7‐Iodo‐8‐aza‐7‐deaza‐2′‐deoxy­adenosine and 7‐bromo‐8‐aza‐7‐deaza‐2′‐deoxyadenosine

The isomorphous structures of the title molecules, 4‐amino‐1‐(2‐deoxy‐β‐d ‐erythro‐pento­furan­osyl)‐3‐iodo‐1H‐pyrazolo‐[3,4‐d]pyrimidine, (I), C₁₀H₁₂IN₅O₃, and 4‐amino‐3‐bromo‐1‐(2‐deoxy‐β‐d ‐erythro‐pento­furan­osyl)‐1H‐pyrazolo[3,4‐d]­pyrimidine, (II), C₁₀H₁₂BrN₅O₃, have been determined. The sugar puckering of both compounds is C1′‐endo (^1′E). The N‐­glycosidic bond torsion angle χ¹ is in the high‐anti range [?73.2 (4)° for (I) and ?74.1 (4)° for (II)] and the crystal structure is stabilized by hydrogen bonds.     

7‐Cyclopropyl‐2′‐deoxytubercidin: a carbocyclic side‐chain derivative of 7‐deaza‐2′‐deoxyadenosine

The title compound {systematic name: 4‐amino‐5‐cyclopropyl‐7‐(2‐deoxy‐β‐D‐erythro‐pentofuranosyl)‐7H‐pyrrolo[2,3‐d]pyrimidine}, C₁₄H₁₈N₄O₃, exhibits an anti glycosylic bond conformation, with the torsion angle χ = −108.7 (2)°. The furanose group shows a twisted C1′‐exo sugar pucker (S‐type), with P = 120.0 (2)° and τ_m = 40.4 (1)°. The orientation of the exocyclic C4′—C5′ bond is ‐ap (trans), with the torsion angle γ = −167.1 (2)°. The cyclopropyl substituent points away from the nucleobase (anti orientation). Within the three‐dimensional extended crystal structure, the individual molecules are stacked and arranged into layers, which are highly ordered and stabilized by hydrogen bonding. The O atom of the exocyclic 5′‐hydroxy group of the sugar residue acts as an acceptor, forming a bifurcated hydrogen bond to the amino groups of two different neighbouring molecules. By this means, four neighbouring molecules form a rhomboidal arrangement of two bifurcated hydrogen bonds involving two amino groups and two O5′ atoms of the sugar residues.     

8‐Aza‐7‐deaza‐7‐propynyladenosine methanol solvate

In the title compound, 4‐amino‐3‐propynyl‐1‐(β‐d ‐ribofur­anosyl)‐1H‐pyrazolo[3,4‐d]pyrimidine methanol solvate, C₁₃H₁₅N₅O₄·CH₃OH, the torsion angle of the N‐glycosylic bond is between anti and high‐anti [χ = −101.8 (5)°]. The ribofuranose moiety adopts the C3′‐endo (³T₂) sugar conformation (N‐type) and the conformation at the exocyclic C—C bond is +sc (gauche, gauche). The propynyl group is out of the plane of the nucleobase and is bent. The compound forms a three‐dimensional network which is stabilized by several hydrogen bonds (O—H·O and O—H·N). The nucleobases are stacked head‐to‐tail. The methanol solvent mol­ecule forms hydrogen bonds with both the nucleobase and the sugar moiety.     

7‐Vinyl‐8‐aza‐7‐de­aza‐2′‐deoxy­adenosine monohydrate

In the title compound, 4‐amino‐1‐(2‐deoxy‐β‐d ‐eythro‐pento­furan­osyl)‐3‐vinyl‐1H‐pyrazolo­[3,4‐d]­pyrimidine monohydrate, C₁₂H₁₅N₅O₃·H₂O, the conformation of the gly­cosyl bond is anti. The furan­ose moiety is in an S conformation with an unsymmetrical twist, and the conformation at the exocyclic C—C(OH) bond is +sc (gauche, gauche). The vinyl side chain is bent out of the heterocyclic ring plane by 147.5 (5)°. The three‐dimensional packing is stabilized by O—H·O, O—H·N and N—H·O hydrogen bonds.     

