Derivatives of 2,6-dihydroxy-4,5-dihydropyrimidines

By the catalytic hydrogenation (5% of Rh on Al₂O₃) of orotic acid and its derivatives, DL-4,5-dihydroorotic and DL-1-methyl- and DL-1,3-dimethyldihydroorotic acids have been obtained. A number of salts of DL-4,5-dihydroorotic acid with amines have been synthesized.     

Molecular and crystal structure of 5,6-diamino-1-methyluracil and 5,6-diamino-1,3-dimethyluracil monohydrate. Semiempirical calculations (AM1 and PM3) on 5,6-diaminouracil derivatives

The crystal and molecular structures of 5,6-diamino-1-methyluracil and 5,6-diamino-1,3-dimethyluracil monohydrate have been determined from X-ray diffraction. Both compounds are planar and the two amino groups have two different conformations. The substituent at the 5 position seems to be a true primary amino group with a strongly sp³ nitrogen, whereas the one at the 6 position is nearly coplanar with the uracil ring, displaying a predominant sp² character.Semiempirical calculations were made on 5,6-diaminouracil, 5,6-diamino-2-thiouracil and their endocyclic N-methylated derivatives using the AM1 and PM3 hamiltonians. These indicate that the stability decreases on increasing methylation, the 2-thio compounds always being less stable than the 2-oxo ones.     

Removal of n-benzyl-and n-benzyloxymethyl substituents from substituted uracils with boron tribromide

N₁,N₃-Dibenzyl uracil derivatives have been successfully deblocked by using boron tribromide in refluxing xylene. Also N₁, N₃-dibenzyloxy methyl uracil derivatives can be easily converted to uracils by treatment with boron tribromide in benzene in the cold and subsequent boiling of the intermediate with water.     

Conformational studies of hydantoin‐5‐acetic acid and orotic acid

Hydantoin‐5‐acetic acid [2‐(2,5‐dioxoimidazolidin‐4‐yl)acetic acid] and orotic acid (2,6‐dioxo‐1,2,3,6‐tetrahydropyrimidine‐4‐carboxylic acid) each contain one rigid acceptor–donor–acceptor hydrogen‐bonding site and a flexible side chain, which can adopt different conformations. Since both compounds may be used as coformers for supramolecular complexes, they have been crystallized in order to examine their conformational preferences, giving solvent‐free hydantoin‐5‐acetic acid, C₅H₆N₂O₄, (I), and three crystals containing orotic acid, namely, orotic acid dimethyl sulfoxide monosolvate, C₅H₄N₂O₄·C₂H₆OS, (IIa), dimethylammonium orotate–orotic acid (1/1), C₂H₈N⁺·C₅H₃N₂O₄⁻·C₅H₄N₂O₄, (IIb), and dimethylammonium orotate–orotic acid (3/1), 3C₂H₈N⁺·3C₅H₃N₂O₄⁻·C₅H₄N₂O₄, (IIc). The crystal structure of (I) shows a three‐dimensional network, with the acid function located perpendicular to the ring. Interestingly, the hydroxy O atom acts as an acceptor, even though the carbonyl O atom is not involved in any hydrogen bonds. However, in (IIa), (IIb) and (IIc), the acid functions are only slightly twisted out of the ring planes. All H atoms of the acidic functions are directed away from the rings and, with respect to the carbonyl O atoms, they show an antiperiplanar conformation in (I) and synperiplanar conformations in (IIa), (IIb) and (IIc). Furthermore, in (IIa), (IIb) and (IIc), different conformations of the acid O=C—C—N torsion angle are observed, leading to different hydrogen‐bonding arrangements depending on their conformation and composition.     

Structures of four types of novel high-valent manganese complexes obtained by the reactions of KMnO4 with tridentate Schiff base ligands

X-ray structure analysis revealed that four types of novel manganese complexes, Mn^IV(N-EtO-sal)₂, Mn^III(N-PhO-sal)(L), [Mn^IV(5,6-Benzo-L)₂(μ-O)]₂ and Mn^III(L-4-Me)₃ have been found to be obtained by the reactions of KMnO₄ with various tridentate Schiff base ligands (N-EtOH-salH, N-PhOH-salH and its derivatives) in dry MeCN, where N-EtOH-salH, N-PhOH-salH, LH, 5,6-Benzo-LH and L-4-MeH denote N-2-hydroxyethyl-salicylideneamine, N-2-hydroxyphenyl-salicylideneamine, 2-(2-hydroxyphenyl)-benzoxazole 2-(2-hydroxynaphthyl)-benzoxazole and 2-(2-hydroxyphenyl)-5-methylbenzoxazole, respectively. The reactions of KMnO₄ and N-PhOH-salH and its derivatives have especially been found to afford benzoxazole derivatives which may be formed by intramolecular oxidative coupling between the phenolic oxygen atom of aminophenol moiety and the carbon atom of imine moiety.     

