Functionalization of pyridyl ketones using deprotolithiation-in situ zincation

Hedidi, Madani; Erb, William; Lassagne, Frédéric; Halauko, Yury S.; Ивашкевич, Олег А.; Матулис, Вадим Э.; Roisnel, Thierry; Bentabed‐Ababsa, Ghenia; Mongin, Florence

doi:10.1039/c6ra11370b

Cited by 24 publications

(34 citation statements)

References 44 publications

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“…Unlike halogens, methoxy is not a suitable group to acidify long‐range positions. [28e] If the yield to convert 1o into 2o was found higher (88 % against 30 % from 1i under similar reaction conditions; Table , Entry 15), it might rather be related to the higher propensity of methoxy to make the pyridine ring less prone to nucleophilic attack …”

Section: Resultsmentioning

confidence: 99%

“…We recently communicated our preliminary studies centered on the functionalization of pyridyl ketones by deprotolithiation‐in situ zincation . We here detail our investigations to better understand the behavior of the ketone function as directing group.…”

Section: Introductionmentioning

confidence: 98%

“…We here detail our investigations to better understand the behavior of the ketone function as directing group. Because CH acidity concept helps understand deprotometalation outcomes, p K a values in tetrahydrofuran (THF) solution were calculated by means of quantum chemistry within the DFT framework by using an approach elaborated earlier , …”

Section: Introductionmentioning

confidence: 99%

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Fused Systems Based on 2‐Aminopyrimidines: Synthesis Combining Deprotolithiation‐in situ Zincation with N‐Arylation Reactions and Biological Properties

et al. 2017

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Various aromatic ketones were first functionalized next to the carbonyl function by deprotolithiation in the presence of a zinc salt followed by iodolysis. The outcome of the reactions was analyzed, and in particular their regioselectivity in the light of the calculated pKa values. Various halogenated ketones were next involved in copper‐catalyzed twofold C–N bond formation to obtain fused systems based on 2‐aminopyrimidines. Besides a potential antibacterial effect, 2‐aminobenzothiopyrano[4,3,2‐de]quinazoline was shown to inhibit PIM1 (IC50: 0.61 µm) and CDK2/cyclin A (IC50: 2.0 µm) kinases.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Fused Systems Based on 2‐Aminopyrimidines: Synthesis Combining Deprotolithiation‐in situ Zincation with N‐Arylation Reactions and Biological Properties

et al. 2017

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“…in the presence of ZnCl 2 · TMEDA (1 equiv. ; more soluble than ZnCl 2 ) as in situ trap, this pair being efficient to ensure accelerated and chemoselective reactions . When employed at –30 °C, products from dimetallation were not observed, and the iodides 1b and 1c were isolated in 50 % and 34 % yield, respectively (Table , entries 5 and 6; Figure ).…”

Section: Resultsmentioning

confidence: 99%

Functionalization of Oxazolo[4,5‐b]pyrazines by Deprotometallation

et al. 2018

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Different 2‐arylated oxazolo[4,5‐b]pyrazines, obtained by palladium(II)‐catalyzed domino reaction from 2,3‐dichloropyrazine and the corresponding carboxamides, were functionalized by deprotometallation. Employing lithium 2,2,6,6‐tetramethylpiperidine, in order to form a lithio derivative, and then trapping it by iodolysis, proved to be inefficient. However, the presence of a zinc‐based in situ trap allowed most substrates to be functionalized. Deprotonation of the pyrazine ring was observed in the presence of tolyl and anisyl groups at the oxazole 2‐position. In contrast, with chlorophenyl and thienyl groups in this 2‐position, deprotonation rather occurred on these groups either competitively or exclusively. The regioselectivities were discussed in the light of calculated pKa values of the substrates in THF. Finally, in the case of 2‐phenyloxazolo[4,5‐b]pyrazine, we converted the mixture of 5‐ and 6‐iodinated products into the corresponding 5,6‐diiodide, which was further functionalized by a double Suzuki coupling.

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“…It is possible to replace Zn(TMP) 2 by ZnCl 2 provided that there is no contact between LiTMP and ZnCl 2 in the absence of the aromatic compound [23,24]. Thus, Method B is limited to activated substrates for which deprotonation is favored over reaction between LiTMP and ZnCl 2 .…”

Section: Resultsmentioning

confidence: 99%

From Quinoxaline, Pyrido[2,3-b]pyrazine and Pyrido[3,4-b]pyrazine to Pyrazino-Fused Carbazoles and Carbolines

et al. 2018

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2,3-Diphenylated quinoxaline, pyrido[2,3-b]pyrazine and 8-bromopyrido[3,4-b]pyrazine were halogenated in deprotometalation-trapping reactions using mixed 2,2,6,6-tetramethyl piperidino-based lithium-zinc combinations in tetrahydrofuran. The 2,3-diphenylated 5-iodo- quinoxaline, 8-iodopyrido[2,3-b]pyrazine and 8-bromo-7-iodopyrido[3,4-b]pyrazine thus obtained were subjected to palladium-catalyzed couplings with arylboronic acids or anilines, and possible subsequent cyclizations to afford the corresponding pyrazino[2,3-a]carbazole, pyrazino[2′,3′:5,6] pyrido[4,3-b]indole and pyrazino[2′,3′:4,5]pyrido[2,3-d]indole, respectively. 8-Iodopyrido[2,3-b] pyrazine was subjected either to a copper-catalyzed C-N bond formation with azoles, or to direct substitution to introduce alkylamino, benzylamino, hydrazine and aryloxy groups at the 8 position. The 8-hydrazino product was converted into aryl hydrazones. Most of the compounds were evaluated for their biological properties (antiproliferative activity in A2058 melanoma cells and disease-relevant kinase inhibition).

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Functionalization of pyridyl ketones using deprotolithiation-in situ zincation

Cited by 24 publications

References 44 publications

Fused Systems Based on 2‐Aminopyrimidines: Synthesis Combining Deprotolithiation‐in situ Zincation with N‐Arylation Reactions and Biological Properties

Fused Systems Based on 2‐Aminopyrimidines: Synthesis Combining Deprotolithiation‐in situ Zincation with N‐Arylation Reactions and Biological Properties

Functionalization of Oxazolo[4,5‐b]pyrazines by Deprotometallation

From Quinoxaline, Pyrido[2,3-b]pyrazine and Pyrido[3,4-b]pyrazine to Pyrazino-Fused Carbazoles and Carbolines

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