Reaction of dialkyl 2-aryl-4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxylates with aliphatic amines

Benzylamine, phenethylamine, and homoveratrylamine reacted with dialkyl 2-aryl-4-hydroxy-4-methyl-6-oxocyclohexane-1,3-dicarboxylates at the endocyclic carbonyl group with conservation of the enolic hydroxy group to give dialkyl 4-alkylamino-2-aryl-6-hydroxy-6-methylcyclohex-3-ene-1,3-dicarboxylates. The reaction of dimethyl 4-hydroxy-4-methyl-6-oxo-2-phenylcyclohexane-1,3-dicarboxylate with tryptamine was accompanied by dehydration with formation of dimethyl 4-[2-(1H-indol-3-yl)ethylamino]-6-methyl-2-phenylcyclohexa-3,5-diene-1,3-dicarboxylate, presumably due to basic properties of the indole nitrogen atom.     

Alkyl nitrate nitration of active methylene compounds. Nitration of 1-methyl4-piperidone, 1-methyl-2-pyrrolidinone and 1,3-dimethyl-2-pyrrolidinone

The reaction of 1-methyl-4-piperidone ( 1 ) with amyl nitrate in the potassium tert-butoxidetetrahydrofuran system gave dipotassium 5-methyl-2-oxo-1,3-piperidinedinitronate ( 4 ) in 78% yield. Similar treatment of 1-methyl-2-pyrrolidinone ( 2 ) afforded potassium 3-methyl-2-oxopyrrolidinenitronate ( 7 ) in 85% yield. In contrast, the nitration of 1,3-dimethyl-2-pyrrolidinone ( 3 ) led to opening of the lactam ring with the formation of amyl 2-aza-2-methyl-5-nitrohexanoate ( 10 ) in 40% yield. Acidification of disalt 4 did not cause ring opening but gave the dipolar ion of 1-methyl-3-nitro 4-hydroxy-5-aci-nitro-Δ³-tetrahydropyridinium (6).     

Crystal structure of diethyl-1-isobutyl-9-hydroxy-9-methyl-7-phenyl-1,4-diazaspiro[4,5] decane-6,8-dicarboxylate C25H38N2O5

The reaction of diethyl-4-hydroxy-4-methyl-2-phenyl-6-oxocyclohexane-1,3-dicarboxylate with Nisobutylethylenediamine is performed and the crystal structure of this reaction product (diethyl-1-isobutyl-9-hydroxy-9-methyl-7-phenyl-1,4-diazaspiro[4,5]decane-6,8-dicarboxylate) is determined by X-ray crystallography.     

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.     

Synthesis of 2H-pyrano[2,3-b]quinolines. Part II. Preparation and 1H-nmr investigations of 4-hydroxy-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]quinolines

Diastereoisomers of 4-hydroxy-2-methyl-3,4-dihydro-2H-pyrano[2,3-b]quinolines 8 and 9 were synthesized starting from the appropriate 2-chloroquinoline-3-carboxaldehydes 1. The relative configuration of the 1,3-diol intermediates 4 and 5 was determined on the basis of the ¹³C-nmr spectra of their acetonides. The relative stereochemistry of title compounds was confirmed by using homonuclear NOE and selective decoupling experiments, as well as by analysis of the coupling patterns observed in their ¹H-nmr spectra.     

Four component tandem Knoevenagel–Michael strategy for the assembly of arylaldehydes,N,N'-dimethylbarbituric acid, 4-hydroxy-6-methyl-2H-pyran-2-one and morpholine into unsymmetrical scaffold with three different heterocyclic rings

A new type of four component tandem Knoevenagel–Michael reaction has been found consisting in the assembly of benzaldehydes, N,N'-dimethylbarbituric acid, 4-hydroxy-6-methyl-2H-pyran-2-one and morpholine in alcohols, other organic solvents or water at room temperature without catalyst or any other additives, which results in the selective formation of unsymmetrical scaffold with three different heterocyclic rings in 63–98% yields. The crystal structure of morpholinium 5-[(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)(4-nitrophenyl)methyl]-1,3-dimethyl-2,6-dioxo-1,2,3,4-tetrahydropyrimidin-6-olate has been confirmed by X-ray diffraction.     

