Synthesis of a protected ribonucleoside phosphoramidite-linked spin label via an alkynyl chain at the 5′ position of uridine

New, spin-labeled nucleosides, and an efficient synthetic route for a modified uridine amidite, were developed. The spin-labeled part was the 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) group, which was linked via an alkynyl chain at the 5 position of uridine. Three typical protecting groups, the t-butyldimethylsilyl (TBDMS) group at 2′, the dimethoxytrityl (DMTr) group at 5′, and the phosphoramidite group at 3′, were introduced to produce an automated nucleic acid synthesizer. The TEMPO group at the 5 position in the uridine structure affected introduction of bulky protecting groups, such as the DMTr group at the 5′ position and the TBDMS group at the 2′ position. The electron paramagnetic resonance (EPR) data revealed a nitroxyl radical in the structure of synthetic nucleoside compounds; however, RNA produced by automated synthesis using a TEMPO-linked uridine phosphoramidite building block was EPR silent.     

Synthesis of a bicyclic analogue of AZT restricted in an unusual O4'-endo conformation.

The [3.2.0]bicyclic beta-nucleoside analogue 5 has been designed as a conformationally restricted analogue of the anti-HIV drug AZT. The synthesis of 5 as well as its alpha-anomer 29 is hereby described. The synthesis was accomplished from D-arabinose via a modified Corey-Link procedure stereoselectively incorporating the azide moiety as well as a methyl ester function. When the tert-butyldiphenylsilyl group was used as a permanent protecting group, a selective formation of an oxetane ring failed. When using the p-methoxyphenyl group as a permanent protecting group, 5 and 29 were efficiently obtained via a selective reduction of the ester, a nucleobase coupling followed by separation of the anomers and ring-closing procedures. The nucleoside 5 is conformationally restricted in an unusual O4'-endo (East) conformation, which is an intermediate between the North- and South-type conformations. Nevertheless, neither 5 nor 29 displayed any anti-HIV activity.     

Reactions of methyl 3-hydroxythiophene-2-carboxylate. Part 4. Synthesis of methyl 5-azolyl-3-hydroxythiophene-2-carboxylates

The indirect introduction of an azolyl group in position 5 of compound 1 by an easy two-step procedure taking place at room temperature is described. A similar procedure yields the 4-chloro derivatives of these 5-azolyl compounds. The same method is applied for the introduction of a 5-azido group and from the 5-azido compounds, 5-v-triazolyl derivatives are obtained by a known method.     

Synthesis of 5-substituted 6-methoxy-1,2,3,4-tetrahydro-β-carbolin-1-ones

The nitration and bromination of 6-methoxy-1,2,3,4-tetrahydro--carbolin-1-one were studied. 5-Nitro and 5-bromo derivatives were obtained. 5-Acetyl-1,2,3,4-tetrahydrocarbolin-1-one oxime was obtained, and its Beckmann rearrangement was studied. The use of lithium aluminum hydride leads to reduction of the 5-acetyl group to give an alcohol group, whereas reduction of the acetyl group to an ethyl group occurs in the case of reduction with a palladium catalyst. Saponification of 5-substituted carbolin-1-ones with alcoholic alkali makes it possible to obtain 4-substituted tryptamines with a carbonyl group in the 2 position. The structures of the compounds were established by means of the PMR and mass spectra.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 80–85, January, 1979.     

Synthesis of 4- and 5-substituted 1-hydroxyimidazoles through directed lithiation and metal-halogen exchange.

Electrophiles were introduced regioselectively at the 5-position of 1-(benzyloxy)imidazole by lithiation at C-5 after protection of C-2 with a chloro or a trimethylsilyl group. Subsequent treatment with an electrophile afforded 5-substituted 1-(benzyloxy)-2-chloroimidazoles 8-13 and 5-substituted 1-(benzyloxy)imidazoles 3-5, the 2-(trimethylsilyl) group being lost during workup. Electrophiles were introduced regioselectively at the 4-position of 1-(benzyloxy)imidazole by bromine-lithium exchange of 4-bromo-2-chloro-1-(benzyloxy)imidazoles, protected at C-5 with chloro or trimethylsilyl groups, followed by reaction with an electrophile. The 5-(trimethylsilyl) group was removed via base-catalyzed desilylation. Chlorine at C-2 and O-benzyl groups were removed by palladium-catalyzed hydrogenolysis.     

Synthesis of new potentially bioactive bicyclic 2-pyridones

Three convenient methods of reduction of the nitro group of 5-nitroimidazoles and 5-nitrothiazole that bear a diethylmethylene malonate group in an ortho-like position with respect to the nitro group and cyclization of the resulting amino derivatives are reported. These reactions afforded the target bicyclic 2-pyridones in good to excellent yields.     

Anchimeric Assistance in the N-Alkylation of 5-alkoxymethyl-2-pyrrolidinone Derivatives

5-Substituted 2-pyrrolidinones are normally difficult to alkylate at nitrogen. The presence of an alkoxymethyl group at C5, however, facilitates alkylation by a neighboring group effect.     

