![Starting 2-arylated oxazolo[4,5-b]pyrazines.](https://www.researchgate.net/profile/Florence-Mongin/publication/325124455/figure/fig1/AS:634216022822912@1528220291079/Starting-2-arylated-oxazolo4-5-bpyrazines_Q320.jpg)
Content uploaded by Florence Mongin
Author content
All content in this area was uploaded by Florence Mongin on Jun 05, 2018
Content may be subject to copyright.
A preview of the PDF is not available
Functionalization of Oxazolo[4,5-b]pyrazines by Deprotometallation
Abstract and Figures
Different 2‐arylated oxazolo[4,5‐b]pyrazines, obtained by palladium(II)‐catalysed 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.
Figures - uploaded by Florence Mongin
Author content
All figure content in this area was uploaded by Florence Mongin
Content may be subject to copyright.
... reaction of 1 with 4 to give 6). We are unaware of any direct reaction of 2 with four nucleophiles; in systems where the chlorines and hydrogens of 2 are all replaced, the reaction of C-5 and C-6 (the hydrogen-bearing carbons) involves reaction with an oxidant (e.g., a molecular halogen), sometimes followed by an organometallic coupling [22,23]. On the other hand, pyrazines bearing leaving groups readily undergo displacement of those leaving groups, by either SNAr or Addition of the Nucleophile, Ring Opening, and Ring Closure (ANRORC) mechanisms [24][25][26]. ...
Herein, we report the synthesis of 5,12-dihydropyrazino[2,3-c:5,6-c′]difuro[2,3-c:4,5-c′]-diquinoline-6,14(5H,12H)diones, 2-(4-hydroxy-2-oxo-1,2-dihydroquinolin-3-yl)-1,4-diphenyl- butane-1,4-diones and 4-(benzo-[d]oxazol-2-yl)-3-hydroxy-1H-[4,5]oxazolo[3,2-a]pyridine-1-one. The new candidates were synthesized and identified by different spectroscopic techniques, and X-ray crystallography.
... The use of in situ metal traps avoids the use of cryogenic conditions to achieve these reactions [16,17]. We have developed mixed lithium-zinc combinations based on TMP (TMP = 2,2,6,6-tetramethylpiperidino) capable of deprotonating sensitive substrates at temperatures close to rt [18][19][20][21]. In order to obtain original scaffolds such as pyrazino-fused carbazoles and carbolines, we decided to combine this deprotometalation under in situ trapping conditions with palladium-and copper-catalyzed coupling reactions. ...
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).
The synthesis of novel 5,7-diaryl and diheteroaryl indoles has been explored via efficient double Suzuki-Miyaura coupling. The method notably employs a low catalyst loading of Pd(PPh3)4 (1.5 mol%/coupling) and water as the reaction solvent to obtain 5,7-diarylated indoles without using N-protecting groups in up to 91% yield. The approach is also suitable for N-protected and 3-substituted indoles and constitutes an important green and convenient arylation strategy for the benzenoid ring of indoles. The synthesized diarylindoles are fluorescent.
Bicyclic 5–6 systems with two heteroatoms in each ring are prevalent in the literature. Pyrazolo–pyrimidines are prominent in this family of heterocycles owing to their close structural relationship with the purine system (covered in a separate chapter), both systems display potent and diverse types of biological activity. This article covers the physical characteristics, reactivity, synthesis, and medicinal chemistry applications of this important family of heterocycles as documented in the literature from 2007 to mid-2019.
We have prepared some benzo-fused N-heterocycles derivatives by regioselective metalation of quinoline, isoquinoline, quinoxaline, and quinazoline with LiTMP in the presence of zinc chloride. Applying this strategy to synthesize an analog of the antitumor verubulin illustrates its relevance for medicinal chemistry. Computational calculations of the pKa values of the aromatic hydrogens have helped us to rationalize substrate reactivity and metalation regioselectivity by the complex-induced proximity effect concept.
This study establishes a new trans-metal-trapping (TMT) procedure based on a mixture of LiTMP (the base) and tris(trimethylsilylmethyl)gallium [Ga(CH2SiMe3)3, GaR3] (the trap) that, operating in a tandem manner, is effective for the regioselective deprotonation of sensitive diazines in hydrocarbon solution, as illustrated through reactions of pyrazine, pyridazine, and pyrimidine, as well as through the N-S heterocycle benzothiazole. The metallo-activated complexes of all of these compounds were isolated and structurally defined.
This study establishes a new trans-metal-trapping (TMT) procedure based on a mixture of LiTMP (the base) and tris(trimethylsilylmethyl)gallium [Ga(CH2 SiMe3 )3 , GaR3 ] (the trap) that, operating in a tandem manner, is effective for the regioselective deprotonation of sensitive diazines in hydrocarbon solution, as illustrated through reactions of pyrazine, pyridazine, and pyrimidine, as well as through the N-S heterocycle benzothiazole. The metallo-activated complexes of all of these compounds were isolated and structurally defined.
The metallation of aryl ketones was achieved by using LiTMP in the presence of ZnCl2·TMEDA, as evidenced by subsequent interception with iodine or by palladium-catalysed cross-coupling reaction. One of the synthesized iodo ketones has been further elaborated to reach derivatives of biological interest.
