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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.




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



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



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


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

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



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

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



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



5.0 Conclusion—————————————————————————– 72

REFERENCES—————————————————————————- 73




  • 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 = alkyl, aromatic or heteroaromatic groups

R1 , R= 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 activity against carbonic anhydrase16. Some of these sulpha drugs that have performed “healing magic” in world of chemotherapy include:




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 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)20glibenclamide (11)21, antidiabetic nonantibiotic glimepiride (12) and the diurectic drug, torasemide (13)22,23.



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)


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.

            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 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.

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 –SO2NHgroup 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 (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 212223, 2425 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.

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)



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.


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




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:

  • Orthogonal tandem catalysis: In this type of tandem catalysis, there are two mechanistically distinct transformations, two or more functionally and ideally non-interfering catalysts and in which all catalysts present from the onset of the reaction36.
  • 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.
  • 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.

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

PdX+ 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.

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.

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:

  1. synthesize phenysulphonyl aminoalkanamide as the reactive intermediate.
  2. use the phenylsulphonyl aminoalkanamide to synthesize novel N-aryl substituted phenylsulphonyl alkanamides via palladium catalysed Buchwald-Hartwig amination protocol.
  • characterize these synthesized products using spectroscopic techniques namely: FT-IR, as well as 1H-NMR and 13C-NMR spectroscopies.
  1. 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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