Presence of an N-6 acetate group shifts the alkylation site of the ambident nucleophile sodium 1-N-methylisoguanide

Inclusion of an N-6 acetate into the ambident nucleophile, sodium 1-N-methylisoguanide, resulted in a shift in alkylation preference from N-9 to N-3. The preparation of the N-6 acetate of 1-N-methylisoguanine, 9-N-acetyl-1-N-methylisoguanine (4) , and related acetate analogs are described and evidence presented for their structural determination. Analysis of long range ¹³C-¹H coupling data facilitated the structural elucidation of the predominant alkylation products and provided evidence for the unusual N-7 hydrogen tautomeric form in one of them, 3-N-benzyl-6-N-acetyl-1-N-methylisoguanine (8).     

New Synthetic Approach to 4-N-Arylaminoazuleno[2,1-d]pyrimides

1-Cyano-2-N,N-dimethylformamidinylazulenes as new synthons directed to heterocycle-fused azulenes were obtained by the condensation of 2-amino-1-cyanoazulenes and N,N-dimethylformamide dimethyl acetal (DMFDMA). 1-Cyano-2-N,N-dimethylformamidinylazulene (2a) and 1-bromo-3-cyano-2-N,N-dimethylformamidinylazulene (2b) reacted with anilines (3a–h) to give 4-N-arylaminoazuleno-[2,1-d]pyrimidines in moderate yields. This reaction provides a new procedure for synthesis of pyrimidine-fused azulenes.     

Synthesis and spectral analysis of (±)-cis-N-[1-(2-hydroxy-2-phenyl-ethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide and (±)-cis-N-[1-(2-hydroxy-1-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide

Treatment of (±)-cis-N-(3-methyl-4-piperidyl)-N-phenylpropanamide (2) with styrene oxide (1) yielded a mixture of (±)-cis-N-[1-(2-hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide (3) and (±)-cis-N-[1-(2-hydroxy-1-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide (4) . The structure of compound 3 was confirmed by an unambiguous synthesis via (±)-cis-N-[1-(2-oxo-2-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropanamide (6) . The proton and carbon-13 resonances of compounds 3 and 4 were assigned with the aid of two-dimensional heteronuclear correlation experiments.     

Allgemeiner Zugang zu Polyaminen mit Ethan-1,2-diamin-Einheiten: Synthese von nicht natürlich vorkommenden homologen und isomeren N1,4-Di(4-cumaroyl)sperminen

█tl="American"█The synthesis of the three N,N′-di(4-coumaroyl)tetramines, i.e., of (E,E)-N-{3-[(2-aminoethyl)amino]propyl}-3,3′-bis(4-hydroxyphenyl)-N,N′-(ethane-1,2-diyl)bis[prop-2-enamide] ( 1a ), (E,E)-N-{4-[(2-aminoethyl)amino]butyl}-3,3′-bis(4-hydroxyphenyl)-N,N′-(ethane-1,2-diyl)bis[prop-2-enamide] ( 1b ), and (E,E)-N-{6-[(2-aminoethyl)amino]hexyl}-3,3′-bis(4-hydroxyphenyl)-N,N′-(ethane-1,2-diyl)bis[prop-2-enamide] ( 1c ), is described. It proceeds through stepwise construction of the symmetric polyamine backbone including protection and deprotection steps of the amino functions. Their behavior on TLC in comparison with that of 1,4-di(4-coumaroyl)spermine (=(E,E)-N-{4-[(3-aminopropyl)amino]butyl}-3,3′-bis(4-hydroxyphenyl)-N,N′-(propane-1,3-diyl)bis[prop-2-enamide]; 2 ) is discussed.     

14H-Naphtho[1′,2′:5,6] pyrano[2,3-b]quinoline derivatives

Reaction of (N-alkyl-N-phenyl)ethoxycarbonylacetamides with β-naphthol in the presence of phosphorus oxychloride afforded 1-oxo-3-(N-alkyl-N-phenyl)amino-1H-naphtho[2,1-b]pyrans. These compounds underwent reaction with N,N-dimethylformamide-phosphorus oxychloride at 95° yielding a mixture of 14H-naphtho[1′,2′:5,6]pyrano[2,3-b]quinoline derivatives and 1-oxo-2-formyl-3-(N-alkyl-N-phenyl)amino-9-oxy-1H-phenalene. When the same reaction was performed at 140°, only 14-oxo-14H-naphtho[1′,2′:5,6]pyrano[2,3-b]quinoline was obtained in a very good yield. The structures of such compounds were demonstrated by spectral data and by chemical transformations. On the other hand, the expected formylation in the 2 position was achieved when 1-oxo-3-(N-alkyl-N-benzyl)amino-1H-naphtho[2,1-b]pyrans reacted with N,N-dimethylformamide-phosphorus oxychloride.     

