Ring Opening in 1- and 3-Methylpyrimidin-4-ones in the Presence of Bases

According to the data of UV and NMR spectroscopy, 1- and 3-methylpyrimidin-4-ones and their 5-fluoro-substituted analogs in water and DMSO in the presence of bases undergo ring opening with formation of -formylaminoacrylamide derivatives. The process involves attack by hydroxide ion on the C² atom, and its rate in DMSO is higher than in water by three orders of magnitude. Ring opening in 1-methylpyrimidin-4-ones occurs more readily than in the corresponding 3-methyl isomers, while the acyclic products formed from 3-methylpyrimidin-4-ones in DMSO are more stable than those derived from 1-methylpyrimidin-4-ones.     

Reactions of 4-acyl-1-alkoxyaryl-5-aryl-3-hydroxy-2,5-dihydro-1H-pyrrol-2-ones with nucleophilic reagents

4-Acetyl-1-alkoxyaryl-5-aryl-3-hydroxy-2,5-dihydro-1H-pyrrol-2-ones reacted with amines to give 1-alkoxyaryl-5-aryl-4-(1-R-aminoethylidene)pyrrolidine-2,3-diones. Reactions of amines with 4-benzoyl-substituted analogs involve nucleophilic attack on the C³ atom in the heteroring to produce the corresponding 3-R-amino-1-alkoxyaryl-5-aryl-4-benzoyl-2,5-dihydro-1H-pyrrol-2-ones. Reactions of the title compounds with hydrazine hydrate, regardless on the substituent on C₄, afforded 4-aryl-3-methyl(phenyl)-5-[2(4)-methoxyphenyl]-4,6-dihydropyrrolo[3,4-c]pyrazol-6-ones.     

1H and 13C NMR study of the conformations of the atropisomers of some 1-(11-naphthyl)-2,4-dioxo-(or 2-thio-4-oxo)-hexahydro-pyriminides

The ¹H and ¹³C NMR spectra of the atropisomers of 6-(or 5-)-methyl-1-(1¹-naphthyl)-2, 4-dioxo-(or 2-thio-4-oxo)-hexahydro-pyrimidines, 1 to 4, are assigned on the basis of NOE and double resonance experiments. The syn-anti configurations of the isomers of 6-methyl-2,4-dioxo-pyrimidine follow from the close similarity of the NMR parameters to those observed with the isomers of the 6-methyl-2-thio derivative of known configuration. That of the 5-methyl derivatives was assigned from NOE and magnetic anisotropy effects of the naphthalene ring and of the (thio) amide group. Allylic strain between the naphthyl and 5-methyl groups makes the axial confomation prefered int he anti isomers. In the syn isomers, however, the equational and axial conformations are approximately equally populated, apparently due to interference between the remote benzene ring and the axial methyl group. The equatorial conformation is prepared with the 5-methyl derivatives.     

Effect of the Structure of 1- and 3-Methyl-5-fluoropyrimidin-4-ones on H-D Exchange in Position 6under Conditions of Base Catalysis

Hydrogen atom in position 6of 5-fluoro-1-methylpyrimidin-4(1H)-one and its 2-methylsulfanyl, 2methoxy and 2-butylamino derivatives is readily replaced by deuterium in 90% methanol-d ₄ at ~20°C under conditions of base catalysis. The rate of H-D exchange decreases in the series H, SMe > OMe >> NHBu. Isomeric 5-fluoro-3-methylpyrimidin-4-ones, as well as their 5-unsubstituted analogs, do not undergo H–D exchange. Ready deuterium exchange in 5-fluoro-1-methylpyrimidin-4-ones is explained by synergistic effect of the zwitterionic structure and 5fluorine atom on the C⁶-H acidity. The gain in energy due to this effect, expressed through the enthalpy of dissociation of the C⁶-H bond, is ~15 kcal/mol provided that effect of the medium is absent; the contribution of the 5-fluorine atom is 5.3-6.0 kcal/mol.     