1,3-dipolar cycloadditions of arylnitrile oxides and 2-diazopropane with 5-hydroxy-3-methyl-1,5-dihydropyrrol-2-one derivatives

The reactions of arylnitrile oxides 2 and 2-diazopropane 5 with 5-hydroxy-3-methyl-1,5-dihydropyrrol-2-one derivatives 1 have been studied. 1,3-dipolar cycloaddition of arylnitrile oxides and 2-diazopropane with 5-hydroxy-3-methyl-1,5-dihydropyrrol-2-one derivatives is taking place regiospecifically. The asymmetric induction expected by the chiral centre of the 5-hydroxy-3-methyl-1,5-dihydropyrrol-2-one derivatives was very effective, diastereoisomers 3 and 4 were formed in an approximate 90:10 ratio. The stereoselectivity of the 1,3-dipolar cycloaddition of the 2-diazopropane with the 5-hydroxy-3-methyl-1,5-dihydropyrrol-2-one derivatives are investigated. The attack of the 1,3-dipole occurred from the less hindered face of the dipolarophile, giving the isomer 6.     

Baeyer–Villiger oxidation of <Emphasis Type="Italic">N</Emphasis> <Superscript>1</Superscript>,<Emphasis Type="Italic">N</Emphasis> <Superscript>3</Superscript>,2-triaryl-6-hydroxy-6-methyl-4-oxocyclohexane-1,3-dicarboxamides

Baeyer–Villiger oxidation of N¹,N³,2-triaryl-6-hydroxy-6-methyl-4-oxocyclohexane-1,3-dicarboxamides with 30% hydrogen peroxide in acetic acid afforded 2-(4-aryl-3-carbamoyl-2-methyl-5-oxooxolan-2-yl)acetic acids.     

Synthesis and structure of phosphorylated nitrocyclohexenes

Diene condensations of 2-nitro-and 2-bromo-2-nitroethenylphosphonates with 2,3-dimethyl-1,3-butadiene, as well as with 2,4-dihydro-and 3-methyl-2,4-dihydrothiophene 1,1-dioxides that generate 1,3-butadiene and isoprene under the reaction conditions were effected. (6-Nitrocyclohex-3-en-1-yl)phosphonates and their dehydrogenation and/or dehydrohalogenation products, namely nitrocyclohexadienyl-and nitrophenylphosphonates were prepared. The structure of the obtained compounds was proved by IR and ¹H and ³¹P NMR spectroscopy, and independent synthesis.     

Reaction of Methylmalonyl Dichloride with Unsaturated Carboxamides

Methylmalonyl dichloride reacts with (2E)-3-phenylacrylamides and (2E)-3-(2-furyl)acrylamide to give the corresponding E-isomeric 2-substituted 4-hydroxy-5-methyl-6H-1,3-oxazin-6-ones. The reaction of methylmalonyl dichloride with acrylamide afforded N-(3-chloropropionyl)-2-methylmalonamic acid. The structure of the products was confirmed by the ¹H and ¹³C NMR, IR, and UV spectra.     

Synthesis of 2H-indazole-4,7-dione derivatives from 3-phenylsydnone and p-toluquinone. The crystal and molecular structure of 6-bromo-5-methyl-2-phenyl-2H-indazole-4,7-dione

The 1,3-dipolar cycloaddition of 3-phenylsydnone with p-toluquinone afforded 5-methyl- and 6-methyl-2-phenyl-2H-indazole-4,7-diones 3a and 3b. No regioselectivity was observed in this cycloaddition yielding an equimolar amount of the regioisomers. Reactions of 3a and 3b with bromine gave the corresponding mono- 4a and 4b and dibromo derivatives 5a and 5b , respectively. The crystal structure of 6-bromo-5-methyl-2-phenyl-2H-indazole-4,7-dione ( 4a ) has been determined by the single crystal X-ray method. The crystals are monoclinic, space group PI with two molecules in a unit cell of dimensions a = 8.029(1), b = 14.309(1), c = 5.895(1)Å, β = 90.24(1)° and V = 621 ų. The structure has been solved by the direct method using 1827 reflections and refined by full-matrix least-squares calculations to R = 0.0739.     

X-ray structure and in silico molecular docking of a natural phaeosphaeride A derivative for targets associated with kinase cascades

The structure of the lead compound, a natural phaeospha- eride A derivative AV-6, (2S,3R,4R)-3-hydroxy-6-methoxy-3-methyl-7-methylene-2-pentyl-4-pyrrolidin-1-yl-3,4,6,7-tetrahydropyrano[2,3-c]pyrrol-5(2H)-one, was unambiguously determined by X-ray crystallography. When modeling in silico the interaction of AV-6 with targets in kinase cascades, high values of the binding energy (below –9 kcal mol^-1) for some protein targets were shown. Our results identified that MAPK11, MAPK12 and AKT1 could be targets of AV-6.     

