Luận văn thạc sĩ Kỹ thuật hóa học: Utilization of ketoxime esters as building blocks for the sythesis of B-ketosulfones and furocoumarins

Novel pathway to β-ketosulfones through ketoxime esters under copper catalysis .... Synthesis of β-ketophosphonates through α-functionalization of ketoxime esters under copper catalysis

Ketoxime esters as versatile building blocks in organic synthesis

Introduction

The early application of oximes started 19th century, which are well-known for the Beckmann rearrangement, the Semmler–Wolff reaction as well as for reagents in organic synthesis and applications in industry [1, 2] In the last decade, oxime derivatives, especially O-acyl oximes, have gained a lot of attention and have been applied as versatile building blocks under many kinds of transition-metal catalysis, such as Pd, Cu, Rh, Ru, etc., especially for the construction of nitrogen containing heterocycles as well as nitrogen containing functional groups In terms of reaction mechanism, highly active imino radicals are generated via single-electron-transfer oxidation of a transition metal with the N–O σ bond (Scheme 1.1a) Oxidative addition of a low-valance metal to the N–O σ bond forming imino-metal complexes is also a proposed pathway to activation of ketoxime esters (Scheme 1.1b) [3] These resulting reactive intermediates could be further utilized to synthesize variety of valuable products

Scheme 1.1 General pathways for N-O bond activation of oxime esters under transition-metal catalysis [3]

Oxime derivatives show their good reactivity in the N-O bond cleavage as aforementioned because of the weak N-O σ bond with an significantly lower energy of

∼57 kcal.mol −1 than other normal σC–X (X = C, N, O) bonds (69–91 kcal.mol -1 ) [4] As a result of this low strength, in the course of a reaction, the N–O bond cleavage of

2 hydroxylamine derivatives are generally more favored than other bonds so this cleavage usually is utilized to initiate further transformation for construction of a broad kinds of functionalized compounds [5]

Among various transition metals employed for this transformation of oxime esters, copper is the most common catalyst which was reported in many publications throughout the literature The usage of oxime esters under copper catalysis will be reviewed in the next part.

Ketoxime esters under copper catalysis

Transition-metal-catalyzed selective functionalization of the C–H bond to direct oxidative coupling forming C–C or C-heteroatom bonds has gained great interest in terms of short step and high atom economy [6-11] However, they also face some challenges: the late transition metal catalysts are expensive and toxic, and stoichiometric amounts of oxidants are needed To address problems cause by using stoichiometric oxidants, they are replaced by green oxidants such as O2 [12-14] or an internal oxidant [5, 15-17]

As aforementioned in Scheme 1.1, the activation of N-O bond of oxime esters are generally along with oxidation of transition metals There is consequently an ingenious synthetic strategy that designs hydroxylamine derivatives as both reactants and oxidants towards transition metal-catalyzed oxidative C–H functionalization [5]

Among the various metals employed, copper has gained significant attention thanks to its availability, low cost, low toxicity as well as ease of use [18-23] The combination of copper salts with these oxime derivatives has emerged as a promising strategy in green chemistry to construct carbon-carbon or carbon-heteroatom bonds [24-29]

The reactions of oxime esters with copper catalysis have been described and they are divided into two main categories: Annulations of oxime esters and α- functionalization of ketoxime esters [3, 5] These two classifications will be reviewed in followed subparts

Annulations of oxime esters under copper catalysis

One of the most classical reactions of oxime esters with copper catalysis was the publication of Guan and co-workers in 2011 In this report, the annulation of two ketoxime ester molecules and an arylaldehyde under copper salt/NaHSO3 catalytic system generated multi-substituted pyridines (Scheme 1.2) [30] This method addressed the current desire of the construction of pyridine rings which are compatible with various functional groups and using readily available starting materials Furthermore, this also marked the first step of the combination of oxime esters and copper catalyst

Scheme 1.2 Annulation of ketoxime esters and aldehydes to pyridines [30]

Another approach to poly-substituted pyridine using ketoxime esters was of Yoshikai and co-worker A new catalytic system, copper salt-iminium, was employed to catalyze a cascade reaction for modular pyridine synthesis from oximes and enals (Scheme 1.3) [31] After optimization study, the authors defined the methods using pyrrolidinium salt or i-Pr2NH This method showed its efficiency for a wide range of ketoxime esters such as aryl, heteroaryl, alkenyl, alkyl and even cyclic ketones

Scheme 1.3 Modular pyridine synthesis from oximes and enals [31]

Followed the same synthetic strategy, Jiang and co-workers developed their own method from oxime esters to poly-substituted pyridines The Michael receptors, enals, in the previous report were replaced by in-situ enones generated via Knoevenagel reaction between aldehydes and activated methylene compounds under catalysis of base (Scheme 1.4) [27]

Scheme 1.4 Three-component approach to poly-substituted pyridines [27]

Another report with the same strategy was reported by Cui and co-workers in 2014 The condensation of malonitrile and aldehydes catalyzed by piperidine generated the Michael receptors for the annulation with ketoxime esters (Scheme 1.5) [26] The remarkable point of this report was the production of 2-aminopyridine products which were vital compounds to construct N-heterocycles

Scheme 1.5 Three-component approach to 2-aminopyridines [26]

In the previously mentioned publication, Cui and co-workers also reported a pathway from ketoxime esters to pyrazolines N-sulfonylimines were coupling partners of ketoxime esters to perform cyclization reaction producing pyrazolines (Scheme 1.6) [26] This was the first time pyrazoline skeletons to be synthesized by ketoxime esters under copper catalysis

Scheme 1.6 Pathway from ketoxime esters to pyrazolines [26]

In 2014, copper-catalyzed cascade reactions of oxime acetates, amines and aldehydes for the preparation of 1,3- and 1,3,4-substituted pyrazoles was reported by Jiang and co-workers The present relay oxidative process involved copper-promoted N–O bond cleavage and C–C/C–N/N–N bond formations to produce pyrazolines

Different to the last report, in-situ generated pyrazolines were gone through dehydrogenative aromatization under Cu/O2 system to afford pyrazoles (Scheme 1.7) [25] This protocol featured inexpensive catalyst, high atom and step-economy, and

5 good functional group tolerance Especially, the combination of oxime esters and O2 made this transformation into a totally redox neutral process

Scheme 1.7 Three-component synthesis of pyrazoles [25]

In the same year, Jiang’s group continued to report another synthetic pathway to pyrazole heterocyles from o-bromophenyl oxime esters and amines The domino reactions of Ullmann-type N-arylation followed by N-N bond formation under copper catalysis and support of base yielded a wide range of benzo-fused pyrazole derivatives (Scheme 1.8) [32]

Scheme 1.8 Synthesis of benzo-fused pyrazoles from o-bromophenyl oxime esters and amines [32]

Another synthetic strategy to pyrazolines involving the combination of aerobic oxidation and internal oxidation was discovered by Huang, Deng and co-workers This copper-catalyzed oxidative cyclization of indoles with oxime acetates provided a concise synthesis of pyrazolo[1,5-a]indole derivatives (Scheme 1.9) [33] High atom- and step-economy were notable features provided by this transformation Mechanistic studies indicated that the reaction proceeds through a radical procedure Oximes as an internal oxidant were demonstrated to be a driver to initiate aerobic oxidation

Scheme 1.9 Pyrazolo[1,5-a]indoles synthesis from ketoxime esters [33]

In 2014, Guan’s group utilized in the same CuBr/NaHSO3 catalytic system of their previous report in 2011 [30] to develop an efficient synthetic pathway for symmetrical pyrroles from aryl alkyl ketoxime acetates in the absence of aldehydes (Scheme 1.10) [34] This transformation required high reaction temperature (140 o C)

Furthermore, limitation of substrate scope was also a drawback when ethyl ketoxime acetates show very low reactivity For example, acetophenone oxime ester affords 2,5- diphenylpyrrole only in 10% yield

Scheme 1.10 Homo-coupling of ketoxime esters to symmetrical pyrroles [34]

For preparation of asymmetrically substituted pyrroles, Jiang and co-workers employed a CuCl/Na2SO3 catalytic system, catalyzed the oxidative [3+2] cycloaddition of ketoximes and electron-deficient alkynes (Scheme 1.11) [35] Generally, the reaction of oxime acetates with dimethyl acetylenedicarboxylate smoothly gave the desired products in moderate to good yields Unlike the previous approach, methyl, non-methyl as well as dialkyl ketoximes provided same high reactivities

Scheme 1.11 Synthesis of asymmetrically substituted pyrroles from ketoximes [35]

Thesis objectives

Ketoxime esters under copper catalysts have been proved to be an efficient tool in organic synthesis through numerous reports Along with aforementioned great achievements reviewed in the previous part, there was still some limitations in ketoxime ester chemistry

First, the used copper-based catalysts were generally copper salts which are homogeneous catalysts The number of research using heterogeneous catalysts in this field is modest Nowadays, green chemistry have gained significant attention from chemists for an environmentally benign chemistry Under viewpoints of green chemistry, there was a reasonable demand for developing new methods which utilize heterogeneous catalysts featuring reusability, recyclability as well as minimizing wastes of whole processes

There are two main trends of publications in this field which are annulation for heterocycle formation and α-functionalization of ketoxime esters In the first sector, most of the synthesized heterocycles are nitrogen-containing but oxygen-containing rings are still rare The C-O bond formation for α-functionalization of ketoxime esters are also scarce

To address the two remaining issues of ketoxime esters under copper catalysis, there were two aims of this master thesis:

1 Improving a known method by applying a copper-based heterogeneous catalyst

2 Developing a novel protocol involving α-functionalized C-O bond formation of ketoxime esters and/or construction of oxygen-containing heterocycles

An efficient access to β-ketosulfones via ketoxime esters

Literature review

Introduction β-ketosulfones is a vital class of compounds in organic synthesis These compound have been widely used in the synthesis of many products, such as olefins [41], disubstituted acetylenes [41], trisubstituted allenes [42], lycopodine alkaloids [43], polyfunctionalized 4H-pyrans [44, 45], quinolines [46], vinyl sulfones [47], and others

Furthermore, facile reductive elimination of β-ketosulfones leads to the formation of ketones [48] They can be easily transformed into the corresponding alkynes [49], epoxy sulfones [50] and β-hydoxysulfones [51-53] (Scheme 2.1) They are also used in antifungal [54] and antibacterial drugs, and are potential nonnucleoside inhibitors [24]

Scheme 2.1 β-ketosulfones as vital intermediates in organic transformation

Because of their broad applications, numerous synthetic routes of them have been reported These methods will be presented in sequence

Owing to their good reactivity and applications, numerous methods have been reported for the preparation of β-ketosufones and were summarized in Scheme 2.2

Scheme 2.2 The summary of common pathways to prepare β-ketosulfones α-Acylation of alkylsulfones was the most classical way to synthesize β- ketosulfones In this method, alkylsulfone derivatives were deprotonated at α-position by being treated with strong bases such as NaH, n-BuLi, t-BuOK or Grignards reagents

The carbanions subsequently underwent nucleophilic substitution with carbonyl chlorides or esters to obtain β-ketosulfone products (Scheme 2.3) [55-63] The usage of such bases, which are very sensitive to the moisture leading to harsh reaction condition, was a remarkable drawback of this pathway

Sulfonylation of silyl enol ethers was an alternative method to obtain β- ketosulfones Sulfonyl chlorides was used as sulfonylating agents that react with silyl enol ethers to produce β-ketosulfones under catalysis of ruthenium(II) phosphine complex (Scheme 2.4) [64] Besides the disadvantage of using homogeneous catalyst,

14 there was a noteworthy drawback that silyl enol ethers are not commercially available and their preparation requires 48 hours to complete Moreover, sulfonyl chlorides are moisture-sensitive compounds that can react violently with water to form hydrogen chloride, a corrosive toxic gas [65]

Scheme 2.4 Sulfonylation of silyl enol ethers [64]

Another common way to prepare β-ketosulfones was sulfonylation of α- haloketones by sodium arenesulfinates via nucleophilic substitution reaction (Scheme 2.5) [66-70] However, this pathway still had drawbacks, which were prolonged reaction times, the use of expensive reagents and the limitation of commercial α-haloketones

Some reports employed special solvents like ionic liquids to dissolve sulfinate salts and to facilitate nucleophilic substitution reaction Some further problems of this method were the limitations of the reaction substrates and halide derivatives are hazardous compounds

Scheme 2.5 Sulfonylation of α-haloketones by sodium arene sulfinates via nucleophilic substitution reaction [66-70]

If metallic sulfinates were not available, thiols could be alternative nucleophiles which reacted with α-haloketones to form β-ketosulfides These products were then treated with oxidants to generate respective β-ketosulfones (Scheme 2.6) [71-73]

Despite the popularity of thiol derivatives as starting materials, this method required stoichiometric strong oxidants and utilization of toxic halides

In conclusion, these traditional approaches had same drawbacks, such as multiple syntheses, unavailable reagents, the requirement of pre-activated reagents, the use of strong additives, the disadvantage of using homogeneous catalyst and specially the limitations of the reaction substrates Therefore, it is meaningful and challenging to develop new methods that use new reagents and go through a new mechanism to obtain β-ketosulfones Such methods will be presented in the next section

Over the past years, oxidative coupling has emerged as an attractive and challenging as well as an eco-friendly and green method to construct carbon–carbon and carbon–heteroatom bonds [74] These reactions have many advantages, such as decreasing number of reaction steps, reducing waste and maximizing atom efficiency

However, they also face some challenges, one of which was utilization of stoichiometric amounts of oxidants To remedy the problems cause by using stoichiometric oxidants, they are replaced by green oxidants such as O2 [12-14]

Leading this trend in β-ketosulfones synthesis, in 2013, Lei and co-workers firstly reported that alkynes could be coupling partners to obtain β-ketosulfones through this approach Oxidative coupling reaction of alkynes and sulfinic acids with the presence of oxygen could produce β-ketosulfones (Scheme 2.7) [75] Although this approach could be carried out under a mild, metal-free and redox neutral condition, it still had drawbacks Limitation of substrate scope was one of them because this transformation seemed to be unsuitable for internal alkynes The production of pyridinium sulfonates as by-products was also a noteworthy disadvantage

Scheme 2.7 The oxidative coupling of alkynes and sulfinic acids [75]

16 Lei’s work opened the new pathway for other groups to developed further methods using oxidative coupling strategy In 2014, Yadav and colleagues modified Lei’s report by sulfinate salts as sulfonyl sources The catalytic system of FeCl3, K2S2O8 and oxygen was employed to create β-ketosulfones (Scheme 2.8) [76] Using water as a green reaction media and avoiding the production of sulfonate by-products were valuable improvements in comparison of the previous work Nevertheless, this work employed FeCl3/K2S2O8 as a homogeneous catalyst system, which was not reusable

Scheme 2.8 The oxidative coupling of alkynes and sulfinates in aqueous media [76]

In the same year, Yadav’s group aslo slightly modified their own method by replacing alkynes with alkenes AgNO3 was also used as a homogeneous catalyst instead of FeCl3 (Scheme 2.9) [77] The disadvantages remaining on their previous work were still unsolved

Scheme 2.9 The oxidative coupling of alkenes and sulfinates in aqueous media [77]

Experimental section

All reagents and starting materials were obtained commercially from Sigma- Aldrich, Acros, Merck, Xilong Chemical, Chemsol and were used as received without further purification unless otherwise noted

XRD patterns were recorded by using a D8 Advance Bruker powder diffractometer with a Cu-Kα radiation source

SEM was conducted by using a S4800 scanning electron microscope

TEM was performed by using a JEOL JEM 1400 transmission electron microscope at 100 kV The Cu2(OBA)2BPY sample was dispersed onto holey carbon grids for TEM observation

N2 physisorption measurements were conducted by using a Micrometrics 2020 volumetric adsorption analyzer system Samples were pretreated by heating under vacuum at 150 o C for 3 h

A Netzsch Thermoanalyzer STA 409 was used for TGA with a heating rate of 10 o C/min under a N2 atmosphere

Fourier transform infrared (FT-IR) spectra was obtained on a Nicolet 6700 instrument, with samples being dispersed on potassium bromide pallets

Gas chromatography (GC) analysis was performed on a Shimadzu GC 2010-Plus equipped with FID detector and a SPB-5 column (length = 30 m, inner diameter 0.25 mm, and film thickness = 0.25 μm) In the GC temperature program, the sample of the reaction was held at 100 o C for 1 min; heated from 100 to 280 o C at 40 o C/min and finally held at 280 o C for 6.5 min GC yields of the reaction were calculated based on the calibration curve of (Z)-2-(phenylsulfonyl)-1-(thiophen-2- yl)ethen-1-amine, using n-dodecane as an internal standard (see Appendices for more details)

A Shimadzu GCMS-QP2010Ultra with a ZB-5MS column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.25 μm) was used for GC–MS analysis In the GC–MS temperature program, the sample was held samples at 50 o C for 2 min; heated from 50 to 280 o C at 10 o C/min and held at 280 o C for 10 min

30 A Bruker AV-500 spectrometer was employed for 1 H NMR and 13 C NMR analysis Residual peaks of solvents or TMS were used as a reference

