SYNTHESIS OF PICHROMENES 1 DERIVATIVES

1.1.1 Condensation between salicyaldehyde and α,β unsaturated compounds using organocatalysts This method is considered as one of the most popular and effective ones to synthesize 2-H ch

VIETNAM NATIONAL UNIVERSITY, HA NOI

VNU UNIVERSITY OF SCIENCE

FACULTY OF CHEMISTRY

Nguyen Thanh Binh

SYNTHESIS OF PICHROMENES 1 DERIVATIVES

Submitted in partial fulfillment of the requirements for the degree of

Bachelor of Science in Chemistry

(Advanced Program)

Ha Noi - 2013

VIETNAM NATIONAL UNIVERSITY, HA NOI

VNU UNIVERSITY OF SCIENCE

FACULTY OF CHEMISTRY

Nguyen Thanh Binh

SYNTHESIS OF PICHROMENES 1 DERIVATIVES

Submitted in partial fulfillment of the requirements for the degree of

Bachelor of Science in Chemistry (Advanced Program)

Supervisor: Dr Mac Dinh Hung Assoc Prof.Dr.Dr Luu Van Boi

Ha Noi - 2013

ACKNOWLEDGMENTS

I would like to express a deep gratitude to my supervisor, Professor Luu Van Boi for his generous support about materials over the past four years despite of

his heavy positions in many big projects

I want to specially thank to my fantastic mentor, Dr Mac Dinh Hung for his

patient guidance and enthusiasm to help me directly in every step in this project He

is really a mirror for me to learn both knowledge and experiences at laboratory He has taught me many valuable techniques which under his observation I was getting better day by day

I also want to express my continuing appreciation to entire Organic Synthetic Laboratory III for sharing and exchanging chemicals and apparatus no matter how insufficient I know our conditions are

Lastly, I am grateful to my family and friends for being there all the time with love and support no matter how downcast I am with the failure of reactions I carried out

Hanoi, May 14th, 2013 Nguyen Thanh Binh

Contents

INTRODUCTION 7

Chapter 1 : OVERVIEW 8

1.1 Application methods to synthesize nitro- chromene derivatives 9

1.1.1 Condensation between salicyaldehyde and α,β unsaturated compounds using organocatalysts 9

1.1.2 Ring-closing metathesis for the synthesis of Chromene 10

1.1.3 Microwave assisted synthesis of 3- Nitro-2H-chromene under solvent- less phase transfer catalytic conditions 10

1.2.Carboxylate chromene derivatives synthesis screening 11

1.3 Biological activities of chromene derivatives 13

Chapter 2 - RESULT AND DISCUSSION 18

2.1.1.Application to synthesize 3-nitro-2-phenyl-2H-chromene ‘s derivatives 19

2.1.2 Spectroscopic data of 3-nitro-2-phenyl-2H-chromene derivatives 19

2.1.3 Proposed mechanism for the condensation of salicyaldehyde and β-nitrostyrene 20

2.1.4 Synthesis of some derivatives of 3-nitro-2-phenyl-2H-chromene 20

2.2.1 Synthesis of 2-phenyl-2H-chromene carboxylate derivatives 25

Chapter 3 : EXPERIMENTS 28

3.1 Chemicals 29

3.2 Instruments 29

3.3 Experiments 29

3.3.1Synthesis of 3-nitro-2-phenyl-2H-chromene derivative 29

3.3.2 Synthesis of ethyl cinnamate 33

3.3.3.Synthesis of methyl 3-(4-fluorophenyl) acrylate 33

3.3.4 Synthesis of carboxylate chromenes derivative 34

CONCLUSION 35

REFERENCES 36

APPENDIX 38

ABBREVIATION

DABCO : 1,4 –diazabicyclo [ 2,2,2] octane DBU : 1,8 – Diazabicycloundec-7-ene DCM : dichlomethane

