New approach for the synthesis of 1-aryl- and 1-heteroaryl-5-nitrouracil derivatives

1-(2,4-Dinitrophenyl)-5-nitrouracil and its 3-methyl derivatives were synthesized and used as substrates in reaction with aromatic amines and amino pyridines. In the reaction of aniline with 1-(2,4-dinitrophenyl)-5-nitrouracil, only the acyclic adduct was isolated. When 1-(2,4-dinitrophenyl)-3-methyl-5-nitrouracil was treated with aniline and other aromatic amines or amino pyridines, the desired 1-aryl-5-nitrouracil derivatives were obtained in satisfactory yield. The influence of the free H-3 proton present in the uracil ring on the course of the reaction is discussed.     

Novel and versatile reactions of trifluoroamine oxide: a new route to polyfluorinated ethers

A series of pyrimidine methyl and polyfluoroalkyl ethers were synthesized from the reactions of trifluoroamine oxide (1) with several 5-substituted uracils in the presence of tetrabutylammonium hydroxide and methanol, 2,2,2-trifluoroethanol (6), or 1H,1H-pentafluoropropanol (7). With 5-(trifluoromethyl)uracil (2), the new ethers formed were 5-fluoro-5-(trifluoromethyl)-6-methoxypyrimidine-2,4-dione (8), 5-fluoro-5-(trifluoromethyl)-6-(trifluoroethoxy)pyrimidine-2,4-dione (9), and 5-fluoro-5-(trifluoromethyl)-6-(1H,1H- pentafluoropropoxy)pyrimidine-2,4-dione (10). With 5-chlorouracil (3), the new ethers 5-chloro-5-fluoro-6-methoxypyrimidine-2,4-dione (11), 5-chloro-5-fluoro-6-(trifluoroethoxy)pyrimidine-2,4-dione (12), and 5-chloro-5-fluoro-6-(1H,1H-pentafluoropropoxy)pyrimidine-2,4-dione (13) were obtained. With 5-fluorouracil (4), the new ethers 5,5-difluoro-6-methoxypyrimidine-2,4-dione (14), 5,5-difluoro-6-(trifluoroethoxy)pyrimidine-2,4-dione (15) and 5,5 difluoro-6-(1H,1H-pentafluoropropoxy)pyrimidine-2,4-dione (16) were found. By reaction of 5-nitrouracil (5), the new ethers 5-nitro-5-fluoro-6 methoxypyrimidine-2,4-dione (17), 5-nitro-5-fluoro-6-(trifluoroethoxy)pyrimidine-2,4-dione (18), and 5-nitro-5-fluoro-6-(1H,1H-pentafluoropropoxy)pyrimidine-2,4-dione (19) were obtained. Each of the new compounds was characterized by using IR, 19F and 1H NMR, and mass spectroscopy, and elemental analysis. A single-crystal X-ray diffraction study of 8 was helpful in confirming compound structure.     

Synthesis of 4-fluororesorcinol and 4-trifluoromethylresorcinol

Less expensive, safer, and easily scaled-up methods for the synthesis of 4-fluororesorcinol and 4-trifluoromethylresorcinol have been established, including two methods to give the former compound. One involves the reaction of Selectfluor™ reagent with 1,3-dimethoxybenzene to give 2,4-dimethoxy-1-fluorobenzene followed by hydrolysis to give 4-fluororesorcinol. The overall yield of this two-step reaction is 54%. In the second case, when Selectfluor reagent is reacted directly with resorcinol, under the best reaction conditions, 4-fluororesorcinol is obtained in 66% yield. It is, however, very difficult to separate the starting material from the mono- and difluororesorcinol products. Consequently, the two-step method is the method of choice to prepare 4-fluororesorcinol. The trifluoromethyl group was incorporated into 2,4-dimethoxy-1-iodobenzene to form 1,3-dimethoxy-4-trifluoromethylbenzene followed by mild hydrolysis to give 4-trifluoromethylresorcinol. © 1998 John Wiley & Sons, Inc. Heteroatom Chem 9:229–239, 1998     

Studies on the chemistry of 5-propynyloxy- and 5-propynylthiopyrimidines: New syntheses of furo- and thieno[3,2-d]pyrimidines

