in the alkynylation acceleration with

in situ prepared dialkynylzinc materials especially di(phenylethynyl)zinc which was found very effective in such cross-coupling Furthermore, an electron-withdrawing acetyl group facilitated further activation of C-Br bond was introduced to enable smooth alkynylation

Scheme 1-3 One-pot synthesis of furocoumarins via sequential Pd/Cu-catalyzed

alkynylation and intramolecular hydroalkoxylation

Although this method paved the way into new road, this procedure still expose several main limitations For instance, the utilization of 3-bromo-4-acetoxycoumarin agent, which is not available in commerce, required not only the two-step and time-consuming synthesis (Scheme 1-4), but also the use of base condition (K2CO3, H2O)

to remove acetyl group Besides, the use of expensive, unstable organometallic reagents, the restriction of substrate scope, and Pd(PPh3)4/CuI/dppf complicated catalyst-ligand system, and long reaction time are also severe disadvantages that should be taken into account in this work

Scheme 1-4 Synthesis of 3-bromo-4-hydroxycoumarins and their derivatives

With following significant effort, the report of Zhou with co-workers, which used visible-light to progress radical alkyne insertion with bromocoumarin, contributed to diversifying novel efficient methods for the generation of furo[3,2-c]coumarin derivatives in organic chemistry[35] (Scheme 1-5)

Scheme 1-5 Synthesis of furo[3,2-c]coumarin derivatives using visible-light

The new point in this manner is that visible light was found to be responsible for directly stimulating photocatalyst IrIII complex into the excited state IrIII*, which was oxidatively quenched by coumarin-derived bromide, to generate the IrIV and radical species respectively It was this radical which plays an essential role in the alkynylation followed by the cyclization Ultimately, base was indispensible for deprotonation to formation furo[3,2-c]coumarin structure In this one-pot route, the coupling reaction between an alkyne and 3-bromo-4-hydroxycoumarin presented some advantages such as conducting at room temperature in good chemical yields under environmentally friendly condition, starting with easily available reagents and

no external stoichiometric oxidants Unfortunately, the use of complicated and expensive photocatalysts was disadvantage in this one-pot route

As can be seen, all of three reactions as mentioned above either required functionalized starting materials or had a restricted substrate scope Thus, a straightforward and efficient themodology for synthesis of furo[3,2-c]coumarins derived from readily available reagents has drawn attention of scientists in organic chemistry To respond the conspicuous demand, the 4-hydroxycoumarins has been considered as an commercial agent and an important precursor in the realm of organic synthesis[36]

pre-Taking advantage of this innovation, Tan and co-workers revealed an novel and compelling method for atom-economical chemoselective synthesis of furocoumarins from readily available 4-oxohydrocoumarins and simple alkens via cascade palladium catalyzed oxidative alkoxylation[37] (Scheme 1-6)

Scheme 1-6 Synthesis of furocoumarins via cascade palladium catalyzed oxidative

alkoxylation of 4-oxohydrocoumarinsand alkenes

In this article, the Pd(CF3COO)2 catalyst was efficiently exploited as a result of development on the transition metal catalyzed C–H functionalization of alkenes Interestingly, a wide range of substrate scope-either internal alkenes or terminal alkens with different substituted group such as Me, OMe, F, Cl and OCOCH3 still obtained these privileged products in good yield under the optimized condition

Recently, with significant effort, Dey and Hajra also described successfully a

angularly fused furans from arylacetylenes and different enols in ambient air[38]

(Scheme 1-7) Among of them, the 4-hydroxycoumarin performed in good yield with the support of FeCl3/ZnI2 catalyzed oxidative radical process Although the yield of annulation products from it with various substituted phenylacetylenes was lower than that in Tan’report and even the temperature is also higher, this method also brings several benefits including high regioselectivity, cost and atom efficiency, broad substrate scope and availability of starting materials

Scheme 1-7 FeCl 3 /ZnI 2 -Catalyzed regioselective synthesis of angularly fused furans

As can be seen from the all mentioned above projects, albeit many advancements, they still revealed the same severe limitation which was the requirement of transition metal as homogeneous catalyst Therefore, from the point of

attention to metal-free methods that few have been reported so far for these privileged products for recent years[23, 39]

In order to tackle the existing problem, in 2013, a novel synthesis of substituted furo[3,2‑c]chromen-4-ones via four component reaction from substituted nitrostyrenes, aromatic aldehydes, coumarins, and ammonium acetate reported by

