An approach to acyclo-1-deazathymidine c-nucleosides via 3,5-dichloro-6-methyl-2H-1,4-oxazin-2-one.

An approach to the synthesis of acyclo-1-deazathymidine nucleosides is described. Diels-Alder reaction of 3,5-dichloro-6-methyl-2H-1,4-oxazin-2-one with acetylenic compounds 4 and 5 yielded the 3-[(tetrahydropyran-2-yl)oxy]-methyl- and 3-bromomethyl-5-methyl-2,6-dichloropyridine intermediates 7 and 8. The bromomethyl group of compound 8 underwent easy substitution with the appropriate nucleophiles, permitting the introduction of acycLo sugar moieties. The resulting 3-substituted 2,6-dichloro-5-methyl pyridines 9a,b - precursors for some acyclo pyridine-C-nucleosides - were treated with sodium phenylmethoride to afford 2,6-dibenzyloxypyridines 10a,b. Debenzylation using a palladium-strontium carbonate catalyst gave the unstable C-nucleosides 2a,b of the 6-hydroxy-1H-pyridin-2-one type. A stable 6-hydroxy-1H-pyridin-2-one 2c, exempt from benzylic oxygen, was obtained via cycloaddition of THP-protected 6-hydroxy-1-hexyne.     

Silver(I) coordination chemistry of 2,6-diarylpyrazines. Pi-stacking,anion coordination,and steric control

The silver(I) coordination chemistry of 2,6-diarylpyrazines is reported. Discrete coordination complexes and two-dimensional coordination networks were characterized. The substitution pattern on the pendant aryl groups controlled the type of coordination chemistry involved. Thus, o-methyl-substituted aryl groups held the aryl groups orthogonal to the central pyrazine ring, opening the "hindered" nitrogen atoms to complexation, and polymeric networks were characterized. In the absence of the o-methyl groups, discrete coordination complexes were characterized. Thus, a dimeric 2:1 ligand-silver(I) complex was isolated and characterized on reaction of 2,6-bis(3',5'-dimethylphenyl)pyrazine with silver(I) trifluoroacetate in acetonitrile solvent, while a 2:2 complex was isolated from dichloromethane solvent. Two trifluoroacetate ligands bridge two silver cations in both complexes. Reaction of the same pyrazine ligand with silver(I) tetrafluoroborate yielded a discrete 2:1 complex. A 2:1 complex was isolated on reaction of 2,6-diphenylpyrazine with silver(I) nitrate. These complexes were interlinked by weakly coordinating nitrate anions to form interwoven one-dimensional ribbons. Two-dimensional networks were obtained on reaction of silver(I) trifluoroacetate with either 2,6-bis(2',6'-dimethylphenyl)pyrazine or 2-(2',6'-dimethylphenyl)-6-(3',5'-dimethylphenyl)pyrazine. The networks comprised pyrazine-silver(I) strands cross-linked with complex bridged silver(I) trifluoroacetates.     

Nucleosides XI. Synthesis and antiviral evaluation of 5'-alkylthio-5'-deoxy quinazolinone nucleoside derivatives as S-adenosyl-L-homocysteine analogs

4-amino-1-(beta-D-ribofuranosyl)quinazolin-2-one (3) was prepared by a direct glycosylation of 4-aminoquinazolin-2-one (7) using the Vorbruggen's silylation method and provided exclusively the beta-anomer. This quinazoline nucleoside and its 2',3'-O-isopropylidene derivative (9) did not undergo the coupling reaction with dialkyl disulfides in the presence of tri-n-butylphosphine unless their 4-amino groups were protected by N,N-dimethylaminomethylidene. This approach provides a viable alternative synthetic route to 5'-alkylthio-5'-deoxy nucleosides.     

Crystal structure and mechanistic investigation of the reaction of 5-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carbonitrile with unsaturated carbonyl compounds

The crystal structure of 1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-6-ethyl-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile was obtained and determined by X-ray crystallography. The reaction mechanism of 5-amino-1-(2,6-dichloro-4-(trifluoromethyl)phenyl)-1H-pyrazole-3-carbonitrile with unsaturated carbonyl compounds was further proposed.     

