Functionalization of bicyclic 2-pyridones targeting pilus biogenesis in uropathogenic Escherichia coli

Substituted bicyclic 2-pyridones, termed pilicides, prevent pilus assembly in uropathogenic Escherichia coli. Based on the bioactive methyl ester protected 2-pyridone 4, further functionalization at C-6 has yielded a set of new compounds, which have been evaluated for their ability to inhibit pilus formation in uropathogenic E. coli. The key intermediate in the synthesis was formylated 2-pyridone 5, which could be obtained via a Vilsmeier reaction. This versatile intermediate was converted into secondary and tertiary amines via reductive amination and could also be converted to other interesting functionalities using simple chemical transformations.     

The participation of alkynylboronates in inverse electron demand [4 + 2] cycloadditions: a mechanistic study

The participation of alkynylboronates in [4 + 2] cycloadditions has been investigated using both kinetic and DFT studies. Kinetic studies of the cycloaddition of tetrazine 1 with alkynylboronate 2 strongly suggest that a concerted cycloaddition mechanism is in operation. This mechanism has been confirmed by DFT calculations; moreover, a highly synchronous transition state appears to operate in this process. The experimentally observed poor reactivity of electron-rich dienes with alkynylboronates has also been confirmed by theoretical studies by analyzing the transition states of the cycloadditions with bis-2,5-trimethylsilyloxyfuran. The surprising conclusion has been made that alkynylboronates are relatively electron rich and have a cycloaddition reactivity that resembles that of acetylene. In contrast, the related dichloroalkynylborane cycloaddition reactivity resembles that of dimethylacetylene dicarboxylate.     

Hydrogen bond energies of 2-aminopyridine dimer and 2-aminopyridine-2-pyridone complex formation

The formation energies of 2-aminopyridine dimer and 2-aminopyridine-2-pyridone complex were measured in C₆D₆ solution by ¹H-NMR spectroscopy and values of 25.1 and 44.6 kJ/mol were obtained. The former value is about twice the magnitude of hydrogen bond energies which are generally observed for the N---HN system, and latter value is about half the sum of the formation energies of the 2-aminopyridine and 2-pyridone dimers. The formation energies of 2-aminopyridine dimer and 2-aminopyridine-2-pyridone complex were calculated by the CNDO/2 method, and their formation energies (−ΔH) were estimated to be 28.5 and 42.8 kJ/mol, respectively.     

Biosynthetic studies on the antibiotics PF1140: a novel pathway for a 2-pyridone framework

Incorporation of labeled acetate and l-serine into PF1140 in Eupenicillium sp. indicated that the skeleton of PF1140 is derived from five acetates and a l-serine. Upon administration of [1,3-¹³C₂]glycerol, a precursor of biotransformation into l-[1,3-¹³C₂]serine, the isotopic labels became contiguous in the resultant 2-pyridone of PF1140. Based on the feeding experiments, a novel and potentially general biosynthetic pathway for a 2-pyridone framework has been proposed, in which an acyl tetramic acid precursor could be converted via a ring expansion with loss of the hydroxyl group.     

One-pot sequential four-component coupling via Cp*RuCl-catalyzed cyclotrimerization and Suzuki-Miyaura coupling

The catalytic intermolecular cyclotrimerization of alkynylboronates, propargyl alcohols, and terminal alkynes was accomplished by means of the ruthenium catalysis and the temporary tethering approach with the C-B-O linkage to give rise to highly substituted arylboronates with excellent selectivity. The resultant arylboronates were further converted to highly substituted biaryls via the Suzuki-Miyaura coupling with various aryl iodides using Pd₂(dba)₃/PCy₃ as a catalyst precursor in aqueous toluene. As a consequence, the four-component coupling approach to highly substituted biaryls was successfully established by combining these two operations into a sequential one-pot process.     

An efficient one-pot synthesis of 1,4-disubstituted 3-amino-2-pyridone derivatives via three-component reactions of alkynyl aldehydes and amines with ethyl 2-((diphenylmethylene)amino)acetate

A facile and efficient one-pot synthesis of 1,4-disubstituted 3-amino-2-pyridone derivatives via three-component reactions of readily available alkynyl aldehydes, amines, and ethyl 2-((diphenylmethylene)amino)acetate has been developed. The alkynyl aldehyde substrates and the amine partners can be flexibly varied to achieve a range of 3-amino-2-pyridone derivatives, which could exert interesting chemical and biological properties. The reaction mechanism for the formation of 3-amino-2-pyridone derivatives is briefly explained.     