Synthesis of 5‐Amino‐3,3‐dimethyl‐7‐phenyl‐3H‐[1,2]oxathiolo[4,3‐b]pyridine‐6‐carbonitrile 1,1‐Dioxides

The reaction of 4‐amino‐5,5‐dimethyl‐5H‐1,2‐oxathiole 2,2‐dioxide ( 1 ) with 2‐(arylidene)malononitriles 2 in ethanol, at reflux, using piperidine as catalyst, afforded 5‐amino‐3,3‐dimethyl‐7‐aryl‐3H‐[1,2]oxathiolo[4,3‐b]pyridine‐6‐carbonitrile 1,1‐dioxides ( 3 ) in moderate chemical yields.     

Preparation of 8‐Aza‐7‐deazaaristeromycin and ‐neplanocin A and Their 5′‐Homologs

The synthesis of new members of the aristeromycin and neplaoncin A families of carbocyclic nucleosides possessing the 1H‐pyrazolo[3,4‐d]pyrimidine ring is reported. For this purpose, an adapted route to 4‐amino‐1H‐pyrazolo[3,4‐d]pyrimidine is described.     

A New Route for Synthesis of 2‐Substituted‐3‐amino‐5‐phenyl‐7‐N,N‐dimethylamino Phenazinium Chloride Salts

2‐Methyl‐3‐amino‐5‐phenyl‐7‐N , N‐dimethylamino phenazinium chloride salts were synthesized in better yields via the cyclization of 4‐amino‐N ,N‐dimethylaniline with toluidine derivatives and aminobenzene under the oxidation of sodium bicarbonate.     

Cinnamoyl Derivatives of 7α‐Amino‐ and 7α‐(Aminomethyl)‐ N‐(cyclopropylmethyl)‐6,14‐endo‐ethanotetrahydronororipavines are High‐Potency Opioid Antagonists

Methods have been developed for the synthesis of 7α‐amino‐ and 7α‐(aminomethyl)‐N‐cyclopropylmethyl‐6,14‐endo‐ethanotetrahydronororipavines and their cinnamoyl derivatives (Schemes 1 and 3). In displacement binding assays, the cinnamoyl derivatives 4c and 5c had high affinity for opioid receptors, but no particular selectivity for any receptor type or differences in affinity between 4c and 5c (Table 1). In tissue assays for opioid receptor function, in which both 4c and 5c were potent antagonists, the aminomethyl derivative 5c was 20‐ to 70‐fold more potent than the amino derivative 4c (Table 2). These data are in keeping with previously reported in vivo data and confirm the major effect of the methylene spacer in 5c .     

Preparation of 5‐methyl‐2‐sulfanyl‐7h‐1,3,4‐thiadiazolo[3,2‐a]‐pyrimidin‐7‐ones

7H‐1,3,4‐Thiadiazolo[3,2‐a]pyrimidin‐7‐ones can be prepared by the acylation of 5‐amino‐1,3,4‐thiadiazoles with diketene and subsequent ring closure (dehydration). Whereas arylthio substituents (SC₆H₅) can be introduced in 2‐position by the replacement of Br, alkylthio groups (SC₂H₅) have to be already presentin the starting 5‐amino‐1,3,4‐thiadiazole. The ambident nucleophile 2‐thiazolidinethione reacts in the Br substitution reaction on the N atom.     

7‐Deaza‐2′‐deoxy­guanosine

In the title compound, 2‐amino‐7‐(2‐deoxy‐β‐d ‐erythro‐pentofuran­osyl)‐3,7‐dihydro­pyrrolo[2,3‐d]pyrimidin‐4‐one, C₁₁H₁₄N₄O₄, the N‐glycosylic bond torsion angle, χ, is anti [−106.5 (3)°]. The 2′‐deoxy­ribofuran­osyl moiety adopts the ³T₄ (N‐type) conformation, with P = 39.1° and τ_m = 40.3°. The conformation around the exocyclic C—C bond is ap (trans), with a torsion angle, γ, of −173.8 (3)°. The nucleoside forms a hydrogen‐bonded network, leading to a close‐packed multiple‐layer structure with a head‐to‐head arrangement of the bases. The nucleobase interplanar O=C—C⋯NH₂ distance is 3.441 (1) Å.     