Liquid crystals with a 5-phenyltropone core

Liquid crystals with a 5-phenyltropone structure were prepared. 5-(4-Alkanoylaminophenyl)tropone derivatives ( 5 and 6 ) showed smectic A and C phases. From the layer spacing, compound 5q formed an interdigitated bilayer smectic A phase. The variable temperature FTIR spectra of 5q indicated the presence of intermolecular hydrogen bonding between the amide carbonyl group and the NH group on the phenyl ring of neighbouring molecules. The amide groups of the 2-alkanoylamino-5-phenyltropones controlled the occurrence of mesophases through not only inter- and intra-molecular hydrogen bonds, but also dipole-dipole interaction with the tropone carbonyl group of neighbouring molecules.     

Nucleotides. Part XLI. The 2-dansylethoxycarbonyl (  2-{[5-(dimethylamino)naphthalen-1-yl]sulfonyl}ethoxycarbonyl; dnseoc) group for protection of the 5′-hydroxy function in oligodeoxyribonucleotide synthesis

Use of the 2-dansylethoxycarbonyl ( ? 2-{[5-(dimethylamino)naphthalen-1-yl]sulfonyl}ethoxycarbonyl; Dnseoc) group as an intermediate 5′-OH protecting group in oligodeoxyribonucleotide synthesis using the automated phosphoramidite approach is described in a model study to an alternative strategy in RNA synthesis.     

Synthesis of benzofuran derivatives—II A new synthesis of visnagin

Starting with 2-methyl-5:7-dihydroxychromone, an allyl group is introduced into the 6-position by Claisen migration of a 5-allyl ether. The initial protection of the 7-hydroxyl is best effected by tosylation. If the tosyl group is removed before Claisen migration and the C-allyl compound subjected to ozonolysis and ring closure, norvisnagin is obtained in a poor yield and can be methylated to visnagin. In an alternative method the tosyl group is removed just before ozonolysis. For this purpose the previous methylation of the 5-position is advantageous. This route gives visnagin directly in good yield.     

A new route to meso-formyl porphyrins

Prior syntheses of porphyrins bearing meso-formyl groups have generally employed the Vilsmeier formylation of an acid-resistant copper or nickel porphyrin. A new approach for the synthesis of free base porphyrins bearing one or two (cis or trans) meso-formyl substituents entails the use of a dipyrromethane bearing an acetal group at the 5-position, a dipyrromethane-1-carbinol bearing an acetal group at the 5-position or carbinol position, or a dipyrromethane-1,9-dicarbinol bearing an acetal group at a carbinol position. Treatment of the resulting meso-acetal-substituted free base porphyrin to gentle acidic hydrolysis yields the corresponding meso-formyl porphyrin.     

Reaction of 5-alkylidenerhodanines with diazonium salts

In the action of diazonium salts on 5-alkylidenerhodanines, azo compounds are formed by the replacement of one or two hydrogen atoms in the methyl group. In the case of 5-ethylidenerhodanines, the formation of an azorhodanine through the replacement of the alkylidene residue by an arylazo group takes place simultaneously. In the formazyl derivatives the long-wave absorption maximum is displaced hypsochromically by 15–20 nm as compared with the dyes having a single azo group.     

Synthesis of the new ring system,Pyrazolo[3,4-d][1,3]diazepine. A novel route for the synthesis of azolo[1,3]diazepines

A reduction of the nitrile group of 5-amino-4-cyano-1-methylpyrazole ( 3 ) has provided the very versatile compound 5-amino-1-methylpyrazole-4-carboxaldehyde ( 4 ). The amino group of 4 was protected using di-methylformamide dimethylacetal and the aldehyde group was then reacted with trimethylsilyl cyanide to afford the moisture sensitive compound 5-[[(dimethylamino)methylene]amino]-4-[cyano(trimethylsiloxy)-methyl]-1-methylpyrazole ( 10 ). The cyano group of the cyanohydrin 10 was reduced using a cobalt boride catalyst to afford an intermediate aminomethyl group which was involved in an in situ annulation. This reaction provided 1-methyl-1,4,5,6-tetrahydropyrazolo[3,4-d][1,3]diazepin-4-ol, a derivative of the new ring system, pyrazolo[3,4-d][1,3]diazepine.     

