Selenium dioxide oxidations of dialkyl-3H-azepines: the first synthesis of 2-azatropone from oxidation of 2, 5-Di-tert-butyl-3H-azepine

Oxidation reactions of 2,5- and 3,6-di-tert-butyl-3H-azepines (1 and 2) with selenium dioxide (SeO(2)) were performed. The oxidation of 1 with SeO(2) gave 3-tert-butyl-7,7-dimethyl-4-oxo-octa-2,5-dienal 3 in 36% yield, 4-tert-butyl-5-(3,3-dimethyl-2-oxo-butylidene)-1, 5-dihydro-pyrrol-2-one 4 in 13% yield, 2, 6-di-tert-butyl-2-pyridinecarbaldehyde 5 in 12% yield, and 4, 7-di-tert-butyl-2H-azepin-2-one (2-azatropone) 6 in 6% yield, respectively. Oxidation of 2 with SeO(2) gave 2, 2-dimethyl-1-[2-(5-tert-butyl)-pyridyl]propanol 7 in 55% yield, and 3,6-di-tert-butyl-2H-azepine 8 in 5% yield, respectively. We found that selenium dioxide oxidation of 1 affords 4-oxo-octa-2,5-dienal 3 by a new ring cleavage reaction of 1, and we described the first synthesis of 2-azatropone 6 from this oxidation of 1. In the case of 2, pyridylpropanol 7 was obtained as the major product. We now report in detail result of these oxidation reactions, which have led to the synthesis of a novel azatropone derivative.     

New synthesis of 3-methoxy-4-substituted pyrazole derivatives

A simple and efficient protocol for the synthesis of 3-methoxy-4-arylmethylene- and 3-methoxy-4-heteroarylmethylenepyrazoles has been developed. These derivatives are obtained in one step from alcohols 3 or 8a-b.     

Reaction of 3-methoxy-2-methylphenol with 2-ethoxyvinylphosphonic dichloride

Condensation of 2-ethoxyvinylphosphonic dichloride with 3-methoxy-2-methylphenol in dioxane in the presence of trifluoroacetic acid results in 5,13-dimethoxy-4,14-dimethyl-1-phospha-2,16-dioxatetracyclo[7.7.1.0^3,8.0^10,15]heptadeca-3,5,7,10,12,14-hexaene 1-oxide and 2-hydroxy-7-methoxy-8-methyl-2-oxobenzo[e]-1,2-oxophosphorine.     

An efficient synthesis of 5-bromo-2-methoxy-6-methylaminopyridine-3carboxylic acid

An efficient synthesis of 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxylic acid (1), a carboxylic acid moiety of a potent dopamine D2 and D3 and serotonin-3 (5-HT3) receptors antagonist, (R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1 ,4-diazepin-6-yl)-2-methoxy-6-methylaminopyridine-3-carboxamide, is described. Reaction of methyl 2,6-difluoropyridine-3-carboxylate (12) with methylamine in EtOH at -25 degrees C gave a mixture of methyl 2-fluoro-6-methylaminopyridine-3-carboxylate (13) and the regioisomer 14 in a ratio of 57 : 43. On the other hand, reaction of 12 and methyl 2,6-dichloropyridine-3-carboxylate (16) with sodium methoxide in tetrahydrofuran (THF) and CH2Cl2 provided the 2-methoxypyridine-3-carboxylic esters 20 and 23, respectively, as main products. Similar reaction of 16 in N,N-dimethylformamide (DMF) and MeOH proved to be highly regioselective for the 6-position. A much greater regioselectivity for substitution at the 6-position (>97%) was observed when 16 was treated with 4-methylbenzenethiolate anion in DMF (quantitative yield). After methoxylation of methyl 2-chloro-6-(4-methylbenzenethio)pyridine-3-carboxylate (25b) and successive oxidation of the 6-benzenethio moiety, nucleophilic substitution of the sulfoxide derivative 28 with methylamine gave the 6-methylamino derivative 8. Finally, bromination of 8 and alkaline hydrolysis produced the desired product 1 in an overall yield of 67%.     