DMF : dimethylformamide

DMSO : dimethyl sulfoxide

NMR : nuclear magnetic resonance

TBAB : tetrabutylammonium bromide TLC : thin layer chromatography

TMG : 1,1,3,3-tetramethyl guadinine

LIST OF FIGURES

Figure 1 : Pichromene 7

Figure 2 : Compounds with 2H-Chromene skeleton 8

Figure 3 : Structure of 2H-chromene isolated from Sargassum micracanthum 14

Figure 4 : Nitro-chromene skeleton 18

Figure 5: Ester chromene skeleton 19

Figure 6 : 1HNMR of 8-ethoxy-3-nitro-2-(3,4,5-trimethoxyphenyl)-2H-chromene 22 Figure 7:13C-NMR of 8-ethoxy-3-nitro-(3,4,5-trimethoxyphenyl)-2H-chromene 23

Figure 8:1H-NMR of ethyl cinnamate 26

Figure 9:1H-NMR of methyl 3-(4-fluorophenyl) acrylate 27

LIST OF TABLES Table 1 : Condensation products between salicyaldehydes and α,β-nitrostyrene 22

Table 2: 1H-NMR and 13C-NMR data of 3-nitro-2-phenyl-2H-chromene derivatives 24

Table 3: Condensation of salicyaldehydes and cinnamates 28

LIST OF SCHEMES Scheme 1 : Syntheis of 3-nitro-2-phenyl-2H-chromene reported by Sakakibara 9

Scheme 2 : Synthesis of 2-H chromene derivatives using catalysts 9

Scheme 3: Synthesis of 2-H Chromene using DABCO as catalyst 10

Scheme 4: Ring-closing metathesis for the synthesis of Chromene 10

Scheme 5: Synthesis of 3-nitrochromene derivative using microwave assistance 11

Scheme 6: Synthesis of chromene starting under the condition of K2CO3 11

Scheme 7: Synthesis of Chromene under the condition of K2CO3 and DMSO 12

Scheme 8: General synthesis of Chromene reported by Cheng 12

Scheme 9: Synthesis of Chromene esters 13

Scheme 10: Synthesis of salicyaldehyde with tert-butyl acrylate 13

Scheme 11: General procedure to synthesize 3-nitro-2-phenyl-2H-chromene 21

scheme 12: Synthesis of ester chromene 25

scheme 13: Esterification between cinnamic acid and ethanol 25

Among of those derivatives from 2H-chromene, pichromene (Figure 1) has been

used as a treatment in blood cancer therapy due to its ability to prevent tumorous cells from growing by inhibiting the expression of D1, D2 and D3 as well as inducing apoptosis in leukemia and myeloma cells

Figure 1 : Pichromene

Aforementioned, pichromene and its derivatives are of considerable current interest for a chemotherapy in blood cancer treatment In Vietnam, not many reports found to learn about those promising biological compounds so this thesis is a compilation of methods that are commonly used to apply for synthesis of pichromene’s derivatives in effective and simple ways The study was carried out at Medicinal Chemistry laboratory and support from Organic Synthetic laboratory III, Faculty of Chemistry, VNU University of Science

Chapter 1 : OVERVIEW

2-H Chromenes are an important class of oxygenated heretocyclic compounds Many biologically active natural products contain a chromene ring

system ( Figure 2) In recent years, there has been increased interest in the synthesis

of 2H-chromenes due to number of compounds that possesses this group, and that shows a variety of activities including as antidepressant, antihypertensive, anti-tubulin, antiviral , antioxidative, activator of potassium channels and inhibition of phosphodiesterase IV or dihydrofolate reductase Based on the importance of these compounds, a number of research groups have developed methodologies to synthesize these compounds The approaches used include intramolecular cyclization of Wittig intermidates, microwave assisted reaction of salicyaldehyde with enamines, catalytic Petasis reaction of salicyaldehydes, ring-closing olefin metathesis, Baylis-Hilman reaction of 2-hydroxy-benzaldehydes with methy vinyl ketones, Claisen rearrangement of propargyl phenol esters, Pd-catalyzed ring closure

of 2-isoprenyl phenols, electrocyclic ring closure of vinylquinone derivatives, and the Ylid annulation reaction Despite the availability of these exisiting methods for the synthesis of chromene derivatives, there remains a demand for general strategies that can more efficiently provide variously substituted chromenes system