The utility of certain 5-alkynyloxy-, 5-alkynylthio, and 5-alkynylsulfinyl-pyrimidines as precursors of 7-substituted furo[3,2-d]- and thieno[3,2-d]pyrimidines has been examined. When treated with sodium methoxide in warm methyl sulfoxide, 1,3-dimethyl-5-(2-propynyloxy)uracil ( 6 ) cyclizes to afford 1,3,7-tri-methylfuro[3,2-d]pyrimidine-2,4-(1H,3H)-dione ( 12 ) in 52% yield, possibly via the allenic ether 9 (R = H). The corresponding 5-(2-butynyloxy)pyrimidine ( 7 ), obtained in good yield by treating 6 with methyl iodide and sodium hydride in methyl sulfoxide, fails to undergo an analogous cyclization. However, compound 7 does undergo a normal alkynyl Claisen rearrangement and cyclization when heated at 130°, giving the 8-methylpyrano[3,2-d]pyrimidine 8 in methyl sulfoxide and the 6,7-dimethylfuro[3,2-d]pyrimidme 11 in dimethylformamide. The 5-(2-propynylthio)pyrimidine 15 affords the allene 19 and the 1-propyne 22 when treated with various bases, but none of the 7-methylthieno[3,2-d]pyrimidine 16. At 145° in methyl sulfoxide, 15 undergoes a thio-Claisen rearrangement process to afford the 6-methylthieno[3,2-d]pyrimidine 17 together with substantial amounts of a product 20 that bears a 7-thiomethoxymethyl substituent derived from the solvent. Heating the 5-(2-propynylsulfinyl)pyriniidine 23 at 105° in methyl sulfoxide, followed by acidification of the reaction mixture, affords 1,3-dimethyl-7-formylthieno[3,2-d]pyrimidine-2,4-(1H,3H)-dione ( 29 ) in 47% yield. Deuterium labelling studies established that the aldehyde proton of 29 is derived from the 3′-proton of 23 . This finding is consistent with a mechanism that involves sequential [2,3] and [3,3] sigma-tropic rearrangements, and the intermediacy of a dihydrothieno[3,2-d]pyrimidine such as compound 30.     

Carbocyclic analogs of cytosine nucleosides

The carbocyclic analogs of cytidine, 2′-deoxycytidine, and 3′-deoxycytidine were synthesized from the analogous uracil derivatives. The route consists of complete benzoylation of the uracil derivative, selective removal of a benzoyl group attached to the pyrimidine ring, conversion of the 4-oxo to a 4-chloro group with the dimethylformamide-thionyl chloride reagent, and replacement of the chloro group with an amino group in methanolic ammonia. When the total products of the deoxychlorination reaction were employed, the desired cytosine derivatives were frequently accompanied by small amounts of the corresponding N,N-dimethylcytosine derivatives, which could be removed by ion-exchange chromatography. Carbodine (VIa), the carbocyclic analog of cytidine, was obtained in 84% yield from the pure 4-chloropyrimidinone intermediate, after the latter was prepared by deoxychlorination in carbon tetrachloride. Carbodine has antileukemic, antiviral, and antibacterial activity.     

Synthesis and configurational assignment of the amino alcohol in the eastern fragment of the GE2270 antibiotics by regio- and stereoselective addition of 2-metalated 4-bromothiazoles to alpha-chiral electrophiles

A synthesis of the eastern fragment of the thiazole peptide GE2270 A (1) has been developed. The synthetic approach relies on the regioselective functionalization of 2,4-dibromothiazole (5) via metalation and nucleophilic addition (at C2) or palladium-mediated cross-coupling (at C2 or C4). The stereochemistry at the N-bearing stereocenter was established by coupling of 2-metalated 4-bromothiazoles (4) to enantiomerically pure mandelic acid derivatives. Both the erythro (2) and threo (3) configurated amino alcohols were prepared with high diastereoselectivities depending on the electrophile employed. More specifically, the threo-configurated (S,R)-4-bromothiazolyl beta-amino alcohol 6 was synthesized from O-TBS protected (R)-mandelonitrile in 62% yield. Its N-PMB protected (R,S)-enantiomer 20 was obtained from O-TBS protected (S)-mandelic aldehyde in 67% yield. The erythro-configurated (S,S)-4-bromothiazolyl beta-amino alcohol 29 was prepared from O-TBS protected (S)-ethyl mandelate in four steps and 33% overall yield. The bithiazole moiety in the desired products 2 and 3 was finally established by the regioselective Negishi coupling of 2,4-dibromothiazole (5) and the 4-zincated, N-Boc protected thiazole derivatives of the diastereomeric 4-bromothiazolyl beta-amino alcohols 6 and 29.     