Cycloaddition-elimination reactions of 4-methyl-5-(substituted)-imino-Δ2-1,2,3,4-thiatriazolines with isocyanates

4-Methyl-5-(substituted)imino-1,2,3,4-thiatriazolines 1 (R² ≠ Me) undergo cycloaddition-elimination reactions with isocyanates to yield 4-methyl-5-(substituted)imino-1,2,4-thiadiazolidine-3-ones 5 via the thermodynamically less stable isomers 4 . The latter have not been isolated, except for 4q which was shown to iso-merize rapidly into 5q with phenylsulfonyl isocyanate. The reactions of 1 are accelerated by using less bulky R² substituents and more electrophilic isocyanates, in accordance with the viewpoint that 1 reacts as a masked 1,3-dipole. The products 4i-n (= 5i-n ), derived from 1b , add isocyanates reversibly to give 2,3,4,5-tetrahydro-6aλ⁴-thia-1,3,4,6-tetraazapentalene-2,5-diones 9i-n , which have been isolated and characterized spectroscopically. Such compounds with a hypervalent sulfur atom thus occur as intermediates during the isomerization of 4 to 5 under the influence of isocyanates.     

Reactions with diazoazoles. Part VI. Unequivocal synthesis of 3-methyl-3h-azolotetrazoles. Correction of the formerly described 3-methylazolotetrazoles in favour of mesoionic 2-methylazolotetrazoles

3-Methyl-3H-pyrazolo[1,5-d]tetrazoles 2 and 3-methyl-6-phenyl-3H-1,2,4-triazolo[1,5-d]tetrazole (4) have been unequivocally synthesized by annulation of the tetrazole moiety to the pyrazole resp. 1,2,4-triazole system. The constitution of some N-methyl substituted azolotetrazoles, formerly described as 3-methyl-3H-pyrazolo[1,5-d]tetrazoles 2, 3-methyl-6-phenyl-3H-1,2,4-triazolo[1,5-d]tetrazole (4) and 1-methyl-6-phenyl-1H-1,2,4-triazolo[4,3-d]tetrazole (5), has to be revised in favour of the corresponding mesoionic 2-methyl derivatives 2′, 4′, 5′. The structures of 3-methyl-3H- as well as of 2-methyl-2H-pyrazolo[1,5-d]tetrazole derivatives 2a, 2c, 2′a have been determined by X-ray analyses. The azapentalenic system is aromatic in all three measured compounds and mesoionic in the case of the 2-methyl-2H- substitution pattern. The phenyl and ester substituents are coplanar with the azapentalene system. 3-, 2-, and 1-Methylpyrazolo[1,5-d]tetrazoles exhibit different behaviour when allowed to react with stannous chloride or sodium ethoxide. Azolotetrazoles with a methyl substituent at N-1, N-2 or N-3 of the tetrazole moiety can be distinguished by a combination of ¹H and ¹³C nmr with respect to the chemical shifts of the N-methyl group and the bridgehead carbon. Results of semiempirical calculations of the pyrazolo[1,5-d]tetrazole anion and of its N-methyl derivatives are discussed.     

Nitration of 7- and 8-methyl-4-R-1H-2, 3-dihydro-1,5-benzodiazepin-2-ones

4-R-8-Methyl-2,3-dihydro-1H-1,5-benzodiazepin-2-ones are nitrated in the 7 position, whereas their 7-methyl analogs are nitrated in the 1, 8, or 9 position. The nitration of 4,8-dimethyldihydrobenzodiazepinone proceeds as primary substitution at the N₁ atom of the amide group. The resulting N₁-nitroamide undergoes prototropic rearrangement to the 9-nitro isomer in strongly acidic media.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 122–126, January, 1978.     

Synthesis and properties of homomologated and contracted dipyrrinone analogs of xanthobilirubic acid

Dipyrrinone analogs of xanthobilirubic acid, 5-[1,5-didehydro-3-ethyl-4-methyl-5-oxo-2H-pyrrol-2-ylidene)-methyl]-2,4-dimethyl-1H-pyrrol-3-propanoic acid, with alkanoic acid chain lengths varying from formic to caproic have been synthesized as their methyl esters and characterized spectroscopically. All of the dipyrrinones studied exhibit intermolecular hydrogen bonding in chloroform, as detected by ¹H-nmr, and the influence of the carboxyl group on the uv-visible spectrum decreases with increasing chain length.     

Reactions of 6-Alkoxy(alkylthio)carbonylamino-4-hydroxy-2H-pyran-2-ones with Some Electrophilic Reagents

Alkoxy(alkylthio)-4-hydroxy-2H-pyran-2-ones readily react with electrophiles to give substitution products at C³. Hard electrophilic reagents replace hydrogen both in position 3 and in position 5 of the pyran ring. Methylation of 6-alkoxy(alkylthio)-4-hydroxy-2H-pyran-2-ones with diazomethane leads to formation of O- and N-methyl derivatives.     

