Synthesis and cytotoxicity of dithiaether derivatives

Synthesis and cytotoxicity of dithiaether derivatives Synthesis and cytotoxicity of dithiaether derivatives

VIETNAM NATIONAL UNIVERSITY, HANOI OF VIETNAM

HANOI UNIVERSITY OF SCIENCE

-

DO THAO THUYEN

SYNTHESIS AND CYTOTOXICITY OF DITHIAETHER DERIVATIVES

MASTER THESIS

VIETNAM NATIONAL UNIVERSITY, HANOI OF VIETNAM

HANOI UNIVERSITY OF SCIENCE

-

DO THAO THUYEN

SYNTHESIS AND CYTOTOXICITY OF DITHIAETHER DERIVATIVES

Major: Organic Chemistry

Major number: 8440112.02

MASTER THESIS

SUPERVISOR: ASSOC PROF LE TUAN ANH

ACKNOWLEDGEMENTS

This research is carried out in Organic Synthesis Lab 2, Faculty ofChemistry, VNU University of Science, Vietnam National University, Hanoi

I would like to express my sincere gratitude to my supervisors Assoc Prof

Dr Le Tuan Anh for your advice, guidance and enthusiatically supporting me during the course of this research I am extremely grateful that you took me on as a student and have a faith in me

Thank you to Prof Dr Peter Huy who spent time reading and giving me a lot

of advices I have benefited greatly from your wealth of knowledge and meticulous editing

Thank you to Assoc Prof Dr Tran Thi Thanh Van and Dr Dao Thi Nhung for encouragement and sharing evaluable experience to me

Thank you to all my colleagues and colaborators who were always willing to help me during the experimental process as well as in my difficult time

Most importantly, I am gratefull for my family’s unconditional, unequivocal and loving support

2.2 Synthesis of cyclic dithiaether derivatives 20

2.2.1 Synthesis dithiaether derivatives containing 2,6-diaryl-piperidin-4-one (7a-c) 20

2.2.2 Synthesis of dithiaether derivatives containing γ-aryl-pyridine (9a-e) 24

CHAPTER 3 RESULTS AND DISCUSSIONS 29

3.1 Synthesis of Thiopodand derivatives 3, 5 29

3.2 Synthesis of thiacrown ethers derivatives 7a-d 30

3.3 Synthesis of thiacrown ethers derivatives 9a-e 34

3.4 Biological evaluation of dithiaether derivatives 37

REFERENCE 41 APPENDIX: SPECTRA 46

LIST OF FIGURES

Figure 1.1 Classes of cyclic and acyclic ligands 2

Figure 1.2 Some podands are found in nature 3

Figure 1.3 Examples of monopodands 3

Figure 1.4 Exemplary Thiopodands.[7] 4

Figure 1.5 Examples of crown ether 5

Figure 1.6 Dialkyldiaza-18-crown-6 lariat ethers 6

Figure 1.7 crown ether ligands were synthezied by Yildiz and co-workers 6

Figure 1.8 Pyridine-containing macrocycles exhibiting toxicity to bacteria and fungi 8

Figure 1.9 (γ-arylpyridino)dibenzoaza-14-crown-4 ether and cytotoxic activity 8

Figure 1.10 (γ-piperidono)- 1,7-diaza-14-crown-4 ethers and cytotoxic activities 9

Figure 1.11 Exemplary thia crown ether (thio-18-crown-5-ether) 9

Figure 1.12 Thiacrown ether 31 and 32 12

Figure 1.13 Macrocyclic thioether–esters 33 12

Figure 1.14 Comparison of ordinary sequential syntheses wirth MCRs 15

Figure 3.1 The structure fomular of compound 78a-c 32

Figure 3.2 Molecular structure of azacrown-thioether 80e in the representation of atoms by anisotropic displacement ellipsoids 36

LIST OF SCHEMES

Scheme 1.1 The synthesis of 1,4,8,11-Tctrathiacyclotetradecane 11 4

Scheme 1.2 Synthesis thiacrownether 24 10

Scheme 1.3 General reaction synthesis off thiacrown ether 10

Scheme 1.4 Synthesis of thia benzo-crown ethers according to Schneider and workers.[28] 11

co-Scheme 1.5 Examples of MCRs developed over the decades.[31, 32, 35] 14

Scheme 1.6 Example for a Mannich reaction 15

Scheme 1.7 General scheme for the Petrenko-Kritschenko piperidone synthesis 16

Scheme 1.8 Gerneral scheme for the Hantzch reaction 16

Scheme 1.9 Hantzch reaction in the synthesis poyridine-containing crown ether 17

Scheme 2.1 Target structures and synthsis plan for the current work 19

Scheme 2.2 Synthesis of 1,5- bis(2-formylphenthio)-3-oxapentane 74 19

Scheme 2.3 Synthesis of 1,5-bis(2-acetylphenthio)-3-oxapentane 76 20

Scheme 2.4 Synthesis of dithiacrown ether 78a 21

Scheme 2.5 Synthesis of dithiacrown ether 78b 22

Scheme 2.6 Synthesis of dithiacrown ether 78c 23

Scheme 2.7 Synthesis of dithiacrown ether 78d 23

Scheme 2.8 Synthesis of dithiacrown ether 80a 25

Scheme 2.9 Synthesis of dithiacrown ether 80b 26

Scheme 2.10 Synthesis of dithiacrown ether 80c 26

Scheme 2.11 Synthesis of dithiacrown ether 80d 27

Scheme 2.12 Synthesis of dithiacrown ether 80e 28

Scheme 3.1 General synthesis of thiopodand derivatives 74 and 76 29

Scheme 3.2 General synthesis of thiacrown ether 78a-d 30

Scheme 3.3 The suggested pathway to synthesis of thiacrown ethers 78a-c 31

Scheme 3.4 The reaction of dialdehyde 74 with benzyl acetoacetate 78d 33

Scheme 3.5 The suggested mechnism for the formation of compound 78d 34 Scheme 3.6 General synthesis of thiacrown ether 80a-e 35