Synthesis and preliminary cytotoxic activity of dimethoxy-acridines and dimethoxynitroacridines

The preparation of a series of dimethoxy and dimethoxynitroacridines and their activity in oxic and hypoxic cells is reported. Anthranilic acids 1,4,14 were prepared according to the Ullmann condensation. 9-chloroacridines were obtained from anthranilic acids by refluxing in phosphorus oxychloride. The synthesis of two new acridine dimers 9,10 is described. Nitration of 9-chloro-2,4-dimethoxyacridine 15 gave 3-nitro isomer 19 . By phenol-mediated coupling reaction from all the 9-chloroacridines, the respective 9-(alkylamino)acridines were obtained. By nitration of 17 a new 2,4-dimethoxy-3,7-dinitroacridine 21 was prepared     

A Facile Synthesis of Ethyl 2,4-Dimethoxy-6-perfluoroalkyl-benzoates via Acyclic Precursors

Introduction Polysubstituted arenes are important intermediates in synthetic medicines and dyestuffs, and the fluorinated analogues are more attractive as a result of their lipo-philicity and the increment of activity.1,2 Therefore, to study the convenient and efficient synthesis of polysub-stituted arenes is valuable in organic synthetic method-ology. We have designed a simple synthesis of fluori-nated polysubstituted arenes through the intramolecular Wittig reaction of a new phosphorous ylid…     

Synthesis and Antiviral Activity of 1-{[2-(Phenoxy)ethoxy]methyl}uracil Derivatives

The synthesis of novel 1-{[2-(phenoxy)ethoxy]methyl}uracil derivatives with different substituents in positions and 6 of the pyrimidine ring has been carried out. It has been shown that the alkylation of trimethylsilyl derivatives of uracil with 2-(4-chlorophenoxy)- and 2-(4-methylphenoxy)ethoxymethyl chloride under Hilbert-Johnson reaction conditions gives N₍₁₎-substitution products. It was found that the 1-{ [2-(phenoxy)ethoxy]methyl}uracil derivatives show viral inhibition properties relative to human immunodeficiency type 1 virus in vitro. The most active compounds are 5-bromo-6-methyluracil derivatives which suppress viral reproduction by 50% at 7.2 and 7.8 micromolar concentrations.__________Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 726–731, May, 2005.     

Fast tin-free hydrodehalogenation and reductive radical cyclization reactions: a new reduction process

The photostimulated reactions of several aryl and alkyl chlorides and bromides with the monoanion of reduced ethyl benzoate 5H furnish the reduced products in high yields. If the aryl moieties have suitable double bonds, the cyclized reduced products are obtained in high yields. The photostimulated reaction of 1-allyloxy-2-bromobenzene (1a) with 5H affords 3-methyl-2,3-dihydro-benzofuran (2a) in 97% yield. When 1-allyloxy-2-chlorobenzene (1b) is used, the yield of 2a is only 55%, which increases up to 91% when acetone enolate ion is added to the reaction mixture as entrainment reagent. With diallyl-(2-bromophenyl)amine (3a), and 2-allyloxy-1-halonaphthalenes (chloro, 4b, and bromo, 4a) the cyclized reduced products are obtained in yields above 96%. By competition experiments, 5H reacts ca. 5 times faster with 1-naphthyl radicals than benzenethiolate ions do, which is near the diffusion limit rate.     

Asymmetric synthesis of optically pure (R)(−)-2-acetyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2-naphthol,a key intermediate for optically active anthracyclinone synthesis

Asymmetric reduction of 2-acetyl-5,8-dimethoxy-3,4-dihydronaphthalene(3) with lithium aluminum hydride partially decomposed with (?)-N-methylephedrine and N-ethylaniline was found to give the optically active allylic alcohol((?)-4) in 92% optical yield. Optically pure (?)-4 obtained in 87% yield based on 3 by recrystallization, was elaborated to the title compound((R)(?)-1) according to the reaction scheme exploited in the preceding paper.     

A new synthetic route towards the mono-O-protected anti-conformationally constrained pyrimidine acyclic nucleoside

Novel synthetic approach to mono-O-protected anti-conformationally constrained pyrimidine acyclic nucleoside was attained from the coupling of lithiated 2,4-dimethoxy-6-methylpyrimidine with 1-benzyloxy-3-(tert-butyldiphenylsilyloxy)propan-2-one, followed by the sequential reactions of methylthiomethylation, cyclization, hydroxylation, and dealkylation.     