Nitrogen bridgehead compounds,Part 31 1H and 13C NMR study of tetra- and octahydro-11H-pyrido[2,1-b]quinazolin-11-ones

Conformational analysis of some tetra-and octahydro-11H-pyrido[2,1-b]quinazolin-11-ones 1-3 by ¹H and ¹³C nmr revealed that the 9-methyl-6,7,8,9-tetrahydro derivative exists mainly in the conformation containing the methyl group in a quasi-axial orientation. Of the 1,2,3,4,5,6,7,8-octahydro compounds, the 9-methyl derivative 3e contains the methyl group in a quasi-axial position, while that in the 7-methyl and the 8-methyl derivatives 3c,d is in the equatorial position, and the 6-methyl derivative 3b is a mixture of the two conformers.     

Studies on isocyanides and related compounds. Investigation on the reaction between (Z)-alkyl 3-dimethylamino-2-isocyanoacrylates and acyl chlorides

The reaction between (Z)-methyl 3-dimethylamino-2-isocyanoacrylate ( 1a ) and acyl chlorides 2a,b did not afford methyl 2-acyl-1-methyl-1H-imidazole-4-carboxylates 3a,b , as previously reported, but 2-acyl-4-dimeth-ylaminomethyleneoxazol-5(4H)-ones 4a,b.     

1-(Pyrimidin-4-yl)pyrazol-5(4<Emphasis Type="Italic">H</Emphasis>)-one derivatives: II. Electrophilic substitution in 5-hydroxy-3-methyl-1-(6-methyl-2-methylsulfanylpyrimidin-4-yl)-1<Emphasis Type="Italic">H</Emphasis>-pyrazole

Electrophilic substitution of hydrogen in bicyclic 5-hydroxy-3-methyl-1-(6-methyl-2-methylsulfanylpyrimidin-4-yl)-1H-pyrazole occurs exclusively at the C⁴ atom of the five-membered heteroring. Unstable electrophilic substitution products are stabilized via addition of the second substrate molecule with formation of bridged adducts.     

Synthesis and some properties of 6-di(tri)fluoromethyl-and 5-di(tri)fluoroacetyl-3-methyl-1-phenylpyrano[2,3-<Emphasis Type="Italic">c</Emphasis>]pyrazol-4(1<Emphasis Type="Italic">H</Emphasis>)-ones

Condensation of 4-acetyl-5-hydroxy-3-methyl-1-phenylpyrazole with R^FCO₂Et (R^F = CF₂H, CF₃) in the presence of LiH affords 4-di(tri)fluoroacetoacetyl-5-hydroxy-3-methyl-1-phenylpyrazoles from which 6-di(tri)fluoromethyl-and 5-di(tri)fluoroacetyl-3-methyl-1-phenylpyrano[2,3-c]pyrazol-4(1H)-ones were synthesized. The reactions of pyrano-pyrazoles with hydrazine hydrate, ethyl mercaptoacetate, or aromatic amines proceed at the C(6) atom with pyrone ring opening and formation of aminoenones, pyrazoles, or thiophenes with the 5-hydroxy-3-methyl-1-phenyl-4-pyrazolyl fragment. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2750–2754, December, 2005.     

1H-, 31P- and 13C-NMR spectra of some 2-arylsulphonylamido-2-thiono-5-methyl-1,3,2-dioxaphospholanes

Some 2-arylsulphonylamido-2-thiono-5-methyl-1,3,2-dioxaphospholanes (1), containing two chiral centres, give NMR spectra in which splittings of the ¹H and ¹³C signals of the 5-methyl substituent and of the ³¹P signal indicate that they exist in an approximately 70:30% ratio of two racemic mixtures, Z and E respectively, diastereomeric to each other. These splittings were invariably observed for compounds 1a, containing a monosubstituted sulphonylamido group (Y = H) and various substituents at position 4′ of the aryl group, X = H, CH₃, OCH₃, F, CI and Br. The methylenic protons in position 4 of the phospholane ring are diastereotopic and therefore magnetically non-equivalent. Benzene-induced shifts were measured for the Z isomers of compounds 1a, X = H, F and for compound 1b, containing an N-disubstituted sulphonylamido group (Y = CH₃) and X = H; the tentative interpretation of these shifts places the more shielded diastereotopic methylene proton on the same side of the ring as the 5-methyl substituent. The H? P and H? H coupling constants indicate that the preferred conformation of the dioxaphospholane ring should be a ‘twisted envelopey’ shape with the 5-methyl substituent in the equatorial position.     