LIST OF TABLE

Table 3.1 The percent of cell survival induced by compounds 74, 76 37

Table 3.2 Results of IC50 tests of compound 74 38

Table 3.3 The percent of cell survival induced by compounds 78a-d 38

Table 3.4 Result of IC50 test of compound 78c 39

Table 3.5 The percent of cell survival induced by compounds 80a-e 39

INTRODUCTION

Crown ethers and their open chain analogues (podands) are of considerable

interest, because they can be used as functional fragments combined with other

groups in organic compounds

Crown ethers constitute one of the most important classes of macrocyclic

compounds Moreover, when replacing one or more oxygen atom with sulfur,

thiacrown ethers result, which have attracted the attention of researchers due to their

wide-spread applications in biology, supramolecular chemistry, new materials,

medicine and the chemical industry Indeed, the presence of a piperidone or pyridine

moiety in thiacrown ethers as part of a single macrocyclic molecule could increase

the potential of biological activity of such derivatives even further

Based on fundamental references along with preparation to initial compounds,

in this thesis, the synthesis of dithiaether derivatives including athiapodand and either

piperidone or pyridine-containing thiacrown ethers is described

CHAPTER 1 OVERVIEW 1.1 Podands

Podands are a family of linear multidentate ligands, which include acyclic polyethers The name “podand” was introduced in 1979 by Vogtle and Weber and has been derived from the combination of the combining form “pod” (having a foot) and ligand.[36] Over time, the type of ligands rapidly developed from podands over very flexible macrocyclic “coronands” to bicyclic “cryptands” (Figure 1.1) Especially, the corodand type of ligands, which are also known as crown ethers, are widely studied and applied today

Figure 1.1 Classes of cyclic and acyclic ligands

Crown ethers and cryptands possess cavities specific for a single size of cation

or neutral host molecule In contrast, the ‘wrap-around’ capability of podands having terminal functionalities allow to adopt the appropriate sizes during complexation with metal cations or neutral molecules in a manner unique among ligands

This is rationalized by the special structure of their flexible donor atoms containing chain and podand receptor sites, which can form complexes with many cations ranging from alkali and alkaline earth metals to various transition metals By chemical modification of the arms (e.g., changing the chain length or the donor atom) and under certain experimental conditions, podand receptors can selectively form complexes with metal ions.[10] As a recognition motif, podand based receptors have been reported to be used successfully as recognition components in electrochemical sensors and optical sensors.[8] In order to construct ionophore model systems, various macrocyclic compounds, such as crown ethers, cryptands, and calixarenes, have been

synthesized and structurally characterized In addition to these macrocyclic compounds, podands have been employed as noncyclic ionophore models.[27]

There are excellent podands found in nature such as monensin 1 and lasalocid

2, which are naturally occurring polyether antibiotics (Figure 1.2).[8]

Figure 1.2 Some podands are found in nature

Compounds 3 and 4 are examples of monopodands, which are acyclic analogs

of crown ethers (Figure 1.3)

Figure 1.3 Examples of monopodands

1.2 Thiopodand

Thiopodands are obtained by replacing oxygen with sulfur atoms (Figure 1.4) They have a profound effect on the coordinating ability, which is reasond by the lower electronegativity and therefore increased Lewis-basicity of sulfur Nevertheless, the size of the cavity remains approximately unaltered

Figure 1.4 Exemplary Thiopodands [7]

The classical method for the synthesis of macrocyclic sulfides with four sulfur atoms from 5 and 6 was first described in 1967 (Scheme 1.1).[7]

Scheme 1.1 The synthesis of 1,4,8,11-Tctrathiacyclotetradecane 11

Initally, 1,3-propanedithiol was alkylated by means of 2-chloropropanol under

basic conditions The resulting diol 5 was next reacted with an excess of thiourea

under acidic conditions, which effects the formation of a dithiouronium intermediate

Eventually, hydrolysis by means of KOH provides dithiol 6 The synthetic sequence

was complemented by nucleophilic substitution using 1,3-dibromopropaen in the presence of cesium carbonat as base

Among the linear polyether derivatives, podanes containing sulfur have been synthesized and applied in chemical engineering as ligands to separate alkali, alkaline

earth and transition metals.[33] In particularly, to protect the environment, thiopodands are harnessed to remove mercury from water [2]

1.3 Crownether

1.3.1 Crownether

Crown ethers are organic cyclic compounds that contain several ether functional groups Common crown ethers are oligomeric macrocycles consisting of ethylene oxide CH2CH2O, of which tetramers (n=4), pentamers (n=5) and hexamers (n=6) are the most important derivatives

