Synthesis Of Pyridazines Research Articles

One pot synthesis of 4,5-dibromo-3,6-diarylpyridazine from 1,4-diarylbuta-1,3-diyne

Pyridazines are an important scaffold present in various pharmacophores due to their significant physiochemical features of drug molecules. Laboratory synthesis of pyridazines is highly important because their natural sources are very rare. A one-pot two-step methodology has been developed for the synthesis of 4,5-dibromo-3,6-diarylpyridazines starting from easily available starting material 1,4-diarylbuta-1,3-diynes. The reaction goes through the electrophilic addition of Br+ ion with alkyne bonds followed by nucleophilic addition of hydrazine and then intramolecular cyclization.

One-Pot and Two-Chamber Methodologies for Using Acetylene Surrogates in the Synthesis of Pyridazines and Their D-Labeled Derivatives.

Acetylene surrogates are efficient tools in modern organic chemistry with largely unexplored potential in the construction of heterocyclic cores. Two novel synthetic paths to 3,6-disubstituted pyridazines were proposed using readily available acetylene surrogates through flexible C2 unit installation procedures in a common reaction space mode (one-pot) and distributed reaction space mode (two-chamber): (1) an interaction of 1,2,4,5-tetrazine and its acceptor-functionalized derivatives with a CaC2 -H2 O mixture performed in a two-chamber reactor led to the corresponding pyridazines in quantitative yields; (2) [4+2] cycloaddition of 1,2,4,5-tetrazines to benzyl vinyl ether can be considered a universal synthetic path to a wide range of pyridazines. Replacing water with D2 O and vinyl ether with its trideuterated analog in the developed procedures, a range of 4,5-dideuteropyridazines of 95-99% deuteration degree was synthesized for the first time. Quantum chemical modeling allowed to quantify the substituent effect in both synthetic pathways.

Solution-Phase DNA-Compatible Pictet-Spengler Reaction Aided by Machine Learning Building Block Filtering.

SummaryThe application of machine learning toward DNA encoded library (DEL) technology is lacking despite obvious synergy between these two advancing technologies. Herein, a machine learning algorithm has been developed that predicts the conversion rate for the DNA-compatible reaction of a building block with a model DNA-conjugate. We exemplify the value of this technique with a challenging reaction, the Pictet-Spengler, where acidic conditions are normally required to achieve the desired cyclization between tryptophan and aldehydes to provide tryptolines. This is the first demonstration of using a machine learning algorithm to cull potential building blocks prior to their purchase and testing for DNA-encoded library synthesis. Importantly, this allows for a challenging reaction, with an otherwise very low building block pass rate in the test reaction, to still be used in DEL synthesis. Furthermore, because our protocol is solution phase it is directly applicable to standard plate-based DEL synthesis.

Synthesis of a Novel 1,4-Dicarbonyl Scaffold – Ethyl 3-Formyl-4,5-dihydrofuran-2-carboxylate – and Its Application to the Synthesis of Pyridazines

The 1,4-dicarbonyl scaffold ethyl 3-formyl-4,5-dihydrofuran-2-carboxylate was obtained through the rearrangement of the parent ethyl 2-(4,5-dihydrofuran-3-yl)-2-oxoacetate and applied to the synthesis of a series of 7-alkoxy-2,3-dihydrofuro[2,3-d]pyridazines. Twelve pyridazines­ were obtained in yields of up to 70%.

Towards discovery of novel scaffold with potent antiangiogenic activity; design, synthesis of pyridazine based compounds, impact of hinge interaction, and accessibility of their bioactive conformation on VEGFR-2 activities

Pyridazine scaffolds are considered privileged structures pertaining to its novelty, chemical stability, and synthetic feasibility. In our quest towards the development of novel scaffolds for effective vascular endothelial growth 2 (VEGFR-2) inhibition with antiangiogenic activity, four novel series of pyridazines were designed and synthesised. Five of the synthesised compounds; namely (8c, 8f, 15, 18b, and 18c) exhibited potent VEGFR-2 inhibitory potency (>80%); with IC50 values ranging from low micromolar to nanomolar range; namely compounds 8c, 8f, 15, 18c with (1.8 µM, 1.3 µM, 1.4 µM, 107 nM), respectively. Moreover, 3-[4-{(6-oxo-1,6-dihydropyridazin-3-yl)oxy}phenyl]urea derivative (18b) exhibited nanomolar potency towards VEGFR-2 (60.7 nM). In cellular assay, the above compounds showed excellent inhibition of VEGF-stimulated proliferation of human umbilical vein endothelial cells at 10 μM concentration. Finally, an extensive molecular simulation study was performed to investigate the probable interaction with VEGFR-2.

Inverse-Electron-Demand Diels-Alder Reactions for the Synthesis of Pyridazines on DNA.

