mportance of heterocyclic compounds in the treatment of cancer

Get Complete Project Material File(s) Now! »

Chapter 2: Results and Discussion

Preparation of substrates

The synthesis of 2ʹ-amino-5ʹ-bromo-3ʹ-iodoacetophenone and 5ʹ-bromo-2ʹ-hydroxy-5ʹ-iodoacetophenone used as precursors in this investigation and their transformation into the corresponding chalcone derivatives are described in the next sections.

Synthesis of 2ʹ-amino-5ʹ-bromo-3ʹ-iodoacetophenone and 5ʹ-bromo-2ʹ-hydroxy-3ʹ iodoacetophenone

Literature review revealed that 2ʹ-amino-5ʹ-bromoacetophenone and the analogous 5ʹ-bromo-2ʹ-hydroxyacetophenone have been prepared before. Baker et al.142 synthesised 2ʹ-amino-5ʹ-bromoacetophenone in 80% yield from the reaction of 2-aminoacetophenone with pyridinium tribromide in dichloromethane (DCM) at room temperature (RT). The analogous 2-hydroxyacetophenone, on the other hand, was previously brominated with NaBr-oxone in methanol or N-bromosuccinimide (NBS) in acetic acid under reflux to afford 2ʹ-hydroxy-5ʹ-bromoacetophenone, exclusively.143 Under the same reaction conditions, 2-aminoacetophenone furnished a 3,5-dibromo product. The 5ʹ-bromo-2ʹ-hydroxyacetophenone has been subjected to further halogenation using pyridinium iodochloride in methanol under reflux to afford 5ʹ-bromo-2ʹ-hydroxy-3ʹ-iodoacetophenone.146 To our knowledge, the 2ʹ-amino-5ʹ-bromoacetophenone has not been transformed into the mixed dihalogenated derivatives. In this investigation we adapted the method described in literature142 and subjected 2-aminoacetophenone 195a (X = NH) to pyridinium tribromide in dichloromethane at room temperature (RT) for 4 h to afford 196a (Scheme 56). Thin layer chromatography of the crude product revealed the presence of 2ʹ-amino-5ʹ-bromoacetophenone 196a (X = NH) as the major product along with traces of the 2ʹ-amino-3ʹ,5ʹ-dibromoacetophenone. The resultant crude product was recrystalized from hexane to afford 196a in high purity. Treatment of 2-hydroxyacetophenone 195b (X = O) with N-bromosuccinimide (NBS) in acetic acid at RT following a literature procedure,142 on the other hand, afforded 5ʹ-bromo-2ʹ-hydroxyacetophenone 196b (X = O).
Although, both the 3- and 5-positions of 195a or 195b are doubly activated by the ortho-para directing effect of the amino or hydroxyl group and the meta-directing effect of the acetyl group, monobromination occurred almost exclusively at the 5-position to generate the 5-bromo– substituted 2-amino- 196a or 2-hydroxyacetophenone 196b, respectively. Bromination of 2-aminoacetophenone 195a by pyridinium tribromide (PTB) is known to release hydrogen bromide, which presumably coordinates with the amino group and reduce its propensity for π-electron delocalization.147 The steric hindrance at the ortho position relative to NH3+ and the meta directing effect of the acetyl group would favour attack at the 5-position by the bulky PTB to form 2ʹ-amino-5ʹ-bromoacetophenone 197a. The observed site-selective 5-monobromination of the 2-hydroxyacetophenone 196b, on the other hand, is presumably due to the formation of hydrogen bonds between the phenolic proton and the acetic acid, which would hinder attack at the ortho position by the bulky NBS and thus favour para attack.148 Compounds 196a and 196b were each subjected to N-iodosuccinimide in acetic acid at RT or under reflux to afford the previously undescribed 2ʹ-amino-5ʹ-bromo-3ʹ-iodoacetophenone 197a (X = NH) and the known 5ʹ-bromo-2ʹ-hydroxy-3ʹ-iodoacetophenone 197b (X = O), respectively (Scheme 56).
The 1H NMR spectra of compounds 196a and 196a each revealed the presence of a broad singlet at δ 6.29 ppm and δ 6.97 ppm, respectively, integrating for two protons of the amino group. The 1H-NMR spectrum of 196a shows the presence of doublet at δ 6.56 ppm (d, J = 8.5 Hz) for H-3, doublet of doublets at δ 7.34 ppm (d, J = 8.5 Hz and 2.5 Hz) for H-4, and doublet due to long range coupling at δ 7.80 ppm (d, J = 2.5 Hz) for H-6. The 1H-NMR spectrum of 197a, on the other hand, is distinguished from that of 196a by the presence of two sets of doublets at δ 7.83 ppm and δ 7.88 with coupling constant (J) value of 2.0 Hz, which correspond to H-4 and H-6, respectively. The hydroxyl proton of compounds 196b and 197b each resonates as a singlet at δ 12.1 ppm and δ 13.1 ppm, respectively. The 1H-NMR spectrum of 196b shows the presence of additional signals in the aromatic region at δ 6.87 ppm (d, J = 8.5 Hz), 7,53 ppm (dd, J = 2.5 and 8.5 Hz) and 7.81 ppm (d, J = 2.5 Hz) corresponding to H-3, H-4 and H-6, respectively. Incorporation of an iodine atom in compound 197b was confirmed by the presence of a set of doublets at δ 7.83 ppm and δ 8.04 with coupling constant (J) value of 2.1 Hz and these signals were assigned to H-4 and H-6, respectively. The melting point values of compounds 196a and 196b were found to be comparable to the literature values (Table 1). Although the observed melting point value for compound 197b was found to be slightly higher than the reported value, its spectroscopic data was found to be consistent with the assigned structure.

