SYNTHESIS OF PICHROMENES 1 DERIVATIVES

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

1


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

2


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

3


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 solventless 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 βnitrostyrene ............................................................................................................ 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

4


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

5


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

6


INTRODUCTION
2H- chromene ( 2H-1 benzopyran) is a compound which resulted from the
fusion of a benzene ring to a heterocyclic pyran ring.
2H-chromenes and its derivatives have been found in many biologically active
natural products that possess variety of activities including as anti-tumorous, antibacterial, antiviral, anti-oxidative agents.
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.

7


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, antitubulin, 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

8

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, 3substituted -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
9

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 solventless 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
tetrabylammonium bromide (TBAB) leads to the synthesis of 3-nitro-2H chromene

10

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 – dimethyl2H-chromenes by the reaction between salicyaldehyde with ethy-3-methyl-2butenoate ( 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 K2CO3
11


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 2Hchromene 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 K2CO3 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]

12


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,βunsaturated 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 -3carboxylates 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].

13


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

14


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 2Hchromene 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

15

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 3positions 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

16


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
dectected in
washes from
patients with
and inflamed

human disease states. For example, elevated levels of LT’s are
sputum from asthmatics, bronchoalverolar lavage fluid and nasal
allergic rhinitics patients following antigen challenge, scales from
psoriasis, synovial fluid from rheumatoid arthritis and gout patients,
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.

17


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 2HChromene 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)

18


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 2Hchromene and its derivative are summarized herein, but based on the previous work
of co-worker in synthetic Organic Laboratory III- Faculty 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 .
13

C-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)

19


2.1.3. Proposed mechanism for the condensation of salicyaldehyde and βnitrostyrene

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 iminiumactivated salicyaldehyde attacks to the double-bond of β-nitrostyrene , force the pielectron pairs to the carbon atom of iminium bond. Lastly, intermediate product
undergo the elimination process to generate 2H-chromene and recover D, Lpipecolinic 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

20


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

Entry R1

R2

Ratio

Product

Yield

1

3,5-

3,4,5-

1:1

46%

dibromo

trimethoxy

2

3-ethoxy

3,4,5trimethoxy

1:1

61%

3

5-bromo

3,4,5-

1:1

52%

trimethoxy

4

3-bromo

3,4,5trimethoxy

1:1

33%

5

1-naphtha

1-bromo

1:1

45%

6

1-naphtha

1-chloro

1:1

40%

21


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

13

C-NMR). 1H-NMR of 3-

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
a characteristic peak at around 74ppm which corresponds to the tertiary carbon.
For a significant example, the entry 2 which was condensed by 3-ethoxysalicyaldehyde and 3,4,5-trimethoxy-nitro styrene resulted 8-ethoxy-3-nitro-2(3,4,5-trimethoxyphenyl)-2H-chromene:

Figure 6 : 1HNMR of 8-ethoxy-3-nitro-2-(3,4,5-trimethoxyphenyl)-2Hchromene

22


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.

Figure 7:13C-NMR of 8-ethoxy-3-nitro-(3,4,5-trimethoxyphenyl)-2H-chromene.
On

13

C-NMR spectrum, the characteristic as shown is at 73.62ppm which

corresponds to the tertiary carbon C at the position 2 ( in the pyran ring ).
Detailed data about 1H -NMR and 13C-NMR of this compound are found in table 2.
The other nitro-chromene derivatives’s spectroscopic data are listed also in table 2

23

Entry

1

2

3

4

δ13C NMR (ppm)

δ1H NMR (ppm)

153.39, 149.57, 142.81, 139.03,
7.93(s, 1H),7.68-7.67 (m,H, CH)3.81(s, 3H, 131.12, 127.36, 120.93, 114.77,
CH3), 3.79(s, 6H, CH3)
112.43, 103.93, 74.27, 60.79, 56.28
8.02(s, 1H), 6.96-6.91(m, 3H), 6.62(s, 2H) 153.29, 147.96, 143.15, 141.50,
4.04(q, J=7.12Hz, J=8.67Hz), 3.78 (s, 6H, CH3), 138.70, 132.19, 129.42, 122.14
3.76 (s, 3H, CH3), 1.38(t, J=6.66Hz)
119.16, 118.41, 103.93, 73.62
64.98, 60.75, 56.05, 14.77
7.99(s, 1H), 7.48-7.42(m, 2H),7.28(s, 1H) 153.56, 152.49, 141.90, 139.29
6.82(d, J=8.58Hz, 1H), 3.830(s,3H CH3), 136.72, 132.26, 131.66, 127.67,
3.803(s, 6H, CH3)
119.04, 114.49, 104.35, 74.56,
60.79, 56.23