A series of methoxy- and fluoro-pyridines have been deprotometalated in tetrahydrofuran at room temperature by using a mixed lithium-zinc combination obtained from ZnCl2·TMEDA (TMEDA = N,N,N’,N’-tetramethylethylenediamine) and LiTMP (TMP = 2,2,6,6-tetramethylpiperidino) in a 1:3 ratio, and the metalated species intercepted by iodine. Efficient functionalization at the 3 position was observed from 4-methoxy, 2-methoxy, 2,6-dimethoxy, 2-fluoro and 2,6-difluoropyridine, and at the 4 position from 3-methoxy and 2,3-dimethoxypyridine. Interestingly, clean dideprotonation was noted from 3-fluoropyridine (at C2 and C4) and 2,6-difluoropyridine (at C3 and C5).
The improvements in the crystal structure refinement program SHELXL have been closely coupled with the development and increasing importance of the CIF (Crystallographic Information Framework) format for validating and archiving crystal structures. An important simplification is that now only one file in CIF format (for convenience, referred to simply as `a CIF') containing embedded reflection data and SHELXL instructions is needed for a complete structure archive; the program SHREDCIF can be used to extract the .hkl and .ins files required for further refinement with SHELXL. Recent developments in SHELXL facilitate refinement against neutron diffraction data, the treatment of H atoms, the determination of absolute structure, the input of partial structure factors and the refinement of twinned and disordered structures. SHELXL is available free to academics for the Windows, Linux and Mac OS X operating systems, and is particularly suitable for multiple-core processors.
The new computer program
SHELXT
employs a novel dual-space algorithm to solve the phase problem for single-crystal reflection data expanded to the space group
P
1. Missing data are taken into account and the resolution extended if necessary. All space groups in the specified Laue group are tested to find which are consistent with the
P
1 phases. After applying the resulting origin shifts and space-group symmetry, the solutions are subject to further dual-space recycling followed by a peak search and summation of the electron density around each peak. Elements are assigned to give the best fit to the integrated peak densities and if necessary additional elements are considered. An isotropic refinement is followed for non-centrosymmetric space groups by the calculation of a Flack parameter and, if appropriate, inversion of the structure. The structure is assembled to maximize its connectivity and centred optimally in the unit cell.
SHELXT
has already solved many thousand structures with a high success rate, and is optimized for multiprocessor computers. It is, however, unsuitable for severely disordered and twinned structures because it is based on the assumption that the structure consists of atoms.
1-Aryl- and 2-aryl-1,2,3-triazoles were synthesized by N-arylation of the corresponding azoles using aryl iodides. The deprotometalations of 1-phenyl-1,2,3-triazole and -1,2,4-triazole were performed using a 2,2,6,6-tetramethylpiperidino-based mixed lithium-zinc combination and occurred at the most acidic site, affording by iodolysis the 5-substituted derivatives. Dideprotonation was noted from 1-(2-thienyl)-1,2,4-triazole by increasing the amount of base. From 2-phenyl-1,2,3-triazoles, and in particular from 2-(4-trifluoromethoxy)phenyl-1,2,3-triazole, reactions at the 4 position of the triazolyl, but also ortho to the triazolyl on the phenyl group, were observed. The results were analyzed with the help of the CH acidities of the substrates, determined in THF solution using the DFT B3LYP method. 4-Iodo-2-phenyl-1,2,3-triazole and 4-iodo-2-(2-iodophenyl)-1,2,3-triazole were next involved in Suzuki coupling reactions to furnish the corresponding 4-arylated and 4,2'-diarylated derivatives. When evaluated for biological activities, the latter (which are resveratrol analogues) showed moderate antibacterial activity and promising antiproliferative effect against MDA-MB-231 cell line.
Es wird die Durchflussmetallierung verschiedener Arene und Heteroarene durch In-situ-Abfangen mit Metallsalzen (ZnCl2⋅2 LiCl, MgCl2, CuCN⋅2 LiCl, LaCl3⋅2 LiCl) unter sehr zweckmäßigen Bedingungen (0 °C, 40 s) beschrieben. Die entstehenden Mg-, Zn-, Cu- oder La-organischen Spezies werden mit verschiedenen Elektrophilen in hohen Ausbeuten abgefangen. In mehreren Fällen werden ungewöhnliche kinetische Regioselektivitäten erzielt. Die Durchflussmetallierungen werden ohne weitere Optimierung schlicht durch Verlängerung der Reaktionszeit skaliert. Verglichen mit den entsprechenden Batch-Prozessen werden die Anwendungsmöglichkeiten durch solche Flussmetallierungen beträchtlich erweitert.
The flow metalation of various arenes and heteroarenes involving an in situ trapping with metal salts (ZnCl2 ⋅2 LiCl, MgCl2 , CuCN⋅2 LiCl, LaCl3 ⋅2 LiCl) under very convenient conditions (0 °C, 40 s) is reported. The resulting Mg, Zn, Cu, or La organic species are trapped with various electrophiles in high yields. In several cases, unusual kinetically controlled regioselectivities are obtained. All these flow metalations can be scaled up simply by extending the reaction time and without further optimization. The reaction scope of such flow metalations is considerably broader than that of the corresponding batch procedures.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
The benzoxazole heterocycle is often found in ligands targeting a plethora of receptors and enzymes. By analysis of published X-ray structures, this review aims at highlighting key interactions which the benzoxazole may engage in with its host protein. Furthermore, bioavailability, metabolism and the use of benzoxazole as a bioisostere are discussed. The review is extended to cover structure-activity relationship studies of 2-substituted benzoxazoles, 2-substituted oxazolopyridines, and in perspective, application of the recently published novel heterocycle oxazolopyrazine in medicinal chemistry studies.
Copyright © 2014 Elsevier Masson SAS. All rights reserved.