Anomalous transformations of acetaldehyde (2,6-dichloro-4-pyridyl)hydrazone under the conditions of the Fischer reaction

Instead of the usual indolization, when acetaldehyde (2,6-dichloro-4-pyridyl)hydrazone is heated with zinc chloride under the conditions of the Fischer reaction one observes the formation of acetone (2,6-dichloro-4-pyridyl)hydrazone, 1-(2,6-dichloro-4-pyridyl)-5-methylpyrazoline, and 2,6-dichloro-4-aminopyridine, the ratio between which depends on the temperature and duration of the reaction.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 374–377, March, 1973.     

A practical preparation of methyl 2-methoxy-6-methylaminopyridine-3-carboxylate from 2,6-dichloro-3-trifluoromethylpyridine.

An effective and practical synthetic route to methyl 2-methoxy-6-methylaminopyridine-3-carboxylate (7), the key intermediate of 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxylic acid (1), from 2,6-dichloro-3-trifluoromethylpyridine (12) was undertaken. Process improvements were highlighted by regioselectivity of 12 with a nitrogen nucleophile and conversion of the 3-trifluoromethyl group into the methoxycarbonyl group. The reaction of 12 with N-benzylmethylamine provided the 6-(N-benzyl-N-methyl)aminopyridine 26a and the regioisomer 26b in >98:<2 ratio in a quantitative yield. Treatment of 2-methoxy-6-methylamino-3-trifluoropyridine (14a) with a large excess of sodium methoxide followed by acid hydrolysis gave the pyridine-3-carboxylic ester 7 in an excellent yield. The potential application of this reaction is also described.     

Reaction of 2,3-dichloro-5,6-dicyanopyrazine with enamines and some tertiary amines

The reaction of 2,3-dichloro-5,6-dicyanopyrazine ( 1 ) with enamines as well as a few tertiary amines as enamine precursors was investigated. Both reactions gave aminovinyl-substituted pyrazine derivatives. During the attempted purification of 3c or 3d by column chromatography on silica gel, 2-chloro-5,6-dicyano-3-(1′-oxocyclopent-2′-yl)pyrazine ( 4 ) was obtained, apparently by hydrolytic cleavage. The products prepared are all of interest as potential pesticides.     

克唑替尼关键中间体(S)-1-(2,6-二氯-3-氟苯基)乙醇的不对称合成

(S)-1-(2,6-二氯-3-氟苯基)乙醇（2）是合成抗癌药物克唑替尼的关键手性前体。本文以1-(2,6-二氯-3-氟苯基)乙酮为起始原料,利用二异松莰基氯化硼［(-)-Ipc₂BCl］不对称还原制得光学纯的2;并将中间体2经Mitsunobu反应、还原、溴代、 Suzuki偶联及脱除Boc保护合成克唑替尼,其结构¹H NMR,¹³C NMR和HR-MS(ESI)确证。对关键中间体2的合成条件进行了优化,并其对反应机理进行了推测。     

Reactivity of some 3-substituted derivatives of 2,6-dihalogenopyridines towards potassium amide in liquid ammonia [a]

Reactions of 2,6-dichloro-3-phenyl-, 2,6-dibromo-3-phenyl-, 2,6-dichloro-3-dimethylamino- and 2,6-dibromo-3-dimethylaminopyridine with potassium amide in liquid ammonia were investigated. Whereas 2,6-dichloro-3-phenylpyridine yields 4-amino-2-benzylpyrimidine, from 2,6-dibromo-3-phenylpyridine as a product of a novel ring fission 2-amino-l-cyano-l-phenyl-but-l-en-3-yne was isolated, together with 4-amino-6-bromo-3-phenylpyridine and 2,6-diamino-3-phenylpyridine. It was shown that neither 2-amino-6-bromo-3-phenyl- nor 6-amino-2-bromo-3-phenylpyridine are intermediates in the formation of the 2,6-diamino derivative, as these bromo compounds are transformed in the basic medium into 1,3-dicyano-l-phenylpropene. From both 2,6-di-chloro-3-dimethylamino- and 2,6-dibromo-3-dimethylaminopyridine mixtures are obtained from which only 2-amino-l-cyano-l-dimethylamino-but-l-en-3-yne and 4-amino-6-halogeno-3-dimethylaminopyridine were isolated. Mechanisms for the reactions studied are proposed, i.e. a S_N(ANRORC) mechanism for the aminodebromination of 2,6-dibromo-3-phenylpyridine into the corresponding 2,6-diamino compound.     

