Synthesis of heteroannulated quinolinones and quinolines

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Synthesis of 2-aryl-6,8-dibromoquinolin-4(1H)-ones 136a-d via dehydrogenation of 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones

The 2-aryl-2,3-dihydroquinolin-4(1H)-ones were previously dehydrogenated using thallium(III) p-tolylsulfonate (TTS) in dimethoxyethane (DME) under reflux74 or iodobenzene diacetate [PhI(OAc)2] with potassium hydroxide (KOH) as a base in methanol (MeOH).75 In this study, we opted for the use of thallium(III) p-tolylsulphonate due to the ease of preparation from thallium(III) nitrate and p-toluene sulphonic acid.74 We treated the 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones 122 with thallium(III) p-tolylsulphonate (TTS) in dimethoxyethane (DME) under reflux to afford the corresponding 2-aryl-6,8-dibromoquinolin-4(1H)-ones 136 exclusively and in good yields without need for purification by column chromatography (Scheme 40). The 1H NMR for these potentially tautomeric compounds reveal the absence of both the aliphatic proton signals present in the spectra of the corresponding substrates and the presence of the olefinic and aromatic signals in the region δ ca. 7.05-8.30 ppm and a less intense broad singlet significantly downfield at δ ca.11.90 ppm for N-H (Figure 8).
The 13C NMR spectra of compounds 136 also reveal the resonances corresponding to the olefinic signals at δ ca. 79.6 and 102.3 ppm for C-2 and C-3, respectively (Figure 9). Although, compounds 136 show potential to coexist in a tautomeric equilibrium with the quinolinol isomer, previous studies have confirmed that only the NH-4-oxo tautomer exists exclusively in solution phase (NMR spectroscopy) and solid state (IR spectroscopy and X-ray diffraction).76 The IR absorption bands at max ca. 3384 cm-1 and 1622 cm-1 attributed to the N-H and CO groups, further confirm their quinolin-4(1H)-one nature.

Palladium-catalyzed Sonogashira cross-coupling of 2-aryl-6,8-dibromo-2,3- dihydroquinolin-4(1H)-ones with terminal alkynes