An efficient synthesis of 3-substituted 3H-pyrimidin-4-ones

[reaction: see text] A novel and practical synthesis of 3-substituted 3H-pyrimidin-4-ones is described. The key step involves the cyclization of enamide esters, derived from readily available beta-keto esters, with trimethylaluminum and various primary amines.     

An efficient synthesis of 2-aryl-3-methoxy-2-cycloalkenones via Suzuki-Miyaura reaction under microwave irradiation

The Suzuki-Miyaura coupling reaction of α-bromocycloalkenones with arylboronic acids has been developed by using microwave heating. This method provides a simple and rapid construction of small molecule libraries of α-arylcycloalkenones with high efficiency.     

Stereocontrolled,straightforward synthesis of 3-substituted methyl 7α-methoxy-1-oxacephems

Stereocontrolled and industrially feasible synthesis of a new antibiotic $\text{1a}$ and related derivatives, which is characterized by using all the carbon atoms of the penicillin skeleton, is described.     

Reaction of 2-acetyl-3-methoxy-5-methyldiazaphospholine with p-toluenesulfonyl azide

Conclusions Tosyl azide reacts with 2-acetyl-3-methoxy-5-methyldiazaphospholine to give an iminodiazaphospholine that is stable as a solid, while in solutions, depending on the nature of the solvent and the temperature, it changes to the tautomer with an NH bond and the dimer. The equilibrium interconversion of these three forms was shown on the basis of the IR and³¹P NMR spectra.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 11, pp. 2635–2638, November, 1981.     

An efficient, general synthesis of racemic 2-substituted ferrocenecarboxaldehydes

A straightforward, high-yielding route to racemic 2-substituted ferrocenecarboxaldehydes has been developed. The synthesis involves the ortho-lithiation/electrophilic quenching of readily accessible 2-ferrocenyl-4,4-dimethyloxazoline (2c), followed by N-methylation, sodium borohydride-mediated reduction, and acidic hydrolysis.     

Heterocumulenes reactions with organometallic reagents: XV. Quantum-chemical investigatiom of skeleton rearrangements of 2-methyl-6-methoxy-3H-azepine originating from valence tautomerism

In the framework of quantum-chemical simulation (DFT) the structure was explored of six potentially probable tautomeric forms of 2-methyl-6-methoxy-3H-azepine and their relative thermodynamic stability was evaluated. In the tautomers obtained the preferred gradient channels are localized of [1,n]-H shifts capable of initiating their tautomerism. The most probable typical concerted reactions were analyzed of the formation of valence isomers, fused three-/six- and four-/five-membered carbo- and heterocycles, azabicyclo[4.1.0]hepta-2,4-dienes (azanorcaradienes) and azabicyclo[3.2.0]hepta-3,6-dienes respectively.     

Regioselective synthesis of 2-substituted 3-diarylmethylenylpiperidines

A simple three-step synthetic routes toward 2-substituted 3-diarylmethylenylpiperidines 7 (Y = CN) and 8 (Y = allyl) starting with 3-diarylmethylenylpiperidines 9 is described. The process was carried out by the bromomethoxylation of skeleton 9 with NBS in MeOH at reflux for 2 h, regioselective α-dehydrobromination with DBU in THF at reflux for 10 h, and BF₃·OEt₂-catalyzed cross-coupling of the corresponding enamine with trimethylsilyl-based nucleophiles (TMS-Y) in DCM at rt for 2 h. α-Amino ester 18 and β-amino acid 19 are also synthesized via the simple three-step synthetic protocol.     

An efficient one-pot four-step domino reaction for the synthesis of C2-substituted 3-methylcyclohex-2-enones

An efficient one-pot four-step domino reaction of substituted β-ketoesters has been optimized giving rise to a large panel of C2-substituted 3-methylcyclohex-2-enones, an important scaffold for the preparation of various initiators for cationic or radical cyclizations. The developed methodology is quite general and applicable to a wide range of β-ketoester substrates, allowing the introduction of various functionalities at the C2 position of the 3-methylcyclohex-2-enones, in good to excellent yields.     