7‐Deaza‐2,8‐diaza­adenosine

In the title compound [systematic name: 4‐amino‐7‐(β‐d ‐ribofuranos­yl)‐7H‐pyrazolo[3,4‐d][1,2,3]triazine], C₉H₁₂N₆O₄, the torsion angle of the N‐glycosylic bond is high anti [χ = −83.2 (3)°]. The ribofuran­ose moiety adopts the C2′‐endo–C1′‐exo (²T₁) sugar conformation (S‐type sugar pucker), with P = 152.4° and τ_m = 35.0°. The conformation at the C4′—C5′ bond is +sc (gauche,gauche), with the torsion angle γ = 52.0 (3)°. The compound forms a three‐dimensional network that is stabilized by several hydrogen bonds (N—H⋯O, O—H⋯N and O—H⋯O).     

Polar aspects of intramolecular interactions in 2‐amino‐5‐nitro‐4‐methylpyridines and 2‐amino‐3‐nitro‐4‐methylpyridines

The dipole moments of twelve 2‐N‐substituted amino‐5‐nitro‐4‐methylpyridines ( I‐XII ) and three 2‐N‐substituted amino‐3‐nitro‐4‐methylpyridines ( XIII‐XV ) were determined in benzene. The polar aspects of intramolecular charge‐transfer and intramolecular hydrogen bonding were discussed. The interaction dipole moments, μ_int, were calculated for 2‐N‐alkyl(or aryl)amino‐5‐nitro‐4‐methylpyridines. Increased alkylation of amino nitrogen brought about an intensified push‐pull interaction between the amino and nitro groups. The solvent effects on the dipole moments of 2‐N‐methylamino‐5‐nitro‐4‐methyl‐( I ), 2‐N,N‐dimethylamino‐5‐nitro‐4‐methyl‐ ( II ) and 2‐N‐methylamino‐3‐nitro‐4‐methylpyridines ( XIII ) were different. Specific hydrogen bond solute‐solvent interactions increased the charge‐transfer effect in I , but it did not disrupt the intramolecular hydrogen bond in XIII.     

Effective Methods for the Synthesis of N‐Methyl β‐Amino Acids from All Twenty Common α‐Amino Acids Using 1,3‐Oxazolidin‐5‐ones and 1,3‐Oxazinan‐6‐ones

N‐Methyl β‐amino acids are generally required for application in the synthesis of potentially bioactive modified peptides and other oligomers. Previous work highlighted the reductive cleavage of 1,3‐oxazolidin‐5‐ones to synthesise N‐methyl α‐amino acids. Starting from α‐amino acids, two approaches were used to prepare the corresponding N‐methyl β‐amino acids. First, α‐amino acids were converted to N‐methyl α‐amino acids by the so‐called ‘1,3‐oxazolidin‐5‐one strategy’, and these were then homologated by the Arndt–Eistert procedure to afford N‐protected N‐methyl β‐amino acids derived from the 20 common α‐amino acids. These compounds were prepared in yields of 23–57% (relative to N‐methyl α‐amino acid). In a second approach, twelve N‐protected α‐amino acids could be directly homologated by the Arndt–Eistert procedure, and the resulting β‐amino acids were converted to the 1,3‐oxazinan‐6‐ones in 30–45% yield. Finally, reductive cleavage afforded the desired N‐methyl β‐amino acids in 41–63% yield. One sterically congested β‐amino acid, 3‐methyl‐3‐aminobutanoic acid, did give a high yield (95%) of the 1,3‐oxazinan‐6‐one ( 65 ), and subsequent reductive cleavage gave the corresponding AIBN‐derived N‐methyl β‐amino acid 61 in 71% yield (Scheme 2). Thus, our protocols allow the ready preparation of all N‐methyl β‐amino acids derived from the 20 proteinogenic α‐amino acids.     

