1.3 Synthesis of γ

Transcription

1.3 Synthesis of γ

Republic of Iraq
Ministry of Higher Education
and Scientific Research
University of Thi-Qar
College of Science
SYNTHESIS AND CHARACTRAZATION OF
SOME NEW γ-LACTAMS
A Thesis
Submitted to the council of the College of Science
In Partial Fulfillment of the Requirements
for the Master Degree of Science in Chemistry
By
Sahib Awadh Gatea Al-Jayyashee
B.Sc.Chemistry(1998)
Supervised by
Prof.Dr
Mahmood Shakir Magtoof Al-Tamemay
2015 A.D
1436 A.H
‫بِسْمِ اهللِ الرَّحْمنِ الرَّحِيمِ‬
‫اقْرَأْ بِاسْمِ رَبِّكَالَّذِي خَلَقَ‬
‫*‬
‫خَلَقَ الْإِنْسَانَ مِنْ عَلَقٍ * اقْرَأْ وَرَبُّكَ الْأَكْرَمُ‬
‫الَّذِي عَلَّمَ بِالْقَلَمِ * عََّلمَ الْإِنْسَانَ مَا لَمْ يَعْلَمْ‬
‫*‬
‫*‬
‫صدق اهلل العلي العظيم‬
‫سورة العلق اآليات (‪)5-1‬‬
CERTIFICATE
We certify that this thesis , SYNTHESIS AND CHARACTRAZATION OF
SOME
NEW γ-LACTAMS , was prepared by Sahib Awadh Gatea under
our supervision at the Department of Chemistry, College of Science ,University
of Thi-Qar, Iraq in partial fulfillment of the requirements for Master degree of
science in chemistry.
Supervisor
Prof.Dr
Mahmood Shakir Magtoof
Department of Chemistry
College of Science
In
In view of the available recommendation, I forward this thesis for
debate by the examining committee.
Asst.Prof.
Dr.Sajid H.Gezar
The Head of Department of Chemistry
College of science
‫المقومين‬
‫المقوم العلمي‬
‫أ‪.‬د‪ .‬جمبذ هرمز توما‬
‫جامعة بغداد ‪ /‬كلية التربية ابن الهيثم‬
‫طبقا ً الى الكتاب ذي الرقم ‪ 03‬س ‪ 242 /‬بتاريخ ‪ 2364 /62/61‬والصادر من كلية العلوم ‪/‬‬
‫جامعة ذي قار‬
‫المقوم اللغوي‬
‫أ‪.‬م‪.‬د‪ .‬خالد شاكر علي‬
‫جامعة ذي قار ‪ /‬كلية التربية للعلوم االنسانية ‪ /‬قسم اللغة االنكليزية‬
‫طبقا ً الى الكتاب ذي الرقم ‪ 03‬س ‪ 681 /‬بتاريخ ‪ 2364 /63/65‬والصادر من كلية العلوم ‪/‬‬
‫جامعة ذي قار‬
Approved by the college committee for graduate studies.
Signature:
Name: Prof. Mohammed Aja'a. PhD
College of Sciences
of Dean Approval
Date :
/ / 2015
Dedication
To that will rise and make the world a paradise
Imam Al-Mahdi (Peace Be Upon Him)
To the symbol of compassion under whose feet paradise
lies down
My mother
To my prides, guide and the existence reason
My father
To those who were my best support
My brothers ,sisters and my wife
To my supervisor who taught me the letters of gold and
words of pearls
Prof.Dr Mahmood shakir
Sahib
Acknowledgements
First and foremost, I must acknowledge my limitless thanks to Allah, the ever thankfulness, for helping me in completing this thesis. Peace and blessings be upon our
Prophet Mohammad and his purified Progeny.
The sincerely I would like to thank my supervisor Prof. Dr. Mohamood Shakir Magtoof
for continuous confidence, advice, patience, and encouragement. I thank him a lot for his
precious time spent on the thesis.
Also my thanks and appreciation to the deanship of the College of Sciences
/University of Thi-Qar Prof. Dr. Mohammed Aja’a Auda , and head of the department of
chemistry Asst.Prof. Dr. sajeed Hassan Kezar for giving all the possible facilities for
completion of the thesis. I am also thankful to Dr. Maged.Al.Safe and wish them lasting
good fortune and progress.
I feel a deep sense of gratitude for my mother and father, who formed part of my
vision and taught me good things that really matter in life. Their infallible love and support
have always been my strength. Their patience and sacrifice will remain my inspiration
throughout my life. May this thesis be a reward for all your sacrifice. I also thank my
brothers , sisters and my wife for their support.
Last, but not least, I thank my friends Abbas Mohson , Saad Shahad , Mohammed
Ismaal, AbbasTalib , Mostafaa Jawad , and my brother Ali Aawdh for their support and
encouragement.
At the end I would like to express my thanks to all individuals who helped me in one
way or another in the fulfillment of this research.
Sahib Awadh
CONTENTS
Title
Contents
Page
I
Abbreviation
III
Summary
V
Chapter One
Introduction
1.1
Lactam
1
1.1.1
γ – Lactam
2
1.2
γ -Lactam-containing natural products
2
1.2.1
Lactacystin
3
1.2.2
Relationship between Lactacystin and omuralide
4
1.2.3
Salinosporamide A
5
1.2.4
Heliotropamide
7
1.3
Synthesis of γ- Lactam
8
1.3.1
8
1.3.3.1
Synthesis of γ- Lactam via ring expansion of βlactam
Synthesis of γ- Lactam via intramolecular BaylisHillman
Synthesis of γ- Lactam include transition metalcatalyzed
Ruthenium-catalysed “ Kharasch cyclisation ”
1.3.3.2
palladium - catalyzed carbonylation
15
1.3.4
17
1.3.4.1
Synthesis of γ- Lactam include cycloaddition
reactions
The cycloaddition of acid halide to imine
1.3.4.2
Cycloaddilion reactions of cyclic anhydrides
19
1.3.5
Synthesis of γ -Lactam-containing natural products
20
1.3.5.1
Total Synthesis of Lactacystin
20
1.3.2
1.3.3
I
12
13
13
17
1.3.5.2
Short total synthesis of Salinosporamide A
22
1.3.5.3
Synthesis of Heliotropamide
23
The aim of the work
25
Chapter Two
Experimental
2.1
Analytical Techniques
26
2.2
Experimental design
29
2.3
30
2.3.1
General Procedure for the preparation of imines
2(a-h).
preparation of mono-imines 2(a-d).
2.3.2
Preparation of bis-imines 2(e-h).
31
2.4
34
2.4.1
General Procedure for the preparation of γlactams 3(a-h).
Preparation of mono-γ-lactams 3(a-d).
2.4.2
Preparation of bis-γ-lactams 3(e-h).
37
Chapter Three
30
34
Results and Discussion
3.1
General
41
3.2
UV spectra
45
3.3
Infrared (IR) spectra
49
3.4
1
52
3.5
13
3.6
APT 13C-NMR spectrum
62
3.7
HSQC 1H-13C – NMR spectrum
64
3.8
Mass spectra
66
3.9
List of spectra
70
References
116
H-NMR spectra
C-NMR spectra
57
II
Abbreviations
Symbols
Meaning
atm
Atmosphere
APT
Attached proton test
bar
Unit of Pressure
Bn
Benzyl
B.D.H
British Drug House
13
C-NMR
Carbon 13 Nuclear Magnetic Resonance
CAN
Ceric Ammonium Nitrate
DEPT
Distortionless Enhancement by Polarization Transfer
DMF
N,N-Dimethylformamide
DMSO
Dimethyl sulfoxide
dd
Doublet of doublets
Et2O
Diethyl ether
Et3N
Hz
Triethylamine
Unite of frequency
1
H-NMR
Proton Nuclear Magnetic Resonance
HOAc
Acetic acid
HMPA
Hexamethylphosphoramide
HSQC
Heteronuclear Single-Quantum Correlation spectroscopy
h
Hour
J
Coupling Constant
hour
LDA
Lithium DiisopropylAmide
m
Multiplet
m.p
Melting Point
NAC
N-acetyl cysteine
III
PMB
4-methoxybenzyl
ppm
Part Per Million
q
Quintet
R.A
Relative Abundance
r.t
Room Temperature
s
Singlet
t
Triplet
THF
Tetrahydrofuran
Thr
Threonine (Amino Acid)
Ts
P-Toluenesulfonyl(tosyl)
IV
Summary
This study is concerned with the synthesis and characterization of mono-γlactams 3(a-d ) and bis-γ-lactams 3(e-h ) . These compounds were prepared by
reaction phenylsuccinic anhydride with the appropriate schiff bases (imines)
2(a-h) , by using chloroform solvent and heated at temperature (51-61˚C) in
moderate yields(70-92)% , and explained spectrum proton nuclear magnetic
resonance (1H-NMR) and nuclear magnetic resonance spectrum carbon 13 (13CNMR) appearance isomers of cis and trans clear where it was clear from the
three protons of the ring pyrrolidine-2-one .
The structures of these γ- lactams were established on the basis of the spectral
data : UV , IR , 1H-NMR , 13C-NMR , APT 13C-NMR , HSQC 1H-13C-NMR ,
Mass .
V
Chapter one
Introduction
Introduction
Chapter one
Introduction
1.1
Lactam
A lactam is a cyclic amide. The name is derived from two chemical
terms, lactone, referring to a cyclic ketone, and amide, a compound
containing the amide group –NH-C=O as part of a ring in the molecule..
Lactams are named according to the size of the cyclic ring in the lactam:
α-lactams, β-lactams, γ-lactams and δ-lactams contain rings made of
three, four, five or six atoms, respectively as in figure (1-1) . A lactam
with a three-membered ring is a α-lactam because the α-carbon from the
carbonyl group is bonded to the heteroatom ( N) of the ring .A lactam
with a four-membered ring is a β-lactam because the β-carbon from the
carbonyl group is bonded to the heteroatom ( N) of the ring . A lactam
with a five-membered ring is a γ-lactam because the γ -carbon from the
carbonyl group is bonded to the heteroatom ( N) of the ring . A lactam
with a six-membered ring is a δ-lactam because the δ-carbon from the
carbonyl group is bonded to the heteroatom ( N) of the ring 1.
Figure (1-1)
1
Introduction
Chapter one
1.1.1 γ – Lactam
Five-membered ring lactams, which are known as γ-lactams or 2oxopyrrolidines as in figure (1-1), are important structural motifs in
biologically active natural products
2
which are also found in medicinal
leads and approved drugs . γ -Lactams have attracted great attention in
recent years because they are valuable building blocks in synthesis and
due to the presence of a γ –lactam core in the structure of several
biologically active molecules
3
. Substituted γ-lactams, in particular,
have potential application in drug synthesis, but the development of
stereoselective synthesis of chiral γ-lactams remains a challenge
4,5
.
Developing effective and simple synthetic methods is important so that
the drug candidates can be screened . A stereoselective addition to a γlactam skeleton provides a direct and efficient method for synthesizing
various γ-lactam derivatives. However, the most commonly used methods
for synthesizing chiral
γ-lactams are based on the cyclization or
cycloaddition of N-containing precursors, which are synthesized
stereoselectively, and there are limited studies on the stereoselective
additions to γ-lactam skeletons 6-8 .
1.2
γ -Lactam-containing natural products
γ-Lactams are important structures for the synthesis of natural
products and biological probes for drug discovery and development
(figure 1).9−14 The prevalence of γ-lactams in biologically significant
molecules has resulted in the development of many syntheses of this
substructure, and has led to the production of diverse libraries of small
molecules for biological evaluation.
15-19
. Molecules of natural origin
containing a functionalized γ-lactam (pyrrolidin-2-one) ring system with
a quaternary stereocenter
20
at C5 hold a prominent position in chemistry
2
Introduction
Chapter one
and biology. Important examples of these γ -lactams include the
proteasome inhibitors lactacystin and salinosporamide A , dysibetaine
,several examples from the oxazolomycin family of antibiotics , scheme
(1-1)
Scheme (1-1)
1.2.1 Lactacystin
In 1991, Omura reported the isolation and characterization of
lactacystin 1 , figure ( 1-2 ) , a natural compound isolated from the
culture broth of Streptomyces lactacystinaeus 21.
Figure (1-2)
3
Introduction
Chapter one
The structure of lactacystin was elucidated by spectroscopic
analyses, including NMR and X-ray crystallography
22
, and found to
possess a non-peptide consisting of two α-amino acids, an N-acetylcysteine and a novel pyroglutamic acid derivative. Lactacystin was
originally isolated and characterized as a result of its ability to induce
neuritogenesis in neuroblastoma cell lines and was later identified as the
first isolated natural proteasome inhibitor 23 . Lactacystin, as well as other
chemical compounds which are able to efficiently and selectively inhibit
the proteasome, have found an application in biology and medicine as a
means to investigate the proteasome and its cellular role
24
.In addition,
inhibition of proteasomal activity may eventually have applications in the
treatment of many diseases including allergies
25
,inflammation
26
,viral
infections 27, ischemic stroke 28, tuberculosis 29 , and cancer 25.
1.2.2 Relationship between Lactacystin and omuralide
Subsequent in vitro studies revealed that lactacystin itself is not
active against proteasomes. Further experiments showed that in aqueous
solutions at pH = 8, lactacystin is spontaneously converted into clastolactacystin β-lactone , scheme (1-2) , later named omuralide 2 , which is
the active proteasome inhibitor 30 .