The synthesis of pyridazines on DNA has been developed on the basis of inverse-electron-demand Diels-Alder (IEDDA) reactions of 1,2,4,5-tetrazines. The broad substrate scope is explored. Functionalized pyridazine products are selected for subsequent DNA-compatible Suzuki-Miyaura coupling, acylation, and SNAr substitution reactions, demonstrating the feasibility and versatility of IEDDA reactions for DNA-encoded library synthesis.

Synthesis of Pyridazine and Pyrrole Analogues of 2‐Aminotetralin as Potential Dopaminergics

Syntheses of pyridazine and pyrrole analogues of 2‐aminotetralin starting from 3‐cyclohexene‐1‐carboxylic acid are reported. All syntheses involve the following key steps: Curtius rearrangement for amine functionality, inverse electron demand Diels–Alder addition with 1,2,4,5‐tetrazine for pyridazine ring synthesis, and pyridazine‐to‐pyrrole ring contraction for pyrrole ring formation.

Recent Progress in the Chemistry of Pyridazinones for Functional Group Transformations.

While N-hetereocycles have received significant attention in organic synthesis and other research fields, the chemistry of pyridazine, a six-membered aromatic ring with two adjacent nitrogen atoms, and its derivatives has been relatively little understood. This Synopsis describes recent progress made in the synthesis of pyridazine derivatives-particularly, pyridazin-3(2H)-ones-and their utility as efficient and recyclable functional group carriers for various important organic reactions.

ChemInform Abstract: Diazo Strategy for the Synthesis of Pyridazines: Pivotal Impact of the Configuration of the Diazo Precursor on the Process.

AbstractZ‐configured vinylogous diazoesters undergo a diaza‐Wittig reaction providing pyridazines.

Diazo Strategy for the Synthesis of Pyridazines: Pivotal Impact of the Configuration of the Diazo Precursor on the Process.

Phosphazenes of vinyldiazocarbonyl compounds having cis stereochemistry of the functional groups on the vinyl bond readily produce pyridazines by a diaza-Wittig process, whereas their counterparts with trans configuration remain intact under similar reaction conditions. Upon UV irradiation trans-phosphazenes furnish pyridazines through a tandem trans-to-cis isomerization followed by intramolecular cyclization. At elevated temperatures trans-(triphenyl)phosphazenes dissociate to give the initial vinyldiazo compounds, which produce pyrazoles in high yields. The first theoretical study on the mechanism of the diaza-Wittig process by DFT calculations at the M06-2X/6-31G(d) level of theory suggest that for the cis-phosphazenes a rapid tandem [2+2] cycloaddition/cycloelimination process with low energy barriers is preferred over trans isomers.

Organophosphorus-catalyzed diaza-Wittig reaction: application to the synthesis of pyridazines.

The elaboration of the first organophosphorus-catalyzed diaza-Wittig reaction is reported. This catalytic reaction is applied to the synthesis of substituted pyridazine and phthalazine derivatives bearing electron-withdrawing groups with good to excellent yields from substrates containing a diazo functionality as the starting material and a phospholene oxide as the catalyst.

Synthesis of Pyridazines and Their Fused Derivatives from 1,3-Diketones

Synthesis of Pyridazines and Their Fused Derivatives from 1,3-Diketones

Strategy for the Synthesis of Pyridazine Heterocycles and Their Derivatives

The first synthesis of novel fused pyridazines has been realized starting from 1,3-diketones involving a Diaza-Wittig reaction as a key step. A convenient strategy was elaborated to access versatile pyridazine derivatives allowing the variation of substituents at position 6 of the heterocyclic ring. In a first part, pyridazines bearing an ester group were synthesized as a model to evaluate the methodology. In a second part, an improved procedure has been used for the synthesis of pyridazines bearing a ketone group and different methods of cyclization were carried out, leading to several hitherto unknown biheterocyclic compounds. This reaction scheme represents an attractive methodology for the synthesis of novel fused pyridazine derivatives.

ChemInform Abstract: Coarctate Cyclization Reactions: A Primer

AbstractReview: for the synthesis of pyridazines, pyrazoles, furans; 53 refs.

A short and convenient strategy for the synthesis of pyridazines via Diaza–Wittig reaction

A convenient and selective synthesis of 6-substituted-4-hydroxy-3-methoxycarbonyl pyridazines has been developed via a diaza-Wittig reaction. The desired products substituted at the C6 position can be obtained from readily available starting materials under mild conditions. This represents an attractive new method for the synthesis of pyridazine derivatives.

ChemInform Abstract: Multicomponent Synthesis of Pyridazine and Pyridazinoquinazoline Derivatives in the Presence of Catalysts such as Magnesium Oxide (MgO) and 12‐Tungstophosphoric Acid (PW).

AbstractA one‐pot three‐component procedure for the synthesis of the compounds (IV), (VI), and (VIII), which includes the use of an inexpensive and readily available catalyst, is presented.

