The base-promoted dehydration of rac.-trans-tetrahydro-6-hydroxy-4-[(2-(dimethylamino)ethyl]-7-(4-methoxyphenyl)-1,4-thiazepin-5(2H)-one

The base-catalyzed alkylation of rac.-trans-tetrahydro-6-hydroxy-7-(4-methoxyphenyl)-1,4-thiazepin-5(2H)-one ( 1 ) with dimethylaminoethyl chloride in dimethyl sulfoxide provided predominantly rac.-trans-tetrahydro-6-hydroxy-4-[(2-dimethylamino)ethyl]-7-(4-methoxyphenyl)-1,4-thiazepin-5(2H)-one ( 2 ) and in addition, 2,3-dihydro-4-[2-(dimethylamino)-ethyl]-7-(4-methoxyphenyl)-1,4-thiazepin-5(4H)-one ( 3 ). A plausible mechanism is postulated for the dehydration of the rac.-trans-amide 2 .     

3-Hydrazino-1,2,4-triazin-5(2H)-ones in Reactions with Compounds Containing Carbonyl and Active Methylene Groups

Boiling of ethyl cyanoacetate with 6-tert-butyl-3-hydrazino-1'2'4-triazin-5(2H)-one in alkalinemedium yielded 6-tert-butyl-3-(5-hydroxy-3-oxo-2'3-dihydro-1H-pyrazol-1-yl)-1'2'4-triazin-5(2H)-one.Acylation of 6-tert-butyl-3-hydrazino-1'2'4-triazin-5(2H)-one with benzoyl chloride furnished 3-benzoyl-hydrazido-1'2'4-triazine that cyclized when treated with POCl₃ providing a derivative of[1'2'4]triazolo[4'3-b][1'2'4]triazine. Boiling of 6-tert-butyl-3-hydrazino-1'2'4-triazin-5(2H)-one in glacialacetic acid gave rise to diacetylated derivative whereas the boiling with acetic anhydride in an inert solventafforded monoacetylated product.     

2,3- and 3,4-Bis(diethoxyphosphorylmethyl)-5-tert-butylfurans

Reduction of 2-, 4-acetoxymethyl derivatives of 5-tert-butylfuran-3-carboxylic acid leads to the corresponding bis(hydroxymethyl)furans. Bis(chloromethyl)furans prepared from the latter were involvedin reaction with sodium diethyl phosphite. In the presence of two equivalents of a phosphorus-containing nucleophile, bis(phosphonomethyl)furans are formed. One equivalent of sodium diethyl phosphite reacts with 3,4-bis(chloromethyl)furan to give a mixture of 3-and 4-phosphorylated products in a 4.5:1 ratio in a low yield. The revealed difference in reactivity between the 3- and 4-chloromethyl groups demonstrates the importance of shielding of the chloromethyl group by the neighboring tert-butyl substituent. Examination of the ¹H NMR spectra of 3,4-bis(hydroxymethyl)-, 3,4-bis(chloromethyl)-, 3,4-bis(diethoxyphosphorylmethyl)-5-tert-butylfurans, and also specially prepared 5-tert-butyl-3-(diethoxyphosphorylmethyl)-4-(ethoxymethyl)-2-methylfuran established that the signal of the substituent neighboring to the tert-butyl group is always shifted downfield.     

ortho effect on the nitrosation of the 2,3-diphenyl-5(2-methoxyphenyl)pyrrole

A comparison of the behaviour on the nitrosation of the isomers 5-(2-methoxyphenyl)- ( 1a ) 5-(3-methoxyphenyl)- ( 1b ) and 5-(4-methoxyphenyl)2,3-diphenylpyrroles ( 1c ) carried out in the usual way with iso-amyl nitrite in a solution of sodium ethoxide in ethanol evidences that 1a is dramatically less reactive with respect to 1b and 1c . The different reactivity was ascribed to the occurrence of a strong hydrogen bond involving pyrrole N? H and the ortho-methoxy group.     

Acid-catalyzed disproportionation of N,N-bis(4-tert-butylphenyl)hydroxylamine. Synthesis and structure of 10-[5-tert-butyl-2-(4-tert-butylphenylamino)phenyl]-3,7-di-tert-butylphenoxazine

New method of synthesis was developed for N,N-bis(4-tert-butylphenyl)hydroxylamine by reduction of the corresponding aminoxyl with hydrazine hydrate. At the treatment with strong acids this hydroxylamine derivative is converted in bis(4-tert-butylphenyl)amine and 10-[5-tert-butyl-2-(4-tert-butylphenylamino) phenyl]-3,7-di-tert-butylphenoxazine. The structure of the latter was established by X-ray diffraction analysis. The mechanism was suggested of the acid-catalyzed disproportionation of N,N-bis(4-tert-butylphenyl) hydroxylamine.     