Preparation and characterization of Cu 2 (OBA) 2 BPY

In a typical procedure, a mixture of copper (II) nitrate trihydrate

(Cu(NO3)2.3H2O) (0.242 g, 1 mmol), 4,4′-oxybis(benzoic) acid (H2OBA) (0.258 g, 1 mmol) and 4,4′-bipyridine (BPY) (0.078 g, 0.5 mmol) were dissolved in the mixture of DMF and distilled water (11 mL, 11:3 v/v) The mixture was magnetically stirred until a clear solution was observed, and then distributed to three 10 mL vials The vials were heated at 85 o C in an isothermal oven for 48 h, and green crystals were formed

After the vials were cooled to room temperature, the solid product in each vial was obtained by decanting mother liquor and washed in DMF (3 x 10 mL) for 3 days Solvent exchange was carried out with methanol (3 x 10 mL) at room temperature for 3 days

The product was then dried at 150 o C for 6 h under vacuum to yield 0.284 g of Cu2(OBA)2BPY in the form of dark green crystals (75% yield) Then, Cu2(OBA)2BPY was characterized by several methods including XRD, SEM, TEM, FT-IR, TGA and N2 physisorption measurements

2.3.1 Synthesis of starting materials a) Prepartion of ketoxime esters

The mixture of ketones (22 mmol), K2CO3 (3.036 g, 22 mmol), hydroxylamine hydrochloride (2.290 g, 33 mmol) and ethanol (10 mL) were magnetically stirred at 60 oC for 1 h The reaction mixture was cooled to room temperature, quenched with H2O then organic components were extracted with ethyl acetate (3 x 20 mL) and washed with brine (3 x 20 mL) then neutralized by HCl 1 M The organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum to obtain the crude oximes which were used directly on the next step without purification

The crude oximes and K2CO3 (3.036 g, 22 mmol) were added to the mixture of anhydride acetic (4.2 mL, 44.4 mmol) and ethyl acetate (20 mL), then stirred at room temperature for 1 h The next work-up procedure was conducted similarly to that of previous step Solid crude oxime acetates were further purified by recrystallization in

31 ethyl acetate and hexane and liquid crude oxime were further purified by silica gel column chromatography using hexane and ethyl acetate as eluent

Scheme 2.17 Synthetic pathway to ketoxime esters b) Preparation of sodium sulfinates

Commercial sodium sulfinates were purchased from suppliers and were used as received without further purification Other sulfinate salts were prepared from their corresponding sulfonyl chlorides by the following procedure (Scheme 2.18)

Scheme 2.18 Reaction to synthesize sodium sulfinates

A mixture of sulfonyl chlorides (20 mmol), sodium sulfite (5.04 g, 40 mmol) and sodium bicarbonate (3.36 g, 40 mmol) were heated and magnetically stirred in water (20 mL) at 80 o C for 8 h After cooling to room temperature, water was removed under vacuum Recrystallization of the residues in ethanol afforded the sodium sulfinates

In a typical catalytic experiment, a mixture of 1-(thiophen-2-yl)ethanone O- acetyl oxime (0.25 mmol, 45.8 mg), sodium benzenesulfinate (0.3 mmol, 49.2 mg), Cu2(OBA)2BPY (10 mol %) in chlorobenzene (1 mL) was added to a 8 mL screw-cap vial with magnetic stirrer bar The catalyst amount was calculated regarding the copper/1-(thiophen-2-yl)ethanone O-acetyl oxime molar ratio The mixture was stirred at 100 °C for 3 h under an argon atmosphere

The GC yield of enamine product were monitored by withdrawing aliquots from the reaction mixture, quenching with brine (1 mL), extracting with ethyl acetate (3 x 1 mL), drying over anhydrous Na2SO4 and being analyzed by GC with reference to n- dodecane After the completion of the reaction, the mixture was cooled to room temperature

2.3.3 Investigation of the heterogeneity and reusability of catalyst

For the leaching test, the 1 st catalytic reaction was stopped after 3 h, monitored the yield by GC, filtered to remove the solid catalyst, and transferred to a new reactor Two reagents and was then added, and the resulting mixture was then stirred for further 3 h, at 100 o C under argon atmosphere and monitored the yield by GC No significant amount of product would increase after the removal of the solid catalyst if this reaction proceeded under real heterogeneous catalysis

To investigate the reusability of Cu2(OBA)2BPY, it was filtered from the reaction mixture after 3 h, then washed with copious amounts of DMF and methanol, dried at 150 o C under vacuum in 6 h prior to being employed for the next run under the identical conditions to the initial one The reused catalyst was also characterized by XRD and FT- IR

For isolation of enamine products, after the reaction as described above was completed The resulting mixture was quenched with brine (5 mL), and the organic components were extracted into ethyl acetate (3 x 5 mL) The combined ethyl acetate solution was dried over anhydrous Na2SO4 The solvent was subsequently removed under vacuum, and the crude enamine product was purified by recrystallization in chlorobenzene and hexane Product structures were subsequently confirmed by GC-MS,

1H NMR, and 13 C NMR (see Appendices for characterization data of products)

In order to achieve β-ketosulfones, enamine products were not isolated after the first step The reaction mixture was cooled to room temperature and filtered to remove the Cu2(OBA)2BPY catalyst The filtrate was then magnetically stirred with aqueous HCl solution (1M, 1 mL) at 80 o C for 3 h After the completion of hydrolysis step, the reaction mixtures were worked-up like previously described The crude products were purified by silica gel column chromatography utilizing hexane and ethyl acetate (3:1, v/v) as eluent to obtain the expected -ketosulfones Product structures were subsequently confirmed by GC-MS, 1 H NMR, and 13 C NMR (see Appendices for characterization data of products)

Results and discussion

Preparation and characterization of Cu 2 (OBA) 2 BPY

3.1.1 Synthesis of Cu 2 (OBA) 2 BPY

Cu2(OBA)2BPY was synthesized according to a slightly modified literature procedure (Figure 2.12) After the solvent exchange and activation, the desolvated Cu2(OBA)2BPY was yielded The dark green crystals were obtained about 0.298 g, yielding 75%

Figure 2.12 Synthesis of Cu2(OBA)2BPY

3.1.2 Characterization of Cu 2 (OBA) 2 BPY

To confirm whether Cu2(OBA)2BPY had been synthesized successfully or not, the activated framework was checked by P-XRD technique As shown in Figure 2.13a, a very sharp peak at 8 o was observed in the diffractogram of Cu2(OBA)2BPY, indicating that a highly crystalline of material was obtained The result was also similar to the simulated patterns previously reported in the literature (Figure 2.13b)

Figure 2.13 Powder X-ray diffraction patterns of Cu2(OBA)2BPY a) The activated

Cu2(OBA)2BPY; b) The simulated Cu2(OBA)2BPY

Furthermore, Cu2(OBA)2BPY was also characterized by FT-IR, SEM, TEM, TGA and nitrogen physisorption measurement, and the results were showed in the Appendices

The reaction of (1a) with (2a) in the presence of Cu2(OBA)2BPY as catalyst was considered as the model reaction for catalytic studies (Scheme 2.19) According to the report of Jiang and co-workers [24], 0.25 mmol of 2.1a, 1 equivalent of 2.2a, 10% mol

35 of Cu2(OBA)2BPY in 1 mL of toluene at the temperature of 100 o C for 3 h under an argon atmosphere were chosen as the starting point

Various parameters including type of solvents, ratio of reactants, catalyst amounts, reaction durations, temperatures and solvent amounts were investigated in sequence to determine the factors that favor the formation of the desired product

Furthermore, to demonstrate outstanding features of Cu2(OBA)2BPY in this reaction, its activity was also compared to those of several homogeneous and heterogeneous catalysts

Scheme 2.19 The model reaction for optimization a) Effect of temperatures on the reaction yield

Initial studies were aimed at the influence of temperature on the generation of

2.3aa The reaction was performed in 1 mL toluene at 10 mol% catalyst for 3h, with

(2.1a)/(2.2a) molar ratio of 1:1, at ambient temperature, 60 o C, 80 o C, 100 o C, 120 o C

Figure 2.14 Effect of temperatures on the reaction yield

36 The reaction could not occur at room temperature or 60 o C, and no trace of 2.3aa was recorded after 3h Boosting the temperature to 80 o C offered 10% yield after 3h As anticipated, increasing the reaction temperature led to a significant improvement in the yield of the expected product Best result was achieved for the reaction conducted at 100 oC, with 60% yield 2.3aa being obtained after 3h However, the GC yield was not improved at the temperature higher than 100 o C Therefore, 100 o C was the most suitable for this reaction

This reaction proceeded via radical mechanism (see subpart 3.2.3 in page 44 for details) and the radical formation significantly depended on temperature Therefore, temperature under 100 o C might be not enough to form free radicals from either 1a or

2.2a, resulting in the very poor formation of the product Exceeding temperature to 100 oC or above was possibly enough to generate radicals of both reactants since the reaction yield was improved considerably Indeed, according to many reported in the literature [24, 29, 35, 150-152], oxime acetates in this kind of reaction generally required temperatures from at least 100 o C b) Effect of reactant molar ratios on the reaction yield

The next parameter to be investigated was the effect of the reactant molar ratio on the reaction yield The reaction was performed at 100 o C with toluene as solvent in the presence of 10 mol% Cu2(OBA)2BPY catalyst with 2.1a/2.2a molar ratios of 2:1, 1:1,

Figure 2.15 Effect of reactant molar ratio on the reaction yield

It was found that reagent molar ratio only exhibited a small effect on the yield of desired product Using 1 equivalent of 2.2a, the oxidative coupling reaction proceeded to 60% yield after 3 h The increase in the amount of 2.2a led to an enhancement in the yield of 2.3aa The Cu2(OBA)2BPY-catalyzed coupling reaction afforded to 68% yield after 3 h with 1.2 equivalents of 2.2a, while 69% yield was observed after 24 h for the reaction using 1.5 equivalents With 2.1a/2.2a molar ratio was 2:1, the reaction yield remained unchanged value, 69% As a result, the reactant molar ratio of 1:1.2 was exploited for further experiments c) Effect of different solvents on the reaction yield

The solvent could exhibit a significant impact on the reaction rate for organic transformations carried out in the presence of solid catalysts Consequently, the impact of solvents on the copper-catalyzed coupling between 2.1a and 2.2a to generate 2.3aa was examined The reaction was conducted at 100 o C for 3 h, with 2.1a/2.2a molar ratio of 1:1.2 with 10 mol% of catalyst in different organic solvents (Figure 2.16)

Figure 2.16 Effect of different solvents on the reaction yield

Both protic and aprotic polar solvents including n-butanol, ethyl acetate, DMSO and DMF were found to be inappropriate for the reaction, only generating product in modest yields (2%-36%) after 3 h Changing to 1,4-dioxane could improve the yield to 65% More importantly, aromatic solvents obviously favored the formation of the expected product In details, reactions conducted in mesitylene and toluene afforded approximately 65% yield while yields around 85% were obtained by using o-, m-, and p-xylene In particular, chlorobenzene was revealed as the solvent of choice for this reaction with 87% yield being achieved after 3 h

Our results shared similarities to those of the previous report by Jiang and co- workers [24] In their homogeneous protocol, toluene, an aromatic solvent, exhibited the best performance for the reaction of acetophenone oxime acetate and sodium p- toluenesulfinate, yielding product in 95% Non-aromatic solvents like DMSO and DMF also gave significantly lower yields d) Effect of reactant concentrations on the reaction yield

In many reactions, using various concentrations of reactant can affect the reaction rate Therefore, concentration of reactant was the next factor to be investigated The reaction was studied at 0.05 M, 0.083 M, 0.1 M, 0.125 M, 0.167 M, 0.25 M and 0.5 M of 2.1a corresponding to 5 mL, 3 mL, 2.5 mL, 2 mL, 1.5 mL, 1 mL, and 0.5 mL of

39 chlorobenzene used The reaction was performed at 100 o C, using reagent molar ratio of 1:1.2, in the presence of 10 mol% catalyst for 3 h

Figure 2.17 Effect of reactant concentrations on the reaction yield

It was indicated that our protocol worked well in high concentrations In specific, high yields of 86% and 87% were achieved at 0.25 M and 0.5 M of 2.1a respectively

The reaction was; however, decelerated dramatically at 0.167 M with less than 40% of product being yielded Indeed, decreasing the concentrations from 0.125 M to 0.05 M generally further decrease the reaction yield from 33% to 8% Because 2.2a had low solubility in chlorobenzene, stirring process seemed to be instable when employing low amount of chlorobenzene Therefore, 0.25 M of 2.1a corresponding to 1 mL of chlorobenzene was chosen for further studies e) Effect of catalyst amount on the reaction yield

Another factor that was previously indicated as a significant effect on the oxidative coupling of 2.1a and 2.2a was the catalyst amount The reaction was carried out in 1 mL chlorobenzene at 100 o C for 3 h, using 2.1a/2.2a molar ratio of 1:1.2 in the presence of 1 mol%, 2.5 mol%, 5 mol%, 7.5 mol% and 10 mol% catalyst respectively (Figure 2.18)

Figure 2.18 Effect of catalyst amount on the reaction yield

Conclusion

A porous material Cu2(OBA)2BPY was synthesized The characterizations of Cu2(OBA)2BPY were achieved by a variety of different techniques, including TGA, FT- IR, SEM, TEM and nitrogen physisorption measurements These results revealed that Cu2(OBA)2BPY in this work has successfully been synthesized and its properties was comparable to previously reported studies

After screening reaction conditions, the catalytic activity of Cu2(OBA)2BPY was compared to other catalysts and showed higher result In particular, leaching and reusing tests not only confirmed the heterogeneous catalysis for this reaction by Cu2(OBA)2BPY but also presented its reusability Indeed, Cu2(OBA)2BPY could be reused at least 9 times without a significant degradation of activity or structure Cu2(OBA)2BPY activity was also tested on a broad substrate scope, yielding wide range of β-ketosulfones in good to excellent yields As compared to the previous report, our work was improved in terms of reaction time and exploitation of reusable catalyst

Besides results achieved, this report still contains limitations that are needed to be researched in the future: The expansion in scope and scale-up test for this protocol should be carried out; and the exploitation of Cu2(OBA)2BPY should be broaden to other organic synthesis and especially in ketoxime ester chemistry

A novel pathway to furo[3,2,c]coumarins via ketoxime esters

Coumarin scaffolds is a vital class of heterocyclic compounds and received major attention from organic chemists due to their existence in numerous natural products, bioactive compounds, pharmaceuticals, food additives, and functional materials [154- 158] Besides, the furans are also privileged heterocyclic skeletons, presenting in a wide range of bio-active natural and unnatural compounds [159-162] Furan derivatives also serve as building blocks of many pharmaceutical agents [163]

Furocoumarins or furanocoumarins are heterocyclic systems containing a furan ring fused to coumarin The furan may be fused in different ways producing several isomers (Figure 3.1) Some reports pointed out that the fusion of furan and coumarin heterocyclic moieties would introduce unique biological activities and pharmacological properties like antimicrobial, insecticidal, antiarrhythmic, antimalarial and sedative [164-166]

Figure 3.1 Structures of some synthetic furanocoumarins

Some furocoumarin derivatives which have noticeable biological properties rarely found in nature Thus, more efforts have been performed to establish new synthetic methods toward this type of compounds Furo[3,2-c]coumarins are one of the most common representatives of this class and the synthetic pathways of this scaffolds will be reviewed in the next part

By retrosynthetic analysis, 4-hydroxycoumarins is one of possible building blocks to construct furo[3,2-c]coumarin skeletons Because of commercial availability as well as a facile preparation from readily accessible reactants and reagents (Scheme 3.1) [167], 4-hydroxycoumarins have emerged the most common starting materials for furo[3,2-c]coumarin synthesis

Scheme 3.1 A possible synthetic pathway of 4-hydroxycoumarins from available compounds [167]

The conventional synthesis of furo[3,2-c]coumarins from 4-hydroxycoumarins employed α-haloketones as coupling partners In particular, nucleophilic substitution reaction between these two compounds was performed then intramolecular 5-exo-trig cyclization of resulting compounds were carried out to obtain furo[3,2-c]coumarins under acid or base catalysis (Scheme 3.2) [168-173] This strategy was the most simple way to synthesize furo[3,2-c]coumarins from 4-hydroxycoumarins, but it still had some drawbacks First, this transformation required α-haloketones as pre-functionalized reactants Moreover, although α-haloketones are commercially available, their synthesis had a low regioselectivity for α-halogenation of ketones having two α-positions, leading to the difficulty of separation of isomer mixtures and high prices of these halogen derivatives

Scheme 3.2 Conventional synthesis of furo[3,2-c]coumarins from 4- hydroxycoumarins and α-haloketones

55 Ketones with other good leaving groups like tosylate at α-position were also candidates for this cyclization In 2012, Kumar and co-workers successfully prepared α- tosyloxyketones from ketones and [hydroxy(tosyloxy)iodo]benzene prior to use them for synthesis of furo[3,2-c]coumarins (Scheme 3.3) [174] This was an alternative method which avoided the use of halogen derivatives However, the utilized hypervalent iodine is a costly compound, reducing the economic efficiency of this transformation

Scheme 3.3 Synthesis of α-tosyloxyketones from hypervalent iodine followed by cyclization of 4-hydroxycoumarins [174]

In general, the domino reactions of nucleophilic substitution and aldolization gave a simple way to furo[3,2-c]coumarins Nevertheless, this approach still required pre-functionalized compounds and costly reagents so that there was a need of developing new methods to overcome these obstacles