Protonenresonanz- und Röntgenstrukturuntersuchungen an unsymmetrisch substituierten Aminoboranen. III—Substituentenabhängigkeit der Struktur

A number of unsymmetrically substituted N-methylaminoboranes, each with a phenyl ring at nitrogen and boron, were synthesized. The ratio of the cis-trans isomers has been investigated by means of ¹H NMR spectroscopy and its dependence on the size of the aromatic moieties and the second substituent on boron is discussed. The structures of the compounds were established from the position of the N-methyl signal and were based on X-ray structure determinations of (4-bromophenylmethylamino) chlorophenylborane and (4-bromo-2-methylphenylmethylamino)chloro(2-methylphenyl)borane. In the case of (methylphenylamino)chlorophenylborane, the isomer with the phenyl group in cis position is highly favoured (90%) in the thermal equilibrium. Substitution of one of the phenyl groups by a 2-methyl- or 2,6-dimethylphenyl group decreases the fraction of the cis isomer. The same occurs when the chlorine substituent at boron is replaced by bromine or the methyl group. In absolute terms, the trans isomers are energetically more stable than the cis isomers only if one of the substituents at boron is a methyl or a 2,6-dimethylphenyl group or if there is a 2-methylphenyl substituent both at the nitrogen and the boron atom. Steric hindrance and electronic repulsion are probably responsible for the observed substitution effects. In addition, these experiments show that the isomer favoured in the crystal also predominates in solution.     

Acidolysis of poly(4-methyl-1,3-dioxolane)

The onset of decomposition of poly(4-methyl-1,3-dioxolane) was lowered to 70°C by 0.1 wt% p -toluene sulfonic acid from 170°C in the absence of acid to produce more than 81% yield of monomer. Protonation forms cyclic oxonium ion followed by depolymerization. Minor products are isomers of hydroxymethyl-2-hydroxyl-2-methyl ethyl ether and bis(2-hydroxyl-2-methyl ethoxyl)methane from rearrangements of the oxonium ions. The first order rate constant of acidolysis of poly(4-methyl-1-1,3-dioxolane) is about 8.5 kcal mol^?1, which is much smaller than about 17 kcal mol^?1 for the acidolysis of poly(1,3-dioxolane).     

Synthesis of the (Z) and (E) isomers of 1,2-diaryl-3-methyl-4,5-dioxo-3-pyrrolidinecarboxylic acid esters. Structural assignment by nmr and mass spectroscopy

Reaction of N-benzylideneaniline, 1a , with 3-methyl-2-oxobutanedioic acid diethyl ester, 2a , produced isomeric 3-methyl-4,5-dioxo-1,2-diphenyl-3-pyrrolidinecarboxylic acid ethyl esters, 3a and 3b . The higher melting isomer, 3a , was shown to have the (Z) configuration by nmr spectroscopy. The (Z) and (E) isomers of 3-methyl-4,5-dioxo-1,2-diphenyl-3-pyrrolidinecarboxylic acid methyl esters, 3c and 3d , were prepared from 1a and 3-methyl-2-oxobutanedioic acid dimethyl ester, 2b . The higher melting isomer, 3c , was shown to have the (Z) configuration. Similarly, N-benzylidene-p-toluidine, 1b , reacted with 2a to form (Z) and (E) isomers of 3-methyl-4,5-dioxo-1-(4-methylphenyl)-2-phenyl-3-pyrrolidinecarboxlic acid ethyl esters, 3e and 3f . Assignment of the ¹³C carbonyl carbon nmr chemical shift was made by preparing 2-methyl-3-oxobutanedioic-1-¹³C acid diethyl ester, 4 , and from it the corresponding (Z) and (E) isomers of 3-methyl-4,5-dioxo-1,2-diphenyl-3-pyrrolidinecarboxylic ¹³C acid ester, 5a and 5b . The mass spectra of the (Z) isomers exhibit prominent ions corresponding to the masses of the Schiff bases used to make them, and ions corresponding to the loss of ArNCOCO from the parent ion. The (E) isomers 3b, 3d and 5b exhibit a prominent ion of mass 264; 3f gives mass 278, corresponding to the loss of the carboalkoxy group.     