Sonogashira cross-coupling of terminal alkynes in the presence of a palladium catalyst is known to proceed well with aryliodides and arylbromides.32,56,57,99 With compounds 122 in hand, we decided to investigate their reactivity in Pd-catalyzed Sonogashira cross-coupling using terminal acetylenes as coupling partners. Initial attempt to effect site-selective cross-coupling of 6,8-dibromo-2-phenyl-2,3-dihydroquinolin-4(1H)-one with phenyl acetylene using 10% Pd/C-PPh3-CuI catalyst complex with K2CO3 as the base in ethanol under reflux and inert atmosphere after 18 hours led to the recovery of the starting material. However, the use of triethylamine (NEt3) in place of potassium carbonate (K2CO3) resulted in the desired monoalkynyl product 137a in low yield <30% along with the starting material. The yield of compound 137a was improved in ethanol using NEt3 as a base and co-solvent. We isolated upon column chromatography on silica gel the corresponding compound 137a in high yield (71%) and purity (Scheme 41). The reaction conditions were extended to other dihaloquinolin-4-ones 122 with phenyl acetylene and 3-butyn-1-ol as coupling partners. We isolated in all cases the corresponding 8-alkynyl-2-aryl-8-bromo-2,3-dihydroquinolin-4(1H)-ones 137a-h (Scheme 41).
Hitherto, 6-chloro-8-iodo-2,3-dihydroquinolin-4(1H)-one has been found to undergo palladium-catalyzed Sonogashira cross-coupling in the presence of 10% Pd/C-PPh3-CuI catalyst complex with phenyl acetylene with ease to afford 8-phenylethynyl-6-chloro-2,3-dihydroquinolin-4(1H)-one.56 The same catalyst complex also promoted C-8 alkynylation of 6-bromo-8-iodoquinolines to afford 8-alkynyl-6-bromoquinolines.55 In these examples, preferential replacement of the 8-iodo atom over the 6-chloro/bromo atom is observed. However, in this study the observed site-selectivity at the C-8 over C-6 of compounds 122 is attributed to the ortho directing effect of NH in analogy with literature precedent for the dihalogenated fused benzo heterocycles bearing two similar halogen atoms.101 Furthermore, selectivity of the transition metal-catalyzed cross-coupling reaction of multiple identical halogen atoms bearing heterocycles with similar carbon-halide bond strengths has been found to depend largely on the heterocycle π* (LUMO)-PdL2 dxy (HOMO) interaction in the oxidative addition step.102 In addition, the interaction of the orbital formed by the lone pair of electrons on the nitrogen atom with the palladium catalyst further favours the initial substitution of the bromine at the C-8 position.102 The selectivity for heteroaryl halides bearing different halogen atoms depend on the trend in reactivity of the halides: I > Br > Cl >> F,55,103 as a function of their Ar-X bond strengths (Dph-X values 65, 81, 96 and 126 kcal mol-1).
Selectivity also depend to a lesser degree on the electronic effect of its position on the heteroaryl moiety.104 The 1H NMR spectra of compounds 137 still retained some of the characteristic features observed in the spectra of corresponding substrates with the aliphatic protons at the position H-3 resonating as a doublet and doublet of doublets at δ ca. 2.76 ppm with Jgem = 15.0 Hz and at δ ca. 2.89 ppm with Jvic = 7.1 and 15.0 Hz. A doublet of doublets at δ ca. 4.75 ppm with J = 7.1 and 9.3 Hz, due to the resonance of the methine proton of the chiral carbon center at the position H-2; a singlet at δ ca. 5.49 ppm correspond to the NH and the two sets of doublet at δ ca. 7.58 ppm and δ ca. 7.90 ppm with coupling constant value J = 2.4 Hz, correspond to the slightly deshielded protons at positions H-7 and H-5, respectively (Figure 10). Their 13C NMR spectra reveal the presence of acetylenic carbons at δ ca. 88.7 and 96.7 ppm, respectively (Figure 11). Their IR spectra also show an intense absorption band at max ca. 2201 cm-1 which confirms the presence of the C≡C group.