4-hydroxycoumarins are enol derivatives so they can tautomerize into ketone type to become 1,3-ketoester compounds having activated methylene groups The 1,3- dicarbonyls can react with aldehydes via aldol condensation under base catalysis These resulting compounds were key intermediates for the construction of furo[3,2- c]coumarins through [4+1] cycloaddtion (Scheme 3.4)

Scheme 3.4 Aldehydes as C-3 sources for construction of furo[3,2-c]coumarins

Isocyanides were the most popular partners for the ring closures following this strategy (Scheme 3.5) The one-pot method including aldol condensation of 4- hydroxycoumarins and aldehydes and [4+1] cycloaddition with isocyanides was firstly

56 reported by Nair and co-workers in 2002 Three components were refluxed in benzene for 16 to 24 hours to afford desired products in moderate to good yields [175] A new pathway was reported with the success in preparing from furo[3,2-c]coumarins available reactants However, this transformation was carried out under harsh condition and used benzene, a very toxic solvent Therefore, some similar reports tried to improve the reaction conditions In 2013, Shaabani’s group replaced benzene by water as a greener solvent [176] A year later, this transformation was further made better with a significant decrease in the reaction time by Shaabani’s and co-workers when was performed by microwave-assisted K10 catalysis under solvent-free condition [177] In the same period of time, Wu also conducted this reaction in DMF under microwave irradiation and achieved the same improvements [178] In 2015, this three-component transformation could met as many green chemistry principles as possible when Sharma and co-workers reported a catalyst-free, solvent-free, microwave-assisted and high yielding synthesis [179] However, there was still a drawback that this method was only suitable for preparation of 3-aryl-4-amino furo[3,2-c]coumarins; consequently, other methodologies should be developed to synthesize more general furo[3,2-c]coumarins

Scheme 3.5 Isocyanides as ring-closure partners

Phosphine zwitterions has gained much attention from chemists owing to both their interesting specific properties and their potential application in organic synthesis [180] In 2012, Lin’s group utilized phosphine zwitterions prepared by reaction of the aforementioned aldol products and tributylphosphine to open a novel two-step route to furo[3,2-c]coumarins Quantitative yields of phosphine zwitterions were obtained after the first step In the second step, furo[3,2-c]coumarins was obtained in good to excellent yield by the treatment of the zwitterions with acyl chlorides in the presence of triethylamine (Scheme 3.6) [181] High yields among a large substrate scope was a remarkable feature of this pathway in comparison of previous approaches Nevertheless,

57 there was a trade-off between efficiency and the use of additives, reactive acyl chlorides and multiple-step strategy

Scheme 3.6 Furo[3,2-c]coumarin synthesis via phosphine zwitterions [181]

In 2012, Shafiee and co-workers observed that an unexpected furo[3,2- c]coumarin was obtained in small amount through sequential transformation including hydrolysis, decarboxylative halogenation, 5-exo-tet cyclization and oxidative aromatization when dicoumarol was prepared by condensation of 4-hydroxycoumarin and formaldehyde in the presence of iodine (Scheme 3.7) This interesting result inspired the authors to develop a general route to access these furo[3,2-c]coumarin derivatives After screening of reaction conditions, a novel one-pot two-step method was described Biscoumarins were firstly produced by reaction of 4-hydroxycoumarins and aldehydes under iodine catalysis The resulting mixtures were then treated with K2S2O8 and Na2CO3, generating 4-(2-hydroxybenzoyl)-4H-furo[3,2-c]coumarins (Scheme 3.8) [182]

Scheme 3.7 Unexpected exploration from dicoumarol synthesis [182]

Scheme 3.8 One-pot pseudo three-component synthesis of furo[3,2-c]coumarins [182]

58 In 2015, Wu, Liu and co-workers improved the conditions of this fascinating reaction by performing the reaction in only one step as well as utilizing greener CuBr2/O2 catalytic system instead of the use of iodine as a promoter and K2S2O8 as a stoichiometric oxidant (Scheme 3.9) [183]

Scheme 3.9 One-pot synthesis of furo[3,2-c]coumarins under CuBr2/O2 catalytic system [183]

1.2.3 Cyclization with β -nitrostyrenes as Michael acceptors

In the presence of base, the ketone type of 4-hydroxycoumarins can be deprotonated at C-3 position, making these heterocycles be good nucleophiles as well as Michael donors Michael addition of C-3 to Michael acceptors followed by cyclization could be applied as an efficient method to construct furo[3,2-c]coumarins β-nitrostyrenes are readily available compounds and commonly used as reactive

Michael acceptors, so they were utilized as main Michael acceptors for this pathway

In 2012, Chen’s group reported the cyclization of 1,3-dicarbonyls and nitroallylic acetates with the presence of base for synthesis of furans via Feist–Bnary addition- elimination This method was also effective for the case of 4-hydroxycoumarins, forming furo[3,2-c]coumarin scaffolds (Scheme 3.10) [184]

Scheme 3.10 Cyclization of 4-hydroxycoumarins and nitroallylic acetates with the presence of base [184]

Brahmbhatt and co-workers employed non-pre-functionalized β-nitrostyrenes for this kind of reaction in 2013 The cyclizations of 4-hydroxycoumarins and β- nitrostyrenes were performed in methanol under microwave-assisted piperidine

59 catalysis (Scheme 3.11) [171] Various furo[3,2-c]coumarins were synthesized in moderate yields ranging from 64% to 75% However, the research did not mention the synthesis of 4-substituted furo[3,2-c]coumarins

Scheme 3.11 Cyclization of 4-hydroxycoumarins and β-nitrostyrenes under microwave irradiation [171]

Annulation of ketoxime esters and aldehydes to pyridines

Another approach to poly-substituted pyridine using ketoxime esters was of Yoshikai and co-worker A new catalytic system, copper salt-iminium, was employed to catalyze a cascade reaction for modular pyridine synthesis from oximes and enals (Scheme 1.3) [31] After optimization study, the authors defined the methods using pyrrolidinium salt or i-Pr2NH This method showed its efficiency for a wide range of ketoxime esters such as aryl, heteroaryl, alkenyl, alkyl and even cyclic ketones.

Modular pyridine synthesis from oximes and enals

Followed the same synthetic strategy, Jiang and co-workers developed their own method from oxime esters to poly-substituted pyridines The Michael receptors, enals, in the previous report were replaced by in-situ enones generated via Knoevenagel reaction between aldehydes and activated methylene compounds under catalysis of base (Scheme 1.4) [27]

Three-component approach to poly-substituted pyridines

Another report with the same strategy was reported by Cui and co-workers in 2014 The condensation of malonitrile and aldehydes catalyzed by piperidine generated the Michael receptors for the annulation with ketoxime esters (Scheme 1.5) [26] The remarkable point of this report was the production of 2-aminopyridine products which were vital compounds to construct N-heterocycles.

Three-component approach to 2-aminopyridines

In the previously mentioned publication, Cui and co-workers also reported a pathway from ketoxime esters to pyrazolines N-sulfonylimines were coupling partners of ketoxime esters to perform cyclization reaction producing pyrazolines (Scheme 1.6) [26] This was the first time pyrazoline skeletons to be synthesized by ketoxime esters under copper catalysis.

Pathway from ketoxime esters to pyrazolines

In 2014, copper-catalyzed cascade reactions of oxime acetates, amines and aldehydes for the preparation of 1,3- and 1,3,4-substituted pyrazoles was reported by Jiang and co-workers The present relay oxidative process involved copper-promoted N–O bond cleavage and C–C/C–N/N–N bond formations to produce pyrazolines

Different to the last report, in-situ generated pyrazolines were gone through dehydrogenative aromatization under Cu/O2 system to afford pyrazoles (Scheme 1.7) [25] This protocol featured inexpensive catalyst, high atom and step-economy, and

5 good functional group tolerance Especially, the combination of oxime esters and O2 made this transformation into a totally redox neutral process.

Three-component synthesis of pyrazoles

In the same year, Jiang’s group continued to report another synthetic pathway to pyrazole heterocyles from o-bromophenyl oxime esters and amines The domino reactions of Ullmann-type N-arylation followed by N-N bond formation under copper catalysis and support of base yielded a wide range of benzo-fused pyrazole derivatives (Scheme 1.8) [32].

Synthesis of benzo-fused pyrazoles from o-bromophenyl oxime esters and

Another synthetic strategy to pyrazolines involving the combination of aerobic oxidation and internal oxidation was discovered by Huang, Deng and co-workers This copper-catalyzed oxidative cyclization of indoles with oxime acetates provided a concise synthesis of pyrazolo[1,5-a]indole derivatives (Scheme 1.9) [33] High atom- and step-economy were notable features provided by this transformation Mechanistic studies indicated that the reaction proceeds through a radical procedure Oximes as an internal oxidant were demonstrated to be a driver to initiate aerobic oxidation.

Pyrazolo[1,5-a]indoles synthesis from ketoxime esters

In 2014, Guan’s group utilized in the same CuBr/NaHSO3 catalytic system of their previous report in 2011 [30] to develop an efficient synthetic pathway for symmetrical pyrroles from aryl alkyl ketoxime acetates in the absence of aldehydes (Scheme 1.10) [34] This transformation required high reaction temperature (140 o C)

Furthermore, limitation of substrate scope was also a drawback when ethyl ketoxime acetates show very low reactivity For example, acetophenone oxime ester affords 2,5- diphenylpyrrole only in 10% yield.

Homo-coupling of ketoxime esters to symmetrical pyrroles

For preparation of asymmetrically substituted pyrroles, Jiang and co-workers employed a CuCl/Na2SO3 catalytic system, catalyzed the oxidative [3+2] cycloaddition of ketoximes and electron-deficient alkynes (Scheme 1.11) [35] Generally, the reaction of oxime acetates with dimethyl acetylenedicarboxylate smoothly gave the desired products in moderate to good yields Unlike the previous approach, methyl, non-methyl as well as dialkyl ketoximes provided same high reactivities.

Synthesis of asymmetrically substituted pyrroles from ketoximes

Ketoxime esters under copper catalysis was also an efficient tool to construct sulfur-containing heterocycles The first report to synthesize thiazoles involving oximes and copper catalyst was published in 2016 by Jiang’s group The cyclization of ketoxime esters and isothiocyanates was performed under CuI/Cs2CO3 catalytic system, generating 2-aminothiazoles with up to 90% yields (Scheme 1.12) [29]

Synthesis of 2-aminothiazoles from ketoxime esters

In 2018, Jiang’s group expanded the application of ketoxime esters in thiazole synthesis to 2-alkoxythiazole derivatives Another sulfur source, xanthates, was employed instead of isothiocyanates to obtain 2-alkoxythiazoles (Scheme 1.13) [36].

Synthesis of 2-alkoxythiazoles from ketoxime esters

Beside pyridines, pyrazoles, pyrroles or thiazoles, the role of ketoxime esters as flexible reagents was also proved by the synthesis of other more complex nitrogen- containing heterocycles such as imidazo[1,2-a]pyridines, quinolines, quinazolines and so on In 2013, Jiang and co-workers were successful to directly functionalize pyridines with ketoxime esters under copper catalysis and oxygen atmosphere () [37] This report provided a straightforward way from pyridines to this scaffold, avoiding the current intensive usage of 2-aminopyridines, which were traditionally derived from pyridines.

A straightforward way from pyridines to imidazo[1,2-a]pyridines

In 2016, based on the previous report in 2014 [32] (Scheme 1.8), which was the arylation of nucleophiles with o-haloaryl oxime acetates followed by annulation to construct nitrogen-containing rings, Jiang’s group developed a novel method to prepare isoquinolines and indolo[1,2-a]quinazolines Indole derivatives were employed as reactants in Ullmann-type N-arylation with o-haloaryl oxime acetates prior to C-N bond formation to generate indolo-fused quinazolines (Scheme 1.15a) Similarly,

8 isoquinolines were also produced with the same approach by reaction of o-haloaryl oxime acetates with activated methylene compounds (Scheme 1.15 b and c) [38].

Cyclization of o-haloaryloxime acetates to construct nitrogen-containing

heterocycles [38] α-functionalization of ketoxime esters under copper catalysis

Along with being the powerful synthetic pathways to nitrogen-containing heterocycles, ketoxime esters under copper catalysis was also used as an efficient strategy to directly α–functionalize ketones or enamines One of the most classical methods in this category was reported by Jiang’s group in 2013 Alkyl aryl oxime esters were employed in direct oxidative C–S bond formation with sodium sulfinates as the coupling partners, providing a novel access to β-sulfonylvinylamines Because β- ketosulfones are an important class of organic synthesis intermediates, β- sulfonylvinylamines were further hydrolyzed to obtain these valuable compounds (Scheme 1.16) [24] A wide substrate scope, available starting materials and avoiding the usage of additives were strong points of this pathway in comparison of the conventional methods to β-ketosulfones.

Novel pathway to β-ketosulfones through ketoxime esters under copper

Because phosphorus-containing compounds had wide applications in many fields, C-P bond formation has gained much attention in organic synthesis There still remains

9 a great challenge in oxidative Csp3-H/P-H cross-coupling, especially the direct ketone α- Csp3-H/P-H coupling In this scenery, Lei and co-workers presented a solution for this current problem by employment of ketoxime esters and copper catalyst in 2015 In details, oxidative Csp3-H/P-H cross-coupling reaction of ketoxime esters and phosphine oxides were performed under CuCl/PCy3 catalytic system to produce α- phosphorylketimines Anhydride acetic was added into the reaction to convert ketimines to enamides, shifting the equilibrium of the first reaction toward the ketimines After that, reaction mixture was treated with aqueous HCl to obtain β-ketophosphonates

Synthesis of β-ketophosphonates through α-functionalization of ketoxime

ketoxime esters under copper catalysis [39]

Copper catalyst also worked for the case of C-C cross-coupling α- functionalization of ketoxime esters Oxidative functionalization of aromatic oxime acetates with α-keto acids was reported by Deng, Jiang and co-workers in 2017 (Scheme 1.18) [40] This process involved N–O/C–C bond cleavages and C–C bond formations to produce enaminones under redox-neutral conditions.

Synthesis of enaminones via C-C cross-coupling α-functionalization of

In the last decade, a variety of oxidative C–H activation methods with the utilization of stoichiometric strong oxidants have been developed Transition-metal- catalyzed C–H functionalization involving the usage of internal oxidant was one of the most powerful methods which could address this remaining issue In this scenery, ketoxime esters, which can be easily prepared from readily available reagents, have emerged as promising internal oxidants Because of the weakness of N-O bond in oxime group, highly active imino radicals are simply produced via single-electron-transfer oxidation of a transition metal with the N–O σ bond Oxidative addition of a low-valance metal to the N–O σ bond forming imino-metal complexes is also a starting point of catalytic cycles of transition-metal catalysts These radicals, high-valance metals and high-valance metal complexes could be versatile materials for construction of numerous valuable products

With the current trend of replacing noble transition metals with first-row transition metals in catalysis field, copper has gained significant attention due to its abundance, low cost and low toxicity The combination of ketoxime esters and copper catalysis was demonstrated to be significantly efficient through many reports Those transformations give convenient routes to a wide range of N-heterocycles such as pyridines, pyrazoles, pyrroles, thiazoles as well as pyridine-fused polycyclic products, and so forth Copper catalysis was also effective for the α-functionalization of ketoxime esters, generating precious α-functionalized enamines and ketones These present methodologies are meaningful and attractive for the fact that N-heterocycles as well as α-functionalized enamines or ketones have wide applications in the many fields

Ketoxime esters under copper catalysts have been proved to be an efficient tool in organic synthesis through numerous reports Along with aforementioned great achievements reviewed in the previous part, there was still some limitations in ketoxime ester chemistry

First, the used copper-based catalysts were generally copper salts which are homogeneous catalysts The number of research using heterogeneous catalysts in this field is modest Nowadays, green chemistry have gained significant attention from chemists for an environmentally benign chemistry Under viewpoints of green chemistry, there was a reasonable demand for developing new methods which utilize heterogeneous catalysts featuring reusability, recyclability as well as minimizing wastes of whole processes

There are two main trends of publications in this field which are annulation for heterocycle formation and α-functionalization of ketoxime esters In the first sector, most of the synthesized heterocycles are nitrogen-containing but oxygen-containing rings are still rare The C-O bond formation for α-functionalization of ketoxime esters are also scarce

To address the two remaining issues of ketoxime esters under copper catalysis, there were two aims of this master thesis:

1 Improving a known method by applying a copper-based heterogeneous catalyst

2 Developing a novel protocol involving α-functionalized C-O bond formation of ketoxime esters and/or construction of oxygen-containing heterocycles

Chapter 2 - An efficient access to β -ketosulfones via ketoxime esters

Introduction β-ketosulfones is a vital class of compounds in organic synthesis These compound have been widely used in the synthesis of many products, such as olefins [41], disubstituted acetylenes [41], trisubstituted allenes [42], lycopodine alkaloids [43], polyfunctionalized 4H-pyrans [44, 45], quinolines [46], vinyl sulfones [47], and others

Furthermore, facile reductive elimination of β-ketosulfones leads to the formation of ketones [48] They can be easily transformed into the corresponding alkynes [49], epoxy sulfones [50] and β-hydoxysulfones [51-53] (Scheme 2.1) They are also used in antifungal [54] and antibacterial drugs, and are potential nonnucleoside inhibitors [24].

β-ketosulfones as vital intermediates in organic transformation

Because of their broad applications, numerous synthetic routes of them have been reported These methods will be presented in sequence

Owing to their good reactivity and applications, numerous methods have been reported for the preparation of β-ketosufones and were summarized in Scheme 2.2.

The summary of common pathways to prepare β-ketosulfones

α-Acylation of alkylsulfones was the most classical way to synthesize β- ketosulfones In this method, alkylsulfone derivatives were deprotonated at α-position by being treated with strong bases such as NaH, n-BuLi, t-BuOK or Grignards reagents

The carbanions subsequently underwent nucleophilic substitution with carbonyl chlorides or esters to obtain β-ketosulfone products (Scheme 2.3) [55-63] The usage of such bases, which are very sensitive to the moisture leading to harsh reaction condition, was a remarkable drawback of this pathway.

α-acylation of alkylsulfones

Sulfonylation of silyl enol ethers was an alternative method to obtain β- ketosulfones Sulfonyl chlorides was used as sulfonylating agents that react with silyl enol ethers to produce β-ketosulfones under catalysis of ruthenium(II) phosphine complex (Scheme 2.4) [64] Besides the disadvantage of using homogeneous catalyst,

14 there was a noteworthy drawback that silyl enol ethers are not commercially available and their preparation requires 48 hours to complete Moreover, sulfonyl chlorides are moisture-sensitive compounds that can react violently with water to form hydrogen chloride, a corrosive toxic gas [65].

Sulfonylation of silyl enol ethers

Another common way to prepare β-ketosulfones was sulfonylation of α- haloketones by sodium arenesulfinates via nucleophilic substitution reaction (Scheme 2.5) [66-70] However, this pathway still had drawbacks, which were prolonged reaction times, the use of expensive reagents and the limitation of commercial α-haloketones

Some reports employed special solvents like ionic liquids to dissolve sulfinate salts and to facilitate nucleophilic substitution reaction Some further problems of this method were the limitations of the reaction substrates and halide derivatives are hazardous compounds.

Sulfonylation of α-haloketones by sodium arene sulfinates via nucleophilic

If metallic sulfinates were not available, thiols could be alternative nucleophiles which reacted with α-haloketones to form β-ketosulfides These products were then treated with oxidants to generate respective β-ketosulfones (Scheme 2.6) [71-73]

Despite the popularity of thiol derivatives as starting materials, this method required stoichiometric strong oxidants and utilization of toxic halides

Oxidation of β-ketosulfides

In conclusion, these traditional approaches had same drawbacks, such as multiple syntheses, unavailable reagents, the requirement of pre-activated reagents, the use of strong additives, the disadvantage of using homogeneous catalyst and specially the limitations of the reaction substrates Therefore, it is meaningful and challenging to develop new methods that use new reagents and go through a new mechanism to obtain β-ketosulfones Such methods will be presented in the next section

Over the past years, oxidative coupling has emerged as an attractive and challenging as well as an eco-friendly and green method to construct carbon–carbon and carbon–heteroatom bonds [74] These reactions have many advantages, such as decreasing number of reaction steps, reducing waste and maximizing atom efficiency

However, they also face some challenges, one of which was utilization of stoichiometric amounts of oxidants To remedy the problems cause by using stoichiometric oxidants, they are replaced by green oxidants such as O2 [12-14]

Leading this trend in β-ketosulfones synthesis, in 2013, Lei and co-workers firstly reported that alkynes could be coupling partners to obtain β-ketosulfones through this approach Oxidative coupling reaction of alkynes and sulfinic acids with the presence of oxygen could produce β-ketosulfones (Scheme 2.7) [75] Although this approach could be carried out under a mild, metal-free and redox neutral condition, it still had drawbacks Limitation of substrate scope was one of them because this transformation seemed to be unsuitable for internal alkynes The production of pyridinium sulfonates as by-products was also a noteworthy disadvantage.

The oxidative coupling of alkynes and sulfinic acids

16 Lei’s work opened the new pathway for other groups to developed further methods using oxidative coupling strategy In 2014, Yadav and colleagues modified Lei’s report by sulfinate salts as sulfonyl sources The catalytic system of FeCl3, K2S2O8 and oxygen was employed to create β-ketosulfones (Scheme 2.8) [76] Using water as a green reaction media and avoiding the production of sulfonate by-products were valuable improvements in comparison of the previous work Nevertheless, this work employed FeCl3/K2S2O8 as a homogeneous catalyst system, which was not reusable.

The oxidative coupling of alkynes and sulfinates in aqueous media

In the same year, Yadav’s group aslo slightly modified their own method by replacing alkynes with alkenes AgNO3 was also used as a homogeneous catalyst instead of FeCl3 (Scheme 2.9) [77] The disadvantages remaining on their previous work were still unsolved.

The oxidative coupling of alkenes and sulfinates in aqueous media

Another approach with the same strategy was of Wang and co-workers β- ketosulfones were obtained in good yields by reaction of arylalkenes with sulfinic acids under FeCl2.4H2O catalysis and oxygen atmosphere (Scheme 2.10) [78].

The oxidative coupling of alkenes and sulfinic acids

These oxidative coupling of alkynes or alkenes with sodium sulfinates or sulfinic acids were generally suitable for terminal alkynes and alkenes, which means only non- α-substituted β-ketosulfone derivatives were synthesized To overcome this difficulty, other approaches were also studied, such as the research of Wang’s group In this study,

17 arylketones reacted with sodium sulfinates catalyzed by CuBr2 with the presence of base and ligand to produce β-ketosulfones (Scheme 2.11) [79] In contrast of aforementioned reports, this method had good yield in the case of α-substituted β-ketosulfones but significantly low in the case of non-α-substituted β-ketosulfones In addition, the ketones whose R1 groups (in Scheme 2.11) were electron donating groups required prolonged reaction time and the use of ligand to reach the desirable yield.

The oxidative coupling of arylketones and sulfinic sodium sulfinates to

Another strategy to prepare β-ketosulfones was the synthesis of β- sulfonylvinylamines followed by the hydrolysis of them Lautens’ method was one of them The addition of arylboronic acids to (arylsulfonyl)acetonitriles was firstly performed follow by the hydrolysis of the product in the acidic media (Scheme 2.12) [80] Despite having very good yield among the large scope of both two reagents, this approach was still a multiple synthesis This is because (arylsulfonyl)acetonitriles were not available in market and could be prepared by a two-step procedure consuming from 17 to 24 hours (Scheme 2.13).

The addition of arylboronics acids to (arylsulfonyl)acetonitriles followed

followed by the hydrolysis to prepare β-ketosulfones [80]

The two-step synthesis of (arylsulfonyl)acetonitriles

As aforementioned trend of oxidative cross-coupling reaction, besides employing oxygen as a green oxidant, utilization of internal oxidants was also a solution for the

18 recent disadvantage of using stoichiometric oxidants [5, 15-17] Oxime esters were such kind of internal oxidants, participating as both oxidant and building blocks in the reaction [3] In 2014, Jiang and co-workers applied ketoxime esters to synthesize β- ketosulfones In details, ketoxime esters reacted with sodium sulfinates under copper salt catalysis to generate β-sulfonylvinylamines β-ketosulfones were later obtained via hydrolysis similar to Lautens’ pathway (Scheme 2.14) [24] In comparison to the recent researches, having large substrate scope with high yield was a notable feature of this approach Although oxime acetates were not available in market, they could be synthesized with quantitative yields by a facile two-step procedure consuming totally only 2 hours of reaction time, using commercial cheap reagents such as hydroxylammonium chloride and acetic anhydride (Scheme 2.15) [81] Furthermore, additives such as oxidant and base were not employed so that the products were easier to be worked-up, separated and purified.

The sulfonylation of oxime acetate followed by the hydrolysis to prepare β-ketosulfones

The preparation of oxime acetates

However, this method still suffers the drawbacks of using homogeneous catalyst such as the lacking of reusability, recyclability and metal trace in the product Nowadays, the green chemistry has been increasingly interested for the more environmental purposes so that there is a need of finding alternative heterogeneous catalysts to resolve these problems And recently, metal-organic frameworks, a new class of material, have been more and more attracted because of their potential catalytic features, with the high promise to be an excellent heterogeneous catalyst for this reaction

Metal-organic frameworks (MOFs) are extended metal–ligand networks with metal nodes and bridging organic ligands, also known as coordination polymers or metal-organic coordination networks (MOCNs) [82-84] For a solid to be labeled as MOF, it should meet these following conditions: strong bonding providing robustness, linking units that are available for modification by organic synthesis, and a geometrically well-defined structure [85] Because of their special structures, MOFs have many noteworthy properties compared with other conventional porous materials

The most important characteristics of MOFs are enormous surface areas, ultrahigh porosity, tunable pore size, sustainable frameworks and predetermined structures [86]

MOFs are constructed by joining secondary building units (SBUs) with organic linkers, using strong bonds to create open crystalline frameworks with permanent porosity (Figure 2.1) [87] The great diversity of metal SBUs and organic linkers has led to thousands of MOFs being synthesized and studied These metal-containing SBUs are essential to the design of directionality for the construction of MOFs and to the achievement of robust frameworks [88] The organic units are ditopic or polytopic organic carboxylates (and other similar negatively charged molecules) Longer organic linkers provide larger storage space and a greater number of adsorption sites within a given material However, the large space within the crystal framework makes it prone to form interpenetrating structures (two or more frameworks grow and mutually intertwine together) [89]

Figure 2.1 (a) The components of MOF-5: the Zn4O(−CO2)6 SBU as an octahedron, the ditopic terephthalate linker as a rod and their assembly into the crystalline net (b) The components of HKUST-1: Cu2(−CO2)4 paddle wheel abstracted as a square, the tritopic linker as a triangle and their combination to form the crystalline net [90]

During the development of MOFs, the lack of a generally unified definition leads to several nomenclatures for MOFs [91] There are mainly three ways to name an MOF structure The first way is indicating the type of components of the material, like in the series MOF-n [92] (metal organic framework), COF-n [93] (covalent organic framework), RPF-n [94] (rare-earth polymeric framework), or MPF-n [95] (metal peptide framework) The second way is indicating the type of structure, such as ZMOF- n [96] (zeolite-like metal organic framework), ZIF-n [97] (zeolitic imidazolate framework) and mesoMOF-n [98] (mesoporous metal organic framework) And the last method is indicating the laboratory in which the material was prepared, like in the series MIL-n [99] (mate´riauxs de l’Institut Lavoisier), HKUST-n [100] (Hong-Kong University of Science and Technology), and CPO-n [101] (coordination polymer of Oslo)

21 A great number of MOF preparation methods have been found and researched: solvothermal/hydrothermal, microwave-assisted, sonochemical, electrochemical, mechanochemical, ionothermal, drygel conversion, microfluidic synthesis methods [102, 103] (Figure 2.2) The most common method generating MOFs is solvothermal synthesis (Scheme 2.16) by heating the mixture of metal salt and organic ligand in a solvent system at certain temperature [103, 104] The advantage of this method is the ability of obtaining MOFs crystals with quality high enough for their structure determination by Single Crystal X-Ray Diffraction (SC-XRD) However, this method exhibits some drawbacks such as long reaction time, difficulty in large-scale synthesis and many trials and errors are needed in order to gain crystals [102, 103, 105]

Nevertheless, other methods could also be used to overcome those obstacles such as microwave-assisted synthesis protocol [106, 107], sonochemical method [108, 109], electrochemical [102, 110, 111], mechanochemical synthesis [112, 113] Yet, these MOF preparations cannot yield the crystals of sufficient quality for their structure determination by SC-XRD as solvothermal method

Figure 2.2 The most commonly used methods for MOF preparation [114]

The general strategy of the solvothermal synthesis

Thanks to the special structure with high porosity and surface area, MOFs have a broad applications such as gas storage and separation [115, 116], drug delivery [117], biomedicine [118] and catalyst [119, 120] Recently, MOFs application in catalysis is immensely increasing, especially in heterogeneous catalysis since they can be easily separated and recycled from the reaction systems [121] Moreover, having open metal sites along with high metal content could assure its highly catalytic activity [104]

Compared with conventional inorganic homogeneous catalysts, MOFs are not only higher effective, but also more environmental – friendly [122] As a result, the number of researches related to MOFs as catalyst have significantly increased in recent years (Figure 2.3) [123]

Figure 2.3 Development of MOF catalysts in comparison to the MOF in the recent years [123]

23 In conclusion, MOF are the attractive materials with promising applications, especially in heterogeneous catalysis due to their unique feature including large internal surface areas, uniform pore and cavity sizes, and the structure containing highly open metal sites and metal content In the next section, Cu2(OBA)2BPY, a typical copper MOF, will be reviewed

1.3.2 Cu 2 (OBA) 2 BPY metal-organic framework a) Structure and properties

The as-synthesized porous frameworks can be divided into three groups, including multidimensional channels, pillared-layer architectures, and 3D nanotubular structures

Among them, pillared layer architectures have been proven to be an effective and controllable route to design 3D frameworks with large channels [124-128] Besides, helical structures have received much attention in coordination chemistry and materials chemistry, that mainly because helicity is an essence of life and is also important in advanced materials, such as optical devices, enantiomer separation, chiral synthesis, ligand exchange, biological systems and, selective catalysis [129-135] The occurrence of pillared-layer complexes with helical character is particularly rare, if any, this structure was expected to create an efficient catalyst because of its large surface area and good stabilities [136] MOF Cu2(OBA)2BPY is one of the catalyst having this complicated form, becoming a potential candidate for catalytic area MOF Cu2(OBA)2BPY was synthesized from Cu(NO3)2.3H2O, 4,4’-oxybis(benzoic acid)

4,4’-oxybis(benzoic acid) (H2OBA) is a typical example of long V-shaped ligands It has been proven to be able to bridge two or more different metal centers and produce neutral architectures because of its two oxo carboxylate groups [137-140] 4,4’- bipyridine (BPY) is an excellent candidate for rigid rodlike organic building unit and shows many interesting supramolecular architectures [141, 142] Hence, metal–organic coordination polymers constructed by mixing ligands of pyridyl groups and carboxylate groups not only incorporate interesting properties of different functional group [143], but also are more adjustive through changing one of the two organic ligands [144-147]

The coordination environment of the Cu(II) ions in Cu2(OBA)2BPY is shown in Figure 2.4 The Cu(II) ions have a trigonal bipyramid geometry formed by four carboxylate oxygen atoms and a nitrogen atom of the BPY The Cu–O bond lengths are

24 in the range 1.952(2)–2.172(2) Å and the Cu–N bond distance has a value of 1.999(2) Å

The O/N–Cu–O/N bond angles are in the range 85.86(9)–172.03(10) Å [136]

Figure 2.4 Link between Cu(II) ions and ligands in MOF Cu2(OBA)2BPY [136]

In this MOF’s structure, each OBA ligand links four Cu(II) ions and adopts a bis(bridging-bidentate) mode (Figure 2.5) The carboxylate groups of OBA ligands have connectivity with the Cu(II) cations forming an eight-membered ring chains, as shown in Figure 2.6, in which the adjacent Cu-Cu distances are alternately 3.0195 Å and 4.414 Å The connectivity between the corner-shared eight-membered ring chains is further bridged by the bent OBA ligands to produce 2D helical layers (Figure 2.7)

These adjacent helical layers are connected by BPY linkers as molecular pillars to form a novel 3D framework (Figure 2.8) [136]

Figure 2.5 The coordination modes of OBA 2- anions with metal: (I) bis(chelating bidentate), (II) bis(bridging-bidentate), (III) both bis(chelating bidentate) and bis(bridging-bidentate) [136]

Figure 2.6 The eight-membered ring chain [136]

Figure 2.8 The 3D pillared-layer structure of MOF Cu2(OBA)2BPY [136]

The most fascinating structural feature of Cu2(OBA)2BPY is that the two distinct helical chains running along the different crystallographic axis coexist in the 3D network

One type of helices is right-handed helical chains, and built from BPY bridges between the Cu centers The other type of helices is the double-stranded helices chains in the 2D helical layer and formed by the V-shaped OBA ligands bridging Cu atoms, displaying a

26 same helical orientation to the former helix A striking feature of Cu2(OBA)2BPY is the alternating interweaving of two types of helices to construct a 3D framework (Figure 2.9)

Figure 2.9 (a) The 3D network with helical channels by BPY bridges in

Cu2(OBA)2BPY viewed along the c-axis, all OBA 2- anions are omitted for clarity (b) Spacefilling diagram of the helical chains in the 2D helical layer (c) The 3D network of Cu2(OBA)2BPY viewed along the c-axis [136] b) Applications in catalysis

Cu2(OBA)2BPY was firstly synthesized by Tang and co-workers in 2008 [136]

In this report, they just presented how to form MOF Cu2(OBA)2BPY and investigated its characterization It indicated that this metal-organic framework had high thermal stability and exhibited antiferromagnetic interactions However, applications of Cu2(OBA)2BPY have not found in this article and other reports over the past years although this MOF has special structure and good properties Until the late 2014, a research about catalytic possibility of Cu2(OBA)2BPY was published [148] This opened a new direction for this material and its applications in catalysis need to be further studied

In this first article using Cu2(OBA)2BPY as heterogeneous catalyst in organic synthesis, Thanh Truong and his co-workers conducted the direct arylation of heterocycles through C-H bond activation with iodoarenes This reaction was conducted at 120 o C in 1,4-dioxane, with the benzothiazole/iodobenzene molar ratio of 1:1.2, in the presence of 2 equivalents of tBuOLi as a base and 3 mol% Cu2(OBA)2(BPY) catalyst, affording the high yield of 92 % (Figure 2.10)

Figure 2.10 Reaction of benzothiazole with iodobenzene using Cu2(OBA)2BPY catalyst [148]

This research demonstrated the potential application of MOF Cu2(OBA)2BPY in catalysis with high reaction yield and good reusability in direct arylation reaction This inspired me to further exploit Cu2(OBA)2BPY as a heterogeneous catalyst for organic synthesis to develop new protocols, which are effective and meet more requirements of green chemistry, for the constructions of important molecules

1.3.3 Our approach and objectives β-ketosulfones are an important class of compounds in organic synthesis Not only are they essential intermediates used to synthesize many kinds of organic compounds including olefins, disubstituted acetylenes, vinyl sulfones, allenes, polyfunctionalized

4H-pyrans and so on, but they also have antifungal and antibacterial activity The traditional routes to synthesize β-ketosulfones were reported as acylation of alkylsulfones, sulfonylation of silyl enol ethers, nucleophilic substitution of α- haloketones by sulfinates and oxidation of β-ketosulfides Most of them required toxic or unavailable substrates, stoichiometric amount of strong additives, multiple-step synthesis, complicated or harsh reaction conditions, prolonged reaction time and homogeneous catalysts The recent approaches based on oxidative cross-couplings appeared and gradually overcome these obstacles Nevertheless, they still need to be improved towards to the reduction of additive amounts, the reaction time and the exploitation of reusable heterogeneous catalysts

On the other hand, the porous crystalline Cu2(OBA)2BPY have recently emerged as a potential material for catalysis Their attractive structure, composed from two kinds of ligands and constructed in the integration of pillared-layer complexes and helical character, features adjustable porosity This promisingly offer high activity and versatility for Cu2(OBA)2BPY when it is used as a catalyst In addition, previous report, in which Cu2(OBA)2BPY exhibited considerable stabilities and could be reused several times without the significant loss of activity, also verify its heterogeneity and reusability

28 All of these reveal that Cu2(OBA)2BPY can possibly be an effective heterogeneous catalyst for organic synthesis; however, there is still very few catalytic study on it

Synthetic pathway to ketoxime esters

Commercial sodium sulfinates were purchased from suppliers and were used as received without further purification Other sulfinate salts were prepared from their corresponding sulfonyl chlorides by the following procedure (Scheme 2.18).