Synthesis of 5-substituted 2-(4- or 3-methoxyphenyl)-4(1H)-quinolones

5-Substituted 7-methoxy-2-(4- or 3-methoxyphenyl)-4(1H)-quinolones 8-17 have been synthesised in good yields from the corresponding 7-methoxy-2-(4- or 3-methoxyphenyl)-5-trifluoromethanesulfonate-4(1H)-quinolones 7 via palladium-mediated cross-coupling reactions or aromatic nucleophilic substitution (SN_Ar) reactions.     

Five-membered 2,3-dioxoheterocycles: LXXXIV. [4+2]-Cycloaddition of styrene to 4,5-diaroyl-1H-pyrrole-2,3-diones. Crystal and molecular structures of 7a-(2,5-dimethylbenzoyl)-4-(2,5-dimethylphenyl)-1-(4-methoxyphenyl)-6-phenyl-7,7a-dihydropyrano[4,3-b]-pyrrole-2,3(1H,6H)-dione

1-Aryl-4,5-diaroyl-1H-pyrrole-2,3-diones react with styrene to form substituted 7,7a-dihydropyrano[4,3-b] pyrrole-2,3(1H,6H)-diones whose structure was confirmed by XRD analysis. The crystal and molecular structure of 7a-(2,5-dimethylbenzoyl)-4-(2,5-dimethyl-phenyl)-1-(4-methoxyphenyl)-6-phenyl-7,7a-dihydropyrano[4,3-b] pyrrole-2,3(1H,6H)dione was examined.     

Synthesis of Halomethyl Derivatives of 3- and 4-(Dialkoxyphosphorylmethyl)-5-tert-butylfuran-2-carboxylic Acid and Their Reactions with Nucleophilic Agents

5-tert-Butyl-4-chloromethyl-, 5-tert-butyl-4-(diethoxyphosphorylmethyl)-3-methylfuran-2-carboxylates are effectively brominated with N-bromosuccinimide by the 3-methyl group. The bis(halomethyl)derivative is phosphorylated under conditions of the Arbuzov reaction to give the corresponding chloromethylphosphonate. The obtained organophosphorus derivatives of bromomethyl- and chloromethylfuran-2-carboxylic acid react with secondary amines and sodium butanethiolate to form the corresponding substitution products. Alkyl 5-tert-butyl-4-chloromethyl-3-(diethoxyphosphorylmethyl)-furan-2-carboxylate reacts with sodium acetate in acetic acid to give a 4-acetoxymethyl derivative. It is the first example of a facile reaction with O-nucleophiles of halomethyl derivatives of phosphonomethylated furans.     

Studies on quinazolinones. 2. Synthesis of 2-(4-benzylpiperazin-1-ylmethyl)-2,3-dihydro-5H-oxazolo[2,3–6]quinazolin-5-one and -2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one

To search for novel antihypertensive heterocycles in the condensed quinazoline series, two representative compounds were synthesized via a suitable reaction sequences. Treating anthranilonitrile with allyl isocyanate gave 2-(allylureido)benzonitrile ( 10 ) in a quantitative yield. Compound 10 was cyclized to 3-allylquinazoline-2(1H, 4(3H)-dione ( 11 ). Bromination of 11 in carbon tetrachloride converted it into the corresponding 3-(2,3-dibromopropyl) derivative ( 12 ) in 92% yield. Ring closure of 12 was effected by the action of alkali to afford 2-bromomethyl-2,3-dihydro-5H-oxazolo[2,3-b]quinazolin-5-one ( 13 ). The title compound, 2-(4-benzylpiperazin-1-ylmethyl)-2,3-dihydro-5H-oxazolo[2,3-b]quinazolin-5-one ( 7 ) could be obtained by a reaction of either 12 or 13 with 1-benzylpiperazine respectively. Starting from the readily available 3-allyl-2H-thioxoquinazolin-4(3H)-one ( 16 ) via the analogous reactions gave the 2-bromomethyl-2,3-dihydro-5H-thiazolo[2,3-b]-quinazolin-5-one ( 19 ) in good yield. However, the reaction of 19 with 1-benzylpiperazine provided another target compound, 2-(4-benzylpiperazin-1-ylmethyl)-2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one ( 8 ) only in poor yield (8%). As major product, the dehydrobrominated compound, 2-methylene-2,3-dihydro-5H-thiazolo[2,3-b]quinazolin-5-one ( 22 ) was isolated. A preliminary pharmacological evaluation revealed that both compounds 7 and 8 are devoid of the antihypertensive activity.     