The acid-catalyzed rearrangement of 1-N-allylindolines

Zinc chloride-catalyzed rearrangement of 1-N-allylindoline and 1-N-(2-methylallyl)indoline proceeds readily in refluxing xylene to give 7-allylindoline and 7-(2-methylallyl)indoline in 73% and 86% yields, respectively. The reaction of 1-N-2-butenylindoline and zinc chloride give rise to the mixture of 7-(1-methylallyl)indoline, 7-(cis- and trans-1-methyl-1-propenyl)indoline, and 7-(trans-2-butenyl)indoline. On the other hand, the similar reaction of 1-N-(3-methyl-2-butenyl)indoline with zinc chloride led to the formation of a mixture of 1,2,5,6-tetrahydro-4,4-dimethyl-4H-pyrrolo[3,2,1-ij]quinoline and 7-(3-methyl-2-butenyl)indoline.     

Über Pterinchemie. 85. Mitteilung. Polyacetylierte 5,6,7,8-Tetrahydro-D- und -L-neopterine. Ein besonderer Fall von N(5)-Alkylierung des 5,6,7,8-Tetrahydroneopterin-Gerüstes

Polyacetylated 5,6,7,8-Tetrahydro-D - and L -neopterins. A Special Case of N(5)-Alkylation of 5,6,7,8-Tetrahydroneopterins Improved conditions are reported for the preparation of the earlier described (6R)- and (6S)-1′-O,2′-O,3′-O,2-N,5-pentaacetyl-5,6,7,8-tetrahydro-L -neopterins, one of which could be obtained as pure crystals. Its structure, determined by X-ray-diffraction analysis, corresponds to the (6R)-enantiomer. The method has also been used to make the corresponding D -diastereoisomers. Further acetylation of (6RS)-1′-O,2′-O,3′-O,2-N-tetraacetyl-5,6,7,8-tetrahydro-D -neopterin under drastic conditions yields a mixture of several polyacetylated D -neopterin derivatives and a polyacetylated ethyl-tetrahydro-D -neopterin which was isolated in crystalline form and established by X-ray-diffraction analysis to be (6R)-1′-O,2′-O,3′-O,4-O,2-N,2-N,8-heptaacetyl-5-ethyl-5,6,7,8-tetrahydro-D -neopterin.     

Order of Reactivity of OH/NH Groups of Glucosamine Hydrochloride and N-Acetyl Glucosamine Toward Benzylation Using NaH/BnBr in DMF

The order of reactivity of OH and NH groups of glucosamine hydrochloride (GlcNH₂^.HCl) and N-acetyl glucosamine (GlcNAc) toward benzylation with NaH/BnBr in DMF was investigated. For GlcNH₂^.HCl, benzyl groups were introduced in the order of N-Bn > N-Bn₂ > 1-O-Bn > 6-O-Bn > 4-O-Bn > 3-O-Bn; for GlcNAc, benzyl groups were introduced in the order of 1-O-Bn > 6-O-Bn > 4-O-Bn > 3-O-Bn > N-Bn. A range of partially benzylated 2-N,N′-dibenzyl glucopyranosides and GlcNAc derivatives were obtained in a single step.     

Synthesis and structural characterization of novel 2-benzimidazolylthioureas: adducts of natural isothiocyanates and 2-amino-1-methylbenzimidazole

Adducts of natural allyl, phenethyl, and benzyl isothiocyanates and 2-amino-1-methylbenzimidazole were synthesized. After optimization of the reaction conditions, the target 2-benzimidazolylthioureas were obtained in reasonable yields. The detailed molecular and crystal structures of these compounds were characterized by spectroscopic and X-ray methods. Spectral analysis demonstrated that N-(1-methylbenzimidazolyl)-N′-allylthiourea, N-(1-methylbenzimidazolyl)-N′-benzylthiourea, and N-(1-methylbenzimidazolyl)-N′-phenethylthiourea exist in solution in an unprecedented three tautomeric forms, whose structures were corroborated unambiguously.     

Reactions of N-substituted pyridinium carbamoylmethylenides with ethyl arylidenecyanoacetates

Condensation of pyridinium N-alkyl-, N-cycloalkyl-, N-benzyl-, and N-phenethylcarb-amoylmethylenides with ethyl arylidenecyanoacetates stereoselectively gives 4,5-trans-1-alkyl-, 4,5-trans-l-cycloalkyl-, 4,5- trans-1-benzyl-, and 4,5-trans-1-phenethyl-4-aryl-3-cyano-6-oxo-5-(3-R-1-pyridinio)-1,4,5,6-tetrahydropyridin-2-olates. However, pyridinium N-arylcarb-amoylmethylenides react with the same esters without ring closure, yielding Michael adducts, viz., ethyl 3-aryl-4-(N-arylcarbamoyl)-2-cyano-4-(1-pyridinio)butyrates.     

Understanding the Deactivation Pathways of Iridium(III) Pyridine-Carboxiamide Catalysts for Formic Acid Dehydrogenation

The degradