ABSTRACT
Palladium catalysed synthesis of substituted 2-[acetyl(phenylsulphonyl)amino]-3-
methylbutanamide (176) is reported. The intermediate 2-[acetyl(phenylsulphonyl)amino]-3-
methybutanamide (175) was obtained by the reaction between 2-[acetyl
(phenylsulphonyl)amino]-3-methybutanoic acid chloride (175) and ammonia. Substituted 2-
[acetyl (phenylsulphonyl)amino]-3-methylbutanamides (176a-f) were obtained by coupling
2-[acetyl (phenylsulphonyl)amino]-3-methylbutanamide (175) with various readily available
substituted aryl halides via a Buchwald-Hartwig-type cross coupling protocol. Structures of
the synthesized compounds were confirmed using Fourier transform infrared (FT-IR), as well
as proton and carbon-13 Nuclear Magnetic Resonance (1HNMR and 13CNMR). The
antimicrobial properties of the synthesized sulphonamides were determined on Bacillus
subtilis, Salmonella typhi, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia
coli, Klebsiella pneumonia, Candida albican and Aspergillus niger using agar diffusion
technique. The antimicrobial activities against some pathogenic microorganism have been
reported in this work. Results showed significant improvement in antimicrobial activities
compared with tetracycline and fluconazole used as reference drugs.
TABLE OF CONTENTS
Title page ——————————————————————————————- i
Approval page ————————————————————————————- ii
Certification ————————————————————————————— iii
Dedication —————————————————————————————– iv
Acknowledgement ——————————————————————————–v
Abstract ———————————————————————————————vi
Table of contents ———————————————————————————-vii
List of Abbreviations——————————————————————————xii
List of tables—————————————————————————————-xiii
List of figures ————————————————————————————-xiv
CHAPTER ONE:
1.0 Introduction ———————————————————————————–1
1.1 Mechanism of Action of Antimircobial Sulphonamides———————————-4
1.1.1 Synthesis of Folic Acid———————————————————————4
1.2 Background of Study ————————————————————————-5
1.3 General Classification of Sulphonamides ————————————————–7
1.4 Tandem Catalysis —————————————————————————–10
1.5 Buckwald-Hartwig Amination and Amidation ——————————————–11
1.6 Mechanism of Buchwald-Hartwig Reaction ———————————————–12
1.7 Statement of the problem———————————————————————13
1.8 Objective of the study ————————————————————————13
1.9 Justification of the study ———————————————————————13
CHAPTER TWO:
2.1 Literature Review —————————————————————————–14
2.1.0 Synthesis of Sulphonamides as anti-malaria agents————————————-14
2.1.1 Synthesis of IH-1,2,4 – triazol-3-ylbenzenesulphonamide derivatives —————14
2.1.2 Synthesis of bisquinoline derived sulphonamides—————————————15
2.2.0 Synthesis of Sulphonamide as Antiepileptic agents————————————-15
2.2.1 Synthesis of Zonisamide ——————————————————————-15
2.3.0 Synthesis of Sulphonamides as Antibacterial and Antifungal Agents —————-16
viii
2.3.1 Synthesis of 4-acetamido-N-(substituted 1,3-benzothiazol-2-yl)
Benzenesulphonamides ———————————————————————16
2.3.2 Synthesized N-4-methylbenzenesulphonyl N-(4-methylbenzenesulphonyl)-
benzimidazol-2-yl methylthio)-benzimidazole —————————————-17
2.3.3 Synthesis of Quiazolonyl Derivatives of 4-oxo-thiazolidinyl sulphonamides ——-18
2.4.0 Synthesis of Sulphonamides as Antihypertensive agents——————————-20
2.4.1 Synthesis of bosentan(4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-
(2-methoxyphonoxy)-2-(2-pyrimidinyl) pyrimidin-4-yl] benzene
sulphonamide monohydrate) ————————————————————-20
2.5.0 Synthesis of Sulphonamides as Antiviral And Anti-HIV agent ———————–21
2.5.1 Synthesis of 5-(chlorophenyl)-substuted-N-1,3,4-thiadiazole-2-sulphonamide —–21
2.5.2 Synthesis of a Sulphonamide bearing 2,5-disubstituted-1,3,4-oxadiazole ———–22
2.6.0 Synthesis Sulphonamides as anticancer agents——————————————23
2.6.1 Synthesis of 4-oxothiazolidine benzenesulphonamides ——————————–23
2.6.2 Synthesis of celecoxib(4-[5-(4-methylphenyl)-3-(trifluoromethyl)
pyrazol -1-yl]benzenesulphonamides. —————————————————24
2.6.3 Synthesis of N-(2-trichloromethyl quinazolin-4-yl) benzene sulphonamides——–25
2.6.4 Synthesis of benzamidobenzimidazole and benzimidazolone
sulphonamide derivatives —————————————————————26
2.7.0 Synthesis of Sulphonamides as antiasthmatic agents ———————————–28
2.7.1 Synthesis of N-alkyl-N-(4,5-dibromo-2-methoxyphenyl)benzene
sulphonamide———————————————————————————28
2.8.0 Synthesis of Sulphonamides as diuretic agents——————————————29
2.8.1 Synthesis of 4-chloro-N-(2-methyl-1-indolinyl)-3-sulphonylbenzamide————-29
2.9.0 Synthesis of Sulphonamides as antioxidants ——————————————–30
2.9.1 Synthesis of 3(Z)-{4-(arylsulphonyl)piperazin-1-ylbenzylidene)-1,3-
dihydro-2H-indole-one ——————————————————————–30
2.10.0 Synthesis of Sulphonamide as anti-inflammatory agents —————————–31
2.10.1 Synthesis of amide derivatives of sulphonamide ————————————–31
2.10.2 Synthesis of methane sulphonamide derivatives—————————————32
2.11.0 Synthesis of Sulphonamides as Anti-impotence agents——————————-33
2.11.1 Synthesis of Sidenafil Citrate ————————————————————33
2.12.0 Synthesis of Sulphonamides as Inhibitors of Butyryl Cholinesterase —————34
2.12.1 Synthesis of N-(2-methoxyphenyl)benzenesulphonamide derivatives ————–34
2.13.0 Synthesis of Sulphonamides as antitumour agents ————————————35
ix
2.13.1 Synthesis of N-(4-(N-pyridin-2-ylsulphonamoyl)phenyl)
acetamide derivative————————————————————————35
2.14.0 Synthesis of Sulphonamides as analgesic agent—————————————-38
2.14.1 Synthesis of monoterpene-based p-toluenesulphonamide—————————38
2.15.0 Synthesis of Sulphonamide as antimigraine sulphonamides ————————-38
2.15.1 Synthesis of avitriptan ——————————————————————–38
2.16.0 Applications of Sulphonamides in Synthetic Organic Chemistry——————-40
2.16.1 Synthesis of isothiourea——————————————————————-40
2.17.0 The use Sulphonamide in differentiating primary, secondary and
tertiary amines —————————————————————————–40
2.18.0 Miscellaneous Applications of Sulphonamides————————————–41
2.19.0 Antimicrobial activities———————————————————————43
CHAPTER THREE:
3.0 Experimental Section————————————————————————44
3.2.1 3-Methyl-2-[(phenylsulphonyl) amino]butanoic acid (173) ————————–44
3.2.2 2- [Acetyl (phenylsulphonyl)]-3-methylbutanoic acid (174) ————————-44
3.2.3 2-[Acetyl(phenylsulphonyl)amino-3-methylbutanamide (175) ———————-45
3.3.0 General procedure for the synthesis of the derivatives of
2-[Acetyl (phenylsulphonyl)amino-3-methylbutanamide 176(a-f) —————46
3.3.1 2-[Acetyl(phenylsulphonyl)amino]-3-methyl-N-(6-nitropyridin-2-yl)
butanamide (176a) ————————————————————————47
3.3.2 2-[Acetyl(phenylsulphonyl)amino]-N-(2,6-diaminopyrimidin-4-yl)-
3-methylbutanamide (176b) ————————————————————48
3.3.3 2-[Acetyl(phenylsulphonyl)amino]-N-(4-aminophenyl)-3-
methylbutanamide (176c)—————————————————————-49
3.3.4 2-[Acetyl(phenylsulphonyl)amino]-N-(4-hydroxyphenyl)-3-
methylbutanamide (176d) —————————————————————-50
3.3.5 2-[Acetyl(phenylsulphonyl)amino]-3-methyl-N-(pyridin-2-yl)
butanamide (176e)————————————————————————50
3.3.6 2-[Acetyl(phenylsulphonyl)amino]-N-(4-methoxylphenyl)-3-
methylbutanamide (176f) —————————————————————-51
3.4 Heteronuclear Single Quantum Coherence (HSQC)————————————52
3.4.1 HSQC OF 2-[Acetylsulphonyl) amino]-3-methly-N-(6-nitropyridin-2-yl)
butanamide (176a)—————————————————————————–52
x
3.4.2 HSQC of compound 2-[Acetylsulphonyl)amino]-N-
(2,6-diaminopyrimidin-4-yl)-3-methylbutanamide (176b)——————————52
3.4.3 HSQC of Compoujnnd 2-[Acetyl(phenylsulphonyl)amino]-N-
(4-aminophenyl)-3- methylbutanaminde (176c)——————————————-53
3.4.4 HSQC of 2-[Acetyl(phenylsulpphonyl)amino]-N-(4-hydroxyphenyl)-3-
Methylbutanamide (176d)———————————————————————-53
3.5 Antimicrobial Activity—————————————————————————-53
3.5.1 Preparation of the Inoculum——————————————————————–54
3.5.2 Antimicrobial Sensitivity Testing of compounds——————————————–54
3.5.3 Minimum Inhibitory Concentration (MIC) Testing Compounds————————-54
CHAPTER FOUR:
4.0 Results and Discussion ———————————————————————–56
4.1 3-Methyl-2-[(phenylsulphonyl) amino] butanoic acid ——————————56
4.2.1 2- [(Acetyl(phenylsulphonyl)]-3-methylbutanoic acid (174) ————————57
4.2.2 2-[Ace(phenylsulphonyl)amino-3-methylbutanamide (175) ———————–58
4.2.3 2-[Acetyl(phenylsulphonyl)amino]-3-methyl-N-(6-nitropyridin-2-yl)
butanamide (176a)———————————————————————– 60
4.2.4 2-[Acetyl(phenylsulphonyl)amino]-3-methyl-N-(2,6-
diaminopyrimidin-4-yl)methylbutanamide (176b) ——————————– 62
4.2.5 2-[Acetyl(phenylsulphonyl)amino]-N-(4-aminophenyl)-3-
methylbutanamide (176c) —————————————————————64
4.2.6 2-[Acetyl(phenylsulphonyl)amino]-N-(4-hydroxyphenyl)-3-
methylbutanamide (176d)—————————————————————-65
4.2.7 2-[Acetyl(phenylsulphonyl)amino]-3-methyl-N-(pyridin-2-yl)
butanamide (176e) ——————————————————————–67
4.2.8 2-[Acetyl(phenylsulphonyl)amino]-N-(4-methoxylphenyl)-3-
methylbutanamide (176f) —————————————————————-68
4.3 Antimicrobial activity Evaluation ———————————————————69
CHAPTER FIVE:
5.0 Conclusion ————————————————————————————-72
REFERENCES ————————————————————————————73
CHAPTER ONE
1.0 Introduction
The sulphonamides constitute a class of organosulphur compounds. They are amide
derivatives of sulphonic acids. These compounds contain the RSO2NH2 group. They are a
family of broad-spectrum synthetic bacteriostatic antibiotics. They are among the most
widely used classes of antibiotics in the world1, with the general structural formula
represented by 1.
R S NR1R2
O
O 1
R = alkyl, aromatic or heteroaromatic groups
R1 , R2 = hydrogen, alkyl, aromatic or heteroaromatic groups
Sulphonamides are known to represent a class of medicinally important compounds which
are extensively used as anticancer2, antitumour3, antiviral4, antimalaria5, antidiabetic6,
antihypertensive7, antituberculosis8, antiosteoarthiritis9, anticataract10, antidiuretics11,
antimigraine12, antiretroviral13, and inhibitors of carbonic anhydrase, among others. Before
the discovery of antibiotics in the 1940s, sulphonamides were the first efficient compounds
used to treat microbial infections. Topical sulphonamides are employed in infections of the
eye, mucous membrane and skin. The emergence of resistant bacterial strains replaced the
therapeutic use of some of the sulphonamides with other drugs. Mixtures of sulphonamides
with other drugs have also been used in the treatment of various infections15. The mixture of
sulphamethoxazole-trimethoprim (septran) is often preferred in treating current urinary tract
infections and especially for opportunistic infections in patients with AIDS. Some of
aromatic/heterocyclic sulphonamides and their derivatives showed very high inhibitory
2
activity against carbonic anhydrase16. Some of these sulpha drugs that have performed
“healing magic” in world of chemotherapy include:
S
H2N
NH
O O
O CH3
N
N
S
H2N
NH
O O
OCH3
OCH3
N N
S
H2N
NH
O O
Sulphonilamide (Analgesic)
2
Sulphadozin (Antimalaria)
Sulphadiazine
(Treatment of Meningitis)
3 4
S
H2N
NH2
O O
N
N
S
NH
O O
OCH3
N
N
CH3
S NH CH3 NH
O
H3C
O
O
N
S
N
CH3 H2N S
O
O
NH
( Anticancer Drug)
Sulphamethazine
(Treatment of Pneumococcal, Sepsis and Gonorrhea)
Sulphanilamide
(Antibactria Drug)
Sulphamethizole
5 6
7 8
Sulphamonomethoxine
(Diurectic drug)
In addition, sulphonamides are also highly relevant both in the animal world and plant life
cycle. In fact, the breaking of cyclic guanosine monophosphate is retarded by sildenafil, a
substituted guanine analog, which keeps cut flowers fresh for another week and also
strengthens plants stems to stand straight even in the midst of storm and wind17. A preserving
3
effect on fruit vegetables was also found, making sildenafil (9) an agent for the treatment of
erectile dysfunction in man. Today, it is marketed under the trade name Viagra which is a
potent drug used in the treatment of erectile dysfunction in man18.
Furthermore, the sulphonamide group has been proved to have remarkable utility in
medicinal chemistry and expectedly features in the structure of a number of clinically
relevant small molecules19. For instance, some currently approved drugs with sulphonamide
structural skeletons include: the antihypertensive agent bosentan (10)20, glibenclamide (11)21,
antidiabetic nonantibiotic glimepiride (12) and the diurectic drug, torasemide (13)22,23.
S
H3C
CH3
CH3
O O
NH
N
N
N
N
O
O
HO
O
CH3
10
Cl
OMe
NH
OH
S
O O
N N
O
H
H
11
N
N
H3C
S
O O
N
HN
O
O CH3
N
N
CH3
CH3
9
4
N
CH3CH2
O
NH
O
S
O O
N NH2
O
CH3
12
N
H3C
H3C N
S
O O
N
HN
CH3
O
H H
13
1.1 Mechanism of Action of Antimicrobial Sulphonamides
Mechanistically, antimicrobial sulphonamides compete with p-amino benzoic acid (14) for
incorporation into folic acid (15), which is required for growth by all cells. Since folic acid
cannot cross bacteria walls by diffusion or active transport, these organisms must then
synthesize folic acid (15) from p-amino benzoic acid (14). Its antimicrobial activity is
explained below.
1.1.1 Synthesis of folic acid24. (15)
Pteridine (16) reacts with p-amino benzoic acid (14) to give pteroic acid (17) which treats
with glutamic acid (18) to give folic acid (15)
N
N
N
N
OH
H2N
Cl+
NH2
O OH
NH
O
OH
N
N
N
N
OH
H2N
OH
O O
HO
H2N
NH
O
N
N
N
N
OH
H2N
OH
O
O
OH
NH
16
14
17a
18
15a
5
The above scheme is for reaction in the absence of sulpha drugs. In the presence of an
antimicrobial sulphonamide, the drug replaces p-aminobenzoic acid (14) to give the
following reaction sequence and product.
N
N
N
N
OH
H2N
Cl +
N
O S O
H2N
H H
NH
N
N
N
N
OH
H2N
S N
O
O
H
H
OH
O O
HO
H2N
NH
S
O
N
N
N
N
OH
H2N
OH
O
O
OH
NH
O
16
14b
18
17b
15b
Clearly, structure 15b is not folic acid and therefore cannot be utilized by the bacteria
cell, leading to starvation and subsequent death of the microorganism.
1.2 Background of Study
Chemotherapy drug design and medicinal chemistry started in the early 20th century.
Modern chemotherapy began with the work of Ehrlich25, particularly with his discovery in
1907 of the curative properties of a dye trypan red. Between 1909 and 1935, tens of
thousands of chemicals, including many dyes, were tested by Ehrlich and others in search for
magic bullets for the treatment of streptococcal infection26. Very few compounds, however,
were found to have effect for the treatment of streptococcal infection. Then in 1935, an
amazing event happened. The daughter of Domagk27, a doctor employed by a German dye
6
manufacturer, contracted a streptococcal infection from a pinprick. As his daughter neared
death, Domagk decided to give her an oral dose of a dye called prontosil. Prontosil had earlier
been developed at Domagk’s firm and tests with mice had shown that prontosil inhibited the
growth of streptocci. Within a short time the girl recovered. This initiated a new and
spectacularly productive phase in the modern in chemotherapy of sulphonamides.
In 1935, a group of investigators, Trefovel, Nitti and Bover28, working under Fourneau at the
Pasteur Institute in Paris reported that, in vivo, the azo linkage of prontosil (19) is reduced by
azo reductase, yielding sulphanilamide (20), which is an active moiety against streptococci.
Hence, the first synthesized sulphonamide was sulphanilamide.
H2N
NH2
N N S
O
O
NH2
reductase S
O
O
H2N NH2
19 20
(in vivo)
In 1940, Woods and Fildes29, advanced the hypothesis that sulphonamides owe their
antibacterial activity to competitive antagonism with p-aminobenzoic acid30.
A retrospective look at sulphonamides31 leaves no doubt that besides providing the first
efficient treatment of bacterial infections, they unleashed a revolution in chemotherapy to
rationally design new therapeutic agents831. The best therapeutic results were obtained from
compounds in which one hydrogen of the –SO2NH2 group was replaced by some other group,
usually a heterocyclic ring31. To get more than ten thousand sulphanilamide derivatives,
analogs and related compounds, especially those related to p-aminobenzoic acid, have been
synthesized. Such syntheses have resulted in the discovery of new compounds with varying
pharmacological properties31. Further structure modification has led to many new types of
drug: antibacterial agents (sulphonamides) leprostatic agents (sulphones), diuretics
7
(heterocyclic sulphonamides) hypoglycaemic agents (sulphonyl urea), antimalarial
(sulphonamides), antithyroid, antitumor (heterocyclic sulphonamides), and antiviral agents
(sulphonamides)32. Among the most successful modification, few derived from
sulphanilamide are represented as compounds 21, 22, 23, 24, 25 and 26 (scheme 1).
Scheme 1: Some biologically active sulphonamides derived from sulphanilamide
1.3 General Classification of Sulphonamides
Various criteria have been used to classify sulphonamides. Such classifications have been
based on chemical structure, duration of action, spectrum of activities and therapeutic
applications32. Commonly, the classification of sulphonamides is based on their duration of
action33. This is elaborated below.
N H2
O S O
NH2
NH2
O S O
NH
O
NH2
O S O
NH N
S
NH 2
O S O
NH N
N
NH2
O S O
N H N
S
N N
N S
O
O
N H2
C
O
R
H
21
22
23
25 24
26
2 – Sulphanitamide Sulphametizole
Sulphalidin Sulphathalidin
8
Short Acting: These sulphonamides are preferred for systemic infections as they are rapidly
absorbed and rapidly excreted. Sulphonamides are referred to as short acting if the blood
concentration levels remain higher than 50 g/mL for less than 12 h after a single therapeutic
dose34. Examples are, sulphamethazine (27) (used for the treatment of urinary tract
infections), sulphadimidine (28), sulphathiazole (29) and trisulphopyrimidine (30)
H2N S
O
O
NH
N
N
CH3
H2N S
O
O
NH
N
N
CH3
H3C
H2N S
O
O
NH
N H
S N
N
S S
S
O
OH
O O
HO
O
O
OH
O
27 28
29
30
Intermediate Acting: Sulphonamides are referred to as intermediate acting if the blood
plasma concentration is higher than 50 g/mL are obtained between 12 and 24 h after
dosing34.They are used for infections requiring prolonged treatment. For example,
sulphamethixole (31), in combination with trimethoprime (32), has been used for various
infections especially active against invasive aspergillosis in AIDS patients.
S
N
N
H2N S NH
O
O
CH3
Sulphamethizole N
N
H2N
CH3
CH3
CH3
31
32
Trimethoprime
9
Long Acting: These are considered long lasting if the blood plasma concentration levels
remain higher than 50 g/mL obtained 24 h after dosing34. They rapidly absorbed and slowly
excreted. For example, sulphasalazine (33) has been used for the treatment of ulceration
coltis. In addition to these, there are different types of sulphonamides which have been used
in various types of infection such as mucous membrane, superficial ocular infections, urinary
infections, anticancer and others. Some examples of long lasting sulphonamide include (33),
(34), (35), (36), (37) and (38).P
N
N
H3CO
H2N S NH
O
O
Sulphalene
36
N
N
H2N S NH
O
O
35
sulphaphenazole
N
N N S
O
O
NH
H3C Sulphasalazine
N N
S
O
O
H2N NH OCH3
33 Sulphamethoxy pyridazine
34
N N
H3CO OCH3
H2N S NH
O
O
37
Sulphadimethoxine
S
N N
CH3
H2N S NH
O
O
38
10
1.4 Tandem Catalysis
The term tandem catalysis represents processes in which “sequential transformation of the
substrate occurs via two (or more) mechanistically distinct processes35 in a single operation
and in which there is no need to isolate individual intermediates .There are three types of
tandem catalysis namely:
(a) Orthogonal tandem catalysis: In this type of tandem catalysis, there are two
mechanistically distinct transformations, two or more functionally and ideally noninterfering
catalysts and in which all catalysts present from the onset of the reaction36.
(b) Auto-tandem catalysis: Here, there are two or more mechanistically distinct
transformations which occur via a single catalyst precursor; both catalytic cycles
occur spontaneously and there is cooperative interaction of all species present at the
outset of the reaction36.
(c) Assisted tantem catalysis: In this type, two or more mechanistically distinct
transformations are promoted by a single catalytic species and addition of a reagent is
needed to trigger a change in catalytic function36.
Transition metal catalyzed reactions are probably the most important area in synthetic organic
chemistry37. Interestingly, palladium catalysed reactions are the most vastly applied
processes. It typically utilizes only 1-5 mol% of the catalyst38. The catalytic system is
generally composed of a metal and a ligand37. For most reactions, the active catalyst is the
zero valent metal, that is Pd (0), and can be added as such, in the form a stable complex such
as Pd (PPh3)4 tetrakis (triphenylphosphine)39. On the other hand, a Pd (II) pre-catalyst such as
palladium acetate, together with a ligand (or as a pre-formed catalyst) can be used and this
arrangement has the benefit of better stability for storage40.
11
An initial step of reduction of Pd (II) to P(0) is required before the catalytic cycle can start41.
This reduction is usually brought by a component of the reaction such as the reaction as
shown below, but sometimes separate reducing agent such as DIBAH can be used42.
2RM + PdX2 R2Pd Pd(0) + R-R2
PdX2 + Ph3P + H2OP Pd(0) + Ph3PO + 2HX
X = halide, M = tansition metals, R = organic moiety.