Synthesis and properties of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-nitroindazole

N-(2-Azido-5-nitrobenzylidene)-3,5-di-tert-butyl-4-hydroxyaniline (3a) and N-(2-azido-5-nitrobenzilidene) aniline (3b), when heated in dimethylformamide yielded 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-nitroindazole (4a) and 2-phenyl-5-nitroindazole (4b), respectively. The structure of4b was confirmed by X-ray analysis. A stable phenoxyl radical was shown to originate from the oxidation of4a with lead (IV) dioxide.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1095–1097, June, 1994.     

Synthesis and Transformations of Ethyl (Z)-2-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)-3-(dimethylamino)propenoate

Ethyl (Z)-2-(2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)-3-(dimethylamino)propenoate was prepared in one step from ethyl (2,3-dihydro-1,3-dioxo-1H-isoindol-2-yl)acetate and bis(dimethylamino)-tert-butoxymethane and treated with various amines and hydrazines to afford the corresponding amino substituted products. Reactions of the titled compound with N,N'-, C,N-, and C,O'-ambident nucleophiles in refluxing acetic acid furnished the corresponding fused pyrimidinones, quinolizinones, and pyranones.     

Synthesis of (-)-(S)-3-sec-butyl- and (+)-(S)-5-sec-butyl-2(1H)-pyridinone

Optically active (+)-(S)-5-sec-butyl- and (-)-(S)-3-sec-butyl-2(1H)-pyridinone are synthesized and the relationship between optical activity and minimum optical purity of the latter is determined.     

Synthese und Struktur von Tetrachloro[4-tert-butyl-2(diphenylphosphanyl-κP-methyl)phenolato-κO]tantal(V), ein neuartiger TaV-Komplex mit einem chelatisierenden Aryloxyphosphanliganden

Synthesis and Structure of Tetrachloro[4- tert -butyl-2(diphenylphosphanyl-κP-methyl)phenolato-κO]tantalum(V), a Novel Ta^V Complex with a Chelating Aryloxy Phosphane Ligand 4-tert-Butyl-2-(diphenylphosphanylmethyl)anisol ( 1 ) is prepared from 2-chlormethyl-4-tert-butylanisol and potassium diphenylphosphide in very good yields as a novel oxygen-phosphorus compound with potentially hemilabile ligand properties. Compound 1 reacts with tantalum pentachloride under cleavage of methylchloride revealing the complex tetrachloro[4-tert-butyl-2-(diphenylphosphanyl-κP-methyl)phenolato-κO]tantalum(V) ( 2 ) with a distorted octahedrally coordinated tantalum atom and a chelating aryloxy phosphane ligand. Complex 2 crystallizes in the tetragonal, chiral space group P4₁2₁2 with a = 11.719(5), c = 37.95(5) Å, V = 5171(7) ų, Z = 8. ³¹P NMR spectroscopic studies of 2 establish the coordination of the phosphane unit to the Ta^V center in solution.     

Collagen cross-links: a convenient synthesis of tert-butyl-(2S)-2-[(tert-butoxycarbonyl)amino]-4-(2-oxiranyl)butanoate

An efficient synthesis of tert-butyl-(2S)-2-[(tert-butoxycarbonyl)amino]-4-(2-oxiranyl) butanoate (5), the key intermediate for preparation of collagen cross-links (+)-pyridinoline (Pyd, 1) and (+)-deoxypyridinoline (Dpd, 2) was described from (4S)-5-(tert-butoxy)-4-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid (6) in six steps. Also, an improved synthesis of iodide (2S)-(−)-4b was presented.     

Crystal structure and quantum chemical calculations of (E)1-benzyl-3-((4-methoxyphenyl)imino)-5-methylindolin-2-one

The known Schiff base compound, (E)1-benzyl-3-((4-methoxyphenyl)imino)-5-methylindolin-2-one, was prepared as before by reacting 1-benzyl-5-methylindoline-2,3-dione with 4-methoxyaniline. The product was unambiguously characterized using elemental analysis, ¹H and ¹³C-NMR spectroscopy, and its new single-crystal X-ray structural analysis. Molecular orbital calculations were conducted in order to investigate the structures and relative stabilities of the (E) and (Z) isomers of 1-benzyl-3-([4 methoxyphenyl]-imino)-5-methylindolin-2-one. Specific attention was paid to the (E) isomer. The available crystallographic experimental data for the latter ensured also validation of the model structures computationally derived at the theoretical B3LYP/6-31G(d,p) level.     