Reaction to synthesize sodium sulfinates

A mixture of sulfonyl chlorides (20 mmol), sodium sulfite (5.04 g, 40 mmol) and sodium bicarbonate (3.36 g, 40 mmol) were heated and magnetically stirred in water (20 mL) at 80 o C for 8 h After cooling to room temperature, water was removed under vacuum Recrystallization of the residues in ethanol afforded the sodium sulfinates

In a typical catalytic experiment, a mixture of 1-(thiophen-2-yl)ethanone O- acetyl oxime (0.25 mmol, 45.8 mg), sodium benzenesulfinate (0.3 mmol, 49.2 mg), Cu2(OBA)2BPY (10 mol %) in chlorobenzene (1 mL) was added to a 8 mL screw-cap vial with magnetic stirrer bar The catalyst amount was calculated regarding the copper/1-(thiophen-2-yl)ethanone O-acetyl oxime molar ratio The mixture was stirred at 100 °C for 3 h under an argon atmosphere

The GC yield of enamine product were monitored by withdrawing aliquots from the reaction mixture, quenching with brine (1 mL), extracting with ethyl acetate (3 x 1 mL), drying over anhydrous Na2SO4 and being analyzed by GC with reference to n- dodecane After the completion of the reaction, the mixture was cooled to room temperature

2.3.3 Investigation of the heterogeneity and reusability of catalyst

For the leaching test, the 1 st catalytic reaction was stopped after 3 h, monitored the yield by GC, filtered to remove the solid catalyst, and transferred to a new reactor Two reagents and was then added, and the resulting mixture was then stirred for further 3 h, at 100 o C under argon atmosphere and monitored the yield by GC No significant amount of product would increase after the removal of the solid catalyst if this reaction proceeded under real heterogeneous catalysis

To investigate the reusability of Cu2(OBA)2BPY, it was filtered from the reaction mixture after 3 h, then washed with copious amounts of DMF and methanol, dried at 150 o C under vacuum in 6 h prior to being employed for the next run under the identical conditions to the initial one The reused catalyst was also characterized by XRD and FT- IR

For isolation of enamine products, after the reaction as described above was completed The resulting mixture was quenched with brine (5 mL), and the organic components were extracted into ethyl acetate (3 x 5 mL) The combined ethyl acetate solution was dried over anhydrous Na2SO4 The solvent was subsequently removed under vacuum, and the crude enamine product was purified by recrystallization in chlorobenzene and hexane Product structures were subsequently confirmed by GC-MS,

1H NMR, and 13 C NMR (see Appendices for characterization data of products)

In order to achieve β-ketosulfones, enamine products were not isolated after the first step The reaction mixture was cooled to room temperature and filtered to remove the Cu2(OBA)2BPY catalyst The filtrate was then magnetically stirred with aqueous HCl solution (1M, 1 mL) at 80 o C for 3 h After the completion of hydrolysis step, the reaction mixtures were worked-up like previously described The crude products were purified by silica gel column chromatography utilizing hexane and ethyl acetate (3:1, v/v) as eluent to obtain the expected -ketosulfones Product structures were subsequently confirmed by GC-MS, 1 H NMR, and 13 C NMR (see Appendices for characterization data of products)

Preparation and characterization of Cu 2 (OBA) 2 BPY

3.1.1 Synthesis of Cu 2 (OBA) 2 BPY

Cu2(OBA)2BPY was synthesized according to a slightly modified literature procedure (Figure 2.12) After the solvent exchange and activation, the desolvated Cu2(OBA)2BPY was yielded The dark green crystals were obtained about 0.298 g, yielding 75%

Figure 2.12 Synthesis of Cu2(OBA)2BPY

3.1.2 Characterization of Cu 2 (OBA) 2 BPY

To confirm whether Cu2(OBA)2BPY had been synthesized successfully or not, the activated framework was checked by P-XRD technique As shown in Figure 2.13a, a very sharp peak at 8 o was observed in the diffractogram of Cu2(OBA)2BPY, indicating that a highly crystalline of material was obtained The result was also similar to the simulated patterns previously reported in the literature (Figure 2.13b)

Figure 2.13 Powder X-ray diffraction patterns of Cu2(OBA)2BPY a) The activated

Cu2(OBA)2BPY; b) The simulated Cu2(OBA)2BPY

Furthermore, Cu2(OBA)2BPY was also characterized by FT-IR, SEM, TEM, TGA and nitrogen physisorption measurement, and the results were showed in the Appendices

The reaction of (1a) with (2a) in the presence of Cu2(OBA)2BPY as catalyst was considered as the model reaction for catalytic studies (Scheme 2.19) According to the report of Jiang and co-workers [24], 0.25 mmol of 2.1a, 1 equivalent of 2.2a, 10% mol

35 of Cu2(OBA)2BPY in 1 mL of toluene at the temperature of 100 o C for 3 h under an argon atmosphere were chosen as the starting point

Various parameters including type of solvents, ratio of reactants, catalyst amounts, reaction durations, temperatures and solvent amounts were investigated in sequence to determine the factors that favor the formation of the desired product

Furthermore, to demonstrate outstanding features of Cu2(OBA)2BPY in this reaction, its activity was also compared to those of several homogeneous and heterogeneous catalysts.

The model reaction for optimization

a) Effect of temperatures on the reaction yield

Initial studies were aimed at the influence of temperature on the generation of

2.3aa The reaction was performed in 1 mL toluene at 10 mol% catalyst for 3h, with

(2.1a)/(2.2a) molar ratio of 1:1, at ambient temperature, 60 o C, 80 o C, 100 o C, 120 o C

Figure 2.14 Effect of temperatures on the reaction yield

36 The reaction could not occur at room temperature or 60 o C, and no trace of 2.3aa was recorded after 3h Boosting the temperature to 80 o C offered 10% yield after 3h As anticipated, increasing the reaction temperature led to a significant improvement in the yield of the expected product Best result was achieved for the reaction conducted at 100 oC, with 60% yield 2.3aa being obtained after 3h However, the GC yield was not improved at the temperature higher than 100 o C Therefore, 100 o C was the most suitable for this reaction

This reaction proceeded via radical mechanism (see subpart 3.2.3 in page 44 for details) and the radical formation significantly depended on temperature Therefore, temperature under 100 o C might be not enough to form free radicals from either 1a or

2.2a, resulting in the very poor formation of the product Exceeding temperature to 100 oC or above was possibly enough to generate radicals of both reactants since the reaction yield was improved considerably Indeed, according to many reported in the literature [24, 29, 35, 150-152], oxime acetates in this kind of reaction generally required temperatures from at least 100 o C b) Effect of reactant molar ratios on the reaction yield

The next parameter to be investigated was the effect of the reactant molar ratio on the reaction yield The reaction was performed at 100 o C with toluene as solvent in the presence of 10 mol% Cu2(OBA)2BPY catalyst with 2.1a/2.2a molar ratios of 2:1, 1:1,

Figure 2.15 Effect of reactant molar ratio on the reaction yield

It was found that reagent molar ratio only exhibited a small effect on the yield of desired product Using 1 equivalent of 2.2a, the oxidative coupling reaction proceeded to 60% yield after 3 h The increase in the amount of 2.2a led to an enhancement in the yield of 2.3aa The Cu2(OBA)2BPY-catalyzed coupling reaction afforded to 68% yield after 3 h with 1.2 equivalents of 2.2a, while 69% yield was observed after 24 h for the reaction using 1.5 equivalents With 2.1a/2.2a molar ratio was 2:1, the reaction yield remained unchanged value, 69% As a result, the reactant molar ratio of 1:1.2 was exploited for further experiments c) Effect of different solvents on the reaction yield

The solvent could exhibit a significant impact on the reaction rate for organic transformations carried out in the presence of solid catalysts Consequently, the impact of solvents on the copper-catalyzed coupling between 2.1a and 2.2a to generate 2.3aa was examined The reaction was conducted at 100 o C for 3 h, with 2.1a/2.2a molar ratio of 1:1.2 with 10 mol% of catalyst in different organic solvents (Figure 2.16)

Figure 2.16 Effect of different solvents on the reaction yield

Both protic and aprotic polar solvents including n-butanol, ethyl acetate, DMSO and DMF were found to be inappropriate for the reaction, only generating product in modest yields (2%-36%) after 3 h Changing to 1,4-dioxane could improve the yield to 65% More importantly, aromatic solvents obviously favored the formation of the expected product In details, reactions conducted in mesitylene and toluene afforded approximately 65% yield while yields around 85% were obtained by using o-, m-, and p-xylene In particular, chlorobenzene was revealed as the solvent of choice for this reaction with 87% yield being achieved after 3 h

Our results shared similarities to those of the previous report by Jiang and co- workers [24] In their homogeneous protocol, toluene, an aromatic solvent, exhibited the best performance for the reaction of acetophenone oxime acetate and sodium p- toluenesulfinate, yielding product in 95% Non-aromatic solvents like DMSO and DMF also gave significantly lower yields d) Effect of reactant concentrations on the reaction yield

In many reactions, using various concentrations of reactant can affect the reaction rate Therefore, concentration of reactant was the next factor to be investigated The reaction was studied at 0.05 M, 0.083 M, 0.1 M, 0.125 M, 0.167 M, 0.25 M and 0.5 M of 2.1a corresponding to 5 mL, 3 mL, 2.5 mL, 2 mL, 1.5 mL, 1 mL, and 0.5 mL of

39 chlorobenzene used The reaction was performed at 100 o C, using reagent molar ratio of 1:1.2, in the presence of 10 mol% catalyst for 3 h

Figure 2.17 Effect of reactant concentrations on the reaction yield

It was indicated that our protocol worked well in high concentrations In specific, high yields of 86% and 87% were achieved at 0.25 M and 0.5 M of 2.1a respectively

The reaction was; however, decelerated dramatically at 0.167 M with less than 40% of product being yielded Indeed, decreasing the concentrations from 0.125 M to 0.05 M generally further decrease the reaction yield from 33% to 8% Because 2.2a had low solubility in chlorobenzene, stirring process seemed to be instable when employing low amount of chlorobenzene Therefore, 0.25 M of 2.1a corresponding to 1 mL of chlorobenzene was chosen for further studies e) Effect of catalyst amount on the reaction yield

Another factor that was previously indicated as a significant effect on the oxidative coupling of 2.1a and 2.2a was the catalyst amount The reaction was carried out in 1 mL chlorobenzene at 100 o C for 3 h, using 2.1a/2.2a molar ratio of 1:1.2 in the presence of 1 mol%, 2.5 mol%, 5 mol%, 7.5 mol% and 10 mol% catalyst respectively (Figure 2.18)

Figure 2.18 Effect of catalyst amount on the reaction yield

It should be noted for Figure 2.18 that no product was detected in the absence of the catalyst, indicating the importance of Cu-MOF for the reaction The presence of Cu2(OBA)2BPY, even in a small amount of 2.5 mol%, obviously accelerated the reaction with 68% of product being yielded As expected, the product formation could be further improved by using more catalyst In details, rising the catalyst from 2.5 mol% to 10 mol% increased the yield from 68% to 87% Nevertheless, exceeding 10 mol% catalyst was found unnecessary since no improvement was observed Despite exploiting solid catalyst, our protocol exhibited the comparable effectiveness to that of the previous report by Jiang and co-workers, in which homogeneous catalyst Cu(OAc)2 was employed with the amount of 10 mol% and afforded 95% yield [24] f) Effect of reaction times on the reaction yield

With these results in mind, we then investigated the effect of the reaction time on the yield of 2.3aa The oxidative coupling reaction between 2.1a and 2.2a with the molar ratio of 1:1.2 was carried out in 1 mL chlorobenzene at 100 o C under an atmosphere of argon for 3 h, in the presence of 10 mol% Cu2(OBA)2BPY catalyst, for 20, 40, 60, 90, 120, 180, 240 and 300 minutes of reaction time, respectively (Figure 2.19)

Figure 2.19 Effect of reaction times on the reaction yield

Figure 2.19 presented that most reactants was converted to the product (79% yield) in a roughly constant rate for the first two hours This increment in yield; however, significantly slowed down in the next hour and reached the value of 87% yield at 180 min No more product was produced in the last two hours The reaction was therefore carried out for 3 h in next experiments Interestingly, the reaction time of 3 h as in our work can be considered as an improvement as compared to that of 4 h under homogeneous catalysis reported by Jiang and co-workers [24] g) Summary of condition screening

Cu2(OBA)2BPY was demonstrated as an efficient heterogeneous catalyst for the synthesis 2.3aa via oxidative coupling of 2.1a and 2.2a Various parameters that affected the reaction were optimized for reaching the best reaction condition The reaction was conducted in chlorobenzene at 100 o C under argon for 3 h, in the presence of 10 mol% Cu2(OBA)2BPY as catalyst, with 1.2 equivalents of 2.2a, at 2.1a concentration of 0.25 M, the best performance was observed for this kind of reaction with the yield of 87% (Scheme 2.20)

The optimal reaction conditions

3.2.2 Investigation of reaction catalyzed by different catalysts

To emphasize the advantages of using Cu2(OBA)2BPY as catalyst for the reaction of 2.1a with 2.2a to form 2.3aa, the catalytic activity of Cu2(OBA)2BPY was compared to that of other MOFs including MOF-199, Cu2(BPDC)2DABCO, Cu2(BPDC)2BPY, Cu(OBA) and VNU-18 The oxidative coupling reaction was carried out in 1 mL chlorobenzene at 100 o C under argon for 3 h, in the presence of 10 mol% catalyst using 2.1a/2.2a molar ratio of 1:1.2

On the one hand, MOFs constructed by two ligands including Cu2(OBA)2BPY, Cu2(BPDC)2DABCO and Cu2(BPDC)2BPY were more highly active than those composed of one ligand namely MOF-199, Cu(OBA) and VNU-18 In details, the formers yielded the product in 71-87% while the product was generated by the latters in 8%-55% It should be noted that the presence of OBA ligand in MOF structure could possibly enhance its activity for this reaction For instances, Cu(OBA) that afforded 55% yield exhibited remarkably superior effectiveness to those of MOF-199 and VNU-18 with less than 10% yield being obtained Similarly, Cu2(OBA)2BPY performed more efficiently than Cu2(BPDC)2DABCO and Cu2(BPDC)2BPY did, resulting in 87% yield as compared to 71% and 74% given by the latters In summary, Cu2(OBA)2BPY was presented as the most effective catalyst for the oxidative coupling of 2.1a and 2.2a to form 2.3aa among examined MOFs (Figure 2.20)

Figure 2.20 Comparison of catalytic activity of Cu2(OBA)2BPY to other copper-based MOFs

The catalytic activity of Cu2(OBA)2BPY in the oxidative coupling of 2.1a and

2.2a to form 2.3aa was also compared to that of common homogeneous copper catalysts, including Cu(OAc)2, Cu(NO3)2, CuBr, CuCl, CuCl2 and CuBr2 The oxidative coupling reaction was carried out in chlorobenzene at 100 o C under argon for three hours, using a 2.1a/2.2a ratio of 1:1.2 in the presence of 10 mol% copper catalyst (Figure 2.21)