2,6-Dihydroxy-4,5-dihydropyrimidine derivatives

Alkylamides of DL-4,5-dihydroorotic acid were synthesized by catalytic hydrogenation (5% Rh on Al₂O₃). The reaction of the n-butyl ester of DL-4,5-dihydroorotic acid with alkylamines and hydrazine gave N,N-dialkylamides, the dihydrazide of DL-ureidosuccinic acid, and the hydrazide of DL-4,5-dihydroorotic acid. The products of the condensation of the latter with aromatic aldehydes were obtained.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 105–108, January, 1972.     

Studies on the preparation and exchange reactions of 5-deuterated uracils

The mechanism of base catalyzed proton exchange at the 5-position of uracil and its N-methylated derivatives has been studied. These reactions proceed by addition — elimination across the 5,6-double bond when the 1-nitrogen is substituted with a methyl group, or with anchimeric assistance of the N-1 anion if the 1-position is unsubstituted. The base catalyzed hydrolyses of 1,3-dimethyluracil and 3-methyluracil also appear to proceed through hydrated intermediates. A facile method for an acid catalyzed preparation of 5-deuterated uracils is described as well as a simple and accurate method for analysis of deuterium content.     

Hypervalent Iodine in Synthesis. Part 86

N‐Arylation of uracil and its derivatives 2 with diaryliodonium salts 1 was investigated in order to explore a new synthetic methodology associated with N‐aryluracil derivatives. In the presence of K₂CO₃, the copper‐catalyzed arylation gave N¹,N³‐diarylation products with high selectivity and in good yields (Table 2). However, the use of NaOAc as the base in the copper‐catalyzed arylation of 6‐methyluracil ( 2a ) resulted in N³‐arylation products with high selectivity, and, in the copper‐catalyzed arylation of uracil ( 2b ) or 5‐methyluracil (=thymine; 2c ), N¹‐arylation products were the major products (Table 3).     

One-pont synthesis of 5-fluoro-6-alkoxy-5,6-dihydrouracils

Fluorine diluted with argon was bubbled into a suspension of uracil in acetic acid at room temperature. Treatment of the reaction mixtur with alcohols gave 5-fluoro-6-alkoxy-5,6-dihydrouracils, which lost alcohols on sublimation under vacuum to give 5-fluorouracil quantitatively.     

Analogs of pyrimidine nucleosides

The reaction of alkoxy bromides with N₁-(-tetrahydrofuryl) derivatives of pyrimidine bases has given a series of 6-alkoxy-5-bromo-1-(-tetrahydrofuryl)-5, 6-dihydrouracils. The hydrogenation of the 1-(-tetrahydrofuryl) derivatives of uracil and of 5-fluorouracil has been studied. It has been shown that in both cases 1-(-tetrahydrofuryl)-5, 6-dihydrouracil is formed.     

Synthesis of (S)-5,6-dibromo-tryptophan derivatives as building blocks for peptide chemistry

5,6-Dibromo-tryptophan is an interesting amino acid whose derivatives and analogues are found in a variety of highly bioactive natural compounds. Notwithstanding its relevance no data concerning this compound are found in the literature. Here an efficient pathway for the synthesis of 5,6-dibromo-tryptophan derivatives is reported. The reaction is performed by using 6-Br-isatin as starting material. Selective bromination at position 5 was followed by BH₃ reduction of the intermediate α-keto-amide and alkylation with Ser-OH in Ac₂O/AcOH. Optical resolution was effected by enzymatic de-acetylation of the obtained racemic mixture. Finally, in situ N^α-Boc protection of the optically pure S form yielded the desired N^α-Boc-(S)-5,6-dibromo-tryptophan.     

Synthesis of [2-(vinyloxy)ethyl]uracil and [2-(allyloxy)ethyl]uracil

A synthesis is reported for N¹-mono- and N¹,N³-disubstituted uracil derivatives containing a terminal carbon-carbon double bond in the side-chain. Alkylation of vinyl 2-chloroethyl ether by uracil potassium salts leads to a mixture of 1-[2-(vinyloxy)ethyl] and 1,3-di[2-(vinyloxy)ethyl] derivatives while treatment of 2,4-bis(trimethylsilyloxy)pyrimidines by vinyl 2-chloroethyl ether leads exclusively to N¹-monosubstituted products. Alkylation of cytosine by this chloroether gave 1-[2-(vinyloxy)ethyl]cytosine. The synthesis of 1-[2-(allyloxy)ethyl]uracil derivatives was carried out by treatment of uracil potassium salts by 1-(allyloxy)-2-(p-toluenesulfonyloxy)ethane.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 393–397, March, 1993.     

Heterocyclization of Amidophenacylation Products of Uracil

When uracil is reacted with benzoylamino(chloro)acetophenone, we obtain two amidophenacylation products depending on the condensation conditions. The first product contains an amidophenacyl moiety at the N¹ center, and in the second product two such moieties are located at the N¹ and N³ centers of the uracil. Treatment of these accessible uracil derivatives with phosphorus oxychloride, thionyl chloride, or phosphorus pentasulfide leads to cyclization of the amidophenacyl side group, which is used to synthesize a number of modified pyrimidine bases with 2,5-diphenyloxazole or 2,5-diphenylthiazole residues.     