Zhou et al was one of the most typical examples for this tendency[7] (Scheme 1-8) The multicomponent reaction involves sequential Michael addition, aza-nucleophilic addition of imine to the double bond, intermolecular nucleophilic addtion, and dehydration reactions

Scheme 1-8 Synthesis of substituted furo[3,2‑c]chromen-4-ones via four component

reaction Table 1-1 Substrate scope exploring different substituted nitrostyrenes, aromatic

Despite being one of the pioneering procedures, the approach using many reagents, base condition, long reaction time with not high yield is still not outstanding solution Meanwhile, Iodine and compounds of iodine in higher oxidation states have emerged as flexible and environmentally benign agents for organic chemistry, recently In particular, scientists discovered the catalytic activity of iodine in a great deal of oxidative conversions leading to the erection of new C-O, C-N, and C-C bonds

in the synthesis of heterocyclic compounds, which is one of the most compelling recent achievements in this field These catalytic characteristics in many circumstances are very similar to the transition metal-catalyzed reactions, but possess the advantages of environmental sustainability and efficient utilization of natural resources There is no room for doubt that iodine is an environmentally friendly and relatively inexpensive element, which is worthy of further scientific researches and industrial applications

To prove the catalytic efficiency of iodine source, Shafiee and co-workers investigated the catalysis of molecular iodine in directly constructing furo[3,2-c]coumarin[40] (Scheme 1-9)

Scheme 1-9 Synthesis of functionalized furo[3,2-c]coumarins via a one-pot oxidative

pseudo three-component reaction in poly(ethylene glycol)

In this work, desired product was derived from the reaction between aldehydes and 4-hydroxycoumarin agents in poly(ethyleneglycol) (PEG) as solvent using a mixture of I2 and K2S2O8 in the presence of Na2CO3 as an oxidative reagent The noticeable characteristics of this method are not only the application of an

good yields, but also the effectively catalytic activity of molecular iodine to promote annulation for generation furocoumarin scaffolds that had not been described yet

Additionally, very recently, Chu’s group successfully reinforced hypothesis that iodine could be substituted for transtion metal catalyst, which has been paving the

new way into the metal-free synthesis of furo[3,2-c]coumarins from

4-hydroxycoumarins in 2018[41] shown in Scheme 1-10 This study achieved some remarkable benefits such as better atom-economy and commercial availability of the starting materials Furthermore, molecular iodine is an environmentally friendly, cheap, easy storage solid reagent and could be found to be a green alternative to transition metals in organic chemistry However, long reaction time and not high yield

as well as the requirement of using base and oxidant still remain challenged that is needed to be overcome

Scheme 1-10 The Synthesis of furo[3,2-c]coumarins via I 2 /TBHP-mediate reaction of

4-hydroxycoumarins with terminal alkynes

In summary, despite of many advantages, these above-mentioned methodologies have still suffered from a large number of limitations such as hazardous reaction conditions, noble, toxic or stoichiometric reagents, not high yield, difficulties in product isolation and purification, and especially the requirement of transition metal

operationally simple protocols for the synthesis of furo[3,2-c]coumarins scaffolds

under mild and facile conditions has still remained highly desirable

1.2.2 Previous methods for the synthesis of heterocycles from Oximes

Oximes, which are a kind of imine, have been widely used in organic chemistry

[42-44] such as the typical Beckmann rearrangement[45], Neber rearrangement[46] and Semmler-Wolff reaction[47, 48] Beside the biological activity of them, oximes and their derivatives have demonstrated to be versatile building block, attractive starting materials for the synthesis of various nitrogen and oxygen containing compounds such

as amine and its derivatives, amides, nitriles, esters and especially hyterocycles

In particular, recently, oxime esters have been considered as important and attractive precursors due to their ready accessibility and high reactivity with a range of transition-metal catalysts, such as Pd, Cu, Rh and Ru, especially for the generation of N-heterocycles[49-51] In 2010, Too et al developed successfully the synthetic method

of isoquinolines from O-acetyl aryl ketoxime derivatives with internal alkynes in the presence of [Cp*RhCl2]2 catalyst[52] shown below Scheme 1-11 The using [Cp*RhCl2]2-NaOAc as the potential catalyst system were well demonstrated to play key role in activation ortho C-H of ketone O-acetyloximes which undergoes insertion

to alkynes

Scheme 1-11 Rhodium(III)-Catalyzed synthesis of isoquinolines from aryl ketone

O-acyloxime derivatives and internal alkynes

Additionally, with significant efforts, Du and co-workers found that ketoxime carboxylates exhibited highly activity for 5-endo-trig cyclization through using copper catalyst system[53] shown in Scheme 1-12 In this works, the presence of Cu catalysts accelerated for N-O bond activation of oximes, generally leading to imino radicals or