Herein, I didn’t give all the methods that listed above but reported typical and efficient ones

Figure 2 : Compounds with 2H-Chromene skeleton

1.1 Application methods to synthesize nitro- chromene derivatives

Synthesis of Pichromene and its derivatives is basically based on the synthesis of 2H-chromene and analogs This section lists out some routes which are used popularly to prepare chromene

1.1.1 Condensation between salicyaldehyde and α,β unsaturated compounds using organocatalysts

This method is considered as one of the most popular and effective ones to synthesize 2-H chromenes and its derivatives by based catalyzed condensation of salicyaldehyde with deficient electron compounds such as ankenes, allenes The reaction is carried under the presence of bases such as triethyl amin, pyridine or DABCO (1,4 –diazabicyclo [ 2,2,2] octane ) which gave different results In 1978, Tohru Sakakibara introduced the synthesis of 3-nitro-2-phenyl-2H-chromene using triethyl amin as basic catalyst, but it resulted both chromene with a modest yield

38% and also a side product up to 31% was formed in chromanol (scheme 1) [1]

Scheme 1 : Syntheis of 3-nitro-2-phenyl-2H-chromene reported by Sakakibara

The reaction between salicyaldehyde with electron deficient olefin was also studied

by a group of Bhaskar C Das As reported (2010), with the same procedure above and extended to other different positioned substituents of salicyaldehyde by using 1,1,3,3- tetramethylguanidine (TMG ) and L- pipecolinic acid as organocatalyst, 3- substituted -2-phenyl-2H-chromene derivatives were synthesized with high yield and poor enantioselectivity using pipecolinic acid while TMG works well with

cynamaldehyde without using co-catalyst( Scheme 2)[2]

Scheme 2 : Synthesis of 2-H chromene derivatives using catalysts

In 2001, Ming-Chung Yan and his co-workers postulated an easy and efficient method for the synthesis of 2,2-dialkyl-3-nitrochromene where the reaction

between salicyaldehyde and β-nitrostyrene underwent with the presence of DABCO

as catalyst and the absence of solvent at 40oC and it gave a range of high yield In the case below, the yield is quite impressive which is up to 99% as reported

(Scheme 3)[3]

Scheme 3: Synthesis of 2-H Chromene using DABCO as catalyst

One year later, in 2002, Perry T Kaye also proposed a convenient general synthesis

of 3-substituted 2H chromene derivatives using DABCO catalyzed which follows a

Baylis- Hilman pathway.[4], [5]

1.1.2 Ring-closing metathesis for the synthesis of Chromene

In 1997, Sukbok Chang reported a practical and highly efficient procedure for preparing diverse chromene derivative using ring closing metathesis ( RCM), a

methodology emerging as a new tool in synthetic organic chemistry.[6]

RCM of the dienes pre-prepared was next attempted using organometallic catalysts For example ruthenium carbene catalyst [ Cl2(PCy)3Ru=CHPh] (Scheme 4)

Scheme 4: Ring-closing metathesis for the synthesis of Chromene

This method gives a good yield but it’s quite costly and the preparation of starting materials meets some difficulties However, it’s still a new approach to generate various substituted chromene system

1.1.3 Microwave assisted synthesis of 3- Nitro-2H-chromene under solvent- less phase transfer catalytic conditions

In 2008, Rafik Koussini and his colleague Ayed S Al-Shihri reported a treatment of substituted 2-hydroxy benzaldehyde with 2-nitro ethanol supported on anhydrous potassium carbonate, in presence of catalytic amount of

derivatives by a solvent less phase-transfer catalytic (PTC) reaction under

microwave irradiation.[7], [8]