It was possible to reveal that Cu (II) salts showed higher activity for this reaction than those of Cu (I) species In specific, reactions employing Cu2(OBA)2BPY and Cu(OAc)2 afforded more than 70% yield, whereas yields less than 65% were observed by using CuCl and CuBr Cu(NO3)2 was Cu (II) salt but it gave low yield (only 19%) maybe because halogen anions and acetate anion were more suitable than nitrate anion for this transformation More importantly, in spite of being a solid catalyst, Cu2(OBA)2BPY offered a better performance than those of investigated copper salts, again emphasizing the considerable efficiency of Cu2(OBA)2BPY for this reaction

Figure 2.21 Comparison of catalytic activity of Cu2(OBA)2BPY to other copper- based homogeneous catalysts

The next information that should be found out was the reaction mechanism To gain more information about the pathway of the reaction, (2,2,6,6-tetramethylpiperidin- 1-yl)oxy (TEMPO) was utilized as a radical scavenger In the first experiment, the reaction was carried out under optimal condition and TEMPO was added at the beginning of the reaction, and no trace amount of product was detected In the second experiment, after the first 1 h reaction time, TEMPO was introduced to the reactor, and the reaction mixture was magnetically stirred under argon at 100 o C for further 2 h

Under is condition, no additional 2.3aa product was observed It was noted that the transformation was considerably affected by this radical scavenger These observations verified that radical species should be involved in the catalytic cycle

With these data, and based on previous report [24], a plausible pathway was proposed (Scheme 2.21) Initially, a copper enamine intermediate was produced from the oxime acetate, while copper (II) were oxidized to copper (III) species A sulfonyl free radical was then formed via a single-electron-transfer (SET) process, releasing the copper (II) species Next, the sulfonyl free radical attacked to the enamide intermediate, followed by the regeneration of the copper(II) species Finally, tautomerization of the imine intermediate afforded the corresponding β-sulfonylvinylamine

Proposed reaction mechanism

3.2.4 Investigation of homogeneity and reusability of Cu 2 (OBA) 2 BPY a) Leaching test

As the oxidative coupling of 2.1a and 2.2a to form 2.3aa, Cu2(OBA)2BPY catalyst was performed in liquid phase, the possibility that some of catalytically active sites on the solid Cu-MOF could migrate into the solution during the course of the reaction should be addressed In several cases, although a solid catalyst was initially employed, the transformation would not proceed under real heterogeneous catalysis conditions due to the leaching problem [153] In order to verify if active copper species dissolved from the solid Cu2(OBA)2BPY catalyst, if any, contributed significantly to the formation of 2.3aa via the oxidative coupling reaction, a control experiment was carried out using a simple centrifugation during the course of the reaction

The oxidative coupling reaction was carried out in chlorobenzene at 100 oC under argon for 3 h, in the presence of 10 mol% Cu2(OBA)2BPY catalyst, using 2.1a/2.2a molar ratio of 1:1.2 After 3 h reaction time, the solid

46 Cu2(OBA)2BPY was separated from the reaction mixture by centrifugation The reaction solution was transferred to a new reactor vessel, followed by adding 1a and 2.2a The mixture was then stirred for further 3 h at 100 o C under argon It was found that no significant amount of product was yielded after the removal of the catalyst (Figure 2.22) Furthermore, the reaction solution obtained after the separation of the catalyst was also analyzed by ICP-MS, revealing the presence of a negligible amount of copper (< 1.6 ppm) It was therefore proposed that there was no considerable contribution of leached active copper species, if any, to the formation of 2.3aa, and the reaction occurred under real heterogeneous catalysis

Figure 2.22 Leaching test results compared to optimal condition b) Reusability test

To further explore the advantages of using the Cu2(OBA)2BPY catalyst in the oxidative coupling of 2.1a and 2.2a to form 2.3aa, the reusability of this copper- based MOF should be investigated When using a solid catalyst for organic reactions, it is expected that the catalyst can be recovered and reused many times before it eventually deactivates completely

10% mol of catalystLeaching test

Figure 2.23 The reutilization of the catalyst

The initial oxidative coupling of 2.1a and 2.2a was carried out in chlorobenzene at 100 o C under argon, in the presence of 10 mol% Cu2(OBA)2BPY catalyst, using

2.1a/2.2a molar ratio of 1:1.2 After 3 h, the catalyst was separated from the reaction mixture by simple centrifugation, washed with copious amounts of DMF and methanol, then activated under vacuum at 150 o C for 3 h The recovered Cu2(OBA)2BPY catalyst was reused for the next run occurring under identical conditions to those of the first run Experimental indicated that the Cu2(OBA)2BPY catalyst could be recovered and reused at least 9 times in this reaction without a significant degradation in catalytic activity Indeed, 86% yield of 2.3aa was still achieved in the 10 th run In addition, the structure of the reused Cu2(OBA)2BPY catalyst was also characterized by FT-IR (Figure 2.24) and XRD (Figure 2.25) , presenting a trivial difference from the fresh Cu2(OBA)2BPY

Figure 2.24 FT-IR analyses of the new (a) and recovered (b) catalyst

Figure 2.25 XRD determination of the new (a) and recovered (b) catalyst

3.2.5 Expansion of the substrate scope

With the significance of β-ketosulfones in pharmaceutical and agrochemical industries, we expanded the work to achieve these valuable structures via a hydrolysis step The reaction was performed at 100 o C in chlorobenzene under argon for 3 h, with 1.2 equivalents of sodium sulfinates and reactant concentration of 0.25 M, in the presence of 10 mol% catalyst After that, the catalyst was filtered off, the reaction mixture was treated with aqueous HCl solution, and the expected β-ketosulfones was

49 purified by silica gel column chromatography (Scheme 2.22) The results of these experiments were showed in Table 2.1 (see Appendices for characterization data of products).

Expansion of the substrate scope

Table 2.1 Synthesis of β-ketosulfones via Cu2(OBA)2BPY-catalyzed direct C-S coupling reaction followed by hydrolysis step Entry Reactant 1 Reactant 2 β-ketosulfone product 4

Following this procedure, 2.4aa was obtained in 76% yield (Entry 1)

Subsequently, catalytic activity of Cu2(OBA)2BPY was tested on ketoxime esters of phenyl ketones (Entry 2 to 7) Ketoxime esters with electron donating groups (Entry 2 to 5) were more favorable for this transformation 4-methyl, 4-methoxy, 3-methoxy and 2-methoxy substrates were tested, generating 2.4ba, 2.4ca, 2.4da and 2.4ea with 88%, 91%, 89% and 83% respectively Ketoxime esters 2.1f and 2.1g having electron withdrawing groups (Entry 6 and 7) were less reactive, yielding product 2.4fa and 2.4ga in 76% and 80% In the next two entries, more specific ketoxime acetates were employed

In particular, ketoxime acetates of 2-acetylpyridine 2.1h and α-tetralone 2.1i yielded respective products in good yields (80% and 82%)

In the next series of experiments, catalytic activity of Cu2(OBA)2BPY on variety of sodium sulfinate salts was surveyed (Entry 10 to 14) Substrates with electron donating groups were more favor than ones with electron withdrawing group 4- methoxy compound 2.2b generated the corresponding product 2.3ba with excellent yield (90%, Entry 10) 4-halo subtrates 2.2c and 2.2d (Entry 11 and 12) showed less reactivity with 78% and 65% yield recorded Cu2(OBA)2BPY also worked on naphthyl- and ethyl- substituted sulfinates with good yields (Entry 13 and 14)

A porous material Cu2(OBA)2BPY was synthesized The characterizations of Cu2(OBA)2BPY were achieved by a variety of different techniques, including TGA, FT- IR, SEM, TEM and nitrogen physisorption measurements These results revealed that Cu2(OBA)2BPY in this work has successfully been synthesized and its properties was comparable to previously reported studies

After screening reaction conditions, the catalytic activity of Cu2(OBA)2BPY was compared to other catalysts and showed higher result In particular, leaching and reusing tests not only confirmed the heterogeneous catalysis for this reaction by Cu2(OBA)2BPY but also presented its reusability Indeed, Cu2(OBA)2BPY could be reused at least 9 times without a significant degradation of activity or structure Cu2(OBA)2BPY activity was also tested on a broad substrate scope, yielding wide range of β-ketosulfones in good to excellent yields As compared to the previous report, our work was improved in terms of reaction time and exploitation of reusable catalyst

Besides results achieved, this report still contains limitations that are needed to be researched in the future: The expansion in scope and scale-up test for this protocol should be carried out; and the exploitation of Cu2(OBA)2BPY should be broaden to other organic synthesis and especially in ketoxime ester chemistry

Chapter 3 - A novel pathway to furo[3,2, c ]coumarins via ketoxime esters

Coumarin scaffolds is a vital class of heterocyclic compounds and received major attention from organic chemists due to their existence in numerous natural products, bioactive compounds, pharmaceuticals, food additives, and functional materials [154- 158] Besides, the furans are also privileged heterocyclic skeletons, presenting in a wide range of bio-active natural and unnatural compounds [159-162] Furan derivatives also serve as building blocks of many pharmaceutical agents [163]

Furocoumarins or furanocoumarins are heterocyclic systems containing a furan ring fused to coumarin The furan may be fused in different ways producing several isomers (Figure 3.1) Some reports pointed out that the fusion of furan and coumarin heterocyclic moieties would introduce unique biological activities and pharmacological properties like antimicrobial, insecticidal, antiarrhythmic, antimalarial and sedative [164-166]

Figure 3.1 Structures of some synthetic furanocoumarins

Some furocoumarin derivatives which have noticeable biological properties rarely found in nature Thus, more efforts have been performed to establish new synthetic methods toward this type of compounds Furo[3,2-c]coumarins are one of the most common representatives of this class and the synthetic pathways of this scaffolds will be reviewed in the next part

By retrosynthetic analysis, 4-hydroxycoumarins is one of possible building blocks to construct furo[3,2-c]coumarin skeletons Because of commercial availability as well as a facile preparation from readily accessible reactants and reagents (Scheme 3.1) [167], 4-hydroxycoumarins have emerged the most common starting materials for furo[3,2-c]coumarin synthesis.

A possible synthetic pathway of 4-hydroxycoumarins from available

The conventional synthesis of furo[3,2-c]coumarins from 4-hydroxycoumarins employed α-haloketones as coupling partners In particular, nucleophilic substitution reaction between these two compounds was performed then intramolecular 5-exo-trig cyclization of resulting compounds were carried out to obtain furo[3,2-c]coumarins under acid or base catalysis (Scheme 3.2) [168-173] This strategy was the most simple way to synthesize furo[3,2-c]coumarins from 4-hydroxycoumarins, but it still had some drawbacks First, this transformation required α-haloketones as pre-functionalized reactants Moreover, although α-haloketones are commercially available, their synthesis had a low regioselectivity for α-halogenation of ketones having two α-positions, leading to the difficulty of separation of isomer mixtures and high prices of these halogen derivatives.

Conventional synthesis of furo[3,2-c]coumarins from 4-hydroxycoumarins

55 Ketones with other good leaving groups like tosylate at α-position were also candidates for this cyclization In 2012, Kumar and co-workers successfully prepared α- tosyloxyketones from ketones and [hydroxy(tosyloxy)iodo]benzene prior to use them for synthesis of furo[3,2-c]coumarins (Scheme 3.3) [174] This was an alternative method which avoided the use of halogen derivatives However, the utilized hypervalent iodine is a costly compound, reducing the economic efficiency of this transformation.

Synthesis of α-tosyloxyketones from hypervalent iodine followed by

In general, the domino reactions of nucleophilic substitution and aldolization gave a simple way to furo[3,2-c]coumarins Nevertheless, this approach still required pre-functionalized compounds and costly reagents so that there was a need of developing new methods to overcome these obstacles

4-hydroxycoumarins are enol derivatives so they can tautomerize into ketone type to become 1,3-ketoester compounds having activated methylene groups The 1,3- dicarbonyls can react with aldehydes via aldol condensation under base catalysis These resulting compounds were key intermediates for the construction of furo[3,2- c]coumarins through [4+1] cycloaddtion (Scheme 3.4).

Aldehydes as C-3 sources for construction of furo[3,2-c]coumarins

Isocyanides were the most popular partners for the ring closures following this strategy (Scheme 3.5) The one-pot method including aldol condensation of 4- hydroxycoumarins and aldehydes and [4+1] cycloaddition with isocyanides was firstly

56 reported by Nair and co-workers in 2002 Three components were refluxed in benzene for 16 to 24 hours to afford desired products in moderate to good yields [175] A new pathway was reported with the success in preparing from furo[3,2-c]coumarins available reactants However, this transformation was carried out under harsh condition and used benzene, a very toxic solvent Therefore, some similar reports tried to improve the reaction conditions In 2013, Shaabani’s group replaced benzene by water as a greener solvent [176] A year later, this transformation was further made better with a significant decrease in the reaction time by Shaabani’s and co-workers when was performed by microwave-assisted K10 catalysis under solvent-free condition [177] In the same period of time, Wu also conducted this reaction in DMF under microwave irradiation and achieved the same improvements [178] In 2015, this three-component transformation could met as many green chemistry principles as possible when Sharma and co-workers reported a catalyst-free, solvent-free, microwave-assisted and high yielding synthesis [179] However, there was still a drawback that this method was only suitable for preparation of 3-aryl-4-amino furo[3,2-c]coumarins; consequently, other methodologies should be developed to synthesize more general furo[3,2-c]coumarins.

Isocyanides as ring-closure partners

Phosphine zwitterions has gained much attention from chemists owing to both their interesting specific properties and their potential application in organic synthesis [180] In 2012, Lin’s group utilized phosphine zwitterions prepared by reaction of the aforementioned aldol products and tributylphosphine to open a novel two-step route to furo[3,2-c]coumarins Quantitative yields of phosphine zwitterions were obtained after the first step In the second step, furo[3,2-c]coumarins was obtained in good to excellent yield by the treatment of the zwitterions with acyl chlorides in the presence of triethylamine (Scheme 3.6) [181] High yields among a large substrate scope was a remarkable feature of this pathway in comparison of previous approaches Nevertheless,

57 there was a trade-off between efficiency and the use of additives, reactive acyl chlorides and multiple-step strategy.

Furo[3,2-c]coumarin synthesis via phosphine zwitterions

In 2012, Shafiee and co-workers observed that an unexpected furo[3,2- c]coumarin was obtained in small amount through sequential transformation including hydrolysis, decarboxylative halogenation, 5-exo-tet cyclization and oxidative aromatization when dicoumarol was prepared by condensation of 4-hydroxycoumarin and formaldehyde in the presence of iodine (Scheme 3.7) This interesting result inspired the authors to develop a general route to access these furo[3,2-c]coumarin derivatives After screening of reaction conditions, a novel one-pot two-step method was described Biscoumarins were firstly produced by reaction of 4-hydroxycoumarins and aldehydes under iodine catalysis The resulting mixtures were then treated with K2S2O8 and Na2CO3, generating 4-(2-hydroxybenzoyl)-4H-furo[3,2-c]coumarins (Scheme 3.8) [182].

One-pot pseudo three-component synthesis of furo[3,2-c]coumarins

58 In 2015, Wu, Liu and co-workers improved the conditions of this fascinating reaction by performing the reaction in only one step as well as utilizing greener CuBr2/O2 catalytic system instead of the use of iodine as a promoter and K2S2O8 as a stoichiometric oxidant (Scheme 3.9) [183]

Scheme 3.9 One-pot synthesis of furo[3,2-c]coumarins under CuBr2/O2 catalytic system [183]

1.2.3 Cyclization with β -nitrostyrenes as Michael acceptors

In the presence of base, the ketone type of 4-hydroxycoumarins can be deprotonated at C-3 position, making these heterocycles be good nucleophiles as well as Michael donors Michael addition of C-3 to Michael acceptors followed by cyclization could be applied as an efficient method to construct furo[3,2-c]coumarins β-nitrostyrenes are readily available compounds and commonly used as reactive

Michael acceptors, so they were utilized as main Michael acceptors for this pathway

In 2012, Chen’s group reported the cyclization of 1,3-dicarbonyls and nitroallylic acetates with the presence of base for synthesis of furans via Feist–Bnary addition- elimination This method was also effective for the case of 4-hydroxycoumarins, forming furo[3,2-c]coumarin scaffolds (Scheme 3.10) [184].

Cyclization of 4-hydroxycoumarins and nitroallylic acetates with the

Brahmbhatt and co-workers employed non-pre-functionalized β-nitrostyrenes for this kind of reaction in 2013 The cyclizations of 4-hydroxycoumarins and β- nitrostyrenes were performed in methanol under microwave-assisted piperidine

59 catalysis (Scheme 3.11) [171] Various furo[3,2-c]coumarins were synthesized in moderate yields ranging from 64% to 75% However, the research did not mention the synthesis of 4-substituted furo[3,2-c]coumarins.

Cyclization of 4-hydroxycoumarins and β-nitrostyrenes under microwave

In 2015, Samanta and co-workers reported a selective synthesis of furo[3,2- c]coumarins by reaction of 4-hydroxycoumarins and nitroallylic alcohols Furo[3,2- c]coumarins were preferred when the reaction was carried out in water under catalyst- free condition On the other hand, pyrano[3,2-c]coumarins were produced as main products in DMSO and L-proline catalyst (Scheme 3.12) [185].