Scheme 1-12 Copper-catalyzed 5-endo-trig cyclization of ketoxime carboxylates: a

facile synthesis of 2-arylpyrroles

Both aforementioned reactions exhibited the possibility of generating N containing heterocycles from O- ketoxime with the aid of transition metal catalyst; however, the using such these catalysts itself is a shortcoming when it comes to green and sustainable chemistry For this reason, scientists have paid attention to a metal-free protocol for the oxime-based heterocycle synthesis[54-57] Notwithstanding considerable challenges, some impressive achievements have been gained For a good example, Huang reported for the first time a metal-free condition for the generation of substituted pyridines derived from the intermolecular assembly of ketoximes and α, β-unsaturated aldehydes[58] (Scheme 1-13)

Scheme 1-13 Metal-Free Assembly of Polysubstituted Pyridines from Oximes and

Acroleins

Taking advantages from this innovation, a highly regio- and chemoselective protocol for synthesis of pharmacologically significant fluorinated pyridines from ketoximes using an NH4I/Na2S2O4 reductive system was achieved in 2017[59] shown below Scheme 1-14

Scheme 1-14 Transition-Metal-Free N-O Reduction of Oximes: A Modular Synthesis

of Fluorinated Pyridines

Obviously, oxime derivatives have been prove to be flexible and reactive reagents for N-containing heterocycles Whereas there are still very few reports for the formation of O-heterocycles from oxime In the year of 2004, Miyata, who is one of few scientists researching this field, successfully explored a novel and potential metal-free synthetic route to 2-arylbenzofurans[60] illustrated in Scheme 1-15

Scheme 1-15 Conversion of Oxime Ethers into 2-Arylbenzofurans

Recently, in 2014 Hummel discovered the possibility of expanding catalyzed aldehyde addition and cyclative capture method in synthesis of highly

Co(III)-functionalized furans from α,β-unsaturated oximes (Scheme 1-16)[61] His work is considered as one of rare achievements that prove the O-heterocycle-generated ability

of oxime ethers

Scheme 1-16 Synthesis Furan from Aldehyde and Oxime ethers

Taking advantages from these innovations, we are desirable to have further investigation of the capability for forming O-heterocycles in particular furan ring by the assembly oximes

1.3 Our approach

With the great growth of furo[3,2-c]coumarin framework containing compounds

in drug discovery, an efficient, straightforward, and selective method may prove itself

a useful instrument for medicinal chemistry Although a considerable number of procedures for establishing these priviledged compounds have been reported, these systems are still confronted with several certain limitations such as harsh condition, by-products generation, requirement of pre-functionalized starting materials, restriction of substrate scope, requirement of toxic, expensive, complicated catalyst, ligand and especially difficulty in separation, recovery and reuse of catalysts In view

of green chemistry development, chemical procedures under metal, ligand, base-free conditions are always of significance especially in the pharmaceutical industry, and that could also bring reduced environmental disruption to water and soil[56, 62]

Additionally, recently, molecular iodine has come out as an inexpensive, readily available and effective catalyst for various organic transformations[63-65] due to its moderate Lewis acidity and water tolerance[66-68]

Inspired by those reasons, we hypothesised that with readily available hydroxycoumarin and the ability of forming O-hyterocycle from oxime, whether furo[3,2-c]coumarin structure containing products could be synthesized from those with the assistance of employing iodine catalysts in one-pot sequential coupling/cyclization strategy Therefore, we immediately carried out primary study and successfully revealed a novel, efficient, straightforward methodology In more details, this strategy was demonstrated as following:

4-Scheme 1-17 Metal,ligand, and base-free reaction for the generation of furo[3,2-c]coumarin framework via molecular iodine catalyst

CHAPTER 2 EXPERIMENTAL SECTION

All starting materials required for the preparation of furo[3,2-c]coumarin scaffold were commercially obtained and ready to use as received without any further purification These chemicals and their features are shown in the following table

Table 2-1 List of chemicals required for the synthesis of furo[3,2-c]coumarins

5 Hydroxylamine hydrochloride NH2OH.HCl Sigma-Aldrich

diameter = 0.25 mm, film thickness = 0.25 μm) The temperature program for GC-MS analysis heated samples at 50 °C for 2 min, from 50 °C to 280 °C at rate of 10 °C/min, then held at 280 °C for 5 min MS spectra were compared with the spectra gathered in the NIST library