SYNTHESIS OF 1,3-THIAZANE-2,4-DIONE AND 2-THIO-5,6-DIHYDROURACIL AND THEIR DERIVATIVES

Abstract

1,3-Thiazane-2,4-diones and 2-thio-5,6-dihydrouracils belong to biologically interesting groups of compounds. The 5-ethyl-6-phenyl derivative (Dolitrone) of the former has shown marked activity as an intravenous general anaesthetic. Several derivatives of 2-thio-5,6-dihydrouracil have been reported to possess antitubercular and antithyroid activity. In the present study these two groups of compounds have been synthesised from common starting materials, namely, different α,β-unsaturated acids and thiourea.     

Methylation of Thiouracils and Thioxanthines with Trimethyl Phosphate

Preparation of alkyl derivatives of thiouracils and thioxanthines has been carried out by ring cyclization¹ and sulfurization of alkyl derivatives of uracil and xanthines with phosphorus pentasulfide.^2–4 However, direct alkylation of thiouracils and thioxanthines has been described by a limited number of papers using dimethyl sulfate,^5,6 methyl iodide,^7,8 etc. Previously we reported that trimethyl phosphate (TMP) was useful for N-methylation of various azaaromatics.⁹ In view of the recent biological interest on methyl derivatives of natural products,¹⁰ we wish to communicate here the reactions of thiouracils and thioxanthines with TMP.     

Synthesis and PMR specta of α- and β-D-arabinofuranosyluracils

The α- and β-anomers of N¹- and N³-monoglycosylated and N¹,N³-diglycosylated nucleosides have been synthesized by the condensation of 1-OMe- or 1-O-acetyl-2,3,5-tri-O-benzoyl-D-arabinose with bis(trimethylsilyl)uracil in the presence of SnCl₄. The structures of the compounds obtained were established from their NMR spectra.     

Investigations into N-aryl-β-amino acids

1-Aryl-5,6-dihydrouracils and 1-aryl-2-thio-5,6-dihydrouracils are synthesized from N-aryl--alanines and esters of N-aryl--ureidopropionic acid. The dihydrouracils were hydrolyzed by 0.1 N alkali.     

Unconventional nucleotide analogues: Reaction of carbenes with uracil and uridine derivatives

Carbenes 2a-d (:CCl₂, :CBr₂, :CFC1, :CHCOOC₂H₅) add to the 5,6-double bond of uracil derivatives la-e to give adducts in modest to good yields The unsymmetrically substituted carbenes :CFC1 2c and CHCOOC₂H₅, 2d lead, as expected, to the formation of mixtures of endo and exo-isomers 3c-n which were separated and identified via their ¹H NMR spectra. Reaction of 2d with pyrimidine derivatives 5a,b resulted in products which can be rationalized in terms of addition at either the 5,6 or the 3,4 double bond. Addition of carbenes 2a-c to uridine derivatives gave diastereomeric adducts 12-16 which were isolated and identified. The two diastereomeric series, referred to as A and B, have been correlated and assigned the configurations 5S, 6S and 5R, 6R, respectively, on the basis of X-ray structure analysis of 12B The adducts of 2a,c and the uridine derivatives 11a,b have been deprotected to give 7,7-dihalocyclothymidines.     

pH/R f diagrams of nucleotide bases

The chromatographic mobilities of uracil, cytosine, thymine, orotic acid, adenine, guanine, hypoxanthine, and xanthine as functions of the pH of buffer systems in the pH range from 0 to 12 have been studied by absorption chromatography on paper. Changes in R _f are observed comparatively rarely in the regions of the pK_a values.     

N-Aminoderivate des Uracils (1. Mitt.)

Zusammenfassung Das N-1-Aminouracil¹ (II) wird auf 2 verschiedenen Wegen erhalten. Es werden einige Aldehydderivate und das Benzophenonderivat dieses cyclischen Semicarbazids dargestellt. Das Na-Salz des Benzylidenderivates von II ist selektiv am N-3 alkylierbar. Das 1-Amino-3-(n-butyl)-uracil (XII) wird mit Toluolsulfochlorid oder mit p-Toluolsulfonylisocyanat acyliert. Das 1-Aminouracil (II) und das 1-Amino-3-methyluracil (XI) gaben mit HNO₂ Uracil bzw. 3-Methyluracil und N₂O. Die Bildung des 3-Methyluracils dient als Strukturbeweis für II. Das 1,3-Diaminouracil tritt beim Umsatz von Uracil mit Hydroxylamin-O-sulfonsäure als Zweitprodukt neben 1-Aminouracil auf.

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N-1-Aminouracil (II) has been obtained in two different ways. Several aldehydes and the benzophenone derivative have been prepared from this cyclic semicarbazide. The sodium salt of the benzylidene derivative of II undergoes selective alkylation at N-3. 1-Amino-3-(n-butyl)-uracil can be acylated with toluenesulfonyl chloride or p-toluenesulfonyl isocyanate. Reaction of II or 1-amino-3-methyl-uracil (XI) with nitrous acid yielded uracil and 3-methyl-uracil, respectively, and N₂O. Formation of 3-methyl-uracil confirms the structure of II. 1,3-Diaminouracil has been found to be a byproduct of the reaction between uracil and hydroxylamine-O-sulfonic acid besides II.