Thesis submitted in fulfilment of the requirements for the Degree of Masters of Technology: Organic Chemistry, Durban University of Technology, 2011. / One of the greatest medical challenges facing mankind is the Human Immunodeficiency
Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) which has now become a major
epidemic with more than 40 million people infected worldwide. Of equal concern is its
implication in high mortality and the onset of a number of opportunist mycobacterial
infections, principally tuberculosis. In spite of the discovery of some relatively effective antiretroviral
(ARV) drugs such as Azido Thymidine (AZT), Nevirapine (NVP) and Efavirenz
(EFV), its’ application as either a single or combinational form causes side effects by
harming the bone marrow. Drug resistance is a key cause of failure for treatment of HIV
infection. Hence greater interdisciplinary efforts, involving both natural and social sciences,
are needed urgently to combat this HIV/AIDS pandemic.
Heterocyclic nitrogen based compounds, obtained from either natural sources or synthesis are
adequately documented to have increased biological activity against several diseases.
Recently a study of drugs containing the naphthyridine scaffold has acquired increasing
attention because of its potential against HIV/AIDS. Generally, naphthyridines demonstrate
good potency in both the enzyme and cellular systems and this prompted our interest in the
synthesis of naphthyridine derivatives from simple and readily available starting compounds.
Furthermore we wanted to form an intermediate quinolone moiety since it has good
biological potential.
In this study we report the synthesis of three naphthyridine derivatives, i.e. 6-phenyl-dibenzo
[b, h] [1, 6] naphthyridine, 4-methyl-6-phenyl-dibenzo [b, h] [1, 6] naphthyridine and 2-
methyl-6-phenyl-dibenzo [b, h] [1, 6] naphthyridine from easily available chemicals such as
aniline, ortho-toludine, para-toluidine and ethyl benzoylacetate via a five step reaction
scheme using either conventional reflux, microwave irradiation or both methodologies. It
was found that microwave irradiation was several folds faster than conventional reflux
methodology and the yield of the product was higher.
The first step of the reaction scheme is a simple condensation reaction: three acrylate
derivatives, viz. ethyl-3-aniline-3-phenyl acrylate, ethyl-3-phenyl-3-(ortho-tolylamino)
acrylate and ethyl-3-phenyl-3-(para-tolylamino) acrylate were synthesized by refluxing ethyl
benzoylacetate in an acidified ethanolic solution with aniline, ortho-toluidine and paratoluidine
respectively for three hours; the yields were 95, 87.5 and 80 % respectively.
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In the second step, thermal cyclisation was achieved for the synthesis of three quinoline
derivatives, viz. 2-phenylquinoline-4(1H)-one, 8-methyl-2-phenylquinoline-4(1H)-one and 6-
methyl-2-phenylquinoline-4(1H)-one from their respective acrylates under microwave
irradiation for 5 minutes at 180 °C and 250 watts; the yields were 92, 84 and 80 %
respectively.
In the third step of the reaction, synthesis of 4-chloro-2-phenylquinoline, 4- chloro-8-methyl-
2-phenylquinoline and 4- chloro-6-methyl-2-phenylquinoline was achieved from a mixture of
POCl3 and their respective quinolines via microwave irradiation for 3 minutes at 75 °C and
150 watts and via conventional reflux for 5 hours. It was found that under microwave
irradiation, the reaction occurred nearly 100 fold faster but the % yield of the product was
marginally higher.
The fourth step of the reaction resulted in the formation of three schiff’s base, viz. 4-(Nphenyl)-
2-phenyl-4-aminoquinoline, 8-methyl-4-(N-phenyl)-2-phenyl-4-aminoquinoline and
6-methyl-4-(N-phenyl)-2-phenyl-4-aminoquinoline from their respective quinolines via
microwave irradiation for 20 minutes at 180 °C and 180 watts and via conventional reflux
for 2 hours. It was found that under microwave irradiation, the reaction occurred nearly 6 fold
faster and the % yield of the product was over 10 % higher.
The final step of the reaction was achieved by a Vilsmeir Haack reaction and in situ base
catalyzed thermal cyclisation: 6-phenyl-dibenzo [b, h] [1, 6] naphthyridine, 4-methyl-6-
phenyl-dibenzo [b, h] [1, 6] naphthyridine and 2-methyl-6-phenyl-dibenzo [b, h] [1, 6]
naphthyridine were synthesized from their respective schiffs base via microwave irradiation
for 20 minutes at 75 °C at 120 watts and via conventional reflux for 21 hours. It was found
that under microwave irradiation, the reaction occurred over 60 fold faster and the % yield of
the product was over 20 % higher.The outline for the five step synthesis of the three
naphthyridines is presented graphically below:
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Key:
(a) R1= H; R2=H
(b) R1 = H; R2 = CH3
(c) R1 = CH3; R2 =H
Reaction Conditions:
1) conc.HCl, EtOH, 3hrs, 50 °C; 2) conc. HCl, hand stirring 10 min;
3) 180 °C, MWI, 250 watts, 5 min; 4) POCl₃, MWI, 75 °C, 150 watts, 2 min;
5) POCl₃, 100 oC, 5 hrs; 6) aniline, t-BuOH, MWI, 180 °C, 180 watts, 20 min;
7) aniline, t-BuOH, 80 °C, 3 hrs; 8) DMF, POCl₃, MWI, 75 °C,120 watts 20
minute; 9) DMF, POCl3, 100 oC, 21 hrs.
| Identifer | oai:union.ndltd.org:netd.ac.za/oai:union.ndltd.org:dut/oai:localhost:10321/704 |
| Date | January 2011 |
| Creators | Ndaba, Hlengiwe Glenrose |
| Contributors | Gengan, Robert Moonsamy |
| Source Sets | South African National ETD Portal |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | 120 p |
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