Scheme (1-2)
4
Introduction
Chapter one
1.2.3 salinosporamide A
Although omuralide 2
inhibition
of
cellular
itself shows good potency towards
proteolytic
activity,
the
introduction
of
salinosporamide A 3 , figure (1-3) in 2003 by Fenical and coworkers
demonstrated how structural changes around the key pharmacophores
of 2 (the β-lactone and γ-lactam fused rings) can lead to even
greater bioactivity. 31
Figure (1-3)
Salinosporamide A 3 is a secondary metabolite of the marine
actinomycete
Salinispora tropica that shows a 22-fold increase in
proteasome inhibitory power (CT-L activity) as compared to omuralide 2
with an IC50 of 2.6 nM
32
. Through cocrystallization of 3 and the 20S
proteasome, it was shown by X-ray crystallography that the mechanism
of action of 3 is the same as that posited for 2 see scheme(1-3) . 33 The
rise in bioactivity of 3 is due to irreversible complexation of 3 to the
proteasome, owing to the chloroethyl substituent. The initial attack
of the hydroxyl group of the proteasome’s -terminal threonine
residue to the β-lactone of 2 and 3 to give complexes 4 and 5 ,
5
Introduction
Chapter one
respectively, is reversible , see scheme(1-3). However , with complex 5
the resulting alkoxide, which may otherwise drive the reaction back to the
left, can substitute the chloride to give a stable tetrahydrofuran (THF)
ring 6 . This ring serves two purposes: it prevents reformation of the
β-lactone and decomplexation, and it prevents hydrolysis of the
complex by occupying the site with the THF ring where a water
molecule is normally positioned in the enzymeactive site, thus preventing
the same hydrolysis mode of omuralide (2). In fact, omuralide (2) is
completely hydrolyzed and decomplexed from the proteasome within 24
h.34
Scheme (1-3)
6
Introduction
Chapter one
1.2.4 Heliotropamide
Heliotropamide (7) , figure (1-4) is an oxopyrrolidine natural product
recently isolated from Heliotropium ovalifolium in aerial parts.Its
structure was elucidated by spectrometric methods and chemical
derivatization.Neither heliotropamide nor its acetylated derivative
showed any antifungal activity against Cladosporium cucumerinum and
Candida albicans, antibacterial activity against Bacillus subtilis.35 This
dehydrodimer of a cinnamic amide (N-feruloyltyramine) that forms the γlactam core has only recently been observed in one other natural product,
namely bis-avenanthramide B (8) .36 ,figure (1-4)
Figure (1-4)
7
Introduction
Chapter one
1.3
Synthesis of γ- Lactam.
γ-Lactams are privileged scaffolds found in naturally occurring
and synthetic biologically active compounds
37-39
. Lactams are useful
synthetic intermediates in the preparation of various materials.40,41
Several synthetic methods have been reported for the preparation of γlactams from readily available precursors.42 For example γ-lactams have
been prepared from ring expansion of β-lactams
43-47
, intramolecular
Baylis-Hillman, transition metal-catalyzed cyclization, cycloadditions
reactions,48
aza-Michael additions,49,50 reduction of nitro compounds
followed by cyclization51 , reduction of γ-azido esters followed by
cyclization,52 the imino-Mukaiyama−Aldol reaction.
53
, synthesis of γ -
Lactam-containing natural products i.e lactacystin and salinosporamide A
.Several methods have also been explored that allow for the
enantioselective formation of γ-lactams utilizing chiral auxiliaries,42,51
enatiomerically enriched starting materials,54,55 and organocatalysts.49,54
Synthesis of γ- Lactam via ring expansion of β-
1.3.1
lactam
the broad synthetic applicability of this β-lactam to γ-lactam ring
expansion reaction was demonstrated through the development of a full
intramolecular version leading to functionalized γ-lactams and bicyclic
γ-lactams , one of the methods in which the ring expands 4-(1-halo-1methylethyl)azetidin-2-ones
into
functionalized
γ-lactams
via
N-
acyliminium intermediates. For example, dissociation of the bromide in
4-(1-bromo-1-methylethyl) azetidin-2-ones 9 gave rise to carbenium
8
Introduction
Chapter one
ions 13 , which in their turn were converted into stable N-acyliminium
intermediates 14 via an intramolecular rearrangement upon stirring in
dimethylsulfoxide (DMSO) . In principle, this ring expansion can be
considered as the aza-analog of the cyclo-butylmethylcarbenium ion
rearrangement toward cyclopentanes or cyclopentenes. Subsequent
attacks of different nucleophiles onto iminium salts
9
led to the
formation of functionalized trans-γ-lactams 10 as the major reaction
products,
besides
the
corresponding
cis-γ-lactams
11
and
4-
isoprenylazetidin-2-ones 12 (obtained via dehydrobromination) as minor
constituents , scheme (1-4) 56 .
Scheme (1-4)
9
Introduction
Chapter one
For another of the example synthesis of bicyclic γ-lactams , 4-(1chloro-1-methylethyl)-1- hydroxyalkyl- azetidin-2-ones 15 were treated
with AgBF4 and pyridine in toluene under reflux, resulting in the
diastereoselective formation of novel trans-1-aza-4-oxabicyclo [3.3.0]
octan-8-ones 16 and trans-1-aza-5-oxa–bicyclo [4.3.0] nonan-9-ones 17 ,
besides minor amounts of the corresponding cis-isomers 18 and 19 ,
scheme (1-5) . These observations could be explained considering the
intramolecular nucleophilic trapping of N-acyliminium intermediates
formed through AgBF4-mediated chloride dissociation, by the hydroxyl
moiety , in analogy with the above described reaction pathway
scheme (1-5) 57 .
Scheme (1-5)
For another method of ring expansion in β-lactam through the
N1– C4 cleavage and C5 carbon insertion in basic conditions, for example
treatment of 1-benzyl-3,3,4-triphenyl-2-azetidinone 20 and 1-benzyl-3,3methyl-4-phenyl-2-azetidinone 22 which has no stereogenic center at C3
with lithium diisopropylamine (LDA) gives the corresponding 3,3,4,510
Introduction
Chapter one
tertraphenyl-2-pyrrolidinone
pyrrolidinone
23
in
21
and
3,3-dimethyl-4,5-diphenyl-2-
good yield . The stereochemistry of the ring
expansion reaction is dependent on the substituents at C3 of the starting βlactam derivatives . In the case of the two phenyl or two methyl
substituents , the anti-relationship stereochemistry at C4 and C5 in γlactam derivatives are predominant Syn relationship stereochemistry at C4
and C5 in γ- lactam derivatives are trace amount . The structure of
stereochemistry was tentatively assigned by relative stability of each
compounds , scheme (1-6) 58.
Scheme (1-6)
11
Introduction
Chapter one
1.3.2
Synthesis of γ- Lactam via intramolecular Baylis-
Hillman
Syntheses of various heterocyclic compounds were accomplished
in the past by the use of iron and acetic acid on various Baylis-Hillman
adducts. Baylis-Hillman is an organic reaction in which aldehydes
react with variety of activated alkenes in the presence of tertiary
bicyclic amines to give multifunctional products. These heterocycles are
present as a framework in numerous structures which are precursors
to natural products or pharmaceutical agents .
Basavaiah, et al
59
reported the synthesis of substituted γ-
lactam 25 which was obtained from the acetate derivative of a BaylisHillman adduct e.g. 24 , in this reaction, the adduct acetate underwent
reductive cyclization in the presence of iron and acetic acid to give the
γ-lactam in a moderate yield of (54%) , scheme (1-7) .
Scheme (1-7)
For another example and in the simple stereoselective total
synthesis of salinosporamide , the intramolecular Baylis-Hillman reacts
to a ketoamide substrate. The reaction was catalyzed by quinuclidine and
the γ-lactam product 26 was formed as a 9:1 mixture of diastereomers
favoring the desired stereoisomer , scheme (1-8) 60 .
12
Introduction
Chapter one
Scheme (1-8)
Synthesis of
1.3.3
γ-Lactam include transition metal-
catalyzed
1.3.3.1 Ruthenium-catalysed “ Kharasch cyclisation”
Lactams are found in an array of natural products and act as
advanced intermediates for the synthesis of antibiotic and anticancer
agents
61
As a result, new methods to synthesize β-, γ-and δ-lactams are
of interest in organic synthesis. Methods that form the lactam system in
ways other than through the formation of the amide linkage are
13
Introduction
Chapter one
particularly interesting. In 1984, Itoh and co-workers reported the
synthesis
of
γ-lactams
through
a ruthenium catalysed Kharasch
cyclisation of allylic trichloroacetamides 62.
In all cases only the γ-lactams were isolated in high yield
showing a preference for a 5-exo-trig cyclisation over a 6-endo-trig
cyclisation , scheme (1-9) .
Scheme (1-9)
The authors went on to propose a general mechanism of the
ruthenium catalysed process 63. The ruthenium(II) catalyst initiates the
process by abstracting a chlorine atom from the trichloro group of
substrate 27 to form a carbon centered radical , scheme (1-10) .
This radical then undergoes a 5-exo-trig cyclisation to form the 5membered lactam ring 28 . Finally, quenching of the terminal radical
occurs with reduction of ruthenium(III) to ruthenium(II) to complete the
catalytic cycle.
14
Introduction
Chapter one
Scheme (1-10)
1.3.3.2 palladium- catalyzed carbonylation
The progress in carbonylation chemistry has been achieved not
only in academic laboratories but also in industry . Hence , it is not
surprising
that
there
are
many carbonylation
reactions
being
employed on an industrial scale 64. In this respect , palladium-catalyzed
cyclocarbonylation 2-(1-alkynyl) benzenamines 29 were converted into
3-(halomethylene)indolin-2-ones 30 in the presence of PdX2 and CuX2 =
Br,C1)
65
. The products are achieved in moderate to good yields ,
scheme (1-11) . The latter reaction mechanism is proposed to start with
the coordination of PdC12 to the triple bond and nitrogen, followed by
cis- and trans-halopalladation to generate a vinyl palladium species.
Afterward, the coordination and insertion of CO occurred, and the
terminal product is formed after reductive elimination. The active Pd(II)
15
Introduction
Chapter one
species can be regenerated by the oxidation of Pd(0) with CuX 2 to start a
new catalytic cycle.
Scheme (1-11)
Aminocarbonylation
tosylhomo- allylamines
products
66
and
under
oxidation
conditions, N-
31 furnished 3-methyl-2-pyrrolidones 32 as
, in the presence of palladium and copper salts, the reactions
were carried out at 1 bar of CO and at room temperature , scheme (1-12).
.
Scheme (1-12)
16
Introduction
Chapter one
1.3.4 Synthesis of γ- Lactam include cycloaddition reactions
The (3+2) cycloaddition provides a way for the synthesis of many
heterocycles compounds, the cycloaddition reaction includes several
examples as the cycloaddition of acid halide to imine .and acid cyclic
anhydride to imine .
1.3.4.1 The cycloaddition of acid halide to imine
Addition of o-iodobenzoyl chlorides 33 to imine 34 affords Nacyliminium ions as adducts. Subsequent reaction of these adducts with
phenyllithium at -78˚C followed by warming to ambient temperature
induces an intramolecular Wurtz-Fittig coupling to afford 2,3dihydroisoindolones 35 in excellent yields , scheme (1-13) 67.
Scheme (1-13)
17
Introduction
Chapter one
Mahmood . et al
68 , 69
have reported straight forward synthesis of γ-
lactam 38 from the reaction between 2-halo benzoyl chloride 36 with
imine 37 in the prescence Phenyl lithium as a base under (N2) atm at -10
in THF solvent to yield product 38 , the mechanism of these reaction as
shown as in , scheme (1-14) .
Scheme (1-14)
18
Introduction
Chapter one
1.3.4.2 Cycloaddilion reactions of cyclic anhydrides
Cycloaddition reactions of cyclic anhydrides have seen wide
application in the synthesis of natural
products medicinal lead
coumpounds, and other molecules of biological interest . In addition,
recent discoveries have revealed new three and four-component reactions
that greatly enhance the utility of cyclic anhydrides as useful reagents for
preparing heterocyclic compounds. A one-step synthesis of γ-lactams is
possible from imines and succinic anhydrides through a formal
cycloaddition process under thermal condition , as first demonstrated by
Castagnoli 70 , scheme (1-15) .
imine
succinic anhydride
γ-lactam
Scheme (1-15)
Ongoing studies of the iminolysis mechanism prompted to explore
the possibility of accessing a zwitterionic enolate intermediate from a
maleic anhydride by a prototropic shift to provide allylic stabilization ,
scheme (1-16) , the zwitterion 41, resulting from iminolysis of anhydride
40, could isomerize to 42 attack of the α- or γ-position of the dienolate
would lead to products 43a or 43b, respectively 71.
19
Introduction
Chapter one
Scheme (1-16)
1.3.5 Synthesis of γ -Lactam-containing natural products
1.3.5.1 Total Synthesis of Lactacystin
The synthesis of
lactacystin described in scheme (1-17) ,
is
noteworthy for a number of reasons. The synthesis is direct and simple
with regard to reaction procedures and isolation of pure products. It is
stereo controlled and economical in terms of reagents. In addition , the
key intermediate 49 allows access to many analogues of lactacystin in
which the isopropyl group is replaced by other lipophilic residues . For
example , reaction of 49 with vinyl , allyl and phenylmagnesium halides
under the conditions described below for the conversion of 49 into 50
afforded in good yield the corresponding analogues of
50 . These
compounds are of special interest in connection with the search for
lactacystin analogues that exhibit species selectivity. Finally, the chiral
acid ester 45 is a versatile intermediate which serves as a synthetic
20
Introduction
Chapter one
equivalent of configurationally unstable chiral methyl
derivatives 72.
Scheme (1-17)
21
malonic acid
Introduction
Chapter one
1.3.5.2 Short total synthesis of Salinosporamide A
The pathway of the synthesis of salinosporamide A is outlined
in scheme (1-18) , and this synthesis of salinosporamide A that is
capable of providing
substantial quantities of this currently rare
substance for further biological study, especially to determine its potential
as an anticancer agent
60
.
Scheme (1-18)
22
Introduction
Chapter one
1.3.5.3 Synthesis of Heliotropamide
73
The core of heliotropamide was efficiently assembled using the
lactam-forming four-component reaction(4CR) under standard conditions
scheme (1-19) .74 Maleic anhydride 67, thiophenol 68 , 4-isopropoxy-3methoxy-benzaldehyde 69 , and 2-(4-isopropoxyphenyl)ethanamine 70
were heated to reflux in toluene with azeotropic removal of water using a
DeanStark trap for 24 h. Conversion of the resultant acid to the methyl
ester allowed isolation of intermediate 71 in 76%yield . Desulfurization
was achieved with TMS3SiH with AIBN added as a radical initiator.*
Epimerization of the resultant cis-lactam was effected with NaOCH3,
which also resulted in complete saponification to acid 73. This
intermediate was coupled with 70 using EDCI/HOBt/DMAP to provide
74, the completed core of heliotropamide .
* Use of Bu3SnH resulted in a slightly higher yield for the desulfurization reaction (91%) on small scale, while TMS3SiH was
used for larger scale Work.
Scheme (1-19) Assembly of the Lactam Core of Heliotropamide
23
Introduction
Chapter one
Conversion of 74 to heliotropamide required aldol condensation with 69.
This transformation was effected in two steps, beginning with aldol
addition of the doubly anionic lithium enolate of 74 to 69. This aldol
reaction proceeded in high yield to provide alcohol 75 as a mixture of
diastereomers along with traces of dehydration product 76. Complete
dehydration of the unpurified mixture was achieved using refluxing
formic acid to provide 76 as a single alkene isomer. The formation of
compound 76 was accompanied with traces of products in which one to
four of the isopropyl groups had been cleaved. After purifying and
characterizing the major product (76), the mixture was treated with BCl3
to cleave all of the isopropyl ethers to yield heliotropamide , scheme (120) .
Scheme (1-20) Completion of Heliotropamide Synthesis
24
Introduction
Chapter one
The aim of the work
The aim of the work is the synthesis mono-γ-Lactam and bis-γ-Lactam
compounds by heating a mixture of various mono-imines and bisimines with
phenylsuccinic anhydride in chloroform
solvent , and
characterization of these compounds by UV, IR , 1H-NMR
APT 13C-NMR , HSQC 1H-13C NMR , Mass spectra .
25
13
C-NMR ,
Chapter Two
Experimental
The Experimental part
Chapter two
2.1 Analytical Techniques :
2.1.1 All the melting points are measured in (°C), in the Department
of Chemistry, College of Science, University of Thi Qar,Iraq . Using
melting point temperature SMP3. .
2.1.2 UV spectra were recorded on LTd +90 plus , PG Instruments,
Germany UV/VIS spectrophotometer, in the Department of Chemistry,
College of Science, of Thi-Qar University , Iraq.
2.1.3 IR spectra were recorded , using Shimadzu FT-IR affinity
spectrophotometer in the Department of Chemistry , College of Science ,
Thi-Qar University , Iraq , as KBr disks. Only principal absorption bands of
interest are reported and expressed in cm-1.
2.1.4 1H-NMR spectra were recorded, using VARIAN spectrophotometer
13
( 300 MHz ) , C-NMR spectra were recorded, using VARIAN
spectrophotometer ( 75 MHz ) , APT
13
C-NMR spectra were recorded,
using VARIAN spectrophotometer (75 MHz ) , HSQC 1H-13C-NMR
spectra were recorded, using VARIAN spectrophotometer (600 MHz, 150
MHz), the above measurements were recorded in National Hellenic
Research Foundation, Institute of Biology Medicinal Chemistry and
Biotechnology , Molecular analysis Group , Athens , Greece. The chemical
shift values are expressed in  (ppm), using tetramethylsilane (TMS) as
internal standard and using d6-DMSO as a solvent.
26
Chapter two
2.1.5 Mass spectra were recorded using in HPLC-LCQ Fleet / Thermo
Scientific spectrophotometer and using ESI , APCI , HESI as source , in
National Hellenic Research Foundation , Institute of Biology Medicinal
Chemistry and Biotechnology , Molecular analysis Group , Athens ,
Greece.
2.1.6 Thin layer chromatography (TLC) was performed using TLC
grade silica gel ‘G’ (Acme Synthetic Chemicals). The spots were made
visible by exposing plates to iodine vapour, and eluted with ethyl acetate :
hexane mixtures unless otherwise stated.
2.1.7 Chemical and materials
The solvent were dried over anhydrous sodium sulphate unless
otherwise
specified
75
. Chemical reagents supplied from different
companies are shown in table ( 2-1) :
27
Chapter two
Table (2-1) : Chemical Material
Purity%
Company
1
1,4-Phenylenediamine
4-Chloroaniline
4-Methylaniline
Sodium sulfate anhydrous
99
98
99
99
Fluka
2
2-Chlorobenzaldehyde
THF
Ethyl acetate
n-Hexane
Glacial acetic acid
Benzene
Butanol
99
98
99
99
98
99
99
B.D.H
3
Ethanol
Methanol
Chloroform
99
99
99
GCC
Phenylsuccinic anhydride
2-Fluorobenzaldehyd
2-Bromobenzaldehyde
4-Methoxybenzaldehyde
1,5-Diaminonaphthalene
99
97
98
99
97
NO.
4
Material
28
Aldrich
Chapter two
2.2 Experimental design
Amine
Aldehyde
UV spectra
Phenylsuccinic
anhydride
Imines
2(a-h)
IR spectra
APT 13C-NMR
spectrum
1
UV spectra
IR spectra
γ- lactams
3(a- h)
13
HSQC H- C NMR spectrum
1
H-NMR spectra
13
C- NMR spectra
Mass spectra
29
Chapter two
2.3 General Procedure for the preparation of imines 2(a-h).76-79
2.3.1 preparation of mono-imines 2(a-d).
The
mono-imines 2(a-d) were prepared
by the reaction of
the
mixture of 0.01 mol amine with 0.01 mol aldehyde in 20 mL of
chloroform and 4-6 drops of glacial acetic acid was heated in water bath
at (51-61˚C) , The reaction mixture was refluxed for (17-20)h with stirring .
The progress of the reaction was followed by TLC . After completion , of
the reaction has been removed the solvent and then conducted
recrystallization from a suitable solvent, the physical data of mono-imines
2(a-d) as shown below :
2.3.1.1 N-(2-Chlorobenzylidene) 4-chloroaniline 2a .
The compound was prepared by reaction of (1.27 g , 0.01 mol) of 4chloroaniline and (1.40 g, 0.01 mol) of 2-chlorobenzaldehyde.The time of
the reaction = 18 h , weight practical = 1.925 g , solvent of recrystallization
= ethanol , color of = yellow , Yield = 76.87 % , m.p = 64-65 ºC , IR
(KBr) : 1620 cm-1 (C=N).
2.3.1.2 N-(2-Bromobenzylidene) -4-chloroaniline 2b .
The compound was prepared by reaction of (1.27 g , 0.01 mol) of 4chloroaniline and (1.85 g, 0.01 mol) of 2-bromobenzaldehyde. The time of
30
Chapter two
= methanol , color = green , Yield = 83 %, m.p = 74-75 ºC , IR (KBr) :
1616 cm-1 (C=N).
2.3.1.3 N-(2-Bromobenzylidene)-4-methylaniline 2c .
The compound was prepared by reaction of (1.07g ,0.01 mol) of 4methylaniline and (1.85 g , 0.01 mol) of 2-bromobenzaldehyde. The time of
= ethanol , color = brown , yield = 80 % , m.p = 43-44 ºC , IR (KBr) : 1616
cm-1 (C=N).
2.3.1.4 N-(2-Fluorobenzylidene)-4-methylaniline 2d.
The compound was prepared by reaction of (1.07 g ,0.01 mol) of 4methylaniline and (1.24 g , 0.01 mol) of 2-fluorobenzaldehyd. The time of
= methanol , color = brown , yield = 90 %, m.p = 44-45 ºC , IR (KBr) :
1624 cm-1 (C=N).
2.3.2 Preparation of bis-imines 2(e-h).
In general, the bis-imines 2(e-h) were prepared by reacting the
mixture of 0.01 mole of amine with 0.02 mole of aldehyde in 20 mL of
chloroform and 4-6 drops of glacial acetic acid was heated in water bath
at (51-61˚C) , The reaction mixture was refluxed for (2-18)h with stirring .
31
Chapter two
The progress of the reaction was followed by TLC . After completion , of
the reaction has been removed the solvent and then conducted
recrystallization from a suitable solvent, the physical data of bis-imines
2(e-h) as shown below :
2.3.2.1 N1,N4-bis(2-Chlorobenzylidene)benzene-1,4-diamine 2e.
The compound was prepared by reaction of (1.08 g , 0.01 mol) of 1,4phenylenediamine and (2.80 g , 0.02 mol) of 2-chlorobenzaldehyde. The
time of the reaction =
18 h , weight practical =
3.12 g , solvent of
recrystallization = butanol , color = green , Yield = 88 % , m.p = 150-151
º
C , IR (KBr) : 1612 cm-1 (C=N).
2.3.2.2 N1,N4-bis(2-Fluorobenzylidene)benzene-1,4-diamine 2f.
The compound was prepared by reaction of (1.08 g , 0.01 mol) of
1,4-phenylenediamine and (2.48 g , 0.02 mol) of 2-fluorobenzaldehyd . The
16 h , weight practical
= 1.92 g , solvent of
recrystallization = ethanol , color = brown ,Yield = 60 %, m.p = 94-96 ºC ,
IR (KBr) : 1612 cm-1 (C=N).
32
Chapter two
2.3.2.3 N1,N5-bis(2-Chlorobenzylidene)naphthalene-1,5-diamine 2g.
The compound was prepared by reaction of (1.58g , 0.01mol) of 1,5diaminonaphthalene and (2.80 g , 0.02 mol) of 2-chlorobenzaldehyde. The
2 h , weight practical
= 3.60 g , solvent of
recrystallization = benzene , color = green , Yield = 89 %, m.p =240-241
º
C , IR (KBr) : 1612 cm-1 (C=N).
2.3.2.4 N1,N5-bis (4-Methoxybenzylidene)naphthalene-1,5-diamine 2h .
The compound was prepared by reaction of (1.58 g , 0.01mol) of 1,5diaminonaphthalene and (2.72g,0.02 mol) of 4-methoxybenzaldehyde. The
time of the reaction = 4 h , weight practical = 3.35 g , solvent of
recrystallization = methanol , color = green , Yield = 85 % , m.p =180182 ºC , IR (KBr) : 1620 cm-1 (C=N).
33
Chapter two
2.4 General Procedure for the preparation of γ- lactams
3( a-h) . 80-82
2.4.1 Preparation of mono-γ-lactams 3(a-d).
The mono-γ- lactams 3(a-d)
was prepared by reaction of the
mixture of 0.01 mol mono-imines 2(a-d) with 0.01 mol of phenylsuccinic
anhydride in 20 mL of chloroform and was heated in water bath at (5161˚C), The reaction mixture was refluxed for (14-16) h with stirring . The
progress of the reaction was followed by TLC . After completion , of the
reaction has been removed the solvent and then conducted recrystallization
from a suitable solvent, the physical data of mono-γ- lactam
3(a-d) as
shown below :
2.4.4.1
( E , Z ) 1-(4-Chlorophenyl)-2-(2-chlorophenyl)-5-oxo-3-phen-
ylpyrrolidine-3-carboxylic acid 3a.
The compound was prepared by reaction of (2.50 g , 0.01 mol) of N(2-chlorobenzylidene) 4-chloroaniline 2a and (1.76 g, 0.01 mol) of
phenylsuccinic anhydride. The time of the reaction = 16 h , weight practical
= 3.32 g , solvent of recrystallization = chloroform , color = white , Yield=
78% , m.p = 153-154 ºC , IR (KBr) : 1658 cm-1 (O=C-OH) ,1705 cm-1(
O=C-N) . For syn isomer : 1H-NMR (300 MHz, d6-DMSO , δ,ppm) : 2.68
(dd, J = 6,18 Hz,1H) , 3.08 (dd,J = 10.5 , 16.5 Hz, 2H) , 4.025 (dd,J =6,
9Hz ,1H) , 7.24-7.61 (m,13H) and 10.11 (s,1H) , 13C -NMR (75 MHz , d6DMSO , δ,ppm) : 39.60 , 46.77 , 120.42-139.32 ,169.27 and 171.03 . For
anti isomer ,1H-NMR (300 MHz, d6-DMSO , δ,ppm) : 2.59 (dd,J= 4.5 ,
34
Chapter two
16.5 Hz,1H) , 3.08 (dd, J = 10.5 , 16.5 Hz,2H) , 4.09 (dd, J=4.5,10.5
Hz,1H) , 7.24-7.61 (m,13H) and 10.29 (s,1H) ,
13
C -NMR (75 MHz ,d6-
DMSO, δ,ppm) : 37.33 , 47.97 , 120.42-139.32 ,172.74 and 174.12 .
2.4.1.2
( E , Z ) 2-(2-Bromophenyl)-1-(4-chlorophenyl)-5-oxo-3-phen-
ylpyrrolidine-3-carboxylic acid 3b .
The compound was prepared by reaction of (2.94g, 0.01 mol) of N(2-bromobenzylidene)-4-chloroaniline 2b and (1.76g,0.01mol) of phenylsuccinic anhydride. The time of the reaction = 16 h , weight practical = 3.29
g , solvent of recrystallization = chloroform , color = white , Yield = 70 %
, m.p = 160-161 ºC , IR (KBr) : 1658 cm-1 (O=C-OH) ,1705 cm-1 (O=C-N-).
For syn isomer(Z-isomer) ,1H-NMR (300 MHz, d6-DMSO, δ,ppm) 2.675 ,
(dd, J = 6, 15 Hz,1H) , 3.08 (dd, J = 9 ,15 Hz, 2H) , 4.02 (dd, J = 6 , 12
Hz,1H) , 7.24-7.61, (m,13H) , 10.12 (s,1H)
,
13
C -NMR (75 MHz , d6-
DMSO, δ,ppm) : 39.60 , 46.78 , 120.41-139.32 , (m,18C-aromatic) , 169.27
and 171.02 . For anti isomer (E-isomer) , 1H-NMR (300 MHz, d6DMSO, δ,ppm) : 2.5825 (dd, J = 4.5 , 16.5 Hz,1H) , 3.08 (dd, J = 9, 15
Hz, 2H) , 4.09 (dd, J = 4.5 , 10.5 Hz,1H) , 7.24-7.61 (m,13H) , 10.29
(s,1H) , 13C -NMR (75 MHz , d6-DMSO, δ,ppm) : 37.33 , 47.97 , 120.41139.32 , 172.74 and 174.11 .
35
Chapter two
2.4.1.3
( E ) 2-(2-Bromophenyl)-5-oxo-3-phenyl-1-(p-tolyl)pyrrolidine
-3-carboxylic acid 3c .
The compound was prepared by reaction of (2.74g,0.01 mol) of N(2-bromobenzylidene)-4-methylaniline 2c and (1.76g , 0.01mol) of phenylsuccinic anhydride. The time of the reaction =
15 h , weight practical =
3.36 g , solvent of recrystallization = ethanol , color = white , Yield = 88
% , m.p = 159-160 ºC , IR (KBr) : 1651 cm-1 (HO-C=O) ,1701 cm-1 (–N–
C=O). 1H-NMR (300 MHz, d6-DMSO, δ,ppm) : 2.22 (s,3H,CH3) , 2.58
(dd, J = 4.5 , 16.5 Hz,1H) 3.08 (dd, J = 10.5, 16.5 Hz, 2H) , 4.09 (dd, J =
4.5 ,10.5 Hz,1H), 7.05-7.46 (m,13H) ; 10.05 (s,1H) , 13C -NMR (75 MHz ,
d6-DMSO, δ,ppm) : 20.20 , 37.15 , 47.67 , 118.73-139.48, 170.36 and
172.57 .
2.4.1.4
( E ) 2-(2-Fluorophenyl)-5-oxo-3-phenyl-1-(p-tolyl)pyrrolidine-
3-carboxylic acid 3d .
The compound was prepared by reaction of (2.13 g,0.01 mole) of N(2-fluorobenzylidene)-4-methylaniline 2d and (1.76 g , 0.01 mole) of
phenylsuccinic anhydride. The time of the reaction = 14 h , weight practical
36
Chapter two
= 3.50 g , solvent of recrystallization = chloroform , color = white , Yield %
= 90 , m.p = 204-205 ºC , IR (KBr) : 1651 cm-1 (HO–C=O) , 1701 cm-1 (–
N–C=O).1H-NMR (300 MHz, d6-DMSO, δ,ppm) : 2.22 (s,3H,CH3) , 2.58
(dd, J = 4.5, 16.5 Hz,1H) , 3.08 (dd, J = 10.5, 16.5 Hz,2H), 4.09 (dd, J =
4.5 , 10.5 Hz,1H) , 6.82-7.46 (m,13H) , 10.04 (s,1H) , 13C -NMR (75 MHz
, d6-DMSO, δ,ppm) : 20.22 , 37.15 , 47.68 ,118.74-139.48 , 170.36 and
172.56 .
2.4.2 Preparation of bis-γ-lactams 3(e-h).
The bis-γ- lactams 3(e-h) was prepared by reaction of the mixture
of 0.01 mole bis-imines 2(e-h) with 0.02 mole of phenylsuccinic
anhydride in 20 mL of chloroform and was heated in water bath at (5161˚C), The reaction mixture was refluxed for (12-15) h with stirring . The
progress of the reaction was followed by TLC . After completion , of the
reaction has been removed the solvent and then conducted recrystallization
from a suitable solvent, the physical data of bis-γ- lactam 3(e-h) as shown
below :
2.4.2.1 ( E , Z ) 1-(4-(3-Carboxy-2-(2-chlorophenyl)-5-oxo-3- phenylpyrrolidin-1-yl)phenyl)-2-(2-chlorophenyl)-5-oxo-3-phenylpyrrolidine-3carboxylic acid 3e.
The compound was prepared by reaction of ( 3.53 g ,0.01 mol) of
N1,N4-bis(2-fluorobenzylidene) benzene-1,4-diamine 2e and ( 3.52 g , 0.02
37
Chapter two
mol) of phenylsuccinic anhydride. The time of the reaction = 12 h , weight
practical of product = 5.01 g , solvent of recrystallization = ethanol , color
of product = brown , Yield = 71% , m.p = 180-181 ºC ,IR (KBr) : 1658 cm1
(HO–C=O) ,1701 cm-1 (–N–C=O) . For syn (Z-isomer) , 1H-NMR (300
MHz, d6-DMSO, δ,ppm) : 2.65 (dd, J = 6, 18 Hz,1H) , 3.0575 (dd, J = 10.5
,13.5 Hz, 2H) , 4.015 (dd, J = 6, 9 Hz,1H) , 7.23 -7.49 (m,22H) , 9.90
(s,1H)
,
13
C -NMR (75 MHz , d6-DMSO , δ,ppm) : 39.65 , 46.86 , 119.18-
139.64 , 168.69 and 170.43 . For anti isomer (E-isomer ) ,1H-NMR (300
MHz, d6-DMSO, δ,ppm) : 2.5725 (dd, J = 4.5 , 16.5 Hz,1H) , 3.0575 (dd, J
= 10.5 , 13.5 Hz, 2H) , 4.08 (dd, J = 6, 10.5 Hz,1H) , 7.23-7.49 (m,22H) ,
10.08 (s,2H) ,13C -NMR (75 MHz, d6-DMSO, δ,ppm) 37.33 , 47.81 ,
119.18-139.34 , 172.75 and 174.15.
2.4.2.2
( E , Z ) 1-(4-(3-Carboxy-2-(2-fluorophenyl)-5-oxo-3-phenylpy-
rrolidin-1-yl)phenyl)-2-(2-fluorophenyl)-5-oxo-3-phenylpyrrolidine-3carboxylic acid 3f.
The compound was prepared by reaction of ( 3.20 g , 0.01 mol) of
N1,N4-bis(2-fluorobenzylidene) benzene-1,4-diamine 2f and (3.52 g , 0.02
mol) of phenylsuccinic anhydride. The time of the reaction = 12 h , weight
practical of product = 6.05 g , solvent of recrystallization = ethanol , color of
product = brown , Yield = 90 % , m.p = 185-186 ºC ,IR (KBr) : 1658 cm-1
(HO–C=O) , 1701 cm-1 (-N-C=O) .For syn isomer (Z-isomer) , 1H-NMR
(300 MHz, d6-DMSO, δ,ppm) : 2.645 (dd, J = 6, 15 Hz,1H) , 3.06 (dd, J =
10.5 , 16.5 Hz, 2H) , 4.015 (dd, J = 6, 9 Hz,1H) ,7.23 -7.64, (m,22H) and
38
Chapter two
9.90 (s,1H) , 13C -NMR (75 MHz, d6-DMSO) : 39.69 , 46.90 , 119.26-139.67
, 168.72 , and 170.46 . HSQC 1H-13C-NMR (600MHz,150MHz,DMSO,
δ,ppm):(2.67,39.40),(3.06,39.40), (4.02,46.61) , (7.26,126.83),(7.27,128.24) ,
(7.32,128.10) , (7.34,128.30) , (7.38,127.33) , (7.43,118.94) (7.45,119.00) ,
(7.46,119.01) . For anti isomer (E-isomer),1H-NMR (300 MHz, d6-DMSO,
δ,ppm) 2.57 (dd, J = 4.5, 16.5 Hz,1H) , 3.06 (dd, J = 10.5 , 16.5 Hz, 2H) ,
4.08 (dd, J = 4.5 , 9 Hz,1H) , 7.23-7.64 (m,22H) and 10.08 (s,2H) , 13C NMR (75 MHz, d6-DMSO, δ,ppm) : 37.37 , 47.84 , 119.26-139.67 ,172.77
and 174.18 . HSQC 1H-13CNMR (600MHz,150MHz, d6-DMSO, δ,ppm ) :
(2.56,37.08) , (3.07,37.09) , (4.08,47.55) , (7.26,126.83) (7.27,128.24) ,
(7.32,128.10) , (7.34,128.30) , (7.38,127.33) , (7.43,118.94) (7.45,119.00) ,
(7.46,119.01) .
2.4.2.3 ( E , Z ) 1-(5-(-3-Carboxy-2-(2-chlorophenyl)-5-oxo-3-phenylpyrrolidin-1-yl)naphthalen-1-yl)-2-(2-chlorophenyl)-5-oxo-3-phenylpyrrolidine-3-carboxylic acid 3g .
The compound was prepared by reaction of (4.03g,0.01 mol) of
N1,N5-bis(2-chlorobenzylidene)1,5-diaminonaphthalene 2g
and (3.52 g ,
0.02 mol) of phenylsuccinic anhydride. The time of the reaction = 15 h ,
weight practical of product = 6.34 g , solvent of recrystallization = ethanol
, color of product = brown , Yield = 84 % , m.p = 244-245 ºC , IR (KBr) :
1654 cm-1
(O=C-OH), 1705 cm-1 (O=C-N-) . 1H-NMR (300 MHz, d6-
DMSO, δ,ppm) : For syn isomer (Z-isomer) : 2.88 , (dd , J = 6, 18 Hz,1H)
, 3.225 (dd, J = 12 , 15 Hz, 2H) , 4.07 ( t , J = 10.5 , 7.5 Hz,1H) , 7.08-8.96,
39
Chapter two
(m,24H) , 9.96 (s,2H) ,
13
C -NMR (75 MHz, d6-DMSO, δ,ppm) : 39.36 ,
47.20 ,120.27-138.93, 169.62 and 171.62 . For anti isomer (E-isomer), 1HNMR (300 MHz, d6-DMSO, δ,ppm) : 2.645 (dd, J = 4.5 , 16.5 Hz,1H) ,
3.225 (dd, J = 12 , 15 Hz, 2H) , 4.36 (dd, J = 4.5 , 10.5 Hz,1H) , 7.08-8.96
(m,24H) , 10.16 (s,2H) ,13C -NMR (75 MHz, d6-DMSO, δ,ppm) : 37.33 ,
47.31 , 120.27-138.93 ,172.86 and 174.17.
2.4.2.4 ( E , Z ) 1-(5-(-3-Carboxy-2-(4-methoxyphenyl)-5-oxo-3-phenylpyrrolidin-1-yl)naphthalen-1-yl)-2-(4-methoxyphenyl)-5-oxo-3-phenylpyrrolidine-3-carboxylic acid 3h.
The compound was prepared by reaction of ( 3.94 g , 0.01 mole) of
N1,N5-bis (4-methoxybenzylidene) 1,5-diaminonaphthalene 2h and ( 3.52 g ,
0.02 mole) of phenylsuccinic anhydride. The time of the reaction = 13 h ,
weight practical of product = 6.341 g , solvent of
recrystallization =
chloroform , color of product = green , Yield = 85 % , m.p = 214-216 ºC ,
IR (KBr) : 1654 cm-1 (HO–C=O) , 1708 cm-1 (-N-C=O) . For syn isomer
(Z-isomer), 1H-NMR (300 MHz, d6-DMSO, δ,ppm) : 2.89
(m,1H) , 3.20
(m, 2H) , 3.86 (s,3H,-CH3O) , 4.085 (dd, J = 6, 15 Hz,1H) , 7.11-8.61
(m,24H) , 9.95 , (s,2H) ,13C -NMR (75 MHz, d6-DMSO, δ,ppm) :
39.34 ,
47.18 , 55.45 , 114.42-144.83 ,169.73 and 171.63 . For anti isomer (Eisomer) ,1H-NMR (300 MHz, d6-DMSO, δ,ppm) : 2.655 (dd, J = 4.5, 18
Hz,1H) , 3.20 (m, 2H) , 3.86 (s,3H,-CH3O) , 4.365 (dd, J = 6, 9 Hz,1H),
7.11-8.61 (m,24H) ,10.16 (s,1H) , 13C -NMR (75 MHz, DMSO, δ,ppm) :
37.33 , 47.32 , 55.65,114.42-144.83, 172.85 and 174.17 .
40
Chapter Three
Results
and
Discussion
Results and discussion
Chapter three
3.1
General
γ-Lactams represent important substructures for the synthesis of
natural products
discovery
89
83-88
and biologically important compounds in drug
. The prevalence of these structures
development of many efficient syntheses
93
90-92
has resulted in the
,which have led to the
production of diverse libraries of small molecules for biological
evaluation 94,95 .
The general reaction of
scheme (3-1). It is
mono-γ- lactams 3(a-d)
a reaction
between
is outlined in
phenylsuccinic
anhydride
with mono-imines 2(a-d ) in chloroform to yield mono-γ-lactams 3(ad).
Scheme (3-1)
The general reaction of
scheme (3-2). It is
a reaction
bis-γ- lactams 3(e-h)
between
phenylsuccinic
with bis-imines 2(e-h ) in chloroform to yield
41
is outlined in
anhydride
bis-γ-lactams 3(e-h) .
Chapter three
Scheme (3-2)
The general mechanism
96-100
of these reactions (mono and bis γ-
lactams) are shown in schemes (3-3),(3-4) respectively. It involve the
formation of
a zwitterionic enolate intermediate 1,3
from a
phenylsuccinic anhydride , and the formation of enolate 2,4 is favored
by delocalization
of the negative charge into the electron deficient
aromatic ring if one is suitably positioned , Which turns to form the
lactam ring .
42
Chapter three
Scheme (3-3)
The required various mono-imines 2(a-d) for the mono-γ-lactam
3(a-d) formation , were prepared from reaction of 0.01 mole amine
with 0.01 mole of of aldehyde
101-103
. The proposed mechanism
for their formations is shown below in scheme (3-5).
43
Chapter three
Scheme (3-5)
The required various bis-imines 2(e-h) for the bis-γ-lactam 3(e-h)
formation were prepared from reacting of 0.01 mole amine with
0.02 mole of aldehyde 104,105 in refluxing chloroform .
44
Chapter three
3.2 UV spectra :
The UV spectra of 10-4 M mono-γ-lactam 3c and its imine 2c at
different
solvents (Tetrahydrofuran (THF), Methanol , Methanol +
glacial acetic acid ) are shown in figures (3-1)-(3-6) and table (3-3).
The UV spectra of 10-4 M bis-γ-lactam 3f and its imine 2f in same
solvents are shown in figures (3-7)- (3-12),and table (3-4) .
The UV spectra of γ- lactams 3(a-h) are include several transitions
due to several Chromophores : π → π* transition due to C=C bond of
aromatic ring because of conjugated double bonds , π → π* , n → π*
transitions due to carbonyl amide group , and carbonyl carboxylic group .
In imines 2(a-h) there are three transitions : π → π* transition for C=C
bond of aromatic ring , and π → π* , n → π*
transitions for azomethine
(C=N) group . The bands of γ- lactams 3(a-h) and its imines 2(a-h)
show in the range (190-400) nm the high wavelength in methanol but
show low wavelength in tetrahydrofuran because the methanol solvent
allow only broad and relatively featureless bands
.With
increasing
methanol solvent polarity (by addition several drops of glacial acetic
acid) , peaks resulting from n → π* transitions are shifted to shorter
wavelengths ( blue shift ) , the reverse (red shift ) is seen for π → π*
transitions .
The figures (1) and (2)
2c in three differents
show the UV spectra of 3c and the imine
solvents (THF , MeOH , MeOH + glacial
acetic acid ). The figures (3) and (4)
show
the UV spectra of 3f
and the imine 2f in three differents solvents (THF , MeOH ,
MeOH + glacial acetic acid ).
45
Chapter three
Solvent : THF
Solvent : MeOH
Solvent : MeOH + glacial acetic acid
Figure (1) UV spectra of 10-4 M mono-γ-lactam 3c in three
solvents THF , MeOH , MeOH + glacial acetic acid .
Solvent : THF
Solvent : MeOH
Figure (2) UV spectra of 10-4 M mono-imine 2c in three solvents
THF , MeOH , MeOH + glacial acetic acid .
46
Chapter three
Solvent : THF
Solvent : MeOH
Figure (3) UV spectra of 10-4 M bis-γ-lactam 3f in three solvents
Solvent : THF
Solvent : MeOH
Figure (4) UV spectra of 10-4 M bis-imine 2f in three solvents
47
Chapter three
Table (3-3) UV spectral analysis of mono-γ-lactam 3c and the imine 2c
No .of compound
3c
Solvent
max / nm
€max / Mol-1. L.cm-1
Assignments
THF
227
248
11050
1450
π → π*
π → π*
210
4410
π → π*
220
15510
π → π*
300
247
223
322
267
218
322
266
220
1150
5690
7080
3890
5920
8320
3670
5420
17040
π → π*
π → π*
π → π*
π → π*
π → π*
π → π*
π → π*
π → π*
π → π*
MeOH
MeOH + glacial
acetic acid
THF
2c
MeOH
MeOH + glacial
acetic acid
Table (3-4) UV spectral analysis of bis-γ-lactam 3f and the mono-imine 2f
No .of compound
Solvent
max / nm
€max / Mol-1.L.cm-1
269
12090
π → π*
223
9880
π → π*
266
4730
π → π*
218
11750
π → π*
MeOH + glacial
266
310
π → π*
acetic acid
219
13350
π → π*
THF
251
223
10800
11630
π → π*
π → π*
MeOH
265
1450
π → π*
219
13720
π → π*
MeOH + glacial
273
940
π → π*
acetic acid
220
1917
π → π*
THF
3f
2f
Assignments
MeOH
48
Chapter three
3.3 Infrared (IR) spectra :
The IR spectra of the mono-imines 2(a-d) and bis-imines 2(e-h) , as KBr
disc are shown in figures (3-13)-(3-20) , as will the IR spectra of mono
and bis imines showed
absorption
band
at (1612-1624)cm-1
corresponding to the azomethine of imines compounds. The IR spectra of
mono-γ-lactams 3(a-d) and bis-γ-lactams 3(e-h) as KBr disk and
representative spectra are shown in table (3-5) and figures (3-21)-(328).The IR spectra of mono-γ-lactam 3(a-d) and bis-γ-lactam 3(e-h) are
characterized by bands corresponding to the stretching vibration of the OH carboxylic , aromatic C-H , aliphatic C-H, carbonyl amide group,
carbonyl carboxylic group , aromatic C=C and substituted ring which
occur within the ranges 2400-3600 , 3025-3082 , 2735-2958 , 1701-1708
, 1651-1658, 1512-1612 and 817-983 cm-1 respectively. The absorption
bands are affected by substitution on the phenyl ring , the substitution by
electron-donating groups such as methyl group decreased the absorption
bands ,where the substitution
group increased
106 ,107
by an electron-withdrawing as chloro
. A comparison between the IR spectra of the
imines and lactams ( figure 5,6) clearly shows the absence of the C=N
stretching vibration from the spectra of the lactams , while bands due to
–COOH and CO-N- are present in the spectra of the lactams indicating
the formation of the lactams .
49
Chapter three
Imine 2b , 2g
γ-lactam 3b , 3g
Figure (5) A comparison between the IR spectra of mono-γ-lactam 3b
and the imine 2b .
Figure (6 ) A comparison between the IR spectra of bis-γ-lactam 3g
and the imine 2g.
50
Chapter three
Table (3-5) IR spectral analysis of mono-γ-lactams 3(a-d) and bis-γlactams 3(e-h) .
Mono-γlactams
-OH
carboxylic
stretching
cm-1
Aromatic
C-H
stretching
cm-1
Aliphatic
C-H
stretching
cm-1
C=O
amide
stretching
cm-1
C=O
carboxylic
stretching
cm-1
Aromatic
C=C
stretching
cm-1
Aromatic
C-H
Bending
3a
2400-3600
3025 w
3055 w
2930w
1705s
1658s
1543s
1608m
cm-1
825m
3b
2400-3600
3032w
3066w
2940w
1705s
1658s
1543s
1608m
825m
3c
2400-3600
3032w
3082w
2862w
2916w
2958w
1701s
1651s
1512m
1550m
1612s
817w
3d
2400-3400
3030w
2870w
2940w
1701s
1651s
1512m
1550m
1612s
817m
918w
Bis-γlactams
-OH
carboxylic
stretching
cm-1
Aromatic
C-H
stretching
cm-1
Aliphatic
C-H
stretching
cm-1
C=O
amide
stretching
cm-1
C=O
carboxylic
stretching
cm-1
Aromatic
C=C
stretching
1612s
cm-1
Aromatic
C-H
Bending
3e
2500-3600
3025m
3060w
2930w
1701s
1658s
1543m
1516m
3f
2500-3600
3025 w
3060 w
2930 w
1701s
1658s
1543s
1516s
837m
2400-3600
3032w
2735w
2931w
1705s
1654s
1543s
1600m
948w
3g
3h
2400-3400
3028w
2840w
2950w
1708s
w: weak. m: medium. s: strong.
51
1654s
1539m
1604m
cm-1
837m
987w
833m
925w
983w
Chapter three
3.4
1
H-NMR spectral analysis :
The 1H-NMR spectra of the mono-γ-lactams 3(a-d) are included in
table(3-6) and the 1H-NMR spectral data of the bis-γ-lactams 3(e-h) are
included in table(3-7) , and their spectra are shown in figures (3-29) - (336) .The 1H-NMR spectra of 1-(4-chlorophenyl)-2-(2-chlorophenyl)-5oxo-3-phenylpyrrolidine-3-carboxylic acid 3a, shows for Syn (Z) isomer
(major isomer) : in pyrrolidine-2-one ring doublet of doublet signal at
2.68 ppm with J = 6 Hz , 18 Hz for one proton (dd,1H,C4-H) , and for
Anti (E) isomer (minor isomer) : in pyrrolidine-2-one ring double
doublet signal at 2.59 ppm with J = 4.5 Hz , 16.5 Hz for one proton
(dd ,1H,C4-H ) , can be seen in figure (7).
Figure (7). Selected 1H-NMR signals for C4-H of the syn-3a and anti-3a isomer
And doublet of doublet signal at 3.08 ppm with J = 10.5 Hz ,
16.5 Hz for two protons (dd,2H,C4-H) of syn isomer and anti isomer,
can be seen in figure (8).
Figure (8) Selected 1H-NMR signals for C4-H of the syn-3a and anti-3a isomer
52
Chapter three
And doublet of doublet signal at 4.025 ppm with J = 6 Hz , 9
Hz for one protons (dd ,H ,C2-H) of syn isomer, and double doublet
signal at 4.09 ppm with J = 4.5 Hz , 10.5 Hz for one proton (dd
,2H,C2-H) of anti isomer , can be seen in figure (9).
Figure (9). Selected 1H-NMR signals for C2-H of the syn-3a and anti-3a isomers
The
1
H-NMR spectra of
the aromatic region of 3a shows
multiplet signal at 7.24-7.61 ppm for thirteen protons of syn isomer
and anti isomer , can be seen in figure (10).
.
Figure (10).Aromatic 1H-NMR signals of the syn-3a and anti-3a isomers
In addition a singlet signal at 10.11 ppm for one proton of
carboxylic group (s,1H,COO-H) of syn isomer and singlet signal at
10.29 ppm for one proton of carboxylic group (s,1H,COO-H) of anti
isomer , can be seen in figure (11).
53
Chapter three
Figure (11). Carboxylic 1H-NMR signals of the syn-3a and anti-3a isomers
Syn isomer (Major)
Anti isomer ( Minor )
54
Chapter three
Table (3-6) 1H-NMR data of the mono-γ-lactams 3(a-d)
Mono-γlactams
C4-H
ring , J
Hz
C4-H ring ,
J Hz
C2-H ring
, J Hz
COOH
Aromatic
protons
C4-H ring , J
Hz
C4-H ring ,
J Hz
Syn isomer (Major)
C23H17Cl2NO3
3a
2.68
(dd)
J=6,18
1H
3.08
(dd)
J = 10.5 ,
16.5, 2H
4.025
(dd)
J=6,9
1H
10.11 (s)
1H
2.675
(dd)
J=6,15
1H
3.08
(dd)
J = 9 ,15
2H
4.02
(dd)
J=6,12
1H
10.12 (s)
1H
COOH
Aromatic
protons
10.29
(s)
1H
(7.24-7.61)
(m)
13H
10.29
(s)
1H
(7.24-7.61)
(m)
13H
Anti isomer (minor)
7.24-7.61
(m)
13H
2.59, (dd)
J = 4.5, 16.5
1H
3.08
(dd)
J = 10.5 ,
16.5, 2H
Syn isomer (Major)
C23H17BrClNO3
3b
C2-H ring
, J Hz
4.09
(dd)
J=4.5,10.5
1H
Anti isomer (minor)
(7.24-7.61)
(m)
13H
2.5825
(dd)
J = 4.5, 16.5
1H
3.08
(dd)
J = 9 ,15
2H
4.09
(dd)
J=4.5,10.5
1H
Mono-γlactams
C4-H ring ,
J Hz
C4-H ring ,
J Hz
C2-H ring ,
J Hz
-CH3
-COOH
(Anti)
C24H20BrNO3
3c
2.58
(dd),J=4.5 16.5 1H
3.08
(dd) J = 10.5, 16.5
2H
4.09
(dd),J=4.5, 10.5
1H
2.22(s)
3H
10.05 (s)
1H
(Anti)
C24H20FNO3
3d
2.58
(dd) J=4.5, 16.5
1H
3.08
(dd) J = 10.5 ,16.5
2H
4.09
(dd),J=4.5,10.5
1H
2.22(s)
3H
10.04 (s)
1H
55
Aromatic protons
(7.05-7.46), (m)
13H
(6.82-7.46), (m)
13H
Chapter three
Table (3-7) 1H-NMR data of bis-γ-lactams 3(e-h)
Bis-γ-lactams
C4-H ring ,
J Hz
C4-H ring , C2-H ring
J Hz
,J Hz
Aromatic
protons
COOH
C4-H ring , C4-H ring , J
J Hz
Hz
Syn isomer (Major)
C40H30Cl2N2O6
3e
2.65
(dd)
J=6,18,)2H(
3.0575
(dd, J =
10.5 ,13.5
(4H)
4.015
(dd),J=6,9
(2H)
2.645
(dd, J = 6,
15 ,(2H)
3.06
(dd, J =
10.5 ,
16.5,(4H)
4.015
(dd, J = 6,
9 , (2H)
9.90
(s),(2H)
(7.23-7.94)
(m)22H
2.5725
(dd), J =
4.5 , 16.5
,(2H)
9.90
(s),(2H)
(7.23-7.69)
(m),22H
2.88
3.225
4.07
9.96
, (dd, J = 6, (dd, J =12 , (t, J = 10.5,
(s),(2H)
18 ,(2H)
15 Hz,(4H) 7.5 Hz ,(2H)
C4-H ring , C4-H ring , C2-H ring
J Hz
J Hz
,J Hz
2.89
(m,2H)
3.20
(m, 4H)
-CH3O
4.085
3.86
(dd), J = (s),3H
6, 15 ,(2H)
3.0575
(dd, J = 10.5
,13.5 (4H)
4.08
(dd), J = 6,
10.5Hz,2H)
10.08
(s),(2H)
(7.23-7.94)
(m),22H
2.57
(dd, J =
4.5, 16.5
,(2H)
3.06
(dd, J = 10.5
, 16.5,(4H)
4.08
(dd, J = 4.5 ,
9 ,(2H)
10.08
(s),(2H)
(7.23-7.69)
(m),22H
Anti isomer (minor)
(7.80-0.49)
(m),29H
Syn isomer (Major)
C46H38N2O8
3h
Aromatic
protons
Anti isomer (minor)
Syn isomer (Major)
C44H32Cl2N2O6
3g
COOH
Anti isomer (minor)
Syn isomer (Major)
C40H30F2N2O6
3f
C2-H ring ,
J Hz
2.645
(dd), J =
4.5 , 16.5
(2H)
3.225
4.36
(dd, J = 12 , (dd), J = 4.5 ,
15 Hz,(4H)
10.5 ,(2H)
10.16
(s),2H
(7.80-0.49)
(m),29H
Anti isomer (minor)
COOH
9.95
(s),
(2H)
56
Aromatic
protons
C4-H ring , C4-H ring , C2-H ring ,J
-CH3O COOH
J Hz
J Hz
Hz
2.655
(7.11-0.61) (dd),J =
, 3.20
4.365 (dd, J
3.86
10.16
(m),29H
4.5, 18
(m, 4H)
= 6, 9 ,(2H) (s),3H (s),2H
(2H)
Aromatic
protons
(7.11-0.61)
(m),29H
Chapter three
13
3.5
C-NMR spectra :
The 13C-NMR spectral of the mono- γ-lactams 3(a-d) are
included in table(3-8) and bis-γ-lactams 3(e-h) are included in table(3-9)
and its spectra are shown in figures (3-37)-(3-44) .
The
13
C-NMR spectra of 1-(4-(3-carboxy-2-(2-chlorophenyl)-5-oxo-3-
phenylpyrrolidin-1-yl)phenyl)-2-(2-chlorophenyl)-5-oxo-3-phenylpyrrolidine-3-carboxylic acid 3e , shows for pyrrolidine-2-one rings : for Syn
(Z) isomer (major isomer) signal at δ 39.65 ppm of carbon (-C4-) ,
and for Anti (E) isomer (minor isomer) signal at δ 37.33 ppm of
carbon (-C4-) , can be seen in figure (12).
Figure (12). -C4- type
13
-C NMR signals of the syn-3e and anti-3e isomers
In addition to a signal at δ 46.86 ppm of carbons (-C2-) for syn
isomer, and signal at δ 47.81 ppm of carbon (-C2-) for anti isomer,
can be seen in figure (13).
Figure (13). -C2- type
13
-C NMR signals of the syn-3e and anti-3e isomers
57
Chapter three
The 13C-NMR spectra of the aromatic region are within the range
( 119.18 - 139.64) ppm for syn isomer and anti isomer , can be seen in
figure (14).
Figure (14).Aromatic 13C-NMR signals of the syn-3e and anti-3e isomers
And shows signal at δ 168.69 ppm due to the carboxylic carbonyl
group , and another signal at 174.15 ppm due to the amide carbonyl
group for syn isomer, and
signal
at δ 170.43 ppm due to
the
carboxylic carbonyl group , and another singlet signal at 172.75 ppm
due to the amide carbonyl groups (equivalent carbon) for anti isomer
,can be seen in figure (15).
Figure (15). Carboxylic and amide 13C-NMR signals of the syn-3e and anti-3e
isomers
58
Chapter three
Syn isomer (Major)
Anti isomer (Minor)
59
Chapter three
Table (3-8) 13C-NMR data of the mono-γ-lactams 3(a-d)
Mono-γ-lactams
C4-ring
ppm
C2-ring
ppm
HO-C=O
ppm
Aromatic
carbons
ppm
-N-C=O
ppm
C4-ring
ppm
C2-ring
ppm
Syn isomer
C23H17Cl2NO3
3a
39.60
46.77
169.27
39.60
46.78
169.27
ppm
N-C=O
ppm
Aromatic carbons
ppm
Anti isomer
174.12
(120.42-139.32)
37.33
47.97
Syn isomer
C23H17BrClNO3
3b
HO-C=O
171.03
172.74
(120.42-139.32)
Anti isomer
174.11
(120.41-139.32)
37.33
47.97
171.02
172.74
(120.41-139.32)
C4-ring
C2-ring
-N-C=O
ppm
-CH3
ppm
HO-C=O
ppm
ppm
ppm
Aromatic carbons
ppm
Anti
C24H20BrNO3
3c
37.15
47.67
20.20
170.36
172.57
(118.73-139.48)
Anti
C24H20FNO3
3d
37.15
47.68
20.22
170.36
172.56
(118.74-139.48)
Mono-γ-lactams
60
Chapter three
Table (3-9) 13C-NMR data of the bis-γ-lactams 3(e-h)
Bis-γ-lactams
C4-ring
ppm
C2-ring
ppm
HO-C=O
ppm
-N-C=O
ppm
Aromatic
carbons
ppm
C4-ring
ppm
C2-ring
ppm
Syn isomer
C40H30Cl2N2O6
3e
39.65
46.86
168.69
174.15
39.69
46.90
168.72
174.18
(119.18-139.64)
37.33
47.81
39.36
47.20
169.73
174.17
(119.26-139.67)
37.33
47.84
39.34
47.18
55.43
-CH3O
169.73
174.17
170.43
172.75
(119.18-139.64)
170.46
172.77
(119.26-139.67)
Anti isomer
(120.27-138.93)
37.33
47.31
Syn isomer
C46H38N2O8
3h
Aromatic carbons
ppm
Anti isomer
Syn isomer
C44H32Cl2N2O6
3g
-N-C=O
ppm
Anti isomer
Syn isomer
C40H30F2N2O6
3f
HO-C=O
ppm
171.62
172.86
(120.27-138.93)
Anti isomer
(114.42-144.83)
61
37.33
47.32
55.65
-CH3O
171.63
172.86
(114..42-144.83)
Chapter three
3.6
APT 13C-NMR spectrum
13
The APT
C-NMR
spectra of
the 1-(5-(-3-carboxy-2-(4-
methoxyphenyl)-5-oxo-3-phenylpyrrolidin-1-yl)naphthalen-1-yl)-
2-(4-
methoxyphenyl)-5-oxo-3-phenylpyrrolidine-3 carboxylic acid 3h ,figure
(3-45) , is shown in pyrrolidine-2-one rings : signal at δ 39.52(-) ppm
(-C4-) for Syn (Z) isomer (major isomer), and singlet signal at δ
37.34(-) ppm of
(-C4-) for Anti (E) isomer (minor isomer), can be
seen in figure (16).
Figure (16). -C4- type ATP 13-C NMR signals of the syn-3e and anti-3e isomers
In addition to a signal at δ 47.18(+) ppm of (-C2-) for syn
isomer, and for anti isomer signal at δ 47.32(+) ppm of (-C2-) , can be
Figure (17). -C2- type ATP 13-C NMR signals of the syn-3e and anti-3e isomers
The APT
13
C-NMR spectra of the 3h shows for syn isomer
singlet signal at δ 55.42(+) ppm for methoxy group (-OCH3), and for
anti isomer signal at δ 55.65(+) ppm for methoxy group (-OCH3), can
be seen in figure (18) .
62
Chapter three
Figure (18).-CH3O- type ATP 13-C NMR signals of the syn-3e and anti-3e
isomers
The APT 13C-NMR spectra of the aromatic region are within the
range
(114.32 - 148.76 ) ppm for syn isomer and anti isomer , can be
Figure (18) Aromatic ATP 13-C NMR signals of the syn-3e and anti-3e isomers
And shows for syn isomer signal at δ 169.73(-) ppm due to the
carboxylic carbonyl group , and another signal at 174.17 (-) ppm due
to the
amide carbonyl group , and shows for anti isomer signal at δ
171.63 (-) ppm due to the
carboxylic carbonyl group , and another
signal at 172.86 (-) ppm due to the amide carbonyl group , can be
seen in figure (19) .
Figure (19) Carboxylic and amide ATP 13-C NMR signals of the syn-3e and anti3e isomers
63
Chapter three
HSQC 1H-13C - NMR spectrum :
3.7
The HSQC 1H-13C- NMR spectral data of the prepared γ-lactam
3f is shown in the figures (3-46)-(3-48) .
The
HSQC1H-13C-NMR
spectra
of
the
1-(4-(3-carboxy-2-(2-
fluorophenyl)-5-oxo-3-phenylpyrrolidin-1-yl)phenyl)-2-(2-fluorophenyl)5-oxo-3-phenylpyrrolidine-3-carboxylic acid 3f , shows for pyrrolidine2-one ring , Syn (Z) isomer (major isomer) , the correlation between
protons and carbons for -CH2- group at δ 2.67 ppm and δ 3.06 ppm with
at δ 39.40 which led to the assignment of this signal to -CH2 group , and
the correlation between protons and carbons for -CH- at δ 4.02 ppm for
and δ 46.61 ppm , which led to the assignment of this signal to -CHgroup.
Syn (Z) isomer (major isomer) , the correlation between protons and
carbons for -CH2- group at δ 2.56 ppm and δ 3.07 ppm with at δ 37.08
which led to the assignment of this signal to -CH2 group , and the
correlation between protons and carbons for -CH- at δ 4.08 ppm for
and δ 47.55 ppm , which led to the assignment of this signal to -CHgroup, figure (7).
And for pyrrolidine-2-one ring , Anti (E) isomer (minor isomer)
: the correlation of protons signals for -CH2- group at δ 2.56 ppm and
δ 3.07 ppm with carbon signal at δ 37.08 of same group which led to the
assignment of this signal to methylene group , and proton signal 4.08 ppm
for -CH- group with carbon signal of same group at 47.55 ppm , which
led to the assignment of this signal to -CH- group , figure (20) .
64
Chapter three
Figure (20)
65
Chapter three
3.8 Mass spectra :
In mass spectra used ESI technique , the charging of the analyte
occurs by transfer of protons , the ionic species noticed are not the true
molecular ions but they are more preferably protonated , all the peaks
appearing in the corresponding ESI-mass spectrum represent the intact
molecular 108 .
The Mass spectra of the prepared mono-γ-lactams 3b , 3c , 3d and
bis-γ-lactams 3e , 3h are shown in the figures (3-49) - ( 3-59) .
The Mass spectra of (E,Z) 2-(2-bromophenyl)-1-(4-chlorophenyl)5-oxo-3-phenylpyrrolidine-3-carboxylic acid 3b , figures (3-49)-( 3-52),
shows the molecular ion peak corresponding to the particular compound
[M+H]+ = 470 , and shows the important peaks in m/z = 304 , m/z = 386
, m/z = 393 , m/z =326 , m/z =474 , m/z = 486 , m/z =607 , m/z =645 ,
m/z = 629 .
The Mass spectra of (E) 2-(2-bromophenyl)-5-oxo-3-phenyl-1-(ptolyl)pyrrolidine-3-carboxylic acid 3c ,figures (3-53) and ( 3-54) , shows
the molecular ion peak corresponding to the particular compound
[M+H]+ = 450 , and shows the important peaks in m/z = 284 , m/z = 266
, m/z = 238 , m/z = 567 , m/z = 476.85 , m/z = 589 , m/z = 605 ,the
scheme (3-6) show this peaks in the mass spectra of 3c .
The Mass spectra of (E) 2-(2-fluorophenyl)-5-oxo-3-phenyl-1-(ptolyl)pyrrolidine-3-carboxylic acid 3d , figures (3-55) and ( 3-56), shows
the molecular ion peak corresponding to the particular compound
[M+H]+ = 390 , [2M+H]+ = 779 , and shows the important peaks in
m/z = 255 , m/z = 371 , m/z = 629 , m/z = 585 , m/z = 429 , m/z = 412
.
66
Chapter three
The Mass spectra of (E,Z) 1-(4-(-3-carboxy-2-(2-chlorophenyl)5-oxo-3-phenylpyrrolidin-1-yl)phenyl)-2-(2-chlorophenyl)-5-oxo-3phenylpyrroli-dine-3-carboxylic acid 3e , figure (3-57) , shows the
molecular ion peak corresponding to the particular compound [M+H]+ =
705 , and shows the important peaks in m/z = 285 , m/z = 300 , m/z =
341, m/z = 383. m/z = 391 , m/z = 443 , m/z = 461, m/z = 579 .
The Mass spectra of (E,Z) 1-(5-(-3-carboxy-2-(4-methoxyphenyl)5-oxo-3-phenylpyrrolidin-1-yl)naphthalen-1-yl)-2-(4-methoxyphenyl)-5oxo-3-phenylpyrrolidine-3-carboxylic acid 3h , figures (3-58) and ( 359), shows
the molecular ion peak corresponding to the particular
compound [M+H]+ = 747 , and shows the important peaks in m/z = 317 ,
m/z = 395 , m/z = 453 , m/z = 533, m/z =689, , m/z = 809 , m/z = 845
m/z = 905 , m/z = 985 , m/z = 963 . the scheme (3-7) show this peaks in
the mass spectra of 3c
67
Chapter three
Scheme (3-6)
68
Chapter three
Scheme (3-7)
69
List of spectra
Chapter three
List of spectra
Figure
Figure name
Page
73
(3-4)
UV spectra of 2-(2-bromophenyl)-5-oxo-3-phenyl-1-(p-tolyl)pyrrolidine-3carboxylic acid 3c in THF .
UV spectra of 2-(2-bromophenyl)-5-oxo-3-phenyl-1-(p-tolyl)pyrrol- idine3-carboxylic acid 3c in MeOH.
UV spectra of 2-(2-bromophenyl)-5-oxo-3-phenyl-1-(p-tolyl)pyrolidine-3carboxylic acid 3c in MeOH + glacial acetic acid .
UV spectra of N-(2-bromobenzylidene)-4-methylaniline 2c in THF .
(3-5)
UV spectra of N-(2-bromobenzylidene)-4- methylaniline 2c in MeOH .
74
74
(3-13)
UV spectra of N-(2-bromobenzylidene)-4-methylaniline 2c in MeOH +
glacial acetic acid .
UV spectra of 1-(4-(3-carboxy-2-(2-fluorophenyl)-5-oxo-3-phenylpyrrolidin-1-yl)phenyl)-2-(2 fluorophenyl)-5-oxo-3-phenylpyrrolidine-3carboxylic acid 3f in THF .
UV spectra of 1-(4-(3-carboxy-2-(2- fluorophenyl)-5-oxo-3-phenylpyrrolidin-1-yl)phenyl)-2-(2-fluorophenyl)-5-oxo-3-phenylpyrrolidine-3carboxylic acid 3f in MeOH .