Preparation of 2‐amino‐5‐methyl‐7H‐1,3,4‐thiadiazolo[3,2‐α]pyrimidin‐7‐ones

2‐Amino substituted 7H‐1,3,4‐thiadiazolo[3,2‐α]pyrimidin‐7‐ones 11a‐e were prepared by the reaction of 2‐bromo‐5‐amino‐1,3,4‐thiadiazole ( 1b ) and diketene ( 8 ), subsequent cyclocondensation ( 9b → 3b ) and displacement of the bromo substituents by the reaction with primary or secondary amines ( 3b → 11a‐e ). The hydrogen atom 6‐H in the heterobicycle 3b is replaced by a Cl or Br atom in the transformation of 3b → 14a,b. The 2‐bromo‐6‐chloro compound 14a reacts chemoselectively in the 2‐position with dimethylamine ( 14a → 15 ). The structure elucidations are based on one‐ and two‐dimensional NMR techniques including a heteronuclear NOE measurement.     

2‐Amino‐8‐(2‐deoxy‐2‐fluoro‐β‐D‐arabinofuranosyl)imidazo[1,2‐a]‐1,3,5‐triazin‐4(8H)‐one: Synthesis and Conformation of a 5‐Aza‐7‐deazaguanine Fluoronucleoside

Nucleobase‐anion glycosylation of 2‐[(2‐methyl‐1‐oxopropyl)amino]imidazo[1,2‐a]‐1,3,5‐triazin‐4(8H)‐one ( 6 ) with 3,5‐di‐O‐benzoyl‐2‐deoxy‐2‐fluoro‐α‐D ‐arabinofuranosyl bromide ( 8 ) furnishes a mixture of the benzoyl‐protected anomeric 2‐amino‐8‐(2‐deoxy‐2‐fluoro‐D ‐arabinofuranosyl)imidazo[1,2‐a]‐1,3,5‐triazin‐4(8H)‐ones 9 / 10 in a ratio of ca. 1 : 1. After deprotection, the inseparable anomeric mixture 3 / 4 was silylated. The obtained 5‐O‐[(1,1‐dimethylethyl)diphenylsilyl] derivatives 11 and 12 were separated and desilylated affording the nucleoside 3 and its α‐D anomer 4 . Similar to 2′‐deoxy‐2′‐fluoroarabinoguanosine, the conformation of the sugar moiety is shifted from S towards N by the fluoro substituent in arabino configuration.     

Synthesis and Characterization of 11‐Amino‐3‐methoxy‐8‐substituted‐12‐aryl‐8,9‐dihydro‐7H‐chromeno[2,3‐b]quinolin‐10(12H)‐one Derivatives

A series of 2‐amino‐7‐methoxy‐4‐aryl‐4H‐chromene‐3‐carbonitrile compounds 2 were obtained by condensation of 3‐methoxyphenol with β‐dicyanostyrenes 1 in absolute ethanol containing piperidine. The intermediate enamines 3 were prepared by compounds 2 with 5‐substituted‐1,3‐cyclohexanedione using p‐toluenesuflonic acid (TsOH) as catalyst. The title compounds 11‐amino‐3‐methoxy‐8‐substituted‐12‐aryl‐8,9‐dihydro‐7H‐chromeno[2,3‐b]quinolin‐10(12H)‐one 4 were synthesized by cyclization of the intermediate enamines 3 in THF with K₂CO₃ /Cu₂Cl₂ as catalyst. The structures of all compounds were characterized by elemental analysis, IR, MS, and ¹H NMR spectra. The crystal structure of compound 4i was determined by single‐crystal X‐ray diffraction analysis.     

Synthesis of N‐aryl‐2‐amino‐4‐oxo‐3,4‐dihydrothieno[2,3‐d]pyrimidine‐6‐carboxamides

Synthetic routes for the preparation of methyl 2‐amino‐4‐methoxythieno[2,3‐d]pyrimidine‐6‐carboxylate (4) ‐ useful intermediate for lipophilic and classical antifolates from 2‐amino‐4,6‐dichloropyrimidine‐5‐car‐baldehyde (1) have been studied. It has been shown that more efficient synthesis of compound 4 includes the preparation of 4‐methoxy derivative 7 and subsequent tandem substitution/annulation reaction with methyl mercaptoethanoate in dimethylformamide in the presence of potassium carbonate and molecular sieves 4 Å. Compound 4 was used for the synthesis of N‐aryl 2‐amino‐4‐oxo‐3,4‐dihydrothieno[2,3‐d]‐pyrimidine‐6‐carboxamides 10a‐c, including an analog of folic acid with amide bridge ‐ N‐(4‐{[(2‐amino‐4‐oxo‐3,4‐dihydrothieno[2,3‐d]pyrirnidin‐6‐yl)carbonyl]amino}‐benzoyl)‐L‐glutamic acid (10c) .     