Figure 1.5 Examples of crown ether

Compound 12 (also known as dibenzo-18-crown-6-ether) has been the frist

crown ether described in literature, which has been synthesized by Charles Pederson

in 1967, was isolated in a yield of 0.4% after reaction of Catechol and chloroethyl) ether in the presence of sodium hydroxide It was also the firstly reported substance that possesses the ability to form a complex with Na+ ions [26] The low yield of the macrocyclization showcases, how challenging these stuctures are to prepare

bis(2-Since Charles Pedersen’s discovery, the chemistry of crown ethers has achieved considerable advancement Macrocyclic compounds based on crown ethers proved to be of tremendous interest in biochemistry, phase transfer catalysis, sensor

as well as in the design and synthesis of various oriented compound with specific

properties and applications Crown ethers are known to have a high affinity toward alkaline and alkali metal cations with high selectivity, improving the solubility of these cations in non-polar solvent.[14] These ligands are also known for useful biological activities such as anti-fungi, antibacteria, or anti-cancer A study by Koji Yagi and co-workers indicated the antifungal activity of crown ethers against

woodecay fungigi, phytopathogenic fungigi and eumycetes, and Trichophytonspp for

the treatment of dermatomycosis.[11] Dialkyldiaza-18-crown-6 lariat ethers having

twin n-octyl, n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl, oxodecyl and

1-oxododecyl sidechains were prepared and studied with regard to their antimicrobial

activity on E coli, B subtilis, and yeast S Cerevisiae by Leevy et al [16]

Figure 1 6 Dialkyldiaza-18-crown-6 ethers

Yildiz and co-workers synthesized four new crown ether ligands of the Schiff base type, which showed ativity on various microorganisms.[38] All compounds show

high anti-yeast activity against the yeast culture and compound 16d is the most

effectual compound

Figure 1 7 Crown ether ligands were synthezied by Yildiz and co-workers

McPhee et al produced propargylic sulfone-armed lariat crown ethers and bis(propargylic) sulfone crown ethers in order to connect the molecular recognition

of specific alkali metal ions to DNA damage under conditions of elevated alkali metal ion levels reported to exist in tumor cells These compounds have been evaluated on their effect on various cancer cell lines and showed promising abilities to inhibit cell growth.[20] To date, only a few studies regarding the cytotoxicity of crown ethers have been published and they mainly refer to certain specialized functionalized crown ethers

1.3.2 Crown Ether Containing Piperidone and Pyridine Heterocyles

Pyridine and piperidone are natural compounds, which have found many applications as pharmaceuticals A lot of crown ethers comprehending either piperidone or pyridine moieties have been synthesized and evaluated regarding biological activities

Several pyridine-containing dibenzo macrocycles, which had been synthesized by Zam and al., exhibited biological activities against microbes, as verfied by disk diffusion and by determination of MIC values (Minimal inhibitory concentration).[39] The compounds of type 17 are represented in Fig 1.8, whereby X

is either CH2, CH2CH2, S, SS or CH2-S-CH2 They are distinguished by activities against a wide range of organisms including Staphylococcus aureus (G+), B cereus (G+), Micrococcus luteus (G+), Mycobacterium smegmatis (G+), Listeria monocytogenes (G+), E coli (G–), Proteus vuVulgaris (G–), K pneumonia (G–), Pseudomonas aeru- ginosa (G–), Kluyveromyces fragilis, Rhodotorula rubra, Candida albicans, Hanseniaspora guilliermondii and Debaryomyces hansenii with the MIC ranging from from ~3 to ~ 50 µg/mL The best overall performace was apparent for the compound with a disulfide bridge (X= SS)

Figure 1.8 Pyridine-containing macrocycles exhibiting toxicity to bacteria and

fungi

Fourteenth different (γ-arylpyridino)dibenzoaza-14-crown-4 ethers were successfully synthesized and investigated towards their biological effects such as cytotoxic activity, antifungal activity, antibacterial activity and antioxidant activity The following compounds have been identified to exhibit good cytotoxic activities

on various human cancer cell lines as given (Figure 1.9).[1]

Figure 1.9 (γ-arylpyridino)dibenzoaza-14-crown-4 ether and cytotoxic activity

In a research project of our working group, five crown-4 ethers were synthesized.[4] One of them inhibited the Hep-G2 and Lu-1 cell lines with IC50 = 4.32 and 6.64 μg/mL, respectively

(γ-piperidono)-1,7-diaza-14-Entry Comp

Cell line

IC 50 (µg/ml) Hep-G2 Lu-1

Figure 1.11 Exemplary thia crown ether (thia-18-crown-5-ether)

Most of the early research on cyclic sulfur compounds focused on investigations regarding the ring formation and ring strain.[30] The reaction between

a dihalide and a dithiol yielded predominantly polymers with high molecular masses and only small amounts of cyclic sulfur compounds In 1920, Ray et al reported the first synthesis of a macrocycles containing three sulfur atoms starting from ethanedithiol In the following years, the number of studies related to thiacrownethers concentrated increased dramatically.[24]

In 1934, Meadow and Reid produced several thiacrown ethers containing two, four and six sulfur atoms.[25] The reaction between various dithiols and dibromides alsoled to the formation of polymers as main products and only small amounts of cyclic compounds One of the macrocycles obtained was a hexathia compound

resulting from a tetra-component cyclization The reaction of ethylene bromide 22

with Dithiol 23 in absolute ethanol using one equivalent of base afforded the thiacrown ether 24 in a low yield of 1.7% (Scheme 1.2)

Scheme 1.2 Synthesis thiacrownether 24.