Gas chromatography (GC) analysis were performed using a Shimadzu GC2010 Plus equipped with a FID detector and a SPB-5 column (length = 30 m, inner diameter

= 0.25 mm, film thickness = 0.25 μm) The temperature program for GC analysis heated sample at 100 °C for 1 minute, from 100 °C to 120 °C at rate of 20 °C/minute, held at 120 °C for 2 minutes And then from 120 °C to 280 °C at rate of 40 °C/minute, held 280 °C for 1 minute 1,2-dichlorobenzene was used as internal standard

The 1H and 13C NMR spectra were recorded on a Bruker AV 500 MHz spectrometer operating at 500 MHz for 1H and 125 MHz for 13C, respectively, using tetramethylsilane as standard The chemical shifts (δ) are expressed as values in parts

per million (ppm) and the coupling constant (J) is given in hertz (Hz) Spin multiplicities are described as s (singlet), d (doublet), t (triplet), q (quartet), and m

(multiplet)

Step 1: Synthesis of ketoximes

In a typical procedure, the mixture of ketones (22 mmol) and hydroxylamine hydrochloride NH2OH.HCl (2.294 g, 33 mmol) was added into erlenmeyer flask (50 mL) containing magnetic bar before pouring 10 mL ethanol into the flask Next, the reaction mixture was magnetically stirred at 60 oC for 1h, and K2CO3 (3.306 g, 22mmol) was slowly added during this time After finishing the conversion (monitored by TLC), the reaction mixture was cooled to room temperature and subsequently extracted with ethyl acetate (20 mL) and water (3 x 10 mL) The organic layer was then dried by using anhydrous Na2SO4, and concentrated under reduced pressure afterward to obtained the crude oximes which were used directly on the next step without purification

Figure 2-1 Synthesis ketoxime derivatives

water 3x10 mL

60 oC, 1h

To room temperature Ethanol (10 mL)

Evaporating

Na2SO4

Step2: Synthesis of ketoxime esters

In the second step, the mixture of the crude oximes and acetic anhydride (44.4 mmol, 2.0 eq.) was magnetically stirred in erlenmeyer flask (50 mL) containing 10

mL ethyl acetate at room temperature for 1h During the reaction time, K2CO3 (22 mmol) was added slowly into this mixture When the reaction was completed (monitored by TLC), the mixture was diluted with EtOAc (25 mL) and washed with

H2O (20 mL) and brine (10 mL) The organic layer was dried over anhydrous Na2SO4

and evaporated in vacuum, and further purified by silica gel column chromatography using hexane and ethyl acetate as eluent

Figure 2-2 Synthesis ketoxime esters

Water 20 mL Brine 10 mL

y

2.3 Procedure for synthesis of furo[3,2-c]coumarins

In a general procedure, 4-hydroxycoumarin (0.1 mmol, 16.2 mg), acetophenol oxime acetate (0.2 mmol, 17.7 mg), iodine (0.01 mmol, 2.54 mg) and toluene (2 mL) was added into the vial containing magnetic stir bar in Ar condition The reaction mixture was tightly sealed, then implemented at 120 oC and continuously stirred in 12 hours After the conversion was finished, the reaction mixture was cooled down to room temperature, supplemented with diphenyl ether (0.1 mmol, 17 mg) as internal standard Subsequently, the resulting solution was washed with saturated Na2S2O3

solution (3x10 mL), and the organic component was then extracted with dichloromethane (30 mL) and H2O (3x10 mL), dried over anhydrous Na2SO4 prior to the removal of solvent under vacuum The resulting residue was purified by column chromatography using hexane and ethylacetate (33:1, v/v) to afford expected product which was further verifed by GC-MS, 1H NMR and 13C NMR methods After that, for determining the GC yield in optimization step, the confirmed product was utilized to construct calibration curve This process was also illustrated in the following diagram:

Organic layer

Acetophenone oxime acetate 0.2 mmol

washing

Room temperature

Evaporating

2.4 GC yield determination

After the transformations were completed, samples were withdrawn from reactors, quenched with water and then eluted with dichloromethane Subsequently, the organic layer was carefully shaked with anhydrous Na2SO4 before being analyzed

by GC system GC yields of the desired products was determined as following:

nPr (mg): Mole of 3-Phenyl-4H-furo[3,2-c]chromen-4-one product obtained

nPr’ (mg): Calculated mole of 3-Phenyl-4H-furo[3,2-c]chromen-4-one when yield

= 100%

nIS (mg): Mole of diphenyl ether in sample

SPr: Peak area of 3-Phenyl-4H-furo[3,2-c]chromen-4-one in sample

SIS: Peak area of diphenyl ether in sample

This formula was determined, relied on the calibration curve achieved by the following process: diphenylether (42.3 mg) and 3-Phenyl-4H-furo[3,2-c]chromen-4-one (19.6 mg) were added to two distinct 8 mL volumetric flasks After that, to dissolve these substances, the flasks were supplemented by dichlobenzene until the solvent masses reach 6494.8 mg and 1995.4 mg, respectively