1,3‐Diaxial Repulsion vs. π‐Delocalization in the 7‐Amino‐2,4‐diazabicyclo[3.3.1]nonan‐3‐one Skeleton

(1R,5S,6S,8R)‐6,8,9‐Trihydroxy‐3‐oxo‐2,4‐diazabicyclo[3.3.1]nonan‐7‐ammonium chloride hydrate ( 3 Cl⋅H₂O) and (1R,5S,6S,8R)‐7‐amino‐6,8,9‐trihydroxy‐2,4‐diazabicyclo[3.3.1]nonan‐3‐one ( 4 ) have been prepared, and their crystal structures have been determined from single‐crystal X‐ray diffraction data. Both compounds consist of a bicyclic skeleton with the three N‐atoms in an all‐cis‐1,3,5‐triaxial arrangement. Considerable repulsion between these axial N‐atoms is indicated by a significant distortion of the two cyclohexane chairs and by increased N⋅⋅⋅N distances. The lone pair of the free amino group of 4 is involved in intermolecular H‐bonding and is turned away from the adjacent carbonyl C‐atom of the urea moiety. The structural properties together with the observed reactivity do not provide any evidence for an intramolecular donor‐acceptor interaction between the carbonyl C‐ and the amine N‐atom.     

Synthesis and Biological Activities of 7‐Arylazo‐7H‐pyrazolo[5,1‐c][1,2,4] Triazol‐6(5H)‐Ones and 7‐Arylhydrazono‐7H‐[1,2,4]triazolo[3,4‐b] [1,3,4]thiadiazines

Two series of 7‐arylazo‐7H‐3‐(2‐methyl‐1H‐indol‐3‐yl)pyrazolo[5,1‐c][1,2,4]triazol‐6(5H)‐ones 4 and 7‐arylhydrazono‐7H‐3‐(2‐methyl‐1H‐indol‐3‐yl)‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazines 7 were prepared via reactions of 4‐amino‐3‐mercapto‐5‐(2‐methyl‐1H‐indol‐3‐yl)‐1,2,4‐triazole 1 with ethyl arylhydrazono‐chloroacetate 2 and N‐aryl‐2‐oxoalkanehydrazonoyl halides 5 , respectively. A possible mechanism is proposed to account for the formation of the products. The biological activity of some of these products was also evaluated.     

An easy route to 2‐substituted‐2,3‐dihydro‐5(7)H‐oxazolo[3,2‐a]pyrimidin‐5‐ones and 7‐ones starting from the corresponding 2‐amino‐2‐oxazolines

The isomeric 2‐substituted‐7(5)‐methyl‐2,3‐dihydro‐5(7)H‐oxazolo[3,2‐a]pyrimidin‐5‐ones 3a‐b and 7‐ones 2a‐b,7a were synthesized by cyclocondensation from the 5‐substituted‐2‐amino‐2‐oxazolines 1a‐b with biselectrophiles. In boiling ethanol, the reaction of 1a‐b with acetylenic esters led to a mixture of 2a‐b,7a with a small amount of (E)‐2‐N‐(2‐ethoxycarbonylethylene)‐5‐substituted‐2‐iminooxazolines 5a‐b . The ring annulation between 1a‐b and diketene gave the 2‐substituted‐7‐hydroxy‐7‐methyl‐2,3,6,7‐tetrahydro‐5H‐oxazolo[3,2‐ a ]pyrimidin‐5‐ones 4a‐b which can be easily dehydrated to provide the 2‐substituted‐7‐methyl‐2,3‐dihydro‐5H‐oxazolo[3,2‐a]pyrimidin‐5‐ones 3a‐b .