In a standard procedure for the preparation of 3-nitro-2H-chromene derivatives, dry potassium carbonate, tetrabutylammonium bromide (TBAB) and salicyaldehyde derivative were added together in a transparent polypropylene beaker 2-nitro ethanol was added dropwise and the mixture then was placed in an unmodified household microwave oven The reaction was irradiated for 2 min using 20% of the maximum power of the oven Upon completion of the reaction, monitored by a TLC, the mixture was cooled to room temperature, then extracted with ethyl acetate and filtered After removing the solvent, crude was purified by column chromatography and recrystallized by a pertinent solvent This environmentally friendly procedure occur remarkably fast and under mild conditions and effort is still

in need to improve the yield ( Scheme 5)[9]

Scheme 5: Synthesis of 3-nitrochromene derivative using microwave assistance 1.2.Carboxylate chromene derivatives synthesis screening

In 1982, Kawase et al reported one step method to synthesize 2,2 –

dimethyl-2H-chromenes by the reaction between salicyaldehyde with

ethy-3-methyl-2-butenoate ( Scheme 6) The reaction was carried out in DMF at 130oC It was reported that methoxy-, methyl-, chloro-, bromo-, and phenyl-substituted salicyaldehydes gave the chromenes in modest yield while nitro-, hydoxy-, ethoxy-,

and acetyl-substituted salicyaldehydes generated in poor yields or nothing at all.[10]

Scheme 6: Synthesis of chromene starting under the condition of K 2 CO 3

Lun-Zhi Dai and his co-worked continued investigating the reaction of salicyaldehyde with ethyl buta-2,3-dienoate or penta-3,4-dien-2-one catalyzed by a catalytic amount of potassium carbonate (K2CO3) produce the corresponding 2H-chromene products in moderate to good yield under mild conditions During the investigation procedure, they found that K2CO3 is an efficient catalyst , giving the corresponding functionalized 2H-chromenes in good yield in dimethyl sulfoxide (DMSO) at 120oC Herein, they reported the reaction of salicyaldehydes with unsubstituted allenic esters or ketones catalyzed by K2CO3 ( Scheme 7) [11]

Scheme 7: Synthesis of Chromene under the condition of K 2 CO 3 and DMSO

Yong- Ling Shi and Min Shi also gave a report that salicyaldehyde could also react with 3-methylpenta- 3,4-dien -2-one, 3- benzylpenta-3,4-dien -2-one or ethyl 2-methyl buta-2,3-dienoate to give the corresponding functionalized 2H-1 chromenes in good to excellent yield and good diastereoselectivities in most of the cases, using DBU as the catalyst in DMSO

In 2003, Cheng et al investigated chromene derivatives as TNF –α Inhibitor (Tumor Necrosis Factor) and summarized the synthesis of chromene derivatives which

follows the scheme 8 below [12]

Scheme 8: General synthesis of Chromene reported by Cheng

Starting from that, a series of chromene esters were prepared The ester formation is

accomplished using the method of Yamaguchi [13]

Scheme 9: Synthesis of Chromene esters

In 1993, Yoshitaka Satoh and his group synthesize and evaluated a series of chromene derivatives by condensation of appropriate salicylaldehydes with α,β-unsaturated carbonyl compounds, followed by transformation to the corresponding hydroxamic acids or N-hydroxyureas Chromene hydroxamic acids were synthesized according to the procedure below And the intermediate chromene -3-carboxylates were prepared by the reaction of appropriately substituted salicyl adldehyde with α,β-unsaturated esters Use of tert-butyl acrylate is essential to

prevent partial hydrolysis of the ester under the reaction conditions.[14]

Scheme 10: Synthesis of salicyaldehyde with tert-butyl acrylate

1.3 Biological activities of chromene derivatives

2H-chromenes and its derivatives have been paid a large attention for their interesting biological activities , in 2006, some chromene compounds extracted from

brown algae, Sargassum micracanthum has been proved to have a potential ability

to be an inhibitor of human cytomegalovirus [15]

Figure 3 : Structure of 2H-chromene isolated from Sargassum micracanthum

As reported , belonging to chromene family, robustic acid is discovered to have protein kinase inhibiting activity, daurichromenic acid as anti-HIV agent meanwhile

terrosin and acronysin are investigated to be anti-tumorous.[16], [17]