Afterwards, Black and McLean were able to improve the yield significantly to

up to 31%.[25] In this work, the reaction was carried out under highly diluted conditions and analogous thiacrown ethers containing oxygen or nitrogen atoms have been accessed unter related reaction conditions Due to their promising properties, many research groups started to investigate into sulfur containing crown ethers after this initial reports In publications by Pedersen[24] and Bradshaw et al[34] the synthesis

of manifold oxathiacrown ethers from an ethylene glycol dichloride and dithiols or sodium sulfide in basic ethanol has been delineated In addition, Ochrymowycz and co-workers examined the synthesis of several polythiacrown compounds, in which only moderate have been achieved.[23] In order to improve the chemicals yields, they follow the procedure of McLean and colleagues were able to improve the yield to 33% by adopting a two-component approach.[5] The enhanced yield was

accomplished through reation of β-chlorothioether 25 with 23 in n-butanol using

sodium, which resulated in the formation of sodium butanolat as base However,

disadvantage of this strategy is the use of -chlorothioether 25, which is a toxic gas

Scheme 1.3 General reaction synthesis of thiacrown ether by Ochrymowycz

One study worthwhile mentioning describes the synthesis of thiacrown ethers based amino acid by T Schneider and their partners (Scheme 1.4).[28] These synthesis

of thiacrown ethers is based on the use of thiol nucleophiles and the installation of

tosylate leaving groups on compound 27 Next, these dithiols were harnessed to construct the thia crown ether scaffold with a ring size of 12 30a and 15 atoms 30b,

Ni2+, Co2+ and Hg2+ .[21] Therefore, oligomeric ligands with thiaether units are often more effective adsorbents for toxic heavy and precious metal ions such as Hg2+ such

as Ag+ from industrial wastewater.[12-13] In addition, thiacrown ethers are evaluated

in terms of anti-inflammatory, antibacterial, antifungal, antiviral and cytotoxic activities, and have shown promising potential as both, antibiotics and anticancer agents.[18]

In the study of S.-T Huang and colleagues the thiacrown ethers 31 and 32

have been synthesized (Figure 1.12).[9] All of the prepared thiacrown ethers showed weak antifungal activities, significant cytotoxicity and strong antibacterial activities against methicillin-resistant Staphylococcus aureus

Figure 1.12 Thiacrown ether 31 and 32

Sseyedi et al synthesized thioether–ester crown ethers 33 (Figure 1.13) A

screening regarding antibacterial and antifungal activity on Klebsiella pneumoniae, Staphilococcus aureus, Pseudomanas aeruginosa and Candida albicans revealed that

thethioether–esters 33 are effective inhibitors against Klebsiella pneumoniae with

MIC values in the range of 25–400 μg/mL.[3]

Figure 1.13 Macrocyclic thioether–esters 33

1.5 Multicomponent Condensation Reaction

Multicomponent reactions (MCRs) are generally defined as reactions, in which three or more starting materials react to form one product All or most of the

atoms contribute to the newly created product.[17] Multicomponent condensations have attracted enormous interest due to their efficacy in the assambly of complex heterocyclic compounds in a single synthetic step Among the multicomponent processes, especially the three-component reactions have been developed into useful organic procedures

MCRs are also often termed as ‘cascade’, ‘domino’ and ‘one-pot’ processes The first example for a multicomponent reaction is the Strecker-condensation of amines, aldehydes and cyanide to yield -aminonitriles (Scheme 1.5).[29]Thereafter, a variety of MCRs have been reported, which include the Hantzsch, Passerini and Ugi reaction as most prominent precedents

Scheme 1.5 Examples of MCRs developed over the decades [31, 32, 35]

Different from traditional multistep methods, the advantages of multicomponent condensation reactions are saving labor time and resources, allow higher overall yields and increased selectivities In addition, it is not necessary to separate intermediate compounds (Fig.1.14)

Figure 1.14 Comparison of ordinary sequential syntheses wirth MCRs

Scheme 1.6 Example for a Mannich reaction

The Petrenko-Kritschenko reaction is a classical protocol to prepare piperidinones by means of a double Mannich reaction from acetone dicarboxylic acid esters, two equivalents of an aldehyde and ammonia (or a primary amine see Scheme 1.7)

Scheme 1.7 General scheme for the Petrenko-Kritschenko piperidone

synthesis

In this reaction, the mixture of reaction components is usually heated to reflux

in an aqueous or alcoholic solution and the resulting producst are often difficult to purify.[22] It has been found that the addition of acid to the reaction medium has a benefical effect on the chemical yield.[37]

1.5.2 Hantzsch dihydropyridine synthesis

In 1882, A Hantzsch carried out a reaction of ethyl acetoacetate with acetaldehyde and ammonia to obtain a fully substituted symmetrical dihydropyridine The one-pot condensation of a β-keto ester or another 1,3-dicarbonyl compound with

an aldehyde and ammonia to prepare 1,4-dihydropyridines is known as the Hantzsch dihydropyridine synthesis The 1,4-dihydropyridine products can be oxidated by an agent such as HNO2, HNO3, (NH4)2Ce(NO3)6, MnO2 or Cu(NO3)2, which delivers substituted pyridine derivatives.[15]