UV spectra of 1-(4-(3-carboxy-2-(2-chlorophenyl)-5-oxo-3-phenylpyrrolidin-1-yl)phenyl)-2-(2chlorophenyl)-5-oxo-3-phenylpyrrolidine-3carboxylic acid 3f in MeOH + glacial acetic acid .
UV spectra of N1,N4-bis(2-fluorobenzylidene)benzene-1,4-diamine 2f in
THF.
UV spectra of N1,N4-bis(2- fluorobenzylidene)benzene-1,4-diamine 2f in
MeOH
UV spectra of N1,N4-bis(2-fluorobenzylidene)- benzene-1,4-diamine 2f in
MeOH +glacial acetic acid.
IR spectra of N-(2-chlorobenzylidene) 4-chloroaniline 2a .
(3-14)
IR spectra of N-(2-bromobenzylidene) -4-chloroaniline 2b
77
(3-15)
IR spectra of N-(2-bromobenzylidene)-4-methylaniline 2c .
78
(3-16)
IR spectra of N-(2-fluorobenzylidene)-4-methylaniline 2d .
78
(3-17)
IR spectra of N1,N4-bis(2-chlorobenzylidene) benzene-1,4-diamine 2e .
79
(3-18)
IR spectra of N1,N4-bis(2-fluorobenzylidene)benzene-1,4diamine 2f.
79
(3-19)
IR spectra of
N1,N5-bis(2-chlorobenzylidene) naphthalene-1,5-diamine 2g.
80
(3-20)
IR spectra of N1,N5-bis (4-methoxybenzylidene)naphthalene-1,5-diamine 2h
80
No.
(3-1)
(3-2)
(3-3)
(3-6)
(3-7)
(3-8)
(3-9)
(3-10)
(3-11)
(3-12)
IR spectra of 1-(4-chlorophenyl)-2-(2-chlorophenyl)-5-oxo-3phenylpyrrolidine-3-carboxylic acid 3a .
IR spectra of 2-(2-bromophenyl)-1-(4-chlorophenyl)-5-oxo-3(3-22)
phenylpyrrolidine-3-carboxylic acid 3b .
IR spectra of 2-(2-bromophenyl)-5-oxo-3-phenyl-1-(p-tolyl)pyrrolidine-3(3-23)
carboxylic acid 3c
(3-21)
70
No.
73
73
74
75
75
75
76
76
76
77
81
81
82
Chapter three
(3-24)
(3-25)
(3-26)
(3-27)
(3-28)
(3-29)
(3-30)
(3-31)
(3-32)
(3-33)
(3-34)
(3-35)
(3-36)
(3-37)
(3-38)
(3-39)
(3-40)
(3-41)
IR spectra of 2-(2-fluorophenyl)-5-oxo-3-phenyl-1-(p-tolyl)pyrrolidine-3carboxylic acid 3d .
IR spectra of 1-(4-(-3-carboxy-2-(2-chlorophenyl)-5-oxo-3-phenylpyrrolidin-1- yl)phenyl)-2-(2-chlorophenyl)-5-oxo-3-phenylpyrrolidine-3carboxylic acid 3e.
IR spectra of 1-(4-(3-carboxy-2-(2-fluorophenyl)-5-oxo-3-phenylpyrrolidin-1-yl)phenyl)-2-(2-fluorophenyl)-5-oxo-3-phenylpyrrolidine-3carboxylic acid 3f.
IR spectra of 1-(5-(3-carboxy-2-(2-chlorophenyl)-5-oxo-3-phenylpyrrolidin-1-yl)naphthalen-1-yl)-2-(2-chlorophenyl)-5-oxo-3-phenylpyrrolidinecarboxylic acid 3g .
IR spectra of 1-(5-(-3-carboxy-2-(4-methoxyphenyl)-5-oxo-3phenylpyrrolidin-1-yl)naphthalen-1-yl)-2-(4-methoxyphenyl)-5-oxo-3phenylpyrrolidine-3-carboxylic acid 3h.
1
H-NMR spectra of 1-(4-chlorophenyl)-2-(2-chlorophenyl)-5-oxo-3phenylpyrrolidine-3-carboxylic acid 3a .
1
H-NMR spectra of 2-(2-bromophenyl)-1-(4-chlorophenyl)-5-oxo-3phenylpyrrolidine-3-carboxylic acid 3b .
1
H-NMR spectra of 2-(2-bromophenyl)-5-oxo-3-phenyl-1-(ptolyl)pyrrolidine-3-carboxylic acid 3c.
1
H-NMR spectra of 2-(2-fluorophenyl)-5-oxo-3-phenyl-1-(ptolyl)pyrrolidine-3-carboxylic acid 3d .
1
H-NMR spectra of 1-(4-(3-carboxy-2-(2-chlorophenyl)-5-oxo-3phenylpyrrolidin-1- yl)phenyl)-2-(2-chlorophenyl)-5-oxo-3phenylpyrrolidine-3-carboxylic acid 3e .
1
H-NMR spectra of 1-(4-(3-carboxy-2-(2-fluorophenyl)-5-oxo-3phenylpyrrolidin-1-yl)phenyl)-2-(2-fluorophenyl)-5-oxo-3-phenylpyrrolidine3-carboxylic acid 3f.
1
H-NMR spectra of 1-(5-(3-carboxy-2-(2-chlorophenyl)-5-oxo-3phenylpyrrolidin-1-yl)naphthalen-1-yl)-2-(2-chlorophenyl)-5-oxo-3phenylpyrrolidine-carboxylic acid 3g .
1
H-NMR spectra of 1-(5-(3-carboxy-2-(4-methoxyphenyl)-5-oxo-3phenylpyrrolidin-1-yl)naphthalen-1-yl)-2-(4-methoxyphenyl)-5-oxo-3phenylpyrrolidine-3-carboxylic acid 3h.
13
C -NMR spectra of 1-(4-chlorophenyl)-2-(2-chlorophenyl)-5-oxo-3phenylpyrrolidine-3-carboxylic acid 3a.
13
C -NMR spectra of 2-(2-bromophenyl)-1-(4-chlorophenyl)-5-oxo-3phenylpyrrolidine-3-carboxylic acid 3b .
13
C -NMR spectra of 2-(2-bromophenyl)-5-oxo-3-phenyl-1-(ptolyl)pyrrolidine-3-carboxylic acid 3c.
13
C-NMR spectra of 2-(2-fluorophenyl)-5-oxo-3-phenyl-1-(ptolyl)pyrrolidine-3-carboxylic acid 3d .
13
C -NMR spectra of 1-(4-(3-carboxy-2-(2-chlorophenyl)-5-oxo-3phenylpyrrolidin-1- yl)phenyl)-2-(2-chlorophenyl)-5-oxo-3phenylpyrrolidine-3-carboxylic acid 3e
71
82
83
83
84
84
85
86
87
88
89
90
91
92
93
94
95
96
97
Chapter three
13
(3-42)
(3-43)
(3-44)
(3-45)
(3-46)
(3-47)
(3-48)
(3-49)
(3-50)
(3-51)
(3-52)
(3-53)
(3-54)
(3-55)
(3-56)
(3-57)
(3-58)
(3-59)
C -NMR spectra of 1-(4-(3-carboxy-2-(2-fluorophenyl)-5-oxo-3phenylpyrrolidin-1-yl)phenyl)-2-(2-fluorophenyl)-5-oxo-3-phenylpyrrolidine3-carboxylic acid 3f.
13
C -NMR spectra signal of 1-(5-(3-carboxy-2-(2-chlorophenyl)-5-oxo-3phenylpyrrolidin-1-yl)naphthalen-1-yl)-2-(2-chlorophenyl)-5-oxo-3phenylpyrrolidine-carboxylic acid 3g .
13
C-NMR spectra of 1-(5-(3-carboxy-2-(4-methoxyphenyl)-5-oxo-3phenylpyrrolidin-1-yl)naphthalen-1-yl)-2-(4-methoxyphenyl)-5-oxo-3phenylpyrrolidine-3-carboxylic acid 3h.
APT 13C-NMR spectra of 1-(5-(3-carboxy-2-(4-methoxyphenyl)-5-oxo-3phenylpyrrolidin-1-yl)naphthalen-1-yl)-2-(4-methoxyphenyl)-5-oxo-3phenylpyrrolidine-3-carboxylic acid 3h.
HSQC 1H-13C- NMR spectra of 1-(4-(3-carboxy-2-(2-fluorophenyl)-5oxo-3-phenylpyrrolidin-1-yl)phenyl)-2-(2-fluorophenyl)-5-oxo-3phenylpyrrolidine-3-carboxylic acid 3f .
HSQC 1H-13C- NMR expanded spectra signal for aliphatic region of 1-(4(3-carboxy-2-(2-fluorophenyl)-5-oxo-3-phenylpyrrolidin-1-yl)phenyl)-2-(2fluorophenyl)-5-oxo-3-phenylpyrrolidine-3-carboxylic acid 3f .
HSQC 1H-13C- NMR expanded spectra signal for aromatic region of 1-(4(3-carboxy-2-(2-fluorophenyl)-5-oxo-3-phenylpyrrolidin-1-yl)pheny l)-2-(2fluorophenyl)-5-oxo-3-phenylpyrrolidine-3-carboxylic acid 3f .
Mass spectra of 2-(2-bromophenyl)-1-(4-chlorophenyl)-5-oxo-3phenylpyrrolidine-3-carboxylic acid 3b .
Mass expanded spectra of 2-(2-bromophenyl)-1-(4-chlorophenyl)-5-oxo-3phenylpyrrolidine-3-carboxylic acid 3b .
Mass expanded spectra of 2-(2-bromophenyl)-1-(4-chlorophenyl)-5-oxo3-phenylpyrrolidine-3-carboxylic acid 3b .
Mass expanded spectra of 2-(2-bromophenyl)-1-(4-chlorophenyl)-5-oxo3-phenylpyrrolidine-3-carboxylic acid 3b .
Mass spectra of 2-(2-bromophenyl)-5-oxo-3-phenyl-1-(p-tolyl)pyrrolidine3-carboxylic acid 3c .
Mass expanded spectra of 2-(2-bromophenyl)-5-oxo-3-phenyl-1-(ptolyl)pyrrolidine-3-carboxylic acid 3c .
Mass spectra of 2-(2-fluorophenyl)-5-oxo-3-phenyl-1-(p-tolyl)pyrrolidine3-carboxylic acid 3d .
Mass expanded spectra of 2-(2-fluorophenyl)-5-oxo-3-phenyl-1-(ptolyl)pyrrolidine-3-carboxylic acid 3d .
Mass spectra of 1-(4-(3-carboxy-2-(2-fluorophenyl)-5-oxo-3phenylpyrrolidin-1-yl)phenyl)-2-(2-fluorophenyl)-5-oxo-3-phenylpyrrolidine3-carboxylic acid 3e.
Mass spectra of 1-(5-(3-carboxy-2-(4-methoxyphenyl)-5-oxo-3phenylpyrrolidin-1-yl)naphthalen-1-yl)-2-(4-methoxyphenyl)-5-oxo-3phenylpyrrolidine-3-carboxylic acid 3h .
Mass expanded spectra of 1-(5-(3-carboxy-2-(4-methoxyphenyl)-5-oxo-3phenylpyrrolidin-1-yl)naphthalen-1-yl)-2-(4-methoxyphenyl)-5-oxo-3phenylpyrrolidine-3-carboxylic acid 3h.
72
98
99
100
101
100
101
102
103
104
105
106
107
108
109
110
111
112
113
Chapter three
Figure (3-1) UV spectra of 2-(2-bromophenyl)-5-oxo-3-phenyl-1-(ptolyl)pyrrolidine-3-carboxylic acid 3c in THF .
Figure (3-2) UV spectra of 2-(2-bromophenyl)-5-oxo-3-phenyl-1-(ptolyl)pyrrolidine-3-carboxylic acid 3c in MeOH.
Figure (3-3) UV spectra of 2-(2-bromophenyl)-5-oxo-3-phenyl-1-(ptolyl)pyrrolidine-3-carboxylic acid 3c in MeOH + glacial acetic acid .
73
Chapter three
Figure (3-4) UV spectra of N-(2-bromobenzylidene)-4-methylaniline 2c in THF
.
Figure (3-5) UV spectra of N-(2-bromobenzylidene)-4- methylaniline 2c in
MeOH .
Figure (3-6) UV spectra of N-(2-bromobenzylidene)-4-methylaniline 2c in MeOH
+ glacial acetic acid .
74
Chapter three
Figure (3-7)
UV spectra of 1-(4-(3-carboxy-2-(2-fluorophenyl)-5-oxo-3phenylpyrrolidin-1-yl)phenyl)-2-(2 fluorophenyl)-5-oxo-3-phenylpyrrolidine-3carboxylic acid 3f in THF .
Figure (3-8) UV spectra of 1-(4-(3-carboxy-2-(2- fluorophenyl)-5-oxo-3phenylpyrrolidin-1-yl)phenyl)-2-(2-fluorophenyl)-5-oxo-3-phenylpyrrolidine-3carboxylic acid 3f in MeOH .
Figure (3-9) UV spectra of 1-(4-(3-carboxy-2-(2-chlorophenyl)-5-oxo-3phenylpyrrolidin-1-yl)phenyl)-2-(2chlorophenyl)-5-oxo-3-phenylpyrrolidine-3carboxylic acid 3f in MeOH + glacial acetic acid .
75
Chapter three
Figure (3-10) UV spectra of N1,N4-bis(2-fluorobenzylidene)benzene-1,4diamine 2f in THF.
Figure (3-11) UV spectra of N1,N4-bis(2- fluorobenzylidene)benzene-1,4diamine 2f in MeOH .
Figure (3-12) UV spectra of N1,N4-bis(2-fluorobenzylidene)benzene-1,4diamine 2f in MeOH + glacial acetic acid .
76
Chapter three
Figure (3-13) IR spectra of N-(2-chlorobenzylidene) 4-chloroaniline 2a .
