JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38
SEPTEMBER, 535–538
RESEARCH PAPER 535
One-pot site-selective Sonogashira cross-coupling–heteroannulation of the 2‑aryl-6,8-dibromoquinolin-4(1H)-ones: synthesis of novel 6‑H-pyrrolo[3,2,1-ij ]quinolin-6-ones Malose J. Mphahlele* and Felix A. Oyeyiola Department of Chemistry, College of Science, Engineering and Technology, University of South Africa, PO Box 392, Pretoria 0003, South Africa The 2‑aryl-6,8-dibromoquinolin-4(1H)-ones were subjected to site-selective Sonogashira cross-coupling with terminal acetylenes as models for Csp2–Csp bond formation in the presence of Pd/C–PPh3 and CuI as catalysts and K 2CO3 as a base in dioxane to afford the 2‑substituted 4‑aryl-8-bromo-4H-pyrrolo[3,2,1-ij ]quinolin-6-ones. These were, in turn, subjected to Suzuki–Miyaura cross-coupling with 4‑fluorophenylboronic acid as coupling partner to afford the 2‑substituted 4,8-diaryl-4Hpyrrolo[3,2,1-ij ]quinolin-6-ones. Keywords: 2‑aryl-6,8-dibromoquinolin-4(1H)-ones, Sonogashira cross-coupling; 2,4-diaryl-8-bromo-4H-pyrrolo[3,2,1-ij] quinolin-6-ones, Suzuki–Miyaura cross-coupling, 2,4,8-triaryl-6H-pyrrolo[3,2,1-ij]quinolin-6-ones The 5,6-dihydro-4H-pyrrolo[3,2-ij]quinoline ring occurs in numerous natural products and this moiety constitutes the central core of different series of compounds exerting platelet activating factor production inhibition.1 Pyrrolo[3,2.1-ij]quinoline derivatives have also shown potent histamine and platelet activating factor antagonism and 5‑lipoxygenase inhibitory properties.2 Moreover, some pyrrolo[3,2-ij]quinolines exhibit antibacterial and antifungal activities for diseases of rice plants.3 The preparation of the 6‑oxopyrroloquinolines has generally been based on the cyclodehydration of a suitably functionalised indole derivative.4 Recently, a great deal of work has been focused on the synthesis of these compounds from halogenated quinolinones and quinoline derivatives by transition metal catalysed cross-coupling with terminal alkynes. This strategy takes advantage of the ease of displacement of the halogen atom/s on the aryl or heteroaryl moiety by metal to facilitate carbon–carbon bond formation and the proximity of the tethered nucleophilic heteroatom to promote heteroannulation. Palladium-mediated cross-coupling of the 8‑iodoquinolin4(1H)-one derivatives with propargyl alcohols, for example, previously afforded the 6‑oxopyrroloquinolines in a singlepot operation albeit in low to moderate yields (8–68%).5 A similar approach was later adapted for the synthesis of N-(4chlorobenzyl)-2-(2-hydroxyethyl)-8-(morpholin-4-ylmethyl)6-oxo-6H-pyrrolo[3,2,1-ij]quinolin-5-carboxamide (PHA529311), which exhibits improved activity against herpes virus DNA polymerase.6 Layek et al.7 also reported a high yielding single-step synthesis of the 2‑substituted 5‑carbethoxy-6Hpyrrolo[3,2,1-ij]quinolin-6-ones by cross-coupling of 8‑iodo4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl esters with a variety of terminal alkynes using Pd/C–PPh3–CuI precatalyst mixture in ethanol. This catalyst mixture has also been found to promote regioselective C‑8 alkynylation of 6‑bromo8-iodoquinolines7 or in situ cross-coupling–heteroannulation of 8‑iodo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl esters8 and 6-(chloro/methyl)-8-iodo-2,3-dihydroquinolin4(1H)-ones4 to afford the 2‑substituted 6‑oxopyrrolo[3,2,1-ij]-quinolines and 4H‑pyrrolo[3,2,1-ij]quinolin-6-ones, respectively. The selectivity in the case of the less readily accessible chloroiodo- and bromoiodoquinolinones has been found to depend largely on the intrinsic reactivity of the halide to be displaced (trend: I > Br > Cl >> F),4,7 which relates to the Ar–X bond strength (DPh–X values 65, 81, 96, and 126 kcal mol–1, * Correspondent. E‑mail:
[email protected]