Analogs of pyrimidine nucleosides

A new method was developed for the synthesis of 1-(2-tetrahydrofuryl) derivatives of uracil, 5-substituted uracils, 6-azauracil, and cytosine by alkylation of 2,4-bis(trimethylsilyl) derivatives of pyrimidine bases with 2-acetoxytetrahydrofuran in the presence of Lewis acids. In contrast to 2-chlorotetrahydrofuran, which is used in a previously described method, 2-acetoxytetrahydrofuran is stable at room temperature and reacts under these conditions with silyl derivatives of uracils in the presence of SnCl₄ to give 1-(2-tetrahydrofuryl) derivatives of pyrimidine bases in 80–85% yields.See [1] for communication X.Deceased.Translated from Khimiya Geterotsiklicheskikh Soedineaii, No. 9, pp. 1258–1259. September, 1977.     

Syntheses of various 5-(3′-substituted phenyl)uracils

The Suzuki Pd(0)-catalysed coupling between arylboronic acids and aryl bromides or iodides in weakly alkaline medium has been used for the preparation of 5-(3′-chlorophenyl)-, 5-(3′-iodophenyl)-, 5-(3′-aminophenyl)-, 5-(3′-azidophenyl)-, 5-(3′-methylthiophenyl)- and 5-(3′-styryl)-substituted 2,4-di-t-butoxypyrimidines. In the coupling between 2,4 di-t-butoxy-5-pyrimidineboronic acid and the six different aryl halides that were used as coupling partners, only 1-azido-3-bromobenzene did not give satisfactory yields, 18%. The other five aryl halides gave the desired 5-(3′-substituted phenyl)-2,4-di-r-butoxypyrimidines in 41–92% yield. Dealkylation of these five 5-(3′-substituted phenyl)-2,4-di-t-butoxypyrimidines in 2.5M hydrochloric acid gave the corresponding 5-(bromoaryl)uracils in almost quantitative yields. 5-(3′-Azidophenyl)uracil was prepared in 43% yield directly from 5-(3′-aminophenyl)-2,4-di-r-butoxypyrimidine.     

Methoxymethyl (MOM) group nitrogen protection of pyrimidines bearing C-6 acyclic side-chains

Novel N-methoxymethylated (MOM) pyrimidine (4-13) and pyrimidine-2,4-diones (15-17) nucleoside mimetics in which an isobutyl side-chain is attached at the C-6 position of the pyrimidine moiety were synthesized. Synthetic methods via O-persilylated or N-anionic uracil derivatives have been evaluated for the synthesis of N-1- and/or N-3-MOM pyrimidine derivatives with C-6 acyclic side-chains. A synthetic approach using an activated N-anionic pyrimidine derivative afforded the desired N,N-1,3-diMOM and N-1-MOM pyrimidines 4 and 5 in good yield. Introduction of fluorine into the side-chain was performed with DAST as the fluorinating reagent to give a N,N-1,3-diMOM pyrimidine 13 with a 1-fluoro-3-hydroxyisobutyl moiety at C-6. Conformational study of the monotritylated N-1-MOM pyrimidine 12 by the use of the NOE experiments revealed the predominant conformation of the compound to be one where the hydroxymethyl group in the C-6 side-chain is close to the N-1-MOM moiety, while the OMTr is in proximity to the CH(3)-5 group. Contrary to this no NOE enhancements between the N-1-MOM group and hydroxymethyl or fluoromethyl protons in 13 were observed, which suggested a nonrestricted rotation along the C-6 side-chain. Fluorinated N,N-1,3-diMOM pyrimidine 13 emerged as a model compound for development of tracer molecules for non-invasive imaging of gene expression using positron emission tomography (PET).     

Reactions of hydro(pero)xy derivatives of polyunsaturated fatty acids/esters with nitrite ions under acidic conditions. Unusual nitrosative breakdown of methyl 13-hydro(pero)xyoctadeca-9,11-dienoate to a novel 4-nitro-2-oximinoalk-3-enal product

13(S)-hydroperoxy- and 13(S)-hydroxyoctadeca-9,11-dienoic acids (1a/b), 15(S)-hydroperoxy- and 15(S)-hydroxyeicosa-5,8,11,13-tetraenoic acids (2a/b), and their methyl esters reacted smoothly with NO2- in phosphate buffer at pH 3-5.5 and at 37 degrees C to afford mixtures of products. 1b methyl ester gave mainly the 9-nitro derivative 3b methyl ester (11% yield) and a peculiar breakdown product identified as the novel 4-nitro-2-oximinoalk-3-enal derivative 4 methyl ester (15% yield). By GC-MS hexanal was also detected among the products. Structures 3b and 4 methyl esters were secured by 15N NMR analysis of the products prepared from 1b methyl ester upon reaction with Na15NO2. 4 methyl ester (14% yield) was also obtained from 1a methyl ester along with the nitrated hydroperoxy derivative 3a methyl ester (10% yield). Under the same conditions, 2a/b methyl esters gave mainly the corresponding nitrated derivatives 5a/b, with no detectable breakdown products, whereas the model compound (E,E)-2,4-hexadienol (6) afforded two main nitrated derivatives identified as 7 and 8. A reaction pathway for 1a/b methyl esters was proposed involving conversion of nitronitrosooxyhydro(pero)xy intermediates which would partition between two competing routes, viz., loss of HNO2, to give 3a/b methyl esters, and a remarkably facile fission leading to 4 methyl ester and hexanal.     