Table 2-2:Calibration curve preparation for 3-Phenyl-4H-furo[3,2-c]chromen-4-one

Product Internal standard

Mass (mg) 19.6 42.3

Dichlobenzene (mg) 1995.4 6494.8

C% (w/w) 0.9727 0.6471

Different fractions of the two solutions were then withdrawn and attributed to six 1.5 mL GC vials which were analyzed by GC method later The areal ratio of 3-Phenyl-4H-furo[3,2-c]chromen-4-one to diphenylether were obtained via GC data As a result, the calibration curve was illustrated in Figure 3-1

Figure 2-4 Calibration curve of furo[3,2-c]coumarin Table 2-3 Calibration curve of 3-Phenyl-4H-furo[3,2-c]chromen-4-one

VIAL Vial 1 Vial 2 Vial 3 Vial 4 Vial 5 Vial 6 Mass of product

0.0 0.2 0.4 0.6 0.8 1.0 1.2

nPr/nIS

SPr/SIS

2.5 Isolated yield determination

After the reaction was completed, the resulting mixture was cooled down to

room temperature, extracted to dichloromethane and then washed with H2O Next, the

organic phase was dried and decanted over anhydrous Na2SO4, subsequently

concentrated under reduced pressure After that, the residue was purified by flash

column chromatography packed with silica gel, employing hexane/ethyl acetate

(33:1, v/v) to yield the 3-Phenyl-4H-furo[3,2-c]chromen-4-one product

CHAPTER 3 OPTIMIZATION, RESULT

AND DISCUSSION

3.1.1 Effect of different types of solvents on the reaction yield

Scheme 3-1 Optimization of reaction condition by changing types of solvent

For innumerable organic reactions, the reaction rate would be drastically regulated according to different solvents Therefore, we initially examined various solvents in a wide span of polarity to explore the most suitable option The reaction was conducted with 0.1 mmol 4-hydroxycoumarin reactant, 0.1 mmol acetophenone oxime acetate in conjunction with 10 mol% I2 catalyst under inert gas as Ar at 120 oC

for 6 hours in 2 mL solvent which is shown in the chart below

2

14 10 3

As can be seen from the figure 3-2, there was a profound influence of different solvents on the reaction yield The screening of a series of solvents indicated that the investigated aprotic polar solvents including DMSO, DMF, ethyl acetate and acetonitrile was found to be inappropriate, while a number of non-polar solvents such

as toluene, chlorobenzene, o-xylene and m-xylene could provide expected product in moderate yield, from 42% to 46% Although ethylbenzene and p-xylene could offer relatively good performance at 48%, compared to mesithylene reaching 51%, mesithylene should be the best choice due to being considered as green solvent when

it comes to green chemistry and sustainable development

Scheme 3-2 Optimization of reaction condition by changing types of catalyst

To emphasize the critical attribute of employing I2 as catalyst for this reaction,

it is necessary to investigate the catalysis of other iodine sources including NIS Iodosuccinimide), TBAI (Tetrabutylammoniumiodide), I2, KI, NH4I, and I2O5 The reactions were set up at 120 oC within 6 h in the presence of 0.1 mmol of 4-hydroxycoumarin, 1 equiv acetophenone oxime acetate and 10 mol% catalyst in 2 mL

(N-of mesitylene under Argon atmosphere

It can be seen from the chart, there was only a trace amount of main product (1%) detected with I2O5 source While the iodine sources like NIS, KI, and NH4I could afford the corresponding product with moderate yields as 37%, 31%, 34% respectively, and iodine exhibited its own greater reactivity (51%) Hence, I2 was ultimately deserved to be suitable catalyst for this reaction

Figure 3-2 Effect of various types of catalyst on the reaction yield

3.1.3 Effect of reaction environment on the reaction yield

Scheme 3-3 Optimization of reaction condition by changing reaction environment

Thereafter, this reaction was proceeded under several gaseous environments including argon, air, nitrogen and oxygen at 120 oC for 6 hours by combining reactivity of 0.1 mmol 4-hydroxycoumarin, 0.1 mmol acetophenone oxime acetate, 10 mol% I2 and 2 mL mesitylene solvent