Figure (3-14) IR spectra of N-(2-bromobenzylidene)-4-chloroaniline 2b .
77
Chapter three
Figure (3-15) IR spectra of N-(2-bromobenzylidene)-4-methylaniline 2c .
Figure (3-16) IR spectra of N-(2-fluorobenzylidene)-4-methylaniline 2d
78
Chapter three
Figure (3-17) IR spectra of N1,N4-bis(2-chlorobenzylidene)benzene-1,4-diamine
2e
Figure (3-18) IR spectra of N1,N4-bis(2-fluorobenzylidene)benzene-1,4 diamine
2f.
79
Chapter three
Figure (3-19) IR spectra of N1,N5-bis(2- chlorobenzylidene)naphthalene-1,5diamine 2g.
Figure (3-20) IR spectra of N1,N5-bis (4-methoxybenzylidene)naphthalene-1,5diamine 2h .
80
Chapter three
Figure (3-21) IR spectra of 1-(4-chlorophenyl)-2-(2-chlorophenyl)-5-oxo-3phenylpyrrolidine-3-carboxylic acid 3a.
Figure (3-22) IR spectra of 2-(2-bromophenyl)-1-(4-chlorophenyl)-5-oxo-3phenylpyrrolidine-3-carboxylic acid 3b .
81
Chapter three
Figure (3-23) IR spectra of 2-(2-bromophenyl)-5-oxo-3-phenyl-1-(p-tolyl)
pyrrolidine-3-carboxylic acid 3c .
Figure (3-24) IR spectra of 2-(2-fluorophenyl)-5-oxo-3-phenyl-1-(p-tolyl)
pyrrolidine-3-carboxylic acid 3d .
82
Chapter three
Figure (3-25) IR spectra of 1-(4-(3-carboxy-2-(2-chlorophenyl)-5-oxo-3phenylpyrrolidin-1- yl)phenyl)-2-(2-chlorophenyl)-5-oxo-3-phenylpyrrolidine-3carboxylic acid 3e .
.
Figure (3-26) IR spectra of 1-(4-(-3-carboxy-2-(2-fluorophenyl)-5-oxo-3phenylpyrrolidin-1-yl)phenyl)-2-(2-fluorophenyl)-5-oxo-3-phenylpyrrolidine-3carboxylic acid 3f .
83
Chapter three
Figure (3-27) IR spectra of 1-(3-carboxy-2-(2-chlorophenyl)-5-oxo-3phenylpyrrolidin-1-yl)naphthalen-1-yl)-2-(2-chlorophenyl)-5-oxo-3phenylpyrrolidine-carboxylicacid 3g .
Figure (3-28) IR spectra of 1-(5-(3-carboxy-2-(4-methoxyphenyl)-5-oxo-3phenylpyrrolidin-1-yl) naphthalen-1-yl)-2-(4-methoxyphenyl)-5-oxo-3phenylpyrrolidine-3-carboxylicacid 3h.
84
Chapter three
Figure (3-29) 1H-NMR spectra of 1-(4-chlorophenyl)-2-(2-chlorophenyl)-5-oxo-3-phenylpyrrolidine-3-carboxylic acid
3a
85
Chapter three
Figure (3-30) 1H-NMR spectra of 2-(2-bromophenyl)-1-(4-chlorophenyl)-5-oxo-3-phenylpyrrolidine-3-carboxylic acid
3b
86
Chapter three
Figure (3-31) 1H-NMR spectra of 2-(2-bromophenyl)-5-oxo-3-phenyl-1-(p-tolyl)pyrrolidine-3-carboxylic acid 3c.
87
Chapter three
Figure (3-32) 1H-NMR spectra of 2-(2-fluorophenyl)-5-oxo-3-phenyl-1-(p-tolyl)pyrrolidine-3-carboxylic acid 3d .
88
Chapter three
Figure (3-33) 1H-NMR spectra of 1-(4-(3-carboxy-2-(2-chlorophenyl)-5-oxo-3- phenylpyrrolidin-1- yl)phenyl)-2-(2chlorophenyl)-5-oxo-3-phenylpyrrolidine-3-carboxylic acid 3e .
89
Chapter three
Figure (3-34) 1H-NMR spectra of 1-(4-(3-carboxy-2-(2-fluorophenyl)-5-oxo-3-phenylpyrrolidin-1-yl)phenyl)-2-(2fluorophenyl)-5-oxo-3-phenylpyrrolidine-3-carboxylic acid 3f.
90
Chapter three
Figure (3-35) 1H-NMR spectra of 1-(5-(3-carboxy-2-(2-chlorophenyl)-5-oxo-3-phenylpyrrolidin-1-yl)naphthalen-1-yl)2-(2-chlorophenyl)-5-oxo-3-phenylpyrrolidine-carboxylic acid 3g .
91
Chapter three
Figure (3-36) 1H-NMR spectra of 1-(5-(-3-carboxy-2-(4-methoxyphenyl)-5-oxo-3-phenylpyrrolidin-1-yl)naphthalen1-yl)-2-(4-methoxyphenyl)-5-oxo-3-phenylpyrrolidine-3-carboxylic acid 3h.
92
Chapter three
Figure (3-37)
3a
13
C-NMR spectra of 1-(4-chlorophenyl)-2-(2-chlorophenyl)-5-oxo-3-phenylpyrrolidine-3-carboxylic acid
93
Chapter three
Figure (3-38)
acid 3b .
13
C-NMR spectra of 2-(2-bromophenyl)-1-(4-chlorophenyl)-5-oxo-3-phenylpyrrolidine-3-carboxylic
94
Chapter three
Figure (3-39)
13
C-NMR spectra of 2-(2-bromophenyl)-5-oxo-3-phenyl-1-(p-tolyl)pyrrolidine-3-carboxylic acid 3c .
95
Chapter three
Figure (3-40)
13
C-NMR spectra of 2-(2-fluorophenyl)-5-oxo-3-phenyl-1-(p-tolyl)pyrrolidine-3-carboxylic acid 3d .
96
Chapter three
Figure (3-41) 13C-NMR spectra of 1-(4-(3-carboxy-2-(2-chlorophenyl)-5-oxo-3- phenylpyrrolidin-1- yl)phenyl)-2-(2chlorophenyl)-5-oxo-3-phenylpyrrolidine-3-carboxylic acid 3e
97
Chapter three
Figure (3-42) 13C-NMR spectra of 1-(4-(3-carboxy-2-(2-fluorophenyl)-5-oxo-3-phenylpyrrolidin-1-yl)phenyl)-2-(2fluorophenyl)-5-oxo-3-phenylpyrrolidine-3-carboxylic acid 3f.
98
Chapter three
Figure (3-43) 13C-NMR spectra of 1-(5-(3-carboxy-2-(2-chlorophenyl)-5-oxo-3-phenylpyrrolidin-1-yl)naphthalen-1-yl)2-(2-chlorophenyl)-5-oxo-3-phenylpyrrolidine-carboxylic acid 3g .
99
Chapter three
Figure (3-44) 13C-NMR spectra of 1-(5-(3-carboxy-2-(4-methoxyphenyl)-5-oxo-3-phenylpyrrolidin-1-yl)naphthalen-1yl)-2-(4-methoxyphenyl)-5-oxo-3-phenylpyrrolidine-3-carboxylic acid 3h.
100
Chapter three
Figure (3-45) APT 13C-NMR spectra of 1-(5-(3-carboxy-2-(4-methoxyphenyl)-5-oxo-3-phenylpyrrolidin-1yl)naphthalen-1-yl)-2-(4-methoxyphenyl)-5-oxo-3-phenylpyrrolidine-3-carboxylic acid 3h.
101
Chapter three
Figure (3-46) HSQC 1H-13C- NMR spectra of 1-(4-(3-carboxy-2-(2-fluorophenyl)-5-oxo-3Phenylpyrrolidiyl)phenyl)-2-(2-fluorophenyl)-5-oxo-3-phenylpyrrolidine-3-carboxylic acid 3f .
102
Chapter three
Figure (3-47) HSQC 1H-13C- NMR expanded spectra signal for aliphatic region of 1-(4-(3-carboxy-2-(2fluorophenyl)-5-oxo-3-phenylpyrrolidin-1-yl)phenyl)-2-(2-fluorophenyl)-5-oxo-3-phenylpyrrolidine-3-carboxylic
acid 3f .
103
Chapter three
Figure (3-48) HSQC 1H-13C- NMR expanded spectra signal for aromatic region of 1-(4-(3-carboxy-2-(2fluorophenyl)-5-oxo-3-phenylpyrrolidin-1-yl)phenyl)-2-(2-fluorophenyl)-5-oxo-3-phenylpyrrolidine-3-carboxylic
acid 3f .
104
Chapter three
Figure (3-49) Mass spectra of 2-(2-bromophenyl)-1-(4-chlorophenyl)-5-oxo3-phenylpyrrolidine-3-carboxylic acid 3b .
105
Chapter three
Figure(3-50) Mass expanded spectra of 2-(2-bromophenyl)-1-(4-chlorophenyl)- 5-oxo-3-phenylpyrrolidine-3-carboxylic acid 3b .
106
Chapter three
Figure(3-51) Mass expanded spectra of 2-(2-bromophenyl)-1-(4-chloro
phenyl)-5-oxo-3-phenylpyrrolidine-3-carboxylic acid 3b .
107
Chapter three
Figure(3-52)
Mass expanded spectra of 2-(2-bromophenyl)-1-(4chlorophenyl)-5-oxo-3-phenylpyrrolidine-3-carboxylic acid 3b .
108
Chapter three
Figure(3-53) Mass spectra of 2-(2-bromophenyl)-5-oxo-3-phenyl-1-(p-tolyl)
pyrrolidine-3-carboxylic acid 3c .
109
Chapter three
Figure (3-54) Mass expanded spectra of 2-(2-bromophenyl)-5-oxo-3phenyl-1-(p-tolyl)pyrrolidine-3-carboxylic acid 3c
110
Chapter three
Figure (3-55) Mass spectra of 2-(2-fluorophenyl)-5-oxo-3-phenyl-1-(ptolyl)pyrrolidine-3-carboxylic acid 3d .
111
Chapter three
Figure (3-56) Mass expanded spectra of 2-(2-fluorophenyl)-5-oxo-3-phenyl1-(p-tolyl)pyrrolidine-3-carboxylic acid 3d .
112
Chapter three
Figure (3-57) Mass spectra of 1-(4-(3-carboxy-2-(2-fluorophenyl)-5-oxo3-phenylpyrrolidin-1-yl)phenyl)-2-(2-fluorophenyl)-5-oxo-3-phenylpyrrolidine3-carboxylic acid 3e.
113
Chapter three
Figure(3-58) Mass spectra of 1-(5-(3-carboxy-2-(4-methoxyphenyl)-5-oxo-3phenylpyrrolidin-1-yl)naphthalen-1-yl)-2-(4-methoxyphenyl)-5-oxo-3-phenylpyrrolidine-3-carboxylic acid 3h .
114
Chapter three
Figure (3-59)
Mass expanded
spectra of 1-(5-(3-carboxy-2-(4methoxyphenyl)-5-oxo-3-phenylpyrrolidin-1-yl)naphthalen-1-yl)-2-(4methoxyphenyl)-5-oxo-3-phenylpyrrolidine-3-carboxylic acid 3h .
115
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122
‫الخالصة‬
‫تضمنت الدراسة تخليق وتشخيص مركبات الكاما الكتامات األاحايةة ) ‪ 3(a-d‬و الثنائية ) ‪3(e-h‬‬
‫الجدةدة ‪ ،‬احيث احضرت هذه المركبات من تفاعل فنيل سكسنيك انهدرةد مع قواعد شيف الثنائية‬
‫واالاحايةة (األةمينات) المناسبة )‪ 2(a-h‬وبأستخدام مذةب الكلوروفورم والتسخين تحت يرجة احرارة‬
‫(‪ )15-15‬م ‪ °‬وبحصيلة أنتاج مناسبة (‪ . % )29-07‬وبين طيف الرنين النووي المغناطيسي البروتوني‬
‫)‪ (1H-NMR‬وطيف الرنين النووي المغناطيسي كاربون ‪ (13C-NMR) 51‬ظهور أةزومرةن‬
‫واضحين سز وترانس احيث كان ذلك واضحا ً من خالل البروتونات الثالثة لحلقة الباةرولدةن‪-2-‬ون ‪.‬‬
‫التراكيب الكيميائية لمركبات الكاما الكتام المحضرة قد ثبتت وشخصت بواسطة أستخدام مطيافيات‬
‫االشعة فوق البنفسجية )‪ (UV‬وتحت الحمراء (‪ (IR‬ومطيافية الرنين النووي المغناطيسي البروتوني‬
‫)‪ (1H-NMR‬ومطيافية الرنين النووي المغناطيسي كاربون ‪ (13C-NMR) 51‬ومطيافية (‪APT 13C-‬‬
‫‪ )NMR‬ومطيافية )‪ (HSQC 1H-13C-NMR‬ومطيافية الكتلة ) ‪. ( Mass spectra‬‬
‫‪A‬‬
‫جمهورية العراق‬
‫وزارة التعليم العالي والبحث العلمي‬
‫جامعـة ذي قـار‪ -‬كـليـة العـلوم‬
‫قسم الكيمياء‪ -‬الدراسات العليا‬
‫تخليق وتشخيص بعض الكاما‪-‬الكتامات الجديدة‬
‫رسالة مقدمة إلى‬
‫مجلس كلية العلوم‪ -‬جامعة ذي قار‬
‫وهي جزء من متطلبات نيل درجة الماجستير علوم‬
‫في الكيمياء‬
‫من قبل‬
‫صـاحـب عوض كاطع الجياشي‬
‫بكالوريوس‬
‫علوم كيمياء (‪)8991‬‬
‫أشراف‬
‫األستاذ الدكتور‬
‫محمود شاكر مكطوف التميمي‬
‫‪ 8416‬هـ‬
‫‪ 1085‬م‬

1.3 Synthesis of γ

Transcription

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