Synthesis of 2-Substituted 7-Methyl-6-(nitroimidazolyl)thiopurines

2-Substituted 7-methyl-6-(nitroimidazolyl)thiopurines have been synthesized by the reaction of 2-chloro(phenylamino, cycloalkylamino)-7-methyl-6-thiopurines with 5(4)-halo-4(5)-nitroimidazoles and the reaction of 2,6-dichloro-(6-chloro-2-dimethylamino)-7-methylpurines with sodium or ammonium salts of 5(4)-mercapto-4(5)-nitroimidazoles.     

Competition between photochemistry and energy transfer in UV-excited diazabenzenes. 4. UV photodissociation of 2,3-, 2,5-, and 2,6-dimethylpyrazine

The quantum yield for HCN formation via 248 nm photodissociation of 2,3-, 2,5-, and 2,6-dimethylpyrazine (DMP, C6N2H8) was measured using diode laser probing of the HCN photoproduct. The total quantum yield is phi = 0.039 +/- 0.07, 0.14 +/- 0.02, and 0.30 +/- 0.06 for 248 nm excitation of 2,3-, 2,5- and 2,6-DMP, respectively. Analysis of the quenching data within the context of a gas kinetic, strong collision model allows an estimate of the rate constant for HCN production via DMP photodissociation, ks = 4.1 x 10(3), 1.0 x 10(3), and 1.3 x 10(4) s(-1) for 2,3-, 2,5- and 2,6-DMP, respectively. Unlike HCN produced from the photodissociation of pyrazine and methylpyrazine, the amount of HCN produced via a prompt, unquenched dissociation channel was essentially zero, suggesting little multiphoton UV absorption. The rate constants for HCN formation together with previously measured rate constants for HCN production from photodissociation of pyrazine and methylpyrazine have been used to investigate possible reaction mechanisms. The position of the methyl group affects the HCN rate constant, suggesting that the mechanism for pyrazine dissociation involves an initial step that is hindered by the addition of the methyl groups. The proposed initial molecular motion of the mechanism, an out-of-plane H atom migration across a N atom, is consistent with (1) the position of the methyl groups, (2) the dissociation lifetime of the various pyrazine molecules studied, and (3) the observed large energy transfer magnitudes from pyrazine near dissociation. These so-called "supercollisions" have been linked to low-frequency, out-of-plane motion, suggesting that the molecular motions leading to efficient energy transfer are the same motions involved in dissociation. In addition, the pyrazine (C4N2H4) 248 nm photoproduct (C3H3N) was identified as acrylonitrile using IR spectroscopy, an observation that aids in understanding the dissociation mechanism.     

Synthesis of carba-analogues of myoseverin by regioselective cross-coupling reactions of 2,6-dichloro-9-isopropylpurine

A series of 9-isopropylpurine derivatives bearing 4-methoxyphenyl, 4-methoxybenzyl, (4-methoxyphenyl)ethynyl and 2-(4-methoxyphenyl)ethyl groups in positions 2 and 6 were prepared as carba-analogues of antimitotic myoseverin. Cross-coupling reactions of 2,6-dichloro-9-isopropylpurine (1) with one equivalent of (4-methoxyphenyl)boronic acid or (4-methoxybenzyl)zinc chloride gave regioselectively the 6-substituted 2-chloropurines which were used for another cross-coupling reaction with a second equivalent of the organometallic reagent. The Sonogashira reaction of 1 with 4-(methoxyphenyl)ethyne gave 2,6-bis[(4-methoxyphenyl)ethynyl]-9-isopropylpurine that was hydrogenated to 2,6-bis[2-(4-methoxyphenyl)ethyl]-9-isopropylpurine. Regioselectivity of the couplings was proved by means of ¹H-¹⁵N HMBC experiments. 2,6-Bis[(4-methoxyphenyl)ethynyl]-9-isopropylpurine showed considerable cytostatic activity, while the other compounds were inactive.     