Scheme 1.8 Gerneral scheme for the Hantzch reaction

-Ketoesters of type 69, which are obtained from transesterification of ethyl

acetoacetate with different (oligo)ethylene glycols, have been converted by means of the Hantzsch condensation with ammonium carbonate and formaldehyde to new crown ethers containing pyridine after oxidation (Scheme 1.9).[34]

Scheme 1.9 Hantzch reaction in the synthesis pyridine-containing crown

ether

(NICOLET Nuclear magnetic resonance spectra 1H-NMR, 13C-NMR were recorded on Bruker 500 MHz machine at the laboratory of pharmaceutical chemistry, Hanoi university of science and technology, Vietnam National University, Ha Noi, and at the Institute of Chemistry – Vietnam Academy of Science and As deuterated solvents DMSO-D6 and CDCl3 with TMS as internal standard were engaged.

- MS spectra were recorded on AutoSpec Premier and LC/MS LTQ Orbitrap

XL (Thermo scientific) at the Faculty of Chemistry, Vietnam University of Science, Vietnam National University, Ha Noi

- The biological activity of substances was tested and recorded in the Laboratory of Experimental Biology, Institute of Natural Compounds, Vietnam Academy of Science and Technology and at the Institute of Chemistry – Vietnam Academy of Science and Technology

In the present work new derivatives of thiacrown ethers should be synthesized according to the Scheme 2.1

Scheme 2.1 Target structures and synthesis plan for the current work

2.1 Synthesis of Acyclic Derivatives

2.1.1 Synthesis of 1,5- bis(2-formylphenthio)-3-oxapentane 74

Scheme 2.2 Synthesis of 1,5- bis(2-formylphenthio)-3-oxapentane 74

A mixture of dithiol 72 (1.00 g, 7.23 mmol, 1.0 equiv), aldehyde 73 (2.03 g,

14.5 mmol, 2 equiv) and K2CO3 (2.00 g, 14.5 mmol, 2 equiv) in DMSO (10 mL) was

heated to 110 °C until TLC indicated full conversion of strating material 72 After

15 h of heating the reaction mixture was poured in a beaker with ice water The solid precipitated was separated by filtration and was washed with water Recristallization

in Ethanol (20 mL) under heating, filtration and drying in high vacuum furnished the

product 74 as colorless crystalls in a yield of 60% (1.50 g, 4.34 mmol)

M (C18H18O3S2) = 343.21 g/mol; Yield: 60% (1.50 g), Rf = 0.55 (ethylacetate/hexane: 1/3 v/v); , mp = 56-58oC 1H NMR spectrum: δ [ppm] = 3.14 [t, 4H, J = 6.5 Hz; 2xSCH2)], 3.68 (t, 4H, J = 6.5 Hz; -CH 2 OCH 2 -), 7.33 (td, 2H, J = 8.0

Hz, 1.0 Hz, HAr); 7.49 (-t, 2H, J = 7.0 Hz), 7,53 (td, 2HAr, J = 8,0 Hz; 1,5 Hz); 7,84 (dd, 2HAr, J = 7,5 Hz; 1,5 Hz), 10.42 (s, 2H, 2xCHO); LCMS, m/z: 346 u [M]+

2.1.2 Synthesis of 1,5-Bis(2-acetylphenthio)-3-oxapentane 76

Scheme 2.3 Synthesis of 1,5-bis(2-acetylphenthio)-3-oxapentane 76

A mixture of bis-(2-mercaptoethyl) ether 72 (1.00 g, 7.23 mmol, 1.0 equiv),

2-chloroacetophenone 75 (2.24 g, 14.46 mmol, 2.0 equiv) và K2CO3 (2.00 g, 14.46 mmol, 2 equiv), was stirred at 120 oC in DMSO (10.0 mL) The reaction was monitored by TLC and completed after 17 h The reaction mixture was poured into

100 mL ice water The precipitation was filtered by Buchner funnel and washed with

20 mL of cold ethanol Crude products were recrystallized in 20 ml ethanol to obtain white solids (1.4 g, 3.75 mmol)

M (C20H22O3S2) = 374.10 g/mol, Yield: 52%, Rf = 0,58 hexane/ethylacetate: 4/1 v/v), mp = 72-74 oC 1H NMR spectrum: δ [ppm] = 2,61 (s,

(n-6H, 2xCH3); 2,82-2,86 [m, 4H, 2x(-S-CH2)]; 3,10-3,13 (m, 4H, -CH2OCH2-); 7,22

(td, 2HAr, J = 8,0 Hz; 1,5 Hz); 7,35 (d, 2HAr, J = 8,5 Hz); 7,44 (td, 2HAr, J = 8,0 Hz; 1,5 Hz); 7,85 (dd, 2HAr, J = 7,5 Hz; 1,5 Hz) LCMS, m/z: 373,9 u [M]-; 375,9 u

[M]+

2.2 Synthesis of Cyclic Dithiaether Derivatives

2.2.1 Synthesis of Dithiaether Derivatives Containing 2,6-diaryl-piperidin-4-one (78a-c)

General procedure A: 1,5-Bis(2-formylphenthio)-3-oxapentane 74 (346 mg, 1.0 mmol, 1.0 equiv) was added to a suspension of the respective ketone 77a-c