Synthesis of 2-Aryl-4-(R-sulfanylmethyl)-3-methyl-6,7-dihydro-2<Emphasis Type="Italic">H</Emphasis>-pyrazolo[3,4-<Emphasis Type="Italic">d</Emphasis>]pyridazin-7-ones

Bromination of ethyl 1-aryl-4-acetyl-5-methyl-1H-pyrazole-3-carboxylates gave ethyl 1-aryl-4-(bromoacetyl)-5-methyl-1H-pyrazol-3-carboxylates which were used to alkylate benzenethiol and heterocyclic thiones at the sulfur atom. Reactions of the resulting S-alkylation products with hydrazine or methylhydrazine involved closure of pyridazine ring to afford 2-aryl-3-methyl-4-[phenyl(or hetaryl)sulfanylmethyl]-6,7-dihydro-2H-pyrazolo[3,4-d]pyridazin-7-ones.     

Halogenation of n-substituted p -quinone monoimines and p -quinone monooxime esters: VIII. Halogenation of N -aroyl(arylsulfonyl)-2,6-di- tert -butyl-1,4-benzoquinone monoimines and their reduced forms

Chlorination of N-aroyl(arylsulfonyl)-2,6-di-tert-butyl-1,4-benzoquinone imines gave Z and E isomers of 4-arylsulfonylimino-2,6-di-tert-butyl-5,6-dichlorocyclohex-2-en-1-ones and Z isomers of 4-aroyl-(arylsulfonyl)imino-2,6-di-tert-butyl-5,5,6-trichlorocyclohex-2-en-1-ones, in which the tert-butyl group on the sp ³-hybridized carbon atom occupies exclusively the axial position. The formation of Z/E-isomeric structures is related to configurational stability of the chlorination products. The chlorination of 4-aroylamino-2,6-di-tertbutylphenols was found to be accompanied by replacement of one tert-butyl group by chlorine atom with formation of 4-aroylimino-6-tert-butyl-2,3,5,6-tetrachlorocyclohex-2-en-1-ones. Original Russian Text ? A.P. Avdeenko, V.V. Pirozhenko, O.V. Shishkin, G.V. Palamarchuk, R.I. Zubatyuk, S.A. Konovalova, O.N. Ludchenko, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 6, pp. 818–824. For communication VII, see [1].     

Synthesis of Tricyclic (λ5)-Phosphoranes; unusual N-demethylation/N-alkylation reactions during the oxidative addition of hexafluoroacetone and tetrachloro-ortho-benzoquinone to benzodiaza-λ3-phosphorinones. Single crystal X-ray diffraction studies of various products

The reaction of methylisatoic acid anhydride 1 with benzylamines led to the N-benzyl-N′-methylanthranilamide derivatives 2 – 4 . Their reaction with phosphorus trichloride furnished the 2-chloro-1-halobenzyl/benzyl-3-methyl-4(1 H)-1,3,2-benzodiazaphosphorin-4-ones 5 – 7 which, upon reaction with bis-(2-chloroethyl)ammonium chloride/triethylamine, were converted into the P-bis-(2-chloroethyl)amino-1-halobenzyl/benzyl-3-methyl-4(1 H)-1,3,2-benzodiazaphosphorin-4-ones 8 – 10 and 12 . With 2-chloroethylammonium chloride/triethyl-amine the P? NHCH₂CH₂Cl-substituted compound 11 was obtained from the P^IIICl-species 6 . The reaction of 8 – 10 and 12 with hexafluoroacetone (HFA) took an unusual course: apart from the oxidative addition of HFA and formation of the perfluoropinacolyl ring system, one of the two CH₂CH₂Cl groups was found to alkylate the CH₃N atom with formation of a five-membered (diazaphospholane) ring in the tricyclic phosphoranes 13 – 16 . The reaction of 11 with HFA also produced a spirophosphorane 17 which involved a λ⁵-oxazaphosphetidine ring system. In the reaction of 8, 10 and 12 with tetrachloro-o-benzoquinone, an oxidative addition reaction with concomitant N-alkylation and formation of the tricyclic phosphoranes 18 – 20 was found to take place. Single crystal X-ray structure determinations are described for the phosphoranes 13, 14 and 16 , and for the precursor compound 9 . The following features are common to the isostructural compounds 13 and 16 and the diethyl ether hemisolvate of 14 : the (λ⁵)-spiro phosphorus atom lies out of the plane of the other atoms of the rings to which it is common, and the dioxaphospholane rings display a twist conformation. In the λ³P-compound 9 the phosphorus atom also lies out of the plane of the other ring atoms.