Study on biological activities of chromene and derivatives reveals that they inhibit the growth of several tumor cells and are also effective against muscle cell proliferation, which plays a key role in atherosclerosis The initial event in several human disease processes involving cancer and atherosclerosis is oxidative damage

to several cellular components such as lipids, proteins, and DNAs So this has

intensified the search for more chromene’s derivatives synthesis [18]

In 2007, Batista and his group studied on the biological activities of some chromene derivatives extracted from natural resources and the result revealed that chromenes exhibit significant anti- trypanocidal activities and indicated that this

class of natural products should be considered further in the development of new

and more potent drugs for use in the treatment of Chagas disease.[19]

The synthesis and biological activity of 3-nitrochromene and derivatives have been reported because of their potential as precursors to a variety of medically important 2H-benzopyran derivatives as flavonols, amines and other important targets

Biological activities of chromene and derivatives have been tested based on factors of compound nature’s and its orientation binding with the protein in cells Bhaska C Das and his group in their chemical biology projects , they were interested in developing chromene’s derivatives that interact with the developmentally important receptor-mediated pathway such as the TGF-pathway , acting as antagonist or agonist From there, they set up a library of 2-substituted 2H-chromene derivatives for their bioactivity on developing zebrafish embryos The zebrafish embryo provides an ideal vertebrate model system for in vivo small molecule screen because of its optical transparency, accessibility during embryonic development and permeability to small molecules Compound BT7(figure ) was found to modulate a specific relevant pathway, namely p-SAPK/JNK, which is known to be down-stream of TGF-β, and can mediate Smad-independent sigalling The group then sought to develop function-oriented BT7 and finally attach biotin

using functional group transformations [20], [21]

Based on the development of domino reactions, nitro-chromenes therefore are versatile synthetic intermediates in organic synthesis owing to the various possible transformations of the nitro group into other useful functional groups which resulted

the function-oriented BT7 analogues.[22], [23]

In 2003, Jei-Fei Cheng and his co-workers who studied on chromene ester derivatives synthesis also reported the bioactivity of those compounds In this project, a series of chromene –based TNF –α inhibitors is described (TNF : Tumor Necrosis Factor α,is a pro-inflamatory cytokine secreted by a variety of cells, including monocytes and macrophages, in response to many inflammatory stimuli or

external cellular stress ).[24]

TNF exerts its biological effects through interaction with one of two ubiquitously expressed cell surface receptors, TNFR1 and TNFR2 and it functions in infectiousm immunological or malignant diseases Herein , they reported a novel series of

chromenes esters based TNF-α inhibitors that may serve as leads for novel therapeutic agents Antioxidants have long been known to inhibit the activation of transcription factors including NF-kB as well as TNF-α production Chromenes ester derivatives with structural features similar to some of the know antioxidants

may also be useful for elucidating the TNF-α signaling pathway.[25]

Before, in 2001, Natsuki Ishizuka and his colleagues also postulated a study structure-activity relationships of a novel class of Endothelin –A Receptor antagonists based on 2H-chromenes ester derivatives

ET receptors belong to a seven transmembrane G-protein-coupled receptor (7TM/GCPR) family and two receptor subtypes, endothelin A (ETA) and endothelin

B (ETB) have been identified.[26]

In mammals, ET receptors are distributed in a wide variety of tissues, and elevated levels of the plasma concentration of ET-1 were observed in several diseases such as hypertention, pulmonary hypertension, acute myocardial infarction, congestive heart failure, renal failure and atherosclerosis Blocking of ETs using a monoclonal antibody or ET receptor antagonists in animal pathological models showed an antihypertensive activity in hypertension , reduction of the myocardial infarct size in acute myocardial ischemia and reperfusion, reduction in neointimal formation in a carotid artery balloon angioplasty model, improvement of survival in chronic heart failure, and improvement of the glomerular filtration rate in acute ischemic renal failure These results strongly indicate that blocking the ET receptors is a powerful

in ameliorating various disease states and ET antagonists could be promising new

therapeutic agents [27]

The results indicate that the hydrophobic substituent at the 4-position plays a crucial role for improving the activity, but its shape is not so important in the receptor recognition A predominant factor for determining the affinity is only the length of the substituent, and the optimal length is estimated to be 6-9 A

Many compounds that contain chromene’s skeleton with different substituents at positions are tested and it is concluded that compounds that act as carboxyl bioisostere, were more active than esters and less potent than the carboxylic acids Obviously, the carboxyl group at the 3-position is an essential functional group The

3-3-carboxyl group should act as a hydrogen bonding donor in the ETA receptor active

site.[28]

Back to the research of Yoshitaka Satoh and his group , they did evaluate in vitro and ex vivo 5-lipoxygenase ( 5-LO) inhibitory activity

Conversion of arachidonic acid (AA) by the 5-LO enzyme results in the formation

of 5-hydroperoxy-6,8,11,14-eicosatetraenoic acid ( 5-HPETE), which is subsequently metabolize to a series of highly potent leukotrienes (LT’s) These

oxygenated eicosanoids are implicated in inflammatory and allergic reactions [29]

It is becoming increasingly evident that leukotrienes are extremely important mediators in human disease states For example, elevated levels of LT’s are dectected in sputum from asthmatics, bronchoalverolar lavage fluid and nasal washes from allergic rhinitics patients following antigen challenge, scales from patients with psoriasis, synovial fluid from rheumatoid arthritis and gout patients, and inflamed colonic mucosa and rectal dialysis fluid from patients suffering from

inflammatory bowel disease [30]

Numerous attempts have been made in the last decade to identify and develop 5-LO inhibitors as therapeutic agents In particular, hydroxamic acid derivatives of arachidonic acid and its analogs exhibit potent 5-LO inhibitory activities in the RBL 5- LO assay, the hydroxamate –based 5- LO inhibitors have been intensely investigated In his work, he disclosed the research effort directed toward the discovery of potent , orally active 5-lipoxygenase inhibitors based on the chromene templates

Chapter 2 - RESULT AND DISCUSSION

As mentioned above, 2H- Chromene and its analogs have been caught with a certain extent of attention from scientists for its interesting biological activities against to blood cancer, and many other serious diseases Many researches about 2H-chromene have been reported with diverse approaches The Chromene family is honored to be one of potent compounds which contribute to enrich the variety of treatments for cancers As reported in many approaches, the synthesis of 2H-Chromene doesn’t meet many hindrances but striving for new methods which are easier and more effective to get positive yield is always an aim for any synthetic organic group The success of synthesizing such potent and promising compounds therefore will lower the cost of the treatment for cancers and bring hope to the patients that are fighting for their life, especially the poor ones who can’t afford the expensive treatment In Vietnam, there are not many investigations that focus on these compounds meanwhile the need of searching for new methods to cure patients that suffer from cancers should really get priority, especially when the method of chemotherapy is nowadays becoming popular And the purpose of this thesis is not

an exception but trying to synthesize a series of nitro-chromene’s derivatives

(Figure 4) based on the previous work of senior lab-mate

Figure 4 : Nitro-chromene skeleton

R1 and R2 are substituents coming from corresponding α,β-nitrostyrenes and salicyaldehydes which will be reported in the experiment section

To expand further more about the variety of Chromene family, in this work, I gave

an attempt to synthesize the ester chromene’s derivatives in which the nitro group would be replaced by an ester group using currently available methods which are

applied on the synthesis of the other chromene’s derivatives (Figure 5)

Figure 5: Ester chromene skeleton 2.1.1.Application to synthesize 3-nitro-2-phenyl-2H-chromene ‘s derivatives

3-nitrochromenes are promising starting materials for the synthesis of functionalized heterocyclic frameworks Pichromene and analogs are also caught an extensive attention by many research groups from all over the world