Computational reexamination of the eclipsed conformation in cis-2-tert-butyl-5-(tert-butylsulfonyl)-1,3-dioxane

The conformational free energy differences, ΔG° values, for the methyl sulfide, methyl sulfoxide, methyl sulfone, tert-butyl sulfide, tert-butyl sulfoxide, and tert-butyl sulfone groups at C(5) in the 1,3-dioxane ring have been calculated at two different levels, B3LYP/6-31G(d) and B3LYP/6-311++G(d,p). There is good agreement between experimental and calculated values, particularly in the case of data obtained at the lower level of theory, B3LYP/6-31G(d). In order to get information that could help understand the nature of the effects present in the molecules of interest, the charge distribution in representative compounds was analyzed by means of the natural bond orbital (NBO) analysis. NBO calculations indicate the existence of substantial negative charges at oxygen and significant positive charge at sulfur. This observation seems to support the argument the existence of electrostatic, attractive interactions between the endocyclic oxygens and the axial sulfonyl group. From the second order perturbation theory analysis of Fock matrix, two σ _C–C → σ*_S–O delocalizing interactions are observed in the methyl-inside conformer of cis-2-tert-butyl-5-(methylsulfonyl)-1,3-dioxane derivative cis-7. These results are in line with anti-periplanar σ _C–C → σ*_S–O hyperconjugative interactions that help stabilize the methyl-inside conformation of cis-7, as previously found by ¹H NMR analysis. By contrast, NBO analysis does not provide evidence for the existence of σ _C–C → σ*_S–O hyperconjugative interactions that might help stabilize the eclipsed tert-butyl—outside conformation previously found in the solid-state crystallographic structure of analog cis-1. Because of the threshold value of the NBO calculations, if present such syn-periplanar stereoelectronic interaction should be less than 0.5 kcal mol^?1. This observation suggests that an anti-periplanar orientation of the interacting orbitals is more effective relatively to the corresponding syn-periplanar orientation.     

Bone collagen cross-links: an efficient one-pot synthesis of (+)-pyridinoline and (+)-dexoypyridinoline

A one-pot reaction of (2S,5R)-(−)-tert-butyl-[(2-tert-butoxycarbonyl)amino]-5-hydroxy-6-aminohexanoate 2b or (S)-(−)-tert-butyl-[(2-tert-butoxycarbonyl)amino]-6-aminohexanoate 2c with (S)-(−)-tert-butyl-6-bromo-[bis-(2-tert-butoxycarbonyl)amino]-5-oxohexanoate 5 in the presence of K₂CO₃ in MeCN–MeOH followed by hydrolysis gave bone collagen cross-links, (+)-Pyd 1b or (+)-Dpd 1c, in 42–48% yield, respectively.     

Metal complexes of tetra(6-tert-butyl-2,3-quinolino)porphyrazine: I. Synthesis

Complexes of tetra(6-tert-butyl-2,3-quinolino)porphyrazine with Cu, Co, Zn, and Ni soluble in hydrophobic liquids were synthesized for the first time by template tetramerization of derivatives of 6-tert-butylquinoline-2,3-dicarboxylic acid formed from the corresponding acid in the course of carbamide synthesis in presence of the bivalent metal ions.     

Short Synthesis of 1-(3-tert-Butyl-1-phenyl-1H-pyrazol-5-yl)-3-(5-(2-morpholinoethoxy)-2H-chromen-8-yl) Urea Derivatives

A short and efficient synthesis of 1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(5-(2-morpholinoethoxy)-2H-chromen-8-yl) urea derivatives (1a–c), a novel type of p38 MAPK inhibitors, is described. The Claisen thermal rearrangement of arylpropargyl ethers was employd as a key step to synthesize the chromene core. The solvent effect on the ratio of the resultant two isomers of Claisen thermal rearrangement, namely 2-methylbenzofuran and 2H-chromen, was also investigated.     

Synthesis,Characterization, and Antiproliferative Activity of 2-(2-Bromo-5-methoxyphenyl)-6-aryl-1,3-thiazolo[3,2b][1,2,4]triazoles

Eight new 2-(2-bromo-5-methoxyphenyl)-6-aryl-1,3-thiazolo[3,2-b][1,2,4]triazoles were synthesized by treating 5-(2-bromo-5-methoxyphenyl)-4H-1,2,4-triazole-3-thiol with phenacyl bromides. The new products were characterized by spectroscopic and analytical methods. Five of the new compounds were evaluated for their antiproliferative activity. 2-(2-Bromo-5-methoxyphenyl)-6-(3,4-dihydroxyphenyl)-1,3-thiazolo[3,2-b] [1,2,4]triazole exhibited promising activity.

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