Reactions of 2-alkylsulfanyl- and 2-alkoxy-4-hydroxy-6<Emphasis Type="Italic">H</Emphasis>-1,3-oxazin-6-ones with O-nucleophiles

Reactions of 2-alkylsulfanyl- and 2-alkoxy-4-hydroxy-6H-1,3-oxazin-6-ones with oxygen-centered nucleophiles were studied. 2-Alkoxy-4-hydroxy-6H-1,3-oxazin-6-ones reacted with water and alcohols to give the corresponding alkyl 3-amino-3-oxopropanoates as a result of opening of the oxazine ring at the C⁶-O bond, whereas their 2-alkylsulfanyl analogs turned out to be stable toward O-nucleophiles. The different reactivities of the title compounds were interpreted in terms of quantum-chemical calculations of their electronic structure.     

Novel type of rearrangement of the carane system into a 2-methyl-4-isopropylbicyclo[3.1.0]hexane skeleton

Conclusions X-ray structural analysis has established that one of the oxidation products of 3-carene by trivalent thallium acetate is 2-methyl-4-(1-hydroxy-1-methylethyl)bicyclo [3.1.0]-hexan-2-ol. Its formation depends primarily on rearrangement of the carane skeleton into a bicyclohexane skeleton via 1,3-trans-annular participation of the C⁶-C⁷ bond in the cyclopropane fragment.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 8, pp. 1777–1779, August, 1988.     

Natural product chemistry,part 137: Oxidation of acridone alkaloids: Synthesis of 5-methoxyacronycine

Summary Epoxidation of the acridone alkaloid acronycine (1) resulted in hydroxylation at the aromatic ring giving 5-hydroxyacronycine (3). The same reaction on 1,3-dimethoxy-10-methyl-9(10H)-acridinone (5) gave 1,3-dimethoxy-2-hydroxy-10-methyl-9(10H)-acridinone (6), 1,3-dimethoxy-2-hydroxy-4-peroxy-10-methyl-9(10H)-acridinone (8), and 1,3-dimethoxy-2,4-diperoxy-10-methyl-9(10H)-acridinone (9).

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Naturstoffchemie, 137. Mitt.: Oxidierung von Acridonalkaloiden: Synthese des 5-Methoxyacronycins (Kurze Mitt.)

Zusammenfassung Die Epoxidierung des Acridonalkaloids Acronycin führte zu einer Hydroxylierung des aromatischen Rings, wobei 5-Hydroxyacronycin (3) entstand. Die gleiche Reaktion mit 1,3-Dimethoxy-10-methyl-9(10H)acridinon (5) ergab 1,3-Dimethoxy-2-hydroxy-10-methyl-9(10H)acridinon (6), 1,3-Dimethoxy-2-hydroxy-4-peroxy-10-methyl-9(10H)acridinon (8) und 1,3-Dimethoxy-2,4-diperoxy-10-methyl-9(10H)acridinon (9).

     

Reactions of regioisomeric 3,3-dimethyl- and 2,2-dimethyl-6-trifluoromethyl-2,3-dihydro-4-pyrones with N-nucleophiles

Reactions of 2,2-dimethyl-6-trifluoromethyl-2,3-dihydro-4-pyrone with ethylenediamine, hydrazine, or hydroxylamine yield 5-methyl-7-trifluoromethyl-2,3-dihydro-1H-1,4-diazepine, 3(5)-(2-hydroxy-2-methylpropyl)-5(3)-trifluoromethylpyrazole, and 5-hydroxy-3-(2-hydroxy-2-methylpropyl)-5-triflouromethyl-Δ², respectively. The same compounds were obtained from 2-amino-1,1,1-trifluoro-6-hydroxy-6-methylhept-2(Z)-en-4-one and 2-hydroxy-6, 6-dimethyl-2-trifluoromethyltetrahydro-4-pyrone.     