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respectively) and to a lesser extend the electronic effect of its position on the heterocycle.9 However, for quinolinones bearing multiple identical halogen atoms particularly on the fused benzo ring, the bond strengths are very similar10 and this makes it difficult to predict easily the selectivity of cross-coupling. Our interest in the synthesis of polysubstituted and heteroannulated quinolinones prompted us to investigate the reactivity of the 2‑aryl-6,8-dibromoquinolin-4(1H)-one derivatives in Sonogashira cross-coupling with phenylacetylene as coupling partner. We envisage that the increased acidity of NH and the proximity of the 8‑alkynyl group to nitrogen of the incipient 8‑alkynyl-2-arylquinolin-4(1H)-ones would facilitate direct one-pot metal-mediated heteroannulation to afford novel 4H‑pyrrolo[3,2,1-ij]quinolin-6-ones with potential to undergo further transformation. The 2‑aryl-6,8-dibromoquinolin-4(1H)-ones required as substrates in this investigation were previously isolated in trace amounts along with the corresponding 2‑aryl-6,8-dibromo-4methoxyquinolines (major) from the oxidative-cyclisation of the corresponding 2‑aminochalcones with iodine in methanol under reflux.11 Hitherto, 6,8-dibromo-2-phenylquinolin-4(1H)one was isolated as a minor product from the reaction of 2‑phenyl-2,3-dihydroquinolin-4(1H)-one with excess bromine (4 equiv.) in chloroform.12 Our first task in this investigation was to synthesise the requisite 2‑aryl-6,8-dibromoquinolin4(1H)-ones in reasonable quantities to serve as substrates for the palladium-catalysed Sonogashira cross-coupling with terminal alkynes. We opted for the use of the known 2‑aryl-6,8dibromo-2,3-dihydroquinolin-4(1H)-ones 1a–d13 as precursors because of the potential of their heterocyclic ring to undergo different degrees of unsaturation by dehydrogenation or oxidative aromatisation. One approach for the dehydrogenation of the 2‑aryl-2,3-dihydroquinolin-4(1H)-ones makes use of iodobenzene diacetate under basic conditions in methanol14 and the other employs thallium(III) p‑tolylsulfonate in dimethoxyethane to afford the 2‑arylquinolin-4-(1H)-ones.15 We opted for the use of the readily prepared and easy-to-handle thallium(III) p‑tolylsulfonate (TTS) in dimethoxyethane (DME) and subjected compounds 1a–d to dehydrogenation to afford the corresponding potentially tautomeric 2‑aryl6,8-dibromoquinolin-4(1H)-ones 2a–d in reasonable yields and high purity without the need for column chromatographic purification (Scheme 1). The analogous 6,8-dibromoflavone has been found to undergo the Heck reaction with methyl acrylate to afford mixtures of both 6- and 8‑monosubstituted and 6,8-disubstituted flavones.16
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536 JOURNAL OF CHEMICAL RESEARCH 2014 O
O
Br
Br
(i) N Br
C6H4R
N
H
Br
C6H4R
H
1a–d
2a–d
4-R % Yield of 2 2a 4-H 86 2b 4-F 80 2c 4-Cl 88 2d 4-OMe 82 Reagents and conditions: (i) TTS, DME, 100 °C, 30 minutes. Scheme 1 Thallium(III) p‑tolylsulfonate (TTS)-promoted dehydrogenation of 1a–d.
Although the 2‑aryl-6,8-dibromo-2,3-dihydroquinolin4(1H)-ones 1a–d undergo Suzuki–Miyaura cross-coupling with arylboronic acids without selectivity to afford the 2,6,8-triaryl2,3-dihydroquinolin-4(1H)-ones,13 the analogous 6‑bromo8-iodoquinolines were found to undergo regioselective C‑8 alkynylation with excess terminal acetylenes (3 equiv.) using Pd/C–PPh3–CuI pre-catalyst mixture.7 We envisage that this catalyst mixture could also affect site-selective Sonogashira cross-coupling of compounds 2a–d with minimum or no effect on the 6‑bromo atom. Based on this hypothesis, we subjected compound 2a to phenylacetylene (2.5 equiv.) in the presence of Pd/C–PPh3–CuI catalyst complex and triethylamine as a base in N,N-dimethyl formamide–water mixture (4 : 1, v/v) at 110 °C as an exploration based on literature precedent. We isolated albeit in low yield (