A novel approach to functionalised pyridazinone arrays

A series of 3,6-dichloro-1H-pyridazin-4-ones have been prepared via the cycloaddition of 3,6-dichlorotetrazine with alkynylboronates, and their employment as useful synthetic intermediates was highlighted through a selection of highly regioselective C-O, C-S and C-C bond forming reactions.     

Alkenyl derivatives of 5-nitro-2-pyridone: Synthesis and halocyclization

Alkylation of 5-nitro-2-pyridone by alkenyl halides in acetone in the presence of K₂СО₃ proceeds with generation of a mixture of N- and О-derivatives with N-isomer prevailing. 1-Allyl- and 1-methylallyl-5-nitro-2-pyridone react with halogens with the formation of 2-halomethyl-6-nitro-2,3-dihydrooxazolo[3,2-a]-pyridinium halides. 1-Prenyl-5-nitro-2-pyridone reacts with bromine with the formation of 3-bromine-2,2-dimethyl-7-nitro-3,4-dihydro-2Н-pyrido[2,1-b][1,3]oxazinium bromide, and with iodine giving 2,2-dimethyl-7-nitro-3,4-dihydro-2Н-pyrido[2,1-b][1,3]oxazinium triiodide.     

Microwave-assisted synthesis of highly substituted aminomethylated 2-pyridones

By employing microwave-assisted organic synthesis (MAOS) efficient conditions to introduce aminomethylene substituents in highly substituted bicyclic 2-pyridones have been established. Primary amino methylene substituents were introduced via a cyanodehalogenation followed by a borane dimethyl sulfide reduction of the afforded nitrile. In both of these transformations, microwave irradiation proved to be superior to traditional conditions and the primary amines were obtained in good overall yields (55-58% over three steps). To incorporate tertiary aminomethylene substituents in the 2-pyridone framework, a microwave-assisted Mannich reaction using preformed iminium salts proved to be effective. Thus highly substituted 2-pyridones were obtained in 48-93% yields.     

Ab initio method study on the isomerization of 3-amino-2-pyridone

Ab initio caculations with RHF/6-31G and MP2/6-31G have been used to study the isomerization of 3-amino-2-pyridone in gas-phase and in water. The results obtained show that 3-amino-2-pyridone is isomerized into 3-amino-2-hydroxy pyridine via a four-center cyclic transition state in the gas-phase, and via a six-center cyclic transition state in water. The activation energies of this reaction are 226.3336(RHF/6-31G) and 171.2269(MP2/6-31G) in gas-phase, and 81.6398(RHF/6-31G) and 59.8668(MP2/6-31G) kJ mol⁻¹ under the condition of a single water molecule as the catalyst, respectively.     

An alkynylboronic ester cycloaddition route to functionalised aromatic boronic esters

A series of functionalised aromatic boronic esters have been prepared via the regioselective cycloaddition of 2-pyrones with alkynylboronates.     

Features of reaction of aromatic nitro-substituted aldehydes with ketones on the matrix of 2(1<Emphasis Type="Italic">H</Emphasis>)-pyridone

Condensation of nitrobenzaldehydes with 3-acetyl-4,6-dimethyl-2(1H)-pyridone gives rise to chalcones with high yield. Condensation of the close analogs of 3-acetyl-4,6-dimethyl-2(1H)-pyridone containing ethyl and benzyl radical was established to give stable products of aldol condensation, the corresponding alcohols, under the same conditions.     

Diverse functionalization of thiazolo ring-fused 2-pyridones

Thiazolo ring-fused 2-pyridones have proven to be highly interesting scaffolds for the development of biologically active compounds. Many methods are today available to introduce a variety of substituents in the 2-pyridone part of the heterocycle. Herein we disclose how a diverse set of substituents can be introduced in the thiazolo ring, with possibilities to vary also the spatial arrangement of the substituents. A key intermediate is the oxidized framework 9 for which an effective synthesis is described. The thiazolo part of this system can be substituted either via conjugate additions, resulting in trans selectivity, or via microwave-assisted Heck couplings that result in unsaturated aryl-substituted analogues. The scaffold can also be lithiated followed by the addition of various electrophiles, which increases the diversification potential substantially, as exemplified with the introduction of halogens, alkyl, acyl, and amide substituents.     