READ  Nanowires Characterization

Chapter 1: Introduction 
1.1 Importance of heterocyclic compounds in the treatment of cancer
1.2 An overview of indoles and indole-appended molecular hybrids of biological Importance
1.3 An overview of benzofuran and benzofuran-appended hybrids of biological importance
1.4 An overview of benzothiophene-based compounds of biological importance
1.5 An overview of quinazolines and quinazoline-based hybrids of biological Importance
1.6 Construction of benzo-fused 5-membered heterocycles containing one heteroatom in the ring
1.7 Methods for the synthesis of chalcones
1.8 Methods for the synthesis of indole- and benzofuran-appended chalcones
1.9 Chalcone moiety as scaffold for heteroannulation with binucleophiles to afford 5- , 6- and 7-membered heterocyclic derivatives
1.10 Methods for the synthesis of quinazolines
1.11 Methods for the synthesis of C–C and C–heteroatom linked indole-quinazoline hybrids
1.12 Main focus of this investigation
Chapter 2: Results and Discussion
2.1 Preparation of substrates
2.2 Design and synthesis of the angular indole- and benzofuran-appended chalcones
2.3 Transformation of the indole-chalcones and benzofuran-chalcone hybrids
2.4 Design and synthesis of the benzofuran-aminoquinazoline hybrids
2.5 Biological activity of the benzofuran-chalcones and benzofuran-aminoquinazolines
Chapter 3: Conclusion 
Chapter 4: Experimental
4.0 General
4.1 Halogenation of 2-aminoacetophenone (195a) and 2-hydroxyacetophenone (195b)
4.2 Synthesis of the (E)-2-amino-5-bromo-3-iodochalcones (197b)
4.3 Sonogashira cross-coupling of compounds 198a–f
4.4 PdCl2-mediated cyclization of compounds 200a–f
4.5 Synthesis of benzofuran-chalcone hybrids (203a-y)
4.6 C-3 Trifluoroacetylation of compounds 201a–f with TFAA in THF
4.13 Crystal Structure Solution and Refinement
4.14 Computational methods
4.15 In Vitro Cytotoxicity Assay
4.16 Cell culturing and evaluation of cytotoxicity for compounds 215a–j against panel of cancer cell lines
4.17 Molecular Docking against Tubulin and EGFR

Related Posts