7.98(s, 1H), 7.48-7.42(m, 2H), 7.29(s,1H)
153.39, 150.42, 142.06, 138.85,
6.82(d,J=8.58Hz,1H),6.58(d,J=10.38Hz, 1H ), 137.35, 131.70, 129.52, 128.65,
3.830(s,3H, CH3), 3,803(s,6H, CH3)
123.64, 119.76, 111.54, 103.87,
74.09, 60.79, 56.22

5

8.67 (s,1H), 7.95(d, J= 8.45Hz,1H), 7.83(d,
J=13.69Hz,1H),CH)
7.75(d,
J=8.92Hz,1H,CH),7.69(d, J=8.92,1H,CH), 7.567.48(m, 1H,CH), 7.38-7.28(m,1H,CH), 7.207.16(m,1H,CH), 7.68(d, J=8.93,1H,CH)
6.59(s,1H,CH)

153.49, 139.16, 137.72,
135.63, 132.76, 132.02,
130.37, 129.12, 128.73,
126.01, 125.22, 124.53,
121.18, 117.79, 73.49

137.51,
130.92,
128.67
123.70,

6

8.65(s, 1H), 7.94(d, J=8.44,1H,CH), 7.84(d,
J=13.69Hz,1H,CH),

7.74(d,J=8.91,1H,CH),
7.67(d,J=8.10,1H,CH), 7.54-7.50(m, 1H,CH),
7.37-7.30(m,1H,CH),
7.26-7.24(m,1H,CH),
7.15-7.13(m,1H,CH), 6.59(s,1H,CH)

137.63, 137.46, 135.62,
129.77, 129.51, 129.12,
128.73, 128.41, 125.99,
124.53, 124.39, 121.17,
118.63, 117.79, 73.44

130.26,
129.06,
125.21,
119.21,

7

8.71(s,1H),
8.04(d,
J=8.87Hz,1H,CH),
7.95(d,J=8.46Hz,1H,CH),
7.80(d,J=8.91Hz,1H,CH),
7.71(d,J=8.12Hz,1H,CH),7.58-7.49(m,1H,CH),
7.40-7.36(m,1H,CH),
7.17(s,1H,CH),
6.72(s,1H,CH)

136.07, 131.23, 129.05,

128.97, 127.80, 126.51,
125.11, 124.52, 124.03,
119.89, 119.37, 118.63,
112.87, 114.81, 72.96

129.19,
126.49,
123.23,
117.52,

Table 2: 1H-NMR and 13C-NMR data of 3-nitro-2-phenyl-2H-chromene
derivatives
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2.2.1 Synthesis of 2-phenyl-2H-chromene carboxylate derivatives
2-phenyl-2H-chromene carboxylate derivatives were proposed to be
synthesized using the methods aforementioned in the methodology section. The
basic condition used mainly in those methods reported before is using K2CO3 under
diverse conditions (solvent, temperature). In this thesis, I was trying to conduct
chromene carboxylate derivatives based on the typical methods used to synthesize 2phenyl-2H-chromene carbaldehyde derivatives.

scheme 12: Synthesis of ester chromene
The reaction were carried out between salicyaldehyde derivatives and cinnamates
under many basic catalyst as TMG, DABCO…and solvents as toluene , DCM,
DMF. The starting materials are stable and not easy to be decomposed in the
reaction conditions and the results gave nothing at all except the starting materials
remained the same by TLC checks.
Likely to the synthesis of 3-nitro-2-phenyl-2H-chromene which is the result from
the condensation of salicyaldehyde and α,β-nitrostyrene and project to the similarity

of the skeleton, here I chose esters of cinnamic acid as starting materialsto form α,βunsaturated ester
To begin with the investigation, here showed a simple starting material resulting
from the esterification between cinnamic acid and ethanol ( ethyl cinnamate) with
the yield is approximately 60%.

Scheme 13: Esterification between cinnamic acid and ethanol
The resulted compound was determined by 1H-NMR data.
On 1H-NMR, the doublet at chemical shift 6.44 ppm is a characteristic peak which
belongs to the hydrogen at double bond CH=C=O. The other hydrogen which is also
at double bond shows peak at 7.26ppm.

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