A simple and general one-pot synthesis of some 2h-pyran-2-ones and fused pyran-2-ones

Kepe, Vladimir; Kočevar, Marijan; Polanc, S.; Vercek, B.; Tišler, M.

doi:10.1016/s0040-4020(01)89774-x

Cited by 42 publications

(7 citation statements)

References 9 publications

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“…The first step ( Scheme 2 ) [ 46 , 47 , 48 , 49 ] of the synthetic route is thus a neat reaction of a suitable carbonyl compound 1a – e possessing an activated α-CH 2 unit with an appropriate C 1 synthon (DMFDMA ( 2a , R 1 = H) in all cases, except for 5b , where the incorporation of 4-methyl group in the 2 H -pyran-2-one product requires the use of a different C 1 synthon, i.e., DMADMA ( 2b , R 1 = Me)), thus forming N , N -dimethylaminomethylenes 3a – f . Thereafter, excess of 2 and methanol (formed as the side product) are removed with vacuum distillation and to the viscous remainder, containing intermediates 3a – f , hippuric acid ( 4 ) and acetanhydride are added.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis and Evaluation of Fused Bicyclo[2.2.2]octene as a Potential Core Scaffold for the Non-Covalent Inhibitors of SARS-CoV-2 3CLpro Main Protease

et al. 2022

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The emergence of SARS-CoV-2, responsible for the global COVID-19 pandemic, requires the rapid development of novel antiviral drugs that would contribute to an effective treatment alongside vaccines. Drug repurposing and development of new molecules targeting numerous viral targets have already led to promising drug candidates. To this end, versatile molecular scaffolds with high functionalization capabilities play a key role. Starting with the clinically used conformationally flexible HIV-1 protease inhibitors that inhibit replication of SARS-CoV-2 and bind major protease 3CLpro, we designed and synthesized a series of rigid bicyclo[2.2.2]octenes fused to N-substituted succinimides to test whether this core scaffold could support the development of non-covalent 3CLpro inhibitors. Inhibition assays confirmed that some compounds can inhibit the SARS-CoV-2 main protease; the most promising compound 11a inhibited 3CLpro in micromolar range (IC50 = 102.2 μM). Molecular simulations of the target-ligand complex in conjunction with dynophore analyses and endpoint free energy calculations provide additional insight and first recommendations for future optimization. The fused bicyclo[2.2.2]octenes can be used as a new potential starting point in the development of non-covalent SARS-CoV-2 3CLpro protease inhibitors and the study also substantiates the potential of this versatile scaffold for the development of biologically active molecules.

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Section: Resultsmentioning

confidence: 99%

Design, Synthesis and Evaluation of Fused Bicyclo[2.2.2]octene as a Potential Core Scaffold for the Non-Covalent Inhibitors of SARS-CoV-2 3CLpro Main Protease

et al. 2022

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“…Elemental analyses (C, H, N) were conducted using a Perkin–Elmer (Waltham, MA, USA) 2400 series II CHNS/O analyzer. The starting compounds 1a , 1b , 1c , 1d , 1e , 1f , 1g , 1h were prepared according to the published procedures: the synthesis of 1a , 1b , 1c starts from appropriate compounds containing activated CH 2 groups (i.e., 4‐methoxyphenylacetone, 3,4‐dimethoxyphenylacetone or ethyl acetoacetate), C 1 ‐synthon (DMFDMA) and hippuric acid as described previously . Starting 1d , 1e , 1f , 1g , 1h are obtained from the parent 3‐benzoylamino compounds (prepared as described earlier), followed by the removal of the benzoyl group and re‐protecting the amine functionality with another aroyl group, as described .…”

Section: Methodsmentioning

confidence: 99%

Chloranil as an Efficient Oxidant of the Cyclohexadiene Intermediates Formed by a Cycloaddition of Substituted 2H‐Pyran‐2‐ones and Styrenes En Route to the Boscalid Derivatives

Suljagić

Juranovič

Krivec

et al. 2016

Journal of Heterocyclic Chem

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We describe a three‐step one‐pot metal‐free domino procedure yielding a set of boscalid derivatives, parent compound being a highly important agrochemical agent. The first step of the process consists of the Diels–Alder reaction between a substituted 2H‐pyran‐2‐one and styrene derivatives, followed by the elimination of CO2 and aromatization (oxidation). The last step was found to be efficiently promoted by the application of chloranil as the oxidant. Alternatively, activated carbon Darco KB could also act as the dehydrogenation catalyst necessitating a larger excess of the styrene to act as the hydrogen acceptor.