Aromatic bromination versus oxidation of indolylmalonates by bromine

The reactions of 5-substituted indolylmalonates (2a-e), carrying an electron-withdrawing group at the N(1) position, with bromine in CCl(4) or AcOH are reported. These substrates undergo oxidation in competition with the well-known aromatic bromination. Under the two sets of conditions, with parent indolylmalonate (2a), chemospecific oxidation is observed, whereas with 5-hydroxyindolylmalonate (2c), bromination at the 4- and 6-position is the dominating reaction. Investigation of the products composition of several 5-substituted indolylmalonates revealed the following trend: with a 5-substituted electron-withdrawing group like fluorine, the indolylmalonate undergoes oxidation rather than bromination. In contrast, with a 5-substituted electron-donating group, like a hydroxyl group, the ring bromination occurs preferentially over the oxidation. When the 5-substituent is an alkoxyl group, a significant amount of brominated-oxidized products is obtained. Monitoring the oxidation reaction by mass spectrometry allowed the characterization of the 2-bromoindolylidenemalonate intermediate. A bromonium ion is considered as possible pathway in the formation of this intermediate. The conformation of unsymmetrical methoxyl and benzyloxyl substituents was determined from (1)H NMR spectra, single-crystal X-ray diffraction and ab initio calculations.     

Synthesis,characterization, and solution properties of 5-ethyl-substituted poly(L-prolines). Synthesis of cis- and trans-5-ethyl-L-proline and optically active poly(cis-5-ethyl-D-proline)

This article reports a continuation of our work on the substituent effects on the preferred helical conformations and the mutarotation of substituted poly(L -prolines). The size of the substituent has been increased from a methyl group to an ethyl group in the 5 position. The purpose is twofold: (i) according to our theoretical conformational energy calculations, an ethyl group in the 5 position can exert a greater steric effect than can a methyl group; and (ii) the rotation-isomerization of the ethyl group introduces a new intriguing fact to the problem. The cis isomer of 5-ethylproline was synthesized by catalytic hydrogenation of Δ′-2-ethylpyrroline-5-carboxylic acid, whereas for trans-5-ethylproline, a chemical separation method involving p-toluenesulfonyl chloride was used. The resolution of cis-5-ethylproline and the assignment of absolute configurations have been carried out by fractional crystallization and circular dichroism spectroscopic techniques, respectively. Poly(cis-5-ethyl-D -proline) was obtained from its corresponding N-carboxyanhydrides via a ring opening polymerization.     

Formation of a bifunctional zirconocene complex that favours intramolecular -B(C6F5)2 addition to a Cp ring over sigma-ligand abstraction

The diphenyl-ansa-zirconocene complex 2 adds HB(C6F5)2 at the C=C double bond of its pendent Cp-allyl functional group to yield 3. During 3 days at room temperature the -B(C6F5)2 group takes part in an electrophilic substitution reaction at the adjacent Cp-ring to form 5 with formation of one equivalent of benzene. Complex 5 was characterized by X-ray diffraction.     

Synthesis of 4-haloserotonin derivatives and synthesis of the toad alkaloid dehydrobufotenine

4-Chloro-, 4-bromo- and 4-iodoserotonin derivatives were synthesized from 4-halo-5-oxyindoles, themselves derived from coumarins. Synthesis of the 4-iodoserotonins involved conjugate addition of an allyl group to a 5-iodocoumarin, followed by conversion of the allyl group into an aminoethyl unit. One of the iodoserotonin derivatives was converted into the toad alkaloid dehydrobufotenine, which was isolated as its hydroiodide.     

Synthesis of pentafluorosulfanylpyrazole and pentafluorosulfanyl-1,2,3-triazole and their derivatives as energetic materials by click chemistry

1-Pentafluorosulfanyl acetylene and its derivatives react with azide or diazomethane giving rise to an SF5-substituted 1,2,3-triazole or pyrazole. The SF5 group increases density remarkably and as a result enhances the detonation performance of the energetic materials relative to the CF3 group.     

Quinazolines and 1,4-benzodiazepines. LXI. Syntheses of 7-Acetyl-1,4-benzodiazepines

Methods for the synthesis of the biologically active 7-acetyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one ( 6 ) are described. This includes two new methods for the preparation of 5-acetyl-2-aminobenzophenone ( 4 ). The crucial steps in these syntheses involve, respectively, the oxidation of an ethyl group to an acetyl group with permanganate or ceric ions ( 2 → 3; 5 → 6 ), the selective reaction of methyl lithium with the cyano group of 7-cyano-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one ( 8 ) and the efficient condensation of benzyl cyanide with the ethylene ketal of p-nitroacetophenone to form the anthranil 11 .     

Post-synthetic modification of oligonucleotides containing 5-trifluoromethylpyrimidine bases

A practical and operationally simple post-synthetic modification of oligonucleotides containing 5-trifluoromethylpyrimidine bases is described. Trifluoromethyl group was used as a post-synthetic precursor and 5-trifluoromethylpyrimidine bases within oligonucleotides were converted into the corresponding 5-carboxy-, 5-cyano-, 5-amidinyl-, and 5-carbamoyl derivatives by treatment with an alkaline solution and amines. Moreover, post-synthetic treatment of fully protected and controlled pore glass (CPG)-attached oligonucleotides proceeded successfully with the simultaneous removal of all protecting groups, cleavage from CPG, and conversion of the trifluoromethyl group to afford the corresponding modified oligonucleotides.