(1.1 mmol, 1.1 equiv), ammonium acetate (770 mg, 10.0 mmol, 10.0 equiv) and

CH3COOH (0.3 mL) in EtOH (10 mL) The mixture was stirred at 50 oC and the reaction progress was monitored by TLC After TLC indicates full conversion of

starting material 74 (15-17 hour stirring over night), the resulting mixture is allowed

to cool down to room temperature and most of the volatile compounds are removed under reduced pressure Next, water (15 mL) is added and the resulting mixture is extracted with dichloromethane (3×30 mL) The combined organic phases are dried over anhydrous Na2SO4 The solvent is removed under reduced pressure and the

residue is purified by column chromatography using EtOAc/n-Hex and subsequent

recristallization from hot ethanol

2.2.1.1 Synthesis of 2 3 ,2 5 dibenzenacyclodecaphan-2 4 -one (78a)

-Diphenyl-7-oxa-4,10-dithia-2(2,6)-piperidina-1,3(1,2)-Scheme 2.4 Synthesis of dithiacrown ether 78a

The compound 78a has been prepared according to the general procedure A using ketone 77a (0.231 g), obtain colorless solid (0.18 g, 0.035 mmol) M

(C33H31NO2S2) = 537.18 g/mol, Yield 35 %, mp 201 - 203oC Rf = 0.51

(hexane/EtOAc: 1/3, v/v) IR (KBr, ν/cm -1): 3304, 3026, 2918, 2850, 1718, 1099 1NMR (500 MHz, CDCl3, TMS): δ [ppm]: =7.65 (d, 3 J = 8.0 Hz, 2H, Ar-H), 7.31 (d,

H-3 J = 8.0 Hz, 2H, Ar-H), 7.22 (t, 3 J = 7.5 Hz, 2H, Ar-H), 7.13 – 7.16 (m, 4H, Ar-H),

7.05 – 7.10 (m, 8H, Ar-H), 5.77 (d, 3 J = 11.5 Hz, 2H, 2 x CHNH), 4.25 (d, 3 J = 11.0

Hz, 2H, 2 x CHCO), 3.48 – 3.50 (m, 2H, CH2), 3.05 – 3.09 (m, 6H, 3 x CH2); NMR (125 MHz, CDCl3, 25 °C, TMS): δ [ppm] = 227.56, 157.41, 144.00, 133.92,

13C-133.63, 129.73, 128.01, 126.81, 111.24, 100.89, 68.53, 62.78, 60.69, 37.44, 29.73, 22.32, 14.20; HRMS (ESI+), m/z, Found: 538.1355 u [M+H]+, 560.1142 u [M+ Na]+

Calc for C33H32NO2S2+: 538.1876 u [M+H]+ and for C33H31NO2S2Na+: 560.1692 u [M+ Na]+

2.2.1.2 Sythesis of 2 3 dibenzenacyclodecaphan-2 4 -one (78b)

-phenyl-7-oxa-4,10-dithia-2(2,6)-piperidina-1,3(1,2)-Scheme 2.5 Synthesis of dithiacrown ether 78b

The compound 78b has been prepared according to the general procedure A using ketone 77b (0.147 g), obtain colorless solid (0.12 g, 0.027 mmol) M

(125 MHz, CDCl3, 25 °C, TMS): δ [ppm] = 207.59, 144.16, 143.68, 135.03, 134.24,

133.79, 133.18, 129.73, 128.76, 128.21, 128.08, 127.84, 127.14, 126.91, 68.59,

68.26, 63.36, 47.57, 37.46, 37.31 HRMS, m/z, Found 519.1743 [M]+ Calc for C29H29NO4S2+: 519.1538 [M+] and 538.1682 [M+ H2O+ H+] Calc for

C29H31NO4S2+ : 538.1716 [M+ H2O+ H+]

2.2.1.3 Synthesis of benzyl 2 4 dibenzenacyclodecaphane-2 3 -carboxylate (78c)

-oxo-7-oxa-4,10-dithia-2(2,6)-piperidina-1,3(1,2)-Scheme 2.6 Synthesis of dithiacrown ether 78c

The compound 78c has been prepared according to the general procedure A using ketone 77c (0.079 g), obtain colorless solid (0.15 g, 0.038 mmol) M

(C22H25NO2S2) = 399.13 g/mol, Yield 38.6 %, mp 160 - 162oC Rf = 0.62

(hexane/EtOAc: 1/1) IR (KBr, ν/cm -1): 3298, 3057, 2960, 2920, 2848, 1703, 1114

1H-NMR (500 MHz, CDCl3, TMS): δ [ppm] = 7.49 – 7.56 (br m, 4H, Ar-H), 7.23 –

7.30 (br m, 4H, Ar-H), 5.01 (br s, 1H, CH), 4.86 (br s, 1H, CH), 3.52 – 3.56 (br m, 2H, CH2), 3.05 –3.16 (br m, 7H, 3 x CH2 & CH(CH3)), 2.97 (br m, 1H, CHax), 2.83 (br s, 1H, CHeq), 0.83 (d, 3J = 6.5 Hz, 3H, CH3); 13C-NMR (125 MHz, CDCl3, ,

25 °C, TMS): δ [ppm] = 210.09, 144.20, 134.80, 134.35, 133.57, 133.39, 128.63,

128.09, 127.16, 115.29, 112.44, 101.78, 68.51, 68.49, 50.07, 47.49, 37.36, 20.23, 10.11 HRMS, (ESI+), m/z, Found: 400.1402 [M+H]+ and 432.1662 [M+MeOH+H]+, Calc for C22H26NO2S2+: 400.1399 [M+H]+ and for C23H30NO3S2+: 432.1662 [M+MeOH+H]+