Fluorinated pyrido[2,3-c]pyridazines. II. Synthesis and antibacterial activity of 1,7-disubstituted 6-fluoro-4(1H)-oxopyrido[2,3-c]pyridazine-3- carboxylic acids

Chemical modification of pyridonecarboxylic acid antibacterials with a 1,8-naphthyridine ring, such as enoxacin and tosufloxacin, to their 2-aza derivatives was studied. A new series of 1,7-disubstituted 6-fluoro-4(1H)-oxopyrido[2,3-c]pridazine-3-carboxylic acids (25-27) was prepared by a route involving either alkylation of ethyl 6-fluoro-4(1H)-oxo-7-(p-tolylthio)pyrido[2,3-c]pyridazine-3-carbox ylate (7) or intramolecular cyclization of ethyl 2-(2,6-dichloro-5-fluoronicotinoyl)-2-[2-(p-fluorophenyl)hydraz ono]acetate, (20), followed by displacement reaction with cyclic amines at C-7; the N-1 substituent in these compounds included of ethyl, 2-fluoroethyl and p-fluorophenyl groups, and the C-7 functional group comprised variously-substituted piperazines and pyrrolidines. Antibacterial activities of these compounds were markedly inferior to those of enoxacin and tosufloxacin.     

Synthesis of pyrazine acetals by the biased reaction of symmetric 2,5-bis(chloromethyl) or 2,3,5,6-tetrakis(chloromethyl) substituents on pyrazine ring with sodium alkoxides

2,5-Bis(chloromethyl)pyrazine reacted with sodium alkoxide to give unexpected 2-dialkoxymethyl-5-methylpyrazine along with normal substitution product, 2,5-bis(alkoxymethyl)pyrazine. The reaction of 2,3,5,6-tetrakis(chloromethyl)pyrazine with sodium alkoxide afforded similar results to yield 2,6-bis(dialkoxymethyl)-3,5-dimethylpyrazine along with other alkoxymethylpyrazines. The ratio of products depended on the solvent and alkoxide used. A general discussion of the mechanism of such a pyrazine acetal synthesis in the basic conditions is given.     

Convenient synthesis of tridentate 2,6-di(pyrazol-1-yl)-4-carboxypyridine and tetradentate 6,6′-di(pyrazol-1-yl)-4,4′-dicarboxy-2,2′-bipyridine ligands

Citrazinic acid is used as a convenient starting material for both tridentate 2,6-di(pyrazol-1-yl)-pyridine and tetradentate 6,6′-di(pyrazol-1-yl)-2,2′-bipyridine ligands containing carboxylic groups useful for further anchoring of sensitizer on TiO₂ for dye-sensitized solar cells (DSCs). Using 2,6-dichloro-4-carboxypyridine, the synthesis of the terdentate ligands was improved compared to previously used 2,6-dibromo-4-carboxypyridine or 2,6-dichloro-4-ethylcarboxylate pyridine. Controlling the reaction conditions, it is possible to efficiently obtain the monosubstituted 2-chloro-6-pyrazol-1-yl-4-carboxypyridine, a key intermediate for the preparation of tetradentate 6,6′-di(pyrazol-1-yl)-4,4′-dicarboxy-2,2′-bipyridine ligand.     

Halogenated 3-pyridylketones

The oxidation of 2,6-dichloro-3-benzylpyridines and bis(2,6-dichloro-3-pyridyl)methanes, respectively, was accomplished using chromic trioxide in a highly acidic medium. The synthesis of several phenyl-3-(2,6-dichloropyridyl)ketones and of bis(2,6-dichloro-3-pyridyl)ketone are reported.     