So far, some popular and classical methods which are used widely to prepare chromene and its derivative are summarized herein, but based on the previous work

2H-of co-worker in synthetic Organic Laboratory III- Faculty 2H-of Chemistry, Hanoi University of Science, VNU I have chosen a simple but effective method to apply on the preparation of 3-nitro-2-phenyl-2H-chromene derivatives With many trials, a variety of solvents and catalysts were studied under different conditions ( temperature, time ) and the optimal condition which was concluded for the synthesis

of 3-nitro-2-phenyl – 2H- chromene’s derivatives is using D, L-pipeconilic acid ( 20%mol) with solvent toluene (reflux, 24h)

The resulted compounds are listed in the Table 1

2.1.2 Spectroscopic data of 3-nitro-2-phenyl-2H-chromene derivatives

The structure of 3-nitro-2-phenyl-2H-chromene derivatives are determined using modern spectroscopic methods 1H-NMR of 3-nitro-2-phenyl-2H-chromene’s derivatives ( Appendix ) generally shows two characteristic peaks at around 8.0 ppm and 6.6 ppm corresponding to the hydrogen of the double bond Hydrogen and the hydrogen that bonds to the tertiary carbon

13C-NMR of 3-nitro-2-phenyl-2H-chromene derivatives shows a typical peak at around 74.0 ppm which corresponding to the tertiary carbon ( 2-position)

2.1.3 Proposed mechanism for the condensation of salicyaldehyde and

β-nitrostyrene

The mechanism of the reaction between salicyaldehyde and β-nitrostyrene follows oxa-Michael reaction Salicyaldehyde reacts with D,L pipecolinic acid caused the removal of a water molecule and forming inimium – activated salicyaldehyde The non-bonding electron pair on the oxygen atom of iminium-activated salicyaldehyde attacks to the double-bond of β-nitrostyrene , force the pi-electron pairs to the carbon atom of iminium bond Lastly, intermediate product undergo the elimination process to generate 2H-chromene and recover D, L-pipecolinic acid

2.1.4 Synthesis of some derivatives of 3-nitro-2-phenyl-2H-chromene

Apply the optimal condition of the condensation of salicyaldehyde and nitrostyrene derivatives, several derivatives of them were obtained in a variety of yield Chemical structure of starting materials of salicyaldehyde, α,β-nitrostyrene

and products are shown in Table 1

Scheme 11: General procedure to synthesize 3-nitro-2-phenyl-2H-chromene

3,5-dibromo

trimethoxy

7 1-naphtha 1-nitro 1:1 44%

Table 1 : Condensation products between salicyaldehydes and α,β-nitrostyrene

The derivatives of 3-nitro-2-phenyl-2H-chromenes products were synthesized and

presented in the table 1 above in which the chemical structures of these compounds

were determined by spectroscopic data ( 1H-NMR and 13C-NMR) 1H-NMR of nitro-2-phenyl-2H chromene derivatives show two characteristic singlets at around 8.00ppm and 6.5 ppm.13CNMR of 3-nitro-2-phenyl-2H chromene derivatives shows

3-a ch3-ar3-acteristic pe3-ak 3-at 3-around 74ppm which corresponds to the terti3-ary c3-arbon For a significant example, the entry 2 which was condensed by 3-ethoxy-salicyaldehyde and 3,4,5-trimethoxy-nitro styrene resulted 8-ethoxy-3-nitro-2-(3,4,5-trimethoxyphenyl)-2H-chromene:

Figure 6 : 1 HNMR of

8-ethoxy-3-nitro-2-(3,4,5-trimethoxyphenyl)-2H-chromene

On 1H-NMR, the two typical singlets at 8.02 ppm and 6.62 ppm which belong to the hydrogen CH-NO2 and CH-O in the pyran ring The other singlets ( whose chemical shifts are 3.79 ppm and 3.78 ppm) belongs to the hydrogen of methoxy group –OCH3

The triplet at 1.38ppm and the quartet at 4.04ppm resulted from the hydrogens bonding with methyl group CH3 and methylene group CH2-O respectively