NEW APPROACHES FOR THE SYNTHESIS OF HYDRAZONE DERIVATIVES AND THEIR ANTITUMOR EVALUATION

The hydrazide-hydrazone 3 reacted with benzenediazonium chloride to give the phenylhydrazone derivative 5. The latter underwent a series of hetero- cyclization reactions to give pyridazine, 1,2,3-triazole and pyrazole derivatives. The antitumor evaluation of the newly synthesized products against the three cancer cells lines namely breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268) showed that some of them have higher inhibitory effects towards the three cell lines compared to the standard. Key word: hydrazide-hydrazone, pyridazine, 1,2,3-triazole, pyrazole, anti-tumor. activities. These observations led us to synthesize novel hydrazide-hydrazones and to investigate their possible antitumor activities. It has been reported in the literature 17,18 that hydrazide-hydrazones can give the corresponding hydrazide and aldehyde metabolites whereas the related hydrazides are known to yield carboxylic acids via hydrolytic route. Based on this knowledge, hydrazide-hydrazones derivative 3 was prepared easily from the reaction of cyanoacetyl hydrazine with benzaldehyde and subsequently used for the synthesis of pyridazine, 1,2,3-triazole and pyrazole derivatives. The newly synthesized compounds were tested to evaluate their in vitro anti-tumor activities against three human tumor cell lines representing different tumor types, namely, breast adenocarcinoma (MCF-7), non-small cell lung cancer (NCI-H460) and CNS cancer (SF-268). It was found that some of these compounds showed inhibitory effects on the three cell lines, indicating their potential use in the development of anti-cancer agents. group of compound 15 using sodium nitrite solution in the presence of acetic/ hydrochloric acids resulted in the formation of intermediate pyrazole-3- diazonium salt 16. Coupling of the latter diazonium salt with malononitrile in ethanol containing sodium acetate afforded the hydrazo derivative 17. The analytical and spectral data of the obtained product were consistence with the proposed structure (Scheme 2).

Multicomponent synthesis of pyridazine and pyridazinoquinazoline derivatives in the presence of catalysts such as magnesium oxide (MgO) and 12‐tungstophosphoric acid (PW)

AbstractA series of 3‐amino‐2,5‐dihydropyridazines and fused pyridazinoquinazolines have been prepared in a one‐step procedure from three‐component reactions of (arylhydrazono)‐propan‐2‐ones, aldehydes and malononitrile or ethyl cyanoacetate in the presence of magnesium oxide (MgO) and 12‐tungstophosphoric acid (PW) as highly effective heterogeneous catalysts. The salient features of these methods include high conversions, short reaction times, cleaner reaction profiles, and the use of inexpensive and readily available catalysts. J. Heterocyclic Chem., 48, 1122 (2011).

Synthesis of pyridazine and thiazole analogs as SGLT2 inhibitors

With anticipation of the improvement in biological aspects in our SGLT2 program, novel pyridazinyl and thiazolyl analogs were designed and efficiently synthesized. The installation of the pyridazine ring at the anomeric carbon of d-glucopyranose was carried out in a stereoselective fashion. On the other hand, a series of thiazolyl analogs was also synthesized through a coupling reaction between perbenzyl gluconolactone 9 and 2-lithiothiazole. Biological activities of the compounds thus prepared were evaluated by the in vitro SGLT2 inhibition assay. Considering assay results, the novel benzylpyridazinyl and benzylthiazolyl analogs, disclosed in this article, could be a quick reference to prospective SGLT2 inhibitors useful for pharmacotherapy.

Chemistry of 2-Arylhydrazonals

Approaches for the preparation of 2-arylhydrazonals as well asthe chemical reactivity profiles and structures of these substancesare reviewed. Emphasis is given to the use of these substances inthe synthesis of five- and six-membered heterocycles. 1 Introduction 2 Synthetic Approaches to 2-Arylhydrazonals 2.1 Synthesis via Coupling of Enamines with Aromatic DiazoniumSalts 2.2 Coupling Reactions of Active Methylenes with Aromatic DiazoniumSalts 2.3 Synthesis of Arylhydrazonals via Condensation Reactions withPhenylhydrazine 2.4 Synthesis of Arylhydrazonals via Oxidation of Methyl and HydroxymethylArylhydrazones 3 Structural Investigations 4 Reactions of Arylhydrazonals 4.1 Reactions Involving the Aldehyde Group 4.1.1 Formation of Formazans 4.1.2 Condensation Reactions with Amines, Hydrazines and [nl]Hydroxylamine 4.1.3 Condensation Reactions with Active Methylene Compounds 4.2 Reactions Resulting in the Formation of Heterocycles 4.2.1 Formation of Hydrazononitriles and 1,2,3-Triazoles 4.2.2 Synthesis of Pyrazoles and Fused Pyrazoles 4.2.3 Synthesis of Pyridazines and Fused Pyridazines 4.2.4 Miscellaneous 5 Conclusion