Hydroacylation of 2-vinyl benzaldehyde systems: an efficient method for the synthesis of chiral 3-substituted indanones

Asymmetric rhodium-catalyzed hydroacylation has been utilized in the synthesis of 3-substituted indanones with high conversions and enantioselectivity. The hydroacylation reaction of 2-vinyl benzaldehyde had been previously reported to give a low yield of indanone and an unidentified product. We have identified this compound as a dimer of the starting material. Substitution at the alpha-position of the 2-vinyl benzaldehyde substrates blocks the competitive dimerization reaction and allows the reaction to proceed with yields generally greater than 90%. Utilization of BINAP as a chiral ligand results in good chemical yields and enantioselectivity greater than 95% in most cases.     

Enantioselective synthesis of 11-substituted 2- or 3-methoxy-17-vinylgona-1,3,5(10)-trien-13-ols

The acylation of the (±)-spiro-γ-lactone 1 lithium enolate (3 equiv) by the O-TBDMS methyl (−)-(S)-lactate, the O-TBDMS methyl (+)-(S)-mandelate, or the diacetone-d-glucose carbonate (1 equiv each) occurs with a kinetic resolution. The (S,S)-enolate is the most reactive with the lactate and it is the (R,R)-enolate, which selectively reacts with the mandelate or the DAG carbonate. After alkylation of the resulting acyl lactones with 4- or 5-methoxy-1-iodobenzocyclobutene and heating, title compounds were obtained and, after deprotection, the structures of the optically pure new steroids were ascertained by single crystal X-ray analysis.     

A novel and efficient synthesis of 2,5-substituted 1,2,4-triazol-3-ones

A novel procedure for preparing 1,2,4-triazol-3-ones is described. Various alkyl, aryl, and heterocyclic groups were introduced successfully at both the N2 and C5 positions. The triazolone ring was constructed through an intramolecular cyclization of a novel acyclic precursor, which in turn was synthesized by treating a mono protected hydrazine with an acyl isocyanate. Under conditions that remove the hydrazine protecting group, the intramolecular cyclization occurs rapidly, to deliver the 2,5-substituted 1,2,4-triazol-3-ones in excellent yields (79-99%) without column purification.     

Reaction of ethyl γ-bromo-β-methoxycrotonate with carbonyl compounds. Synthesis of 4-methoxy-6-substituted-5,6-dihydro-2H-pyran-2-ones and 3-substituted 3-pyrazolin-5-ones

Ethyl β-methoxycrotonate I reacts with substituted carbonyl compounds II in benzene to give 4-methoxy-6-substituted-5,6-dihydro-2H-pyran-2-ones III. The reaction of IIIa and j with hydrazine hydrate in ethanol leads to 3-[(1′-thienyl-1-hydroxy)methyl]-5-hydroxy-1H-pyrazole (IVa) and 3-[1′-styryl-1′-hydroxy)methyl]-5-hydroxy-1H-pyrazole (IVj) in good yields. The structure of the products were assigned and confirmed on the basis of their elemental analysis and the electronic absorption, infrared and nmr spectra.     

A simple and efficient synthesis of 3-substituted derivatives of pentane-2,4-dione

A novel and efficient method of synthesis of 3-substituted derivatives of pentane-2,4-dione is proposed, wherein cheaper and easily accessible chloro derivatives are conversed into more reactive iodo derivatives. The method is based on the Finkelstein reaction for which the literature suggests highly polar organic solvents as ideal reaction media. In the presented work, the use of industrially used ketones, especially methyl isobutyl ketone, is proposed. The use of MIBK as a solvent additionally allows an azeotropic removal of water from the reaction mixture, enabling the application of moisture sensitive alkylating agents i.e. (3-chloropropyl)trimethoxysilane. The obtained products are isolated through distillation, which does however not allow the separation of C-alkylation products from O-alkylation ones. The products not containing water-sensitive substituents were isolated as copper complexes. The pure product of C-alkylation was obtained by decomposition of the copper complex with a hydrochloric acid solution and extraction of the formed ligand to an organic phase i.e. hexane. The obtained ligand can be further purified by distillation. Presented at the 35th International Conference of the Slovak Society of Chemical Engineering, Tatranské Matliare, 26–30 May 2008.