PHOSPHONOMETHYLATION OF AMINOALKANOLS PREPARATION OF 4-(PHOSPHONOMETHYL)-2-HYDROXY-2-OXO-1,4,2-OXAZAPHOSPHORINANES1

Abstract

Treatment of aminoalkanols 1 with phosphorous acid and formaldehyde in presence of conc. hydrochloric acid gave mixtures of [(2-hydroxy alkyl)imino] dimethylene diphosphonic acids 3 and 4-(phosphonomethyl)-2-hydroxy-2-oxo-1,4,2-oxazaphosphorinanes 2 from which 2 were isolated as crystalline solids. Similar treatment of 2-amino-2-methyl-1,3-propanediol 8 gave a complex mixture from which dimethylene diphosphonic acid of 5-amino-5-methyl-1,3-dioxane 9 was isolated. 2-Aminoethanethiol, when subjected to phosphonomethylation. gave an unexpected novel quarternary nitrogen product 11. N-Alkylaminoalkanols 4 on phosphonomethylation gave 3:1 mixtures of [N-alkyl-N-(2-hydroxyalkyl)amino] methane phosphonic acid 6 and N-alkyl-2-hydroxy-2-oxo-1,4,2-oxazaphosphorinane 5. Treatment of the crude mixtures of 5 and 6 with aqueous sodium hydroxide gave disodium salts of [N-alkyl-N-(2-hydroxyalkyl)amino] methanephosphonic acid 7. The ratio of the cyclic to the open chain structures obtained as well as the formation of any unexpected novel products is dependent on the structure of the aminoalkanol that is phosphonomethylated. The ¹H, ¹³C and ³¹P spectra are reported for all new compounds.     

Synthesis of 4H-pyrazolo- and 4H-pyrrolophenothiazin-4-one derivatives

5-Methyl- and 6-methyl-2-phenyl-2H-indazole-4,7-diones were condensed with 2-aminobenzenethiol or 6-substituted-3-aminopyridine-2(1H)thiones 4 to produce a new type of 5-methyl-2-phenyl-4H-pyrazolophenothiazin-4-ones or 8-substituted-7-aza-5-methyl-2-phenyl-4H-pyrazolophenothiazin-4-one derivatives. From 6-bromo-2,5-dimethyl-1,3-diphenyl-2H-isoindole-4,7-dione and 4 8-substituted-7-aza-2,5-dimethyl-1,3-diphenyl-4H-pyrrolophenothiazin-4-one derivatives were also prepared.     

Zur Synthese der 4-Dialkylamino-5,6-dihydro-2(1H)-pyridinthione sowie entsprechender 4-Alkylamino- bzw. 4-Arylaminoverbindungen

The rearrangement of 1-alkyl- and 1-aryldihydro-6-methyl-2(1H)-pyrimidinethiones (1 a) or-ones (1 b) and of methylene compounds (2a, 2b) resp., to 4-alkylamino- and 4-arylaminodihydro-2(1H)-pyridinethiones (4 a) or-ones (4 b) takes place via the corresponding 3-alkylamino- and 3-aryl-amino-3-butenylisothiocyanates (3 a) or-isocyanates (3 b). Dialkylamino-dihydro-2(1H)-pyridinethiones (10) are formed by heating dihydro-6-methyl-2(1H)-pyrimidinethiones (6 a) and 3,4-dihydro-6-methyl-1,3-thiazin-2-thiones (6 b) with dialkylformamides and by the reaction of secondary amines with tetrahydro-6-hydroxy-6-methyl-1,3-thiazin-2-thiones (5 a), with N,N-dialkyl-N-(3-oxobutyl)-thioureas (7) and 3-oxobutyl isothiocyanates (8). A general method for the preparation of10 is the reaction of dialkylammoniumrhodanides12, N,N-dialkylthioureas13 and dialkylammonium chlorides and KCNS, resp., with 3-alken-2-ones14 and 4-hydroxy-2-alkanones15, resp. Methyl ketones such as acetone, which readily undergo the aldol condensation, behave analogously. The reactions described take place via the intermediate aminoalkenyl isothiocyanates (9).     

Poly-Diels-Alder Addition with a Bisoxazole as Bisdiene and a Bismaleinimide as Bisdienophile

Abstract

The poly-Diels-Alder addition between the new bisdiene 1,4-bis(5-methoxy-2-oxazolyl)benzene (4) and N,N′-hexamethylene-bis[2-(2,5-dihydro-2,5-dioxo-pyrrole-1-yl) acetamide] (7) is described. The structure of the resulting polyadduct 12 was proved by ¹H NMR spectroscopy with the aid of the low-molecular-weight model compounds 1,4-bis(1,3-dihydro-7-hydroxy-1,3-dioxo-2-phenyl-pyrrolo[3,4-c] pyridine-4-yl)benzene (9) and N,N'-hexamethylene-bis[2-(1, 3-dihydro-7-hydroxy-6-methyl-1,3-dioxo-4-phenyl-pyrrolo [3,4-c]pyridine-2-yl)acetamide] (11). The reaction proceeds via the aromatization of the primarily formed cycloadducts. Polyadduct 12 shows a number average degree of polymerization P_n of about 11 – 12 (M_n = 8500 ? 9200 g/mol), calculated from ¹H NMR endgroup signals.