Fortuneanosides G-L, dibenzofuran glycosides from the fruit of Pyracantha fortuneana

Six new dibenzofuran glycosides, fortuneanosides G (1), H (2), I (3), J (4), K (5), and L (6), were isolated from the fruit of Pyracantha fortuneana (MAXIM) LI. Their structures were determined to be 3,7-dihydroxy-2,4-dimethoxy-dibenzofuran 7-O-beta-D-glucopyranoside, 3,7-dihydroxy-2,4-dimethoxy-dibenzofuran 7-O-(alpha-L-rhamnopyranosyl)-(1-6)-beta-D-glucopyranoside, 3,6-dihydroxy-2,4-dimethoxy-dibenzofuran 6-O-beta-D-glucopyranoside, 2,4-dimethoxy-3,6,9-trihydroxy-dibenzofuran 6-O-beta-D-glucopyranoside, 3,9-dihydroxy-2,4-dimethoxy-dibenzofuran 3-O-beta-D-glucopyranoside, and 2-methoxy-3,4,9-trihydroxy-dibenzofuran 4-O-beta-D-glucopyranoside based on spectroscopic analysis. Fortuneanosides G-J showed more potent tyrosinase-inhibitory activity than arbutin.     

2+2] Photocycloaddition reaction dynamics of triplet pyrimidines

Taking the 266 nm excited pyrimidine (uracil or thymine) with cyclopentene as model reaction systems, we have examined the photoproduct formation dynamics from the [2 + 2] photocycloaddition reactions of triplet pyrimidines in solution and provided mechanistic insights into this important DNA photodamage reaction. By combining two compliment methods of nanosecond time-resolved transient IR and UV-vis laser flash-photolysis spectroscopy, the photoproduct formation dynamics as well as the triplet quenching kinetics are measured. Characteristic IR absorption bands due to photoproduct formation have been observed and product quantum yields are determined to be ～0.91% for uracil and ～0.41% for thymine. Compared to the measured large quenching rate constants of triplet uracil (1.5 × 10(9) M(-1)s(-1)) or thymine (0.6 × 10(9) M(-1)s(-1)) by cyclopentene, the inefficiency in formation of photoproducts indicates competitive physical quenching processes may exist on the route leading to photoproducts, resulting in very small product yields eventually. Such an energy wasting process is found to be resulted from T(1)/S(0) surface crossings by the hybrid density functional calculations, which compliments the experiments and reveals the reaction mechanism.     

新型酰基供体用于酶法动力学拆分制备(R)-1-(2-萘基)乙胺的研究

首次成功实现了光学纯(R)-1-(2-萘基)乙胺的高效酶法动力学拆分制备,考察了脂肪酶种类、溶剂、酰基供体、底物浓度、反应温度等对拆分效果的影响,发现新型酰基供体——正戊酸对氯苯酯能够很好地抑制非酶促自催化酰胺化效应.在甲苯溶剂中,底物浓度300 mmol/L,40℃条件下,采用该供体在脂肪酶Novozym 435催化下,动力学拆分反应8 h转化率达到理论最佳值50%,eep>99%.     

Facile Synthesis of Enantiomerically Pure 1-（5-Bromo-2-chlorophenyl）-1-（4-ethoxyphenyl）ethane

A facile 7-step procedure for the synthesis of enantiomerically pure 1-（5-bromo-2-chlorophenyl）-1-（4-ethoxyphenyl）ethanes[（R）-2 and（S）-2] that started from （5-bromo-2-chlorophenyl）（4-ethoxyphenyl）methanone 3 was developed.The key step was the resolution of 2-（5-bromo-2-chlorophenyl）-2-（4-ethoxyphenyl）acetic acid 6 by crystallizations of its L-and D-menthyl esters 7 and 8 from petroleum ether to give optically pure enantiomers 9 and 10,respectively.The absolute configurations of the products were unambiguously determined by single-crystal X-ray diffractions of four key intermediates,9,10,13 and 14.This procedure is characterized by inexpensiveness,scalability and ability to produce two individual enantiomers of a diarylethane with unambiguously determined absolute configurations and high enantiomeric purities.