Selective synthesis of furo[3,2-c]coumarins by reaction of 4-

Wang and co-workers pointed out that 4-arylideneamino-4H-furo[3,2- c]coumarins could be also synthesized by this strategy via four-component reactions In details, besides 4-hydroxycoumarins and β-nitrostyrenes, arylaldehydes and ammonium acetate were also utilized as reactants for this transformation (Scheme 3.13) [186]

Four-component reaction producing furo[3,2-c]coumarins

4-hydroxycoumarin derivatives could give three atoms for the five-membered ring furans so alkenes are plausible candidates to build two other apexes The first strategy to construct furo[3,2-c]coumarins from 4-hydroxycoumarin and alkenes was based on the oxidative addition of active methylene compounds to electron-rich alkenes promoted by metal oxidants like cerium (IV) ammonium nitrate (CAN) or manganese (III) acetate (Scheme 3.14) [187, 188] Substituted dihydrofuro[3,2-c]coumarins were produced in moderate to high yields regarding to substituents The use of stoichiometric metallic oxidants was a notable disadvantage of this approach.

Oxidative addition of 4-hydroxycoumarins to electron-rich alkenes

The disadvantage of previous approaches was addressed by report of Pan, Chen and co-workers in 2015 The oxidative cyclization between 4-hydroxycoumarins and alkenes was catalyzed by palladium (II) via aerobic oxidation, generating dihydrofuran intermediatates which subsequently underwent oxidative aromatization to form final products (Scheme 3.15) [189] 4-aryl- and 3,4-diaryl-substituted furo[3,2-c]coumarins were synthesized from 70% to 85% yields It was notable that alkylethylenes were unsuitable for this transformation owing to the fact that no product was obtained when 1-heptene was used

Aerobic oxidative cyclization of 4-hydroxycoumarins and alkenes

Along with 4-hydroxycoumarins, pre-functionalized 4-hydroxycoumarins were also a possible building blocks for the synthesis of furo[3,2-c]coumarins Pre- functionalization of 4-hydroxycoumarin at C-3 position would enhanced the reactivity of these molecules and enable them to react with more kinds of reagents to construct furo[3,2-c]coumarins In this field, terminal alkynes, were the most common coupling partners and reactions were generally carried out through organometallic pathways under noble transition metal catalysis

In 2001, 3-diazo-4-hydroxycoumarins and terminal alkynes were employed for furo[3,2-c]coumarin preparation via heterocyclization catalyzed by rhodium (II) (Scheme 3.16) [190] This was the first research to use alkynes to synthesize furo[3,2- c]coumarins Nevertheless, modest yields of the desired products were obtained and the selectivity was low due to the production of furo[2,3-b]coumarins as side-products via the cyclization of C-2, C-3 and alkynes.

Cyclization of 3-diazo-4-hydroxycoumarins and terminal alkynes

The production of furo[2,3-b]coumarin by-products was avoided through Monteiro’s publication in 2009 In this report, 3-alkynyl-4-methoxycoumarins were firstly prepared from respective 3-iodo-4-methoxycoumarins and terminal alkynes under PdCl2(PPh3)2/CuI catalytic system Subsequently, the resulting derivatives participated in reaction with aryl halides catalyzed by Pd(PPh3)4, finally generating di- substituted furo[3,2-c]coumarins (Scheme 3.17) [191] Although this pathway

62 overcame the drawback of the previous method and a wide range of multi-substituted furo[3,2-c]coumarins were prepared in good yields but it was a multiple-step synthesis so required the isolation of the intermediates.

Two-step synthesis of furo[3,2-c]coumarins catalyzed by palladium

Another improvement of the research in 2001 was the work of Xu’s group in 2010 Instead of 3-diazo-4-hydroxycoumarins, 3-bromo-4-acetoxycoumarins were employed as building blocks for this transformation These compounds underwent the Pd/Cu-catalyzed reaction with dialkynylzincs generated in situ from terminal alkynes and dimethylzinc (Scheme 3.18) [192] One-pot synthesis, high yields of products and no side-product were strong points of this method compared to the two previous approaches.

Sequential Pd/Cu-catalyzed alkynylation and intramolecular

Based on their previous study in synthesis of poly-substituted furans using visible-light-promoted alkyne insertion with 2-bromodicarbonyls, Tan, Yu and co- workers expand this potential synthetic pathway to coumarin-fused furans An iridium complex were used as a photo-catalyst for the reaction of 3-bromo-4-hydroxycoumarins and terminal alkynes in the presence of base (Scheme 3.19) [193] Milder conditions and large substrate scope with high yields were remarkable points of this transformation

Visible-light-promoted iridium-catalyzed alkyne insertion with 3-bromo- 4-hydroxycoumarins followed by annulation

bromo-4-hydroxycoumarins followed by annulation [193]

The most recent study to utilize terminal alkynes for the construction of furan- fused coumarins was of Hajra’s group in 2017 The authors used iron and zinc, first-row transition metals, instead of the noble metals to catalyze the aerobic oxidative annulation of un-activated 4-hydroxycoumarins and terminal alkynes (Scheme 3.20) [194] In spite of being performed under high temperature, the replacement of late transition metals by first-row transition metals and the use of non-pre-functionalized derivatives were noteworthy improvements of this study.

Aerobic oxidative annulation of un-activated 4-hydroxycoumarins and

terminal alkynes catalyzed by FeCl3/ZnI2 [194]

Both coumarins and furans appear in numerous natural products, bio-active compounds and pharmaceuticals Furocoumarins and especially furo[3,2-c]coumarins, which are heterocycles combined from these two scaffolds, are expected to have special features and applications

Owing to these promising properties, various pathways were reported to synthesize this skeleton; especially from 4-hydroxycoumarins as starting materials

However, there were still four major limitations that should be improved in future researches First, pre-functionalized or reactive reactants such as halide derivatives and isocyanides were usually required Second, most reactions were carried out using additives and stoichiometric amount of oxidants, resulting in production of more wastes

Third, most of these reports had a narrow substrate scope, only producing specific structure of furo[3,2-c]coumarins Finally, in the reports utilized metal catalysis, late

64 transition metals, which were expensive and highly toxic were usually employed as catalysts for these transformations

To overcome the aforementioned remaining drawbacks of furo[3,2-c]coumarin synthesis, we aimed to develop a novel method that features: (1) directly coupling and cyclization or using pre-functionalized reactants easily synthesized from available reagents, (2) additive-free condition and using internal oxidants, (3) having a more general substrate scope, (4) replacing noble late transition metals by abundant first-row transition metals In this scene, ketoxime esters under copper catalysis has emerged as a powerful synthetic tool in organic synthesis As earlier mentioned in Chapter 1, a process with this combination could offer all of these four features and would be a perfect solution for the current issues

According to our previous study in Chapter 2, we observed that the nucleophilic substitution of α-haloketones could be replaced by radical coupling at the α-position of ketoxime esters for the α-functionalization of ketones (Scheme 3.21a and Scheme 3.21b) It was remarkable that the conventional approach for preparation of furo[3,2- c]coumarins also initiated by nucleophilic substitution of α-haloketones followed by cyclization (Scheme 3.21c) Inspired by this observation, we would develop a novel method for furo[3,2-c]coumarin construction based on radical coupling of ketoxime esters and 4-hydroxycoumarins prior to annulation (Scheme 3.21d) Additionally, this new reaction consisting of the α-functionalization through C-O bond formation and the construction of oxygen-containing heterocycles, completely conforming the second objective of this thesis To the best of our knowledge, this transformation has not been mentioned in the literature

The observation from our previous study

66 To actualize this new idea, there are three important objectives in this chapter:

(1) Experiments confirming the possibility of this idea (2) Optimization of the reaction conditions

(3) Investigation of the reaction mechanism (4) Expansion of the substrate scope

All reagents and starting materials were obtained commercially from Sigma- Aldrich, Acros and Merck, and were used as received without any further purification unless otherwise noted

Gas chromatographic (GC) analyses were performed using a Shimadzu GC 2010- Plus equipped with a flame ionization detector (FID) and an SPB-5 column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.25 μm) The temperature program for GC analysis held samples at 160 o C for 1 min; heated them from 160 to 280 o C at 40 oC/min; held them at 280 o C for 8 min Inlet and detector temperatures were set constant at 280 o C The GC yield was calculated using diphenyl ether as the internal standard (see Appendices for more details)

GC-MS analyses were analyzed on a Shimadzu GCMS-QP2010Ultra with a ZB- 5MS column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.25 μm)

The temperature program for GC-MS analysis held samples at 50 o C for 2 min; heated samples from 50 to 280 o C at 10 o C/min and held them at 280 o C for 10 min Inlet temperature was set constant at 280 o C MS spectra were compared with the spectra gathered in the NIST library

The 1 H NMR and 13 C NMR were recorded on Bruker AV 500 spectrometers using residual solvent peak or TMS as a reference

FT-IR spectra were recorded on a Bruker Tensor 27 and samples were prepared as KBr plates

HR-MS spectra were recorded by an Agilent HPLC 1200 Series coupled to Bruker micrOTOF-QII

The mixture of ketones (22 mmol), K2CO3 (3.036 g, 22 mmol), hydroxylamine hydrochloride (2.290 g, 33 mmol) and ethanol (10 mL) were magnetically stirred at 60 oC for 1 h The reaction mixture was cooled to room temperature, quenched with H2O then organic components were extracted with ethyl acetate (3 x 20 mL) and washed with

68 brine (3 x 20 mL) then neutralized by HCl 1 M The organic layers were dried over anhydrous Na2SO4 and concentrated under vacuum to obtain the crude oximes which were used directly on the next step without purification

The crude oximes and K2CO3 (3.036 g, 22 mmol) were added to the mixture of anhydride acetic (4.2 mL, 44.4 mmol) and ethyl acetate (20 mL), then stirred at room temperature for 1 h The next work-up procedure was conducted similarly to that of previous step Solid crude oxime acetates were further purified by recrystallization in ethyl acetate and hexane and liquid crude oxime were further purified by silica gel column chromatography using hexane and ethyl acetate as eluent.

Synthetic pathway to ketoxime esters

In a typical experiment, a solution of CuBr2 (1 mol%) in toluene (1 mL) were added to a 8 mL screw-capped vial containing 4-hydroxycoumarin (0.2 mmol, 32.4 mg), propiophenone oxime acetate (0.3 mmol, 57.3 mg) and diphenyl ether (0.2 mmol, 34.0 mg) as internal standard The mixture was stirred at 120 °C for 1 h under an argon atmosphere The GC yield of product were monitored by withdrawing aliquots from the reaction mixture, quenching with brine (1 mL), extracting with ethyl acetate (3 x 1 mL), drying over anhydrous Na2SO4 and being analyzed by GC with reference to diphenyl ether (see Appendices for GC yield calculation)

After the completion of the reaction, the mixture was cooled to room temperature

Resulting solution was quenched with distilled water (5 mL), extracted by dichloromethane (3 x 5 mL), dried over anhydrous Na2SO4 prior to the removal of solvent under vacuum The crude product was purified by silica gel column chromatography using hexane and dichloromethane as an eluent The product identity was further confirmed by 1 H NMR, 13 C NMR, FT-IR and HR-MS (see Appendices for characterization data of products)

We initiated our investigation into the sequential transformation consisting of α- functionalized C-O bond formation prior to the annulation to produce furo[3,2,c]coumarins The reaction of 4-hydroxycoumarin (3.1a) and propiophenone O- acetyl oxime (3.2a) was chosen as a model reaction to investigate this transformation

Based on our previous study on Chapter 2 as well as reported publications regarding to oxime esters, 0.2 mmol of 3.1a, 0.2 mmol of 3.2a, 5% mol of Cu(OAc)2 catalyst, 1 mL of toluene solvent, temperature of 100 o C, 1 h of reaction time were chosen as the starting conditions of our study (Scheme 3.23) A simple calculation of the electron transfer of this redox reaction showed that the use of one molecular 2a as both reactant and internal oxidant was enough for this transformation so the reaction was carried out under inert gas atmosphere and no external oxidant was added.

Model reaction and starting conditions

The result of this first reaction was very promising A new peak was recorded in the GC spectrum of the reaction mixture A new spot also appeared in TLC plate of the reaction solution Subsequently, isolation of this product was performed and the pure product was identified by 1 H NMR, 13 C NMR, HR-MS and FT-IR As our expectation, characterization data of this compound matched 4-methyl-3-phenyl-4H- furo[3,2,c]coumarin (3.3aa) that was previously reported in the literature [172]

With the first positive result on hand, the screening of reaction conditions was then carried out with these starting conditions The α-functionalization by C-O bond formation followed by cyclization under different conditions including kinds of catalyst, kinds of solvent, reactant molar ratios, temperatures and catalyst amounts were performed to determine the parameters that favor the formation of the desired product

Afterwards, several control experiments were conducted to gain insight into the mechanism of this reaction Finally, the expansion of substrate scope were investigated

3.1.1 Effect of catalysts on the reaction yield

For a reaction process using catalyst, kinds of catalyst might have significant influence with the reaction yield Consequently, the first factor to be investigated was types of copper catalyst The reaction was performed in the presence of 5% mol of various copper-based catalysts, 0.2 mmol of 3.1a and 0.2 mmol of 3.2a in 1 mL toluene under argon atmosphere at 100 o C for 1 h GC yields of these experiments were calculated and summarized in Figure 3.2

Figure 3.2 Effect of catalysts on the reaction yield

According to the figure, most of the copper-based catalysts had catalytic activity on this reaction, excepting CuO with trace amount of product obtained after 1 h Among different copper salts, CuBr2 emerged as the best choice with 76% yield being recorded

CuBr and Cu(OAc)2 also showed high efficiency and could be alternative catalysts Thus, CuBr2 was chosen for further studies

3.1.2 Effect of solvents on the reaction yield

The impact of solvents on liquid-phase organic transformations has to be addressed with careful consideration In various circumstances, the yield of the major product was remarkably changed when performing the reaction in different solvents

We therefore tried to find the best solvent for the annulation reaction to form furo[3,2,c]coumarins The reaction was performed in 1 mL of different solvents in the

CuCl CuBr CuI Cu2O CuF2 CuCl2 CuBr2 Cu(OAc)2 CuO

71 presence of 5% mol of CuBr2, 0.2 mmol of 3.1a and 0.2 mmol of 3.2a under argon atmosphere at 100 o C for 1 h The results of this series was displayed in the following figure

Figure 3.3 Effect of solvents on the reaction yield

As can be seen in Figure 3.3, the nature of solvents had considerable effect on the yield of product Aromatic solvent was the most suitable solvent group for this transformation with the yields ranging from 38% to 76% Similar results were also reported by many other works regarding to ketoxime esters [24, 29] Polar solvents like DMSO, DMF, n-butanol and dioxane were absolutely inappropriate, yielding trace amounts of product Interestingly, diethyl carbonate, a green aprotic polar solvent, could be an alternative solvent for this transformation with 59% yield being observed Among the aromatic solvents being tested, toluene showed the best performance, offering 76% yield of the product Toluene, thus, was the best reaction media for further investigations

3.1.3 Effect of reaction molar ratios on the reaction yield

The reactant ratio is also a crucial point that should be explored when studying the reaction between 3.1a and 3.2a We subsequently conducted the reaction in 1 mL toluene with 5% mol of CuBr2 under argon atmosphere at 100 o C for 1 h, using 0.2 mmol of limiting reactant and amounts of excessive reactants depending on respective molar ratios The results were illustrated in Figure 3.4

Toluene p-xylene PhCl DCB DMSO DMF DEC n-BuOH Dioxane

Figure 3.4 Effect of reaction molar ratios on the reaction yield

76% yield of 3aa was obtained when the reaction was carried out with equal amounts of two reactants Using excessive amounts of 3.1a or 3.2a seemed to have similar effects on the GC yield The yields were slightly upgraded to 83% and 87% when the molar ratios of 3.1a and 3.2a were 1.5:1 and 1:1.5 respectively Increasing the amount of 2aa to 2 equivalents did not further improve the yield of 3aa With the best result, the molar ratio of 1:1.5 was chosen for next studies

3.1.4 Effect of temperatures on the reaction yield

Temperature is a factor having remarkable effect on the dynamic of a chemical reaction so it would be the next parameter to be optimized The reaction was performed in 1 mL of toluene in the presence of 5% mol of CuBr2, 0.2 mmol of 3.1a and 0.2 mmol of 3.2a under argon atmosphere at different temperatures for 1 h The results of these experiments were showed in Figure 3.5

Figure 3.5 Effect of temperatures on the reaction yield

According to the data, the reaction difficultly processed at room temperature with a trace of 3.3aa was recorded after 1 h Boosting the temperature to 80 o C offered a modest yield of 14% yield after 1 h As expected, increasing the reaction temperature to 100 o C significantly facilitated this transformation, proving by 87% yield of the desired product Subsequently, the GC yield was slightly improved to 91% when the temperature was risen to 120 o C We did not try to further increase the temperature due to the high risk of explosion Therefore, 120 o C was the most suitable for this reaction

The reaction proceeded through a radical pathway (see subpart 3.2 in page 75 for details) As previously explained in subpart 3.2.1.a) of the second chapter, the temperature had a considerable impact on the formation of radicals from ketoxime esters

The temperatures in the region of 100 o C were well suited for this kinds of reaction, which also confirmed by many reports in this field [24, 29, 30, 32, 34-38, 40, 150]

3.1.5 Effect of catalyst amounts on the reaction yield

Amount of catalyst was the last factor to be surveyed on our optimization procedure We subsequently performed the reaction in 1 mL toluene with various amounts of CuBr2 under argon atmosphere at 100 o C for 1 h, using 0.2 mmol of 3.1a and 0.2 mmol of 3.2a GC yields of this series was displayed in Figure 3.6

Figure 3.6 Effect of catalyst amounts on the reaction yield

Catalytic performance of CuBr2 was fully maintained when utilizing a 1% mol of this salt, 5 times less than our expectation Increasing the amount of catalyst to higher levels could not further enhanced the yield of desired product It should be noted that a trace amount of 3.3aa was obtained when the reaction was carried out in the absence of catalyst, demonstrating the crucial role of the copper-based catalyst in this transformation

In summary, various parameters that affected the reaction were studied for reaching the best reaction condition The reaction was implemented in 1 mL of toluene at 120 o C under an argon atmosphere for 1 h, in the presence of 1% mol CuBr2 as catalyst, with 0.2 mmol of both 3.1a and 1.5 equivalents of 3.2a The best performance was observed with the yield of 91% (Scheme 3.24).