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“…The starting 2H-pyran-2-one 1 was prepared by the method devised by Kepe, Kočevar et al 18 as follows: from acetylacetone, N,N-dimethylformamide dimethyl acetal (DMFDMA) and hippuric acid by heating in acetic anhydride according to the published procedure 5-acetyl-3-benzoylamino-6-methyl-2H-pyran-2-one was obtained; followed by the removal of the benzoyl group (in concentrated H 2 SO 4 upon heating) analogously as previously described 19,20 and subsequent derivatization of the free 3-amino group with acetyl chloride the 2H-pyran-2-one 1 was obtained. 21 Dienophile 2 was prepared by a modification of the procedures published by Cava et al 22 All other reagents and solvents were used as received from commercial suppliers.…”

Section: Materials and Measurementsmentioning

confidence: 99%

“…acetylacetone), a C 1 -synthon such as N,N-dimethylformamide dimethyl acetal (DMFD-MA) and hippuric acid (2) as an N-acylglycine derivative as previously described by Kepe, Kočevar and co-workers. 18 The synthesis takes place under heating (approx. 65-70 °C) in acetic anhydride (or in a mixture with acetic acid) as the solvent yielding the substituted 3-benzoylamino-2H-pyran-2-one.…”

Section: Synthesismentioning

confidence: 99%

A 26-Membered Macrocycle Obtained by a Double Diels–Alder Cycloaddition Between Two 2H-Pyran-2-one Rings and Two 1,1'-(Hexane-1,6-diyl)bis (1H-pyrrole-2,5-dione)s

Turek

Kočevar

Kranjc

et al. 2017

ACSi

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With the application of a double dienophile 1,1'-(hexane-1,6-diyl)bis(1H-pyrrole-2,5-dione) for a [4+2] cycloaddition with a substituted 2H-pyran-2-one a novel 26-membered tetraaza heteromacrocyclic system 3 was prepared via a direct method under solvent-free conditions with microwave irradiation. The macrocycle prepared is composed of two units of the dienophile and two of the diene. The structure of the macrocycle was characterized on the basis of IR, 1 H and 13 C NMR and mass spectroscopy, as well as by the elemental analysis and melting point determination. With X-ray diffraction of a single crystal of the macrocycle we have determined that the two acetyl groups (attached to the bridging double bond of the bicyclo[2.2.2]octene fragments) are oriented towards each other (and also towards the inside of the cavity of the macrocycle), therefore, mostly filling it completely.

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A simple and general one-pot synthesis of some 2h-pyran-2-ones and fused pyran-2-ones

Cited by 42 publications

References 9 publications

Design, Synthesis and Evaluation of Fused Bicyclo[2.2.2]octene as a Potential Core Scaffold for the Non-Covalent Inhibitors of SARS-CoV-2 3CLpro Main Protease

Design, Synthesis and Evaluation of Fused Bicyclo[2.2.2]octene as a Potential Core Scaffold for the Non-Covalent Inhibitors of SARS-CoV-2 3CLpro Main Protease

Chloranil as an Efficient Oxidant of the Cyclohexadiene Intermediates Formed by a Cycloaddition of Substituted 2H‐Pyran‐2‐ones and Styrenes En Route to the Boscalid Derivatives

A 26-Membered Macrocycle Obtained by a Double Diels–Alder Cycloaddition Between Two 2H-Pyran-2-one Rings and Two 1,1'-(Hexane-1,6-diyl)bis (1H-pyrrole-2,5-dione)s

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