Assignment of the vibrational spectra of 2(1H)-pyridinone (2-pyridone) in the solid state,and in solution as centrosymmetrical dimer. Comparison with 1-methyl-2(1H)-pyridinone (N-methyl-2-pyridone)

The complete assignment of the vibrational spectra of 2(1H)-pyridinone (2-pyridone), 1-D-2(1H)-pyridinone (2-pyridone ND) and 1-methyl-2(1H)-pyridinone (N-methyl-2-pyridone) is obtained from a comparative analysis of their IR and Raman spectra (condensed phase and molar solutions in CHCl₃ or CDCl₃). For the 2-pyridone centrosymmetrical dimer, the strength of the NH…O hydrogen bond association is discussed. Comparison is made with the recent work of Medhi and of Nowak et al.     

Ru(II)-catalyzed chemo- and regioselective cyclotrimerization of three unsymmetrical alkynes through boron temporary tether. One-pot four-component coupling via cyclotrimerization/Suzuki-Miyaura coupling

The Ru(II)-catalyzed [2+2+2] cyclotrimerization of alkynylboronates, propargyl alcohol, and terminal alkynes proceeded chemo- and regioselectively to give rise to arylboronates, which were subjected to Suzuki-Miyaura cross-coupling with aryliodides to afford highly substituted biaryls in 53-76% yields.     

A practical procedure for the selective N-alkylation of 4-alkoxy-2-pyridones and its use in a sulfone-mediated synthesis of N-methyl-4-methoxy-2-pyridone

It has been found that selective N-alkylation of 4-alkoxy-2-pyridones can be achieved under anhydrous, mild conditions with tetrabutylammonium iodide and potassium tert-butoxide being employed as the catalyst and the base, respectively. The procedure was applied to the preparation of 4-methoxy-1-methyl-2-pyridone, a valuable building block for heterocycle synthesis.     

Rapid microwave-assisted solution phase synthesis of substituted 2-pyridone libraries

2-Pyridone and 2-quinolone analogues are well-known biologically active heterocyclic scaffolds. Libraries of 3,5,6-substituted 2-pyridone derivatives are generated by rapid microwave assisted solution phase methods using a one-pot, two-step protocol. The three-component condensation of CH-acidic carbonyl compounds, N,N-dimethylformamide dimethylacetal and methylene active nitriles, leads to 2-pyridones and fused analogues in moderate to good overall yields and high purities. The proposed mechanism of this novel multi-component reaction, structure elucidation of products and intermediates are discussed.     

Structure and chemistry of 4-hydroxy-6-methyl-2-pyridone

The structure of 4-hydroxy-6-methyl-2-pyridone formed by the reaction of 6-methyl-2H-pyran-2,4(3H)-dione and ammonia is characterized. A method is discussed for the structure determination of pyridone type compounds. Reaction of 4-hydroxy-6-methyl-2-pyridone with an equivalent amount of benzenesulfonyl chloride gives 4-benzenesulfonyloxy-6-methyl-2-pyridone. With two equivalent amounts of benzenesulfonyl chloride, 2,4-dibenzenesulfonyloxy-6-picoline is formed. 4-Hydroxy-6-methyl-2-pyridone is preferentially attacked by electrophiles at the 3 position.     

A facile synthesis of 5,6-dihydro-5-hydroxy-2(1H)-pyridone

A short synthesis of 5,6-dihydro-5-hydroxy-2(1H)-pyridone was achieved from l-serine employing Horner-Emmons olefination as the key step.     

Asymmetric synthesis of 2-alkyl- and 2-aryl-3-aminopropionic acids (beta2-amino acids) from (S)-N-acryloyl-5,5-dimethyloxazolidin-2-one SuperQuat derivatives

Conjugate addition of lithium amides to (S)-N-acryloyl- or (S)-N-2'-alkylacryloyloxazolidinones and alkylation or protonation of the resulting enolates with 2-pyridone respectively provides a highly stereoselective and product complementary route to a range of (R)- and (S)-2-alkyl-3-aminopropionic acids in good yield and in high ee.