The optimal reaction conditions

In a research of a novel reaction, it is important that reaction mechanism should be explored thoroughly To gain insight into the reaction pathway, some control experiments were carried out (Scheme 3.25).

Control experiments

As aforementioned in Scheme 1.1, a reaction of ketoxime esters under metal catalyst could proceed via radical pathway or organometallic pathway An experiment of performing reaction in the presence of a radical scavenger would illustrate which pathway was more reasonable (Scheme 3.25a) The result indicated that 3.3aa was not produced in the presence of (2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO) as a radical scavenger This observation verified that the cyclization reaction progressed via a radical pathway, and the combination of TEMPO with radical species produced during catalytic cycle would stop the transformation

To further confirm this hypothesis, in the next two experiments, we tried to trap the radical produced by 2a using TEMPO and 1,1-diphenylethylene (Scheme 3.25b and Scheme 3.25c) The resulting reaction mixtures were analyzed by GC-MS and respective radical coupling products were detected

76 On the basis of these results and previous reports in the literature as well as our previous work in Chapter 2, a plausible reaction mechanism was proposed for the copper-catalyzed cyclization reaction between 3.1a and 3.2a to form 3.3a (Scheme

3.26) Initially, iminium radical A was generated by oxidation of Cu II to AcOCu III , and this radical was rapidly tautomerized to B [28-30] The phenolic radical C was then formed via a single-electron-transfer (SET) process between AcOCu III and 3.1a, releasing AcOH and regenerating the Cu II species back to the catalytic cycle

Subsequently, the intermediate product D was produced by the radical coupling reaction of B and C The intramolecular nucleophilic addition of C-3 to the imine group consequently occurred under in situ AcOH catalysis, creating intermediate product E

[172] Finally, NH3 was eliminated from E, producing the furocoumarin product 3.3aa, and then neutralized by AcOH.

Plausible reaction mechanism

Expansion of the substrate scope

With the optimal conditions in hand, the substrate scope was subsequently studied to check the effectiveness of our new method among various kinds of reactant (Scheme 3.27) The results were summarized in Table 3.1 (see Appendices for characterization data of products).

Expansion of the substrate scope

Table 3.1 Synthesis of substituted furo[3,2, c ]coumarins via copper-catalyzed 4- hydroxycoumarins with ketoximes

Following this protocol, the reaction between 3.1a and 3.2a afforded 3.3aa (Entry

1, Table 2) in 81% yield Propiophenone O-acetyl oximes containing a substituent on benzene ring were also reactive towards the cyclization reaction Indeed, 3.3ab (Entry 2, Table 2), 3.3ac (Entry 3, Table 2), and 3.3ad (Entry 4, Table 2) were generated in

79%, 89%, and 60% yields, respectively Moving to substituted 4-hydroxycoumarins, 80% yield of 3.3ba (Entry 5, Table 2) was obtained for the case of 3.1b Similarly, 3.3ca (Entry 6, Table 2), 3.3da (Entry 7, Table 2), and 3.3ea (Entry 8, Table 2) were achieved in 75%, 70%, and 86% yields, respectively

Additionally, other kinds of oxime esters were surveyed in order to prepare other 4-substituted derivatives Firstly, acetophenone O-acetyl oximes were also reactive in this transformation, and corresponding furocoumarins (products 3.3ae to 3.3aj, entries 9-14, Table 2) were obtained in moderate to good yields ranging from 49% to 79% It should be noted that this transformation also worked on heteroaryl ketoxime, yielding

Other 4-substituted products were synthesized using this protocol (Entries 16-17, Table 2) 4-Ethyl derivative 3.3al, and 4-phenyl derivative 3.3am were generated in 73%, and 77% yields, respectively Interestingly, our catalytic system was also efficient for aliphatic ketoxime ester, proving by 75% yield of 3.3an when 3.2n was utilized

In summary, we have developed a novel method to synthesize furo[3,2,c]coumarins A plausible mechanism was proposed for this transformation Our protocol were also effective among a wide range of substrate scope In comparison to the previous methods, the significant aspects of this protocol are (1) directly coupling and cyclization; (2) readily available starting materials; (3) additive-free condition and using internal oxidants; (4) large substrate scope; and (5) CuBr2 as low cost catalyst

This synthetic scheme is a satisfactory solution to the current issues of previous approaches in the synthesis of these bicyclic scaffolds, and might attract considerable attention from the pharmaceutical and chemical industries

On the other hand, more works should be carried out to further develop this method which are applying copper-based heterogeneous catalyst and expanding the application of this protocol to other similar reactant structures

The chemistry of ketoxime esters under copper catalysis have gained considerable achievements in the last decade However, there are still some limitations in this fields, which are the lack of research employing heterogeneous catalysts and the shortage of products relating to C-O bond formations This master thesis has satisfied these two demands

In the first study, copper-based MOF Cu2(OBA)2BPY was demonstrated to be an efficient heterogeneous catalyst for the sulfonylation of ketoxime esters to form β- sulfonylvinylamines which were then hydrolyzed to obtain β-ketosulfones The

Cu2(OBA)2BPY offered properties of a good heterogeneous catalyst: the high catalytic activity comparing to other catalysts and the reusability of many times without significant degradation in the catalytic performance This work provided a typical example for the promising combination of copper-based MOFs as heterogeneous catalysts and reactive ketoxime esters

In our second study, a novel pathway to furo[3,2,c]coumarins through a copper- catalyzed direct Cα-O bond formation of ketoxime esters followed by cyclization was presented The new approach featured a facile synthesis of wide range of these bicyclic skeletons in good yields form readily available ingredients and cheap CuBr2 catalyst, overcoming the present limitations of previous methods

In the future, with the first successful example of a copper-based MOF as heterogeneous catalyst in ketoxime ester reaction, we aim to further broaden the catalyst application of MOFs in this field Additionally, novel reactions based on copper catalysis and ketoxime esters should be explored

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Appendix 1 FT-IR spectra of Cu2(OBA)2BPY and ligands: a) BPY; b) H2OBA; c) Cu2(OBA)2BPY 94Appendix 2 SEM micrograph of Cu2(OBA)2BPY 94Appendix 3 TEM micrograph of Cu2(OBA)2BPY 95Appendix 4 TGA curve of Cu2(OBA)2BPY 95Appendix 5 Isotherm plot of Cu2(OBA)2BPY 96Appendix 6 Pore size distribution of Cu2(OBA)2BPY 96Appendix 7 A typical GC spectrum of reaction in Chapter 2 97Appendix 8 A typical GC spectrum of reaction in Chapter 3 97Appendix 9 Calibration curve calculation for 2.3aa 98Appendix 10 Calibration curve calculation for 3.3aa 99Appendix 11 Optimization data of reaction in Chapter 2 101Appendix 12 Optimization data of reaction in Chapter 3 102Appendix 13 MS spectrum of 2.3aa 104Appendix 14 MS spectrum of 2.4aa 104Appendix 15 MS spectrum of 3.3aa 105Appendix 16 MS spectrum of product in Scheme 3.25b 105Appendix 17 MS spectrum of product in Scheme 3.25c 106Appendix 18 1 H NMR spectra of 2.3aa 107Appendix 19 13 C NMR spectra of 2.3aa 108Appendix 20 1 H NMR spectra of 2.4aa 109Appendix 21 13 C NMR spectra of 2.4aa 110Appendix 22 1 H NMR spectra of 2.4ba 111Appendix 23 13 C NMR spectra of 2.4ba 112Appendix 24 1 H NMR spectra of 2.4ca 113Appendix 25 13 C NMR spectra of 2.4ca 114Appendix 26 1 H NMR spectra of 2.4da 115Appendix 27 13 C NMR spectra 2.4da 116Appendix 28 1 H NMR spectra of 2.4ea 117Appendix 29 13 C NMR spectra of 2.4ea 118

92 Appendix 30 1 H NMR spectra of 2.4fa 119Appendix 31 13 C NMR spectra of 2.4fa 120Appendix 32 1 H NMR spectra of 2.4ga 121Appendix 33 13 C NMR spectra of 2.4ga 122Appendix 34 1 H NMR spectra of 2.4ha 123Appendix 35 13 C NMR spectra of 2.4ha 124Appendix 36 1 H NMR spectra of 2.4ia 125Appendix 37 13 C NMR spectra of 2.4ia 126Appendix 38 1 H NMR spectra of 2.4ab 127Appendix 39 13 C NMR spectra of 2.4ab 128Appendix 40 1 H NMR spectra of 2.4ac 129Appendix 41 13 C NMR spectra of 2.4ac 130Appendix 42 1 H NMR spectra of 2.4ad 131Appendix 43 13 C NMR spectra of 2.4ad 132Appendix 44 1 H NMR spectra of 2.4ae 133Appendix 45 13 C NMR spectra of 2.4ae 134Appendix 46 1 H NMR spectra of 2.4af 135Appendix 47 13 C NMR spectra of 2.4af 136Appendix 48 1 H NMR spectra of 3.3aa 137Appendix 49 13 C NMR spectra of 3.3aa 138Appendix 50 1 H NMR spectra of 3.3ab 139Appendix 51 13 C NMR spectra 3.3ab 140Appendix 52 1 H NMR spectra of 3.3ac 141Appendix 53 13 C NMR spectra of 3.3ac 142Appendix 54 1 H NMR spectra 3.3ad 143Appendix 55 13 C NMR spectra of 3.3ad 144Appendix 56 1 H NMR spectra of 3.3ba 145Appendix 57 13 C NMR spectra of 3.3ba 146Appendix 58 1 H NMR spectra of 3.3ca 147Appendix 59 13 C NMR spectra of 3.3ca 148Appendix 60 1 H NMR spectra of 3.3da 149Appendix 61 13 C NMR spectra of 3.3da 150

93 Appendix 62 1 H NMR spectra of 3.3ea 151Appendix 63 13 C NMR spectra of 3.3ea 152Appendix 64 1 H NMR spectra of 3.3ae 153Appendix 65 13 C NMR spectra of 3.3ae 154Appendix 66 1 H NMR spectra of 3.3af 155Appendix 67 13 C NMR spectra of 3.3af 156Appendix 68 1 H NMR spectra of 3.3ag 157Appendix 69 13 C NMR spectra of 3.3ag 158Appendix 70 1 H NMR spectra of 3.3ah 159Appendix 71 13 C NMR spectra of 3.3ah 160Appendix 72 1 H NMR spectra of 3.3ai 161Appendix 73 13 C NMR spectra of 3.3ai 162Appendix 74 1 H NMR spectra of 3.3aj 163Appendix 75 13 C NMR spectra 3.3aj 164Appendix 76 1 H NMR spectra of 3.3ak 165Appendix 77 13 C NMR spectra of 3.3ak 166Appendix 78 1 H NMR spectra of 3.3al 167Appendix 79 13 C NMR spectra of 3.3al 168Appendix 80 1 H NMR spectra of 3.3am 169Appendix 81 13 C NMR spectra of 3.3am 170Appendix 82 1 H NMR spectra of 3.3an 171Appendix 83 13 C NMR spectra of 3.3an 172

Appendix 1 FT-IR spectra of Cu2(OBA)2BPY and ligands: a) BPY; b) H2OBA; c) Cu2(OBA)2BPY

Appendix 2 SEM micrograph of Cu2(OBA)2BPY

T ra n sm it ta n ce (% )

Appendix 3 TEM micrograph of Cu2(OBA)2BPY

Appendix 4 TGA curve of Cu2(OBA)2BPY

Appendix 5 Isotherm plot of Cu2(OBA)2BPY

Appendix 6 Pore size distribution of Cu2(OBA)2BPY

Appendix 7 A typical GC spectrum of reaction in Chapter 2

Appendix 8 A typical GC spectrum of reaction in Chapter 3

Appendix 9 Calibration curve calculation for 2.3aa

99 From the calibration curve, GC yield of 2.3aa can be calculated by this formula:

Where: nPr (mole): Mole of 2.3aa obtained nPr’ (mole): Calculated mole of 2.3aa when yield = 100%

SPr: Peak area of 2.3aa in sample

SIS: Peak area of internal standard in sample nIS (mole): mole of n-dodecane in sample

Appendix 10 Calibration curve calculation for 3.3aa

GC yield (%) = n Pr × 100% n Pr ' = (S Pr

100 From the calibration curve, GC yield of 3.3aa can be calculated by this formula:

Where: nPr (mole): Mole of 3.3aa obtained nPr’ (mole): Calculated mole of 3.3aa when yield = 100%

SPr: Peak area of 3.3aa in sample

SIS: Peak area of internal standard in sample nIS (mole): mole of diphenyl ether in sample

GC yield (%) = n Pr × 100% n Pr ' = (S Pr

Appendix 11 Optimization data of reaction in Chapter 2

Reactions were carried out in 0.25 mmol scale for 3 h with the respective conditions

Appendix 12 Optimization data of reaction in Chapter 3

Entry Catalyst Solvent Reactant ratio Temp ( o C) GC yield(%)

Reaction condition unless noted: 4-hydroxycoumarin (0.2 mmol); catalyst (5% mol); solvent (1 mL); argon atmosphere; 1 h

Appendix 13 MS spectrum of 2.3aa

Appendix 14 MS spectrum of 2.4aa

Appendix 15 MS spectrum of 3.3aa

Appendix 16 MS spectrum of product in Scheme 3.25b

Appendix 17 MS spectrum of product in Scheme 3.25c

Appendix 18 1 H NMR spectra of 2.3aa

Appendix 19 13 C NMR spectra of 2.3aa

Prepared as shown in the general experimental procedure and purified by recrystallization in chlorobenzene and hexane: white crystal, 76% yield 1 H NMR (500 MHz, CDCl3) δ 7.96 – 7.93 (m, 2H), 7.58 – 7.40 (m, 1H), 7.53 – 7.48 (m, 2H), 7.40 – 7.37 (m, 1H), 7.35 – 7.33 (m, 1H), 7.05 (dd, J = 5, 4 Hz, 1H), 5.96 (br, 2H), 5.28 (s, 1H)

Appendix 20 1 H NMR spectra of 2.4aa

Appendix 21 13 C NMR spectra of 2.4aa

Prepared as shown in the general experimental procedure and purified on silica gel (hexane/ethyl acetate = 3:1): white solid, 76% yield 1 H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 7.5 Hz, 2H), 7.81 – 7.77 (m, 1H), 7.76 – 7.72 (m, 1H), 7.68 – 7.63 (m, 1H), 7.57 – 7.52 (m, 2H), 7.18 – 7.13 (m, 1H), 4.63 (s, 2H) 13 C NMR (125 MHz, CDCl3) δ

Appendix 22 1 H NMR spectra of 2.4ba

Appendix 23 13 C NMR spectra of 2.4ba

Prepared as shown in the general experimental procedure and purified on silica gel (hexane/ethyl acetate = 3:1): white solid, 88% yield 1 H NMR (500 MHz, CDCl3) δ 7.90 – 7.89 (m, 1H), 7.89 – 7.87 (m, 1H), 7.68 – 7.64 (m, 1H), 7.56 – 7.52 (m, 2H), 7.27 (d, J = 8.0 Hz, 2H), 4.70 (s, 2H), 2.42 (s, 3H) 13 C NMR (125 MHz, CDCl3) δ = 187.60, 145.76, 138.98, 134.31, 133.52, 129.72, 129.61, 129.32, 128.74, 63.62, 21.91

Appendix 24 1 H NMR spectra of 2.4ca

Appendix 25 13 C NMR spectra of 2.4ca

Prepared as shown in the general experimental procedure and purified on silica gel (hexane/ethyl acetate = 3:1): yellow solid, 91% yield 1 H NMR (500 MHz, CDCl3) δ 7.95 – 7.91 (m, 2H), 7.90 – 7.87 (m, 2H), 7.66 (t, J = 7.5 Hz, 1H), 7.55 (t, J = 7.5 Hz, 2H), 6.96 – 6.92 (m, 2H), 4.68 (s, 2H), 3.89 (s, 3H) 13 C NMR (125 MHz, CDCl3) δ 186.3, 164.7, 138.9, 134.3, 132.0, 129.3, 129.0, 128.7, 114.2, 63.6, 55.8

Appendix 26 1 H NMR spectra of 2.4da