The ligand is the main variable in the catalyst system. Phosphines can be varied in steric bulk
or in their donor strength, or finely tuned as chelating diphosphines. Alkyl groups on
phosphorous increase the donor strength, increasing in the electron density on the metal
which enhances the oxidative addition step and thus the susceptibility of the catalyst to less
reactive substrate such as chlorides. Steric bulk decreases the number of ligands that can
coordinate to the metal atom therefore increasing its reactivity by accelerating reductive
elimination37.
1.5 Buckwald-Hartwig Amination
The Buchwald-Hartwig amination reaction is an organic reaction involving a coupling
reaction between an aryl halide and amine in the presence of a base and a palladium catalyst
resulting in a new carbon-nitrogen bond43.
The first example of a Buchwald-Hartwig amination reaction was realised in Kiev, Ukraine in
1985, by Yagupolskii and co-researchers43. Polysubstituted activated chloroarenes and
anilines underwent a C-N coupling reaction catalysed by [PdCl2(PPh3)2] (1 mol%) in
moderate yield44.
RCl + NH2R RNHR
[PdCl2(PPh3)2]
12
Buchwald-Hartwig amination usually requires catalytic systems containing four components
in order to efficiently generate the desired C-N bond.45
The four components are:
• Ligands: ligands stabilize the palladium precursor in solution and also raise the
electron density of the metal in order to facilitate oxidation addition and provide
sufficient bulkiness46 to accelerate reductive elimination.
• Bases: A base is required to deprotonate the amine substrate prior to or after
coordination to the palladium centre.
• Solvent: The solvent dissolves the coupling partners as well as the base and allowing
for a respective temperature window for the reaction and also plays a crucial role in
stabilizing intermediates in the catalytic cycle47.
• A palladium precursor: Palladium acts as a catalyst in the system.
1.6 Mechanism of the Buchwald-Hartwig Reaction
In the mechanism of Buchwald-Hatwig reaction, the first step in the catalytic cycle is the
oxidative addition of an aryl halide to Pd(0); in the second step the Pd(II) aryl amide can be
formed by either direct displacement of the halide or by amide via a Pd (II) alkoxide
intermediate. Finally, reductive elimination results in the formation of the desired C-N bond
and the Pd(0) catalyst is regenerated48. Below is a sketch of the reaction mechanism.
L (n-1) Pd (II)
Ar
NR 2
Reduction
elimination
Ar NR 2
L nPd (0)
oxidative
addition
Ar X
L n Pd (II)
Ar
X
L nPd (II)
O- t -Bu
Ar
M + ( -O t -Bu)
HNR M-X 2
HO- t -Bu
13
1.7 Statement of the Problem
Although several synthetic routes to sulphonamides have been reported, many of the methods
are often not applicable for the preparation of a wide variety of derivatives with excellent
yields and good pharmacological activity. Furthermore, although there has been monumental
application of transition metal complexes as catalysts in organic synthesis in the past three
decades, the application of these procedures in the synthesis of sulphonamide scaffolds
remains scantily explored. Therefore, the aim of this work is to synthesize
phenylsulphonylaminoalkanamides via palladium catalysed tandem reaction.
1.8 Objectives of the Study
The specific objectives of this research are to:
i. synthesize phenysulphonyl aminoalkanamide as the reactive intermediate.
ii. use the phenylsulphonyl aminoalkanamide to synthesize novel N-aryl substituted
phenylsulphonyl alkanamides via palladium catalysed Buchwald-Hartwig amination
protocol.
iii. characterize these synthesized products using spectroscopic techniques namely: FT-IR,
as well as 1H-NMR and 13C-NMR spectroscopies.
iv. investigate the biological activities of the new compounds.
1.9 Justification of the Study
Because of the challenges associated with drug usage and multi-drug resistance by
microorganisms, there is a great need to design and synthesize new antimicrobial drugs for
the control of the rapid spread of the harmful microorganisms. Although many
sulphonamides have been synthesized, only a few phenylsulphonylaminoalkanamides have
been synthesized and evaluated. For this reason, there is the need to carry out the synthesis of
this category of sulphonamides and evaluate their antimicrobial potentials.
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