Chapter 1: Introduction
1.1 General overview
1.2 Synthesis of heteroannulated quinolinones and quinolines
1.2.1 Synthesis of furoquinolinones and furoquinolines
1.2.2 Synthesis of thienoquinolinones and thienoquinolines
1.2.3 Synthesis of pyrrolo[3,2,1-ij]quinolinones and pyrrolo[3,2,1-ij]quinolines
1.3 Methods for the synthesis of 2-substituted quinolin-4(1H)-ones
1.3.1 Synthesis of 2-aryl-2,3-dihydroquinolin-4(1H)-ones
1.3.2 Methods for the synthesis of 2-substituted quinolin-4(1H)-ones
1.4 Halogenation of the 2-aryl-2,3-dihydroquinolin-4(1H)-ones and the 2-arylquinolin-4(1H)-ones
1.5 Aromatization of 2-arylquinolin-4(1H)-ones into 4-halogenoquinolines
1.6 Research hypothesis
1.7 Aims and objectives
Chapter 2: Results and Discussion 
2.0 General overview
2.1 Preparation of substrates
2.1.1 Synthesis of 1-(2′-aminophenyl)-3-aryl-2-propen-1-ones
2.1.2 Synthesis of 2-aryl-2,3-dihydroquinolin-4(1H)-ones
2.2 Synthesis of 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones
2.3 Synthesis of 2-aryl-6,8-dibromoquinolin-4(1H)-ones via dehydrogenation of 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones
2.4 Palladium-catalyzed Sonogashira cross-coupling of 2-aryl-6,8-dibromo-
2,3-dihydroquinolin-4(1H)-ones with terminal alkynes
2.5 One-pot Sonogashira cross-coupling: Synthesis of 6,8-dialkynylated 2-aryl-2,3- dihydroquinolin-4(1H)-ones
2.6 Synthesis of 4-aryl-8-bromo-2-phenyl-6H-4,5-dihyropyrrolo[3,2,1-ij]quinolin-6- ones
2.7 Synthesis of 2-aryl-6-bromo-8-(4-hydroxybutanoyl)-2,3-dihydroquinolin- 4(1H)-ones
2.8 Synthesis of 8-substituted 4-aryl-2-phenyl-6H-4,5-dihydroquinolin-6-ones
2.9 Synthesis of 2-substituted 4-aryl-8-bromo-6-oxopyrrolo[3,2,1-ij]quinolines
2.10 Synthesis of 2,8-disubstituted 4-aryl-6-oxopyrrolo[3,2,1-ij]quinoline derivatives via palladium-catalyzed Sonogashira cross-coupling reaction
2.11 Synthesis of 2,8-disubstituted 4-aryl-6-oxopyrrolo[3,2,1-ij]quinoline derivatives via Pd-catalyzed Suzuki-Miyaura cross-coupling reaction
2.12 Palladium-catalyzed Suzuki-Miyaura cross-coupling: synthesis of 2,6,8-triaryl-
2.13 Preparation of 2,6,8-triarylquinolin-4(1H)-ones via dehydrogenation of 2,6,8- triaryl-2,3-dihydroquinolin-4(1H)-ones
2.14 Synthesis of 2,6,8-triaryl-3-iodoquinolin-4(1H)-ones
2.15 Synthesis of 2,6′,8′-trisubstituted 2′-arylfuro[3,2-c]quinoline derivatives
2.16 Evaluation of antimicrobial activity of compounds synthesize
Chapter 3: Conclusion 
Chapter 4: Experimental 
4.0 General
4.1 Preparation of 1-(2′-aminophenyl)-3-aryl-2-propen-1-ones
4.2 Preparation of 2-aryl-2,3-dihydroquinolin-4(1H)-ones
4.3 Preparation of 2-aryl-6,8-dibromo-2,3-dihydroquinolin-4(1H)-ones
4.4 Preparation of 2-aryl-6,8-dibromoquinolin-4(1H)-ones
4.5 Preparation of 8-alkynyl-2aryl-6-bromo-2,3-dihydroquinolin-4(1H)-ones via Pd- mediated Sonogashira cross-coupling reaction
4.6 Preparation of 6,8-bis(alkynyl)-2-aryl-2,3-dihydroquinolin-4(1H)-ones via Pd- mediated Sonogashira cross-coupling reaction
4.7 Preparation of 4-aryl-8-bromo-2-phenyl-4,5-dihydro-6H-pyrrolo[3,2,1-ij]quinolin- 6-ones via palladium-promoted intramolecular cyclization
4.8 Preparation of 2-aryl-6-bromo-8-(4-hydroxybutanoyl)-2,3-dihydroquinolin-4(1H)- ones
4.9 Preparation of 2,8-disubstituted 4-aryl-4,5-dihydro-6H-pyrrolo[3,2,1-ij]quinolin- 6-ones via Pd promoted Suzuki-Miyaura cross-coupling reaction
4.10 Preparation of 2-substituted 4-aryl-8-bromo-6-oxopyrrolo[3,2,1-ij]quinoline derivatives
4.11 Preparation of 2,8-disubstituted 4-aryl-6-oxopyrrolo[3,2,1-ij]quinoline derivatives
4.12 Preparation of 2,8-disubstituted 4-aryl-6-oxopyrrolo[3,2,1-ij]quinoline derivatives via palladium-catalyzed Suzuki-Miyaura cross-coupling reaction
4.13 Preparation of 2,6,8-triaryl-2,3-dihydroquinolin-4(1H)-ones
4.14 Preparation of 2,6,8-triarylquinolin-4(1H)-ones
4.15 Preparation of 2,6,8-triaryl-3-iodoquinolin-4(1H)-ones
4.16 Preparation of 2,6′,8′-trisubstituted 2′-arylfuro[3,2-c]quinoline derivatives
4.17 Antimicrobial susceptibility evaluation of selected synthesized compounds

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