Palladium catalyzed reactions on chloropyridazines

Maes, Bert U. W.; Kosmrly, Janey; Lemier, Guy L. F.

doi:10.1002/jhet.5570390309

Cited by 25 publications

(4 citation statements)

References 56 publications

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“…If the nitrogen is not protected, the base necessary for the coupling reactions will ionize the N 2 position and result in an increase of the electron density at the halogen that will decrease the rate of palladium insertion [60,61]. With the protected halogenated precursor in hand, however, it is possible to couple the pyridazine scaffold with a variety of boronic acids, tin reagents, alkynes and alkenes, giving rise to extensive diversity at the R 4 /R 5 position using standard Suzuki, Sonogashira, Stille and Heck reactions [62][63][64][65][66][67]. These couplings result in the formation of carbon-carbon bonds and extend single, double and triple bonds from the R 4 or R 5 position to create a diverse set of compounds.…”

Section: Main Textmentioning

confidence: 98%

De Novo and Molecular Target-Independent Discovery of Orally Bioavailable Lead Compounds for Neurological Disorders

Wing¹,

Behanna²,

Eldik³

et al. 2006

CAR

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There is immediate potential to enhance success and innovation in drug development by pairing newly emerging approaches in medicinal chemistry and computational biology with knowledge gained from the recent era of high throughput screens and the early years of modern drug discovery when in vivo efficacy was an early "Go/No Go" project management decision. Focused, in-parallel synthetic chemistry platforms, combined with computational analyses serving as decision aids in planning, minimize the total number of compounds synthesized while maximizing the probability of creating bioavailable compounds that sample diverse chemical space. Incorporating a hierarchal strategy that emphasizes early selection of synthesized compounds based on biological or biophysical endpoints presents fewer and more relevant compounds for secondary evaluation of in vivo efficacy using animal screens with disease relevant or clinically translatable endpoints. We summarize here an interdisciplinary approach at the chemistry-biology interface that is used for the rapid discovery of novel lead compounds for neurodegenerative disorders, such as Alzheimer's disease (AD). The chemistry platform uses established chemistries amenable to in-parallel strategies to create synthetic diversifications of the privileged pyridazine chemotype that sample a restricted chemical space. The hierarchal biology platform uses primary screens for in vitro activity and selectivity with the target cell type, and rapid secondary screens for in vivo efficacy and toxicity in animal models with good phenotypic penetrance for disease relevant pathophysiological endpoints or clinically translatable surrogate endpoints. For the AD case study, novel lead compounds were developed in less than two years by a small academic group, and corporate sponsored clinical trials are planned.

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Section: Main Textmentioning

confidence: 98%

De Novo and Molecular Target-Independent Discovery of Orally Bioavailable Lead Compounds for Neurological Disorders

Wing¹,

Behanna²,

Eldik³

et al. 2006

CAR

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“…For the direct synthesis of selectively 5-aryl-substituted chloropyridazinones starting from the 4,5-dichloro pyridazinone 17 via Suzuki reaction, which under standard conditions solely furnished 4,5-diarylpyridazinones bearing the same aryl moiety, He and Gong performed a catalyst screening with a variety of commercially available palladium catalysts . Typical screening conditions were 2 equiv of 17 in combination with 5 mol % of Pd catalyst and 2 equiv of Na 2 CO 3 in a 1:1 mixture of acetonitrile/water at 120 °C for 10 min (Scheme a).…”

Section: 1 Suzuki Reactionsmentioning

confidence: 99%

Microwave-Assisted Synthesis in Water as Solvent

2007

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“…In general, two methods are reported which consist of: (i) Cyclisation reactions using 1,4-dicarbonilic precursors and hydrazine [26,27,28,29,30,31,32], in order to construct the pyridazine ring or (ii) by functionalization through nucleophilic substitution [33,34,35,36,37,38], ortho-metallation [39,40,41] and cross-couplings reactions (Suzuki, Stille, Sonogashira, etc.) [42,43,44,45,46,47,48,49,50] or a combination of cyclisation and cross-coupling reactions [51]. …”

Section: Introductionmentioning

confidence: 99%

Synthesis of Pyridazine Derivatives by Suzuki-Miyaura Cross-Coupling Reaction and Evaluation of Their Optical and Electronic Properties through Experimental and Theoretical Studies

et al. 2018

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A series of π-conjugated molecules, based on pyridazine and thiophene heterocycles 3a–e, were synthesized using commercially, or readily available, coupling components, through a palladium catalyzed Suzuki-Miyaura cross-coupling reaction. The electron-deficient pyridazine heterocycle was functionalized by a thiophene electron-rich heterocycle at position six, and different (hetero)aromatic moieties (phenyl, thienyl, furanyl) were functionalized with electron acceptor groups at position three. Density Functional Theory (DFT) calculations were carried out to obtain information on the conformation, electronic structure, electron distribution, dipolar moment, and molecular nonlinear response of the synthesized push-pull pyridazine derivatives. Hyper-Rayleigh scattering in 1,4-dioxane solutions, using a fundamental wavelength of 1064 nm, was used to evaluate their second-order nonlinear optical properties. The thienylpyridazine functionalized with the cyano-phenyl moiety exhibited the largest first hyperpolarizability (β = 175 × 10−30 esu, using the T convention) indicating its potential as a second harmonic generation (SHG) chromophore.

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Palladium catalyzed reactions on chloropyridazines

Cited by 25 publications

References 56 publications

De Novo and Molecular Target-Independent Discovery of Orally Bioavailable Lead Compounds for Neurological Disorders

De Novo and Molecular Target-Independent Discovery of Orally Bioavailable Lead Compounds for Neurological Disorders

Microwave-Assisted Synthesis in Water as Solvent

Synthesis of Pyridazine Derivatives by Suzuki-Miyaura Cross-Coupling Reaction and Evaluation of Their Optical and Electronic Properties through Experimental and Theoretical Studies

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