DOTTADs--readily made novel metal ligands with multivariant functionality--trans-DOTTADs and semi-DOTTADs

Two new ligand systems related to the previously described DOTTADs have been generated in a simple one step reaction. The first, trans-DOTTADs, were formed by Vilsmeier formylation (followed by cyclisation and N-demethylation) of 2,6-dimethyl-3,5-pyrazine-dicarboxylic acid, to give the novel bis-pyridinopyrazine dialdehyde ligands. The corresponding pyrazine diester, reacted similarly to an intermediate iminium ion stage, which gave trans-DOTTAD imines on work-up with amines. The treatment of Hantzsch ester with two equivalents of benzaldehyde gave 7-phenyl-2-(2-phenylethenyl)-7,8-dihydropyrano[4,3-b]pyridin-5-one-3-carboxylic acid. This product underwent similar cyclisation with Vilsmeier reagents to give, for example, 6-methyl-2-(2-phenylethenyl)-8-(phenylhydroxymethyl)-6H-[1,6]naphthyridin-5-one-3-carboxylic acid, an example of a semi-DOTTAD.     

SOME CHLOROHYDROXYBENZENESULFONYL DERIVATIVES

Abstract

2,4-; 2,6-; 2,3-; 3,4-; 2,5-; and 3,5-dichlorophenols by reaction with chlorosulfonic acid were converted to the following substituted benzenesulfonyl chlorides: 3,5-dichloro-2-hydroxy-; 3,5-dichloro-4-hydroxy-; 2,3-dichloro-4-hydroxy-; 4,5-dichloro-2-hydroxy-; 2,5-dichloro-4-hydroxy-; and 2,6-dichloro-4-hydroxy-respectively. In addition o-chlorophenol gave 5-chloro-4-hydroxybenzene-1,3-bis-sulfonyl chloride. The various sulfonyl chlorides have been condensed with nucleophilic reagents, e.g. ammonia, amines, hydrazine, phenylhydrazine, N, N-dimethylhydrazine, and sodium azide. 3,5-Dichloro-2-hydroxybenzenesulfonyl azide has been reacted with norbornene, triphenylphosphine, dimethylsulfoxide, and cyclohexene. 3,5-Dichloro-2-hydroxybenzenesulfonyl chloride with phenylisocyanate gave the 2-(N-phenyl-carbamoyloxy) derivative which on heating gave a heterocyclic compound. The chlorohydroxybenzenesulfonyl derivatives are of interest as potential herbicides and their ir and nmr spectral characteristics are briefly discussed.     

Mannich-type C-nucleosidations in the 5,8-diaza-7,9-dicarba-purine family

[structure: see text] C-Nucleosidation with cyclic iminium salts occurring under mild reaction conditions and affording C-nucleosides that are isosteric with N-nucleosides of natural purines is shown to be a consistent property of the entire family of 2,6-(oxo or amino)-disubstituted 5,8-diaza-7,9-dicarba-purines.     

Modular synthesis of 5-substituted thiophen-2-yl C-2'-deoxyribonucleosides

A new modular methodology of preparation of 5-substituted thiophene-2-yl C-nucleosides was developed. A Friedel-Crafts-type of C-glycosidation of 2-bromothiophene with toluoyl-protected methylglycoside 2 gave the desired protected 1beta-(5-bromothiophen-2-yl)-1,2-dideoxyribofuranose 4a in 60%. The key intermediate 4a was then subjected to a series of palladium-catalyzed cross-coupling reactions. The cross-coupling reactions with alkyl organometallics gave beta-(5-alkylthiophen-2-yl)-2-deoxyribonucleosides 4 and 7 in moderate yields accompanied by side-products of reduction. On the other hand, cross-couplings with arylstannanes proceeded smoothly to give a series of beta-(5-arylthiophen-2-yl)-2-deoxyribonucleosides 4 in good yields. Deprotection of toluoylated nucleosides by NaOMe in MeOH and silylated nucleosides by Et 3N.3HF gave a series of free C-nucleosides 6. Alternatively, other types of 5-arylthiophene C-nucleosides 6 were prepared in one step by the aqueous-phase cross-coupling reactions of unprotected 1beta-(5-bromothiophen-2-yl)-1,2-dideoxyribofuranose with boronic acids. Title 5-arylthiophene C-nucleosides 6 exhibit interesting fluorescent properties with emission maxima varying from 339 to 396 nm depending on the aryl group attached.