2.2.1.4 Sythesis of 2 3 dibenzenacyclodecaphan-2 4 -one (78d)

-phenyl-7-oxa-4,10-dithia-2(2,6)-piperidina-1,3(1,2)-Scheme 2.7 Synthesis of dithiacrown ether 78d

1,5-Bis(2-formylphenthio)-3-oxapentane 74 (346.0 mg, 1.0 mmol) was added

to a solution of phenylacetoacetate 77d (178.0 mg, 1.0 mmol), ammonium acetate

(770.0 mg, 10.0 mmol) and CH3COOH (0.3 mL) in EtOH (10.0 mL) The mixture was stirred at 50 oC and the reaction progress was monitored by TLC After 24 h, the resulting solution was allowed to cool to room temperature and extracted with dichloromethane (3×30 ml) The organic phases were combined and dried with anhydrous Na2SO4 The solvent was removed at reduced pressure affording the residue which was purified by column chromatography and recrystallized from

ethanol to obtain pure products 78d (0.20 g, 0.39 mmol)

33.96, 33.61, 21.36 HRMS, m/z, Found 519.1743 [M]+ Calc for C29H29NO4S2+: 519.1538 [M+] and 538.1682 [M+ H2O+ H+] Calc for C29H31NO4S2+ : 538.1716 [M+ H2O+ H+]

2.2.2 Synthesis of dithiaether derivatives containing γ-aryl-pyridine (80a-e)

General procedure B: 1,5-bis(2-acetylphenylsulfanyl)-3-oxapentane 76 (374

mg, 1.0 mmol, 1.0 equiv) was added to a mixture of the respective aldehyde 79a-e (1.1 mmol, 1.1 equiv) and NH4OAc (770 mg, 10.0 mmol, 10 equiv) in AcOH (10 mL) and the reaction mixture heated under reflux for 15 - 17 h After cooling down

to ambient temperature, the reaction was neutralized by the addition of saturated aqueous K2CO3 solution Next, the products are extracted with CH2Cl2 (3×30 mL)

and dried over Na2SO4 After filtration, the solvent was evaporated in vacuo and the

residue was purified by column chromatography with a gradient elution by n-hexane

– EtOAc (ratio varied from 10:1 to 8:1) affording the products as colorless solids

2.2.2.1 Synthesis of 2 4 1,3(1,2)-dibenzenacyclodecaphane (80a)

-(3-methoxyphenyl)-7-oxa-4,10-dithia-2(2,6)-pyridine-Scheme 2.8 Synthesis of dithiacrown ether 80a

The compound 80a has been prepared according to the general procedure B using aldehyde 79a (0.160 g), obtain colorless solid (0.14 g, 0.03 mmol) M

(C28H25NO2S2) = 471.13 g/mol, Yield 30 %, mp 221 - 222oC Rf = 0.6

(hexane:EtOAc = 3:1) IR spectrum, ν, cm–1: 3049, 2920, 2852, 1598, 1581, 1492,

1463, 1492, 1392, 1242, 1089, 1028, 748 1H NMR spectrum, δ [ppm] (J, Hz) = 7.70 (2H, s, H-22,24); 7.64 (2H, dd, J = 7.5, J = 1.5, H-3,19); 7.57 (2H, dd, J = 7.5, J = 1.5, H-6,16); 7.49 (1H, dd, J = 7.5, J = 2.0, H-31); 7.29–7.44 (5H, m, H-4,5,17,18,31); 7.06 (1H, td, J = 7.5, J = 1.0, H-30); 7.00 (1H, dd, J = 8.5, J = 1.0, H-28); 3.85 (3H,

s, OCH3); 3.29 (4H, br s, 2xCH2O); 2.77 (4H, br s, 2xCH2S) 13C NMR spectrum, δ

Scheme 2.9 Synthesis of dithiacrown ether 80b

The compound 80b has been prepared according to the general procedure B using aldehyde 79b (0.17 g), obtain colorless solid (0.20 g, 0.04 mmol) M

(C28H25N2O3S2) = 486.10 g/mol Yield 43 %, mp 176 - 177oC Rf = 0.65

(hexane:EtOAc = 3:1) IR spectrum, ν, cm–1: 3051, 2914, 2852, 1604 1527, 1471,

1396, 1340, 1109, 999, 885, 748, 734, 682 1H NMR spectrum, δ [ppm] (J, Hz) = 8.61

(1H, s, H-27); 8.38 (1H, dd, J = 8.0, J = 2.0, H-29); 8.11 (1H, d, J = 8.0, H-31); 7.82 (2H, s, H-22,24); 7.75 (1H, t, J = 8.0, H-30); 7.72 (2H, dd, J = 7.0, J = 1.5, H-3,19);

The compound 80c has been prepared according to the general procedure B using aldehyde 79c (0.201 g), obtain colorless solid (0.12 g, 0.02 mmol) M

(C28H25BrNOS2) = 519.03 g/mol, Yield 23 %, mp 190 - 191oC Rf = 0.59 (hexane/EtOAc: 3/1, v/v) 1H NMR spectrum, δ [ppm] (J, Hz) = 7,88 (2H, S, H-

Scheme 2.11 Synthesis of dithiacrown ether 80d

The compound 80d has been prepared according to the general procedure B using aldehyde 79d (0.154 g), obtain colorless solid (0.18 g, 0.038 mmol) M

(C28H25ClNOS2) = 475.08 g/mol, Yield 38%, mp 185 - 186oC Rf = 0.55 (hexane/EtOAc: 3/1, v/v) 1H NMR spectrum, δ [ppm] (J, Hz) = 7.64 (2H, dd, J - 7.5,

2.2.2.5 Synthesis of [γ-(3-chlorophenyl)pyridino]dibenzoazadithiocrownophane (80e)

Scheme 2.12 Synthesis of dithiacrown ether 80e

The compound 80e has been prepared according to the general procedure B using aldehyde 79e (0.154 g), obtain colorless solid (0.18 g, 0.035 mmol) M

(C28H25ClNOS2) = 475.08 g/mol, Yield 35 %, mp 182 - 184oC Rf = 0.50 (hexane/EtOAc: 3/1, v/v) 1H NMR spectrum, δ [ppm] (J, Hz) = 7.70 (1H, s, H-27);

7.67 (2H, dd, J = 7.5, J = 1.0, H-29, 31); 7.64 (2H, s, H-22,24); 7.62 – 7.61 (1H, m, H-30); 7.55 (2H, d, J = 5.5, H-3,19); 7.43–7.40 (4H, m, H-4,5,17,18); 3.48 (4H, br

s, 2CH2O); 7.39 (2H, d, J = 6.5, H-6,16); 3.29 (4H, br s, 2CH2O), 2.80 (4H, br s, 2CH2S) 13C NMR spectrum, δ [ppm] = 135.36, 135.20, 133.31, 130.40, 129.88,

129.28, 128.25, 127.50, 125.55, 68.85, 37.51, 30.91 Found, m/z: 476.0882 [M+H]+

(Cl35), 478.0853 [M+H]+ (Cl37).C27H22ClNOS2 Calculated, m/z: 475.0831

CHAPTER 3 RESULT AND DISCUSSIONS

3.1 Synthesis of thiopodand Derivatives 74 and 76

Thiopodand derivatives 74 and 76 were synthesized based on the William

reaction from bis-(2-mercaptoethyl) ether 73 and the corresponding hetereoarene 74,

76 in the presence of K2CO3 in DMSO as shown in Scheme 3.1

Scheme 3.1 General synthesis of thiopodand derivatives 74 and 76

In order to optimize the formation of thiopodand 74, the reaction was carried

out at different temperatures The best yield has been accomplished after heating to

110 oC for 15 hours Below 100 °C almost no product formation could be observed, which is rationalized by a slow reaction rate Temperatures above 120 °C result in lower yields and the reaction mixture turned black, which is a sign for decomposition

Meanwhile, in the case of the reaction of bis-(2-mercaptoethyl) ether 72 with

acetophenone must be are reaction temperature of 120 oC turned out to be optimal Other polar solvents were also probed Among the tested solvents DMF and CH3CN

were the only ones besides DMSO that enabled the synthesis of product 76 in

reasonable yields, among which acetonitrile was the least suitable

The structures of thiopodands 74 and 76 were confirmed by Nuclear magnetic

resonance spectroscopy (NMR) and Mass spectroscopy (MS) In the 1H - NMR

spectrum of thiopodand 74, the singlet of the aldehyde proton could be observed at

10.42 ppm (2H) The protons of methylene group 2x(-S-CH 2 -) and (-CH 2 -O-CH2-) appeared as two tripletsat 3.13 and 3.68 ppm, respectively

A similar signal pattern was also visible in the 1H – NMR spectrum of podand

76, which is derived from diphenyl acetone The two methyl groups of the acetyl

moiety show a characteristic singlet at 2.61 ppm with 6H (2 x CH3) Moreover, the

molecular and structural formula of compounds 74 and 76 were confirmed by

molecular ion peak [M+] = 346 u and [M+] = 376 u, respectively

3.2 Synthesis of Thiacrown Ethers Containing a γ–Piperidone 78a-d

Scheme 3.2 General synthesis of thiacrown ether 78a-d

Based on the Petrenko – Krischenko multicomponent condensation reaction,

thiacrown ethers 78a-d were synthesized from oxapentane 74 with ketones and ammonium acetate in absolute ethanol In this work,

1,5-bis(2-formylphenthio)-3-a sm1,5-bis(2-formylphenthio)-3-all 1,5-bis(2-formylphenthio)-3-amount of 1,5-bis(2-formylphenthio)-3-acetic 1,5-bis(2-formylphenthio)-3-acid w1,5-bis(2-formylphenthio)-3-as used 1,5-bis(2-formylphenthio)-3-as c1,5-bis(2-formylphenthio)-3-at1,5-bis(2-formylphenthio)-3-alyst Moreover, the re1,5-bis(2-formylphenthio)-3-action temperature was kept at 50 oC to prevent the formation of by-products at higher temperatures Ammonium acetate was applied as ammonia source, which allowed to form NH3 in situ for the construction of the pyridine scaffold Based on previous

studies, thiacrown ethers including piperidone heterocycles were expected to be formed.[4] The most probable mechanism for this condensation reaction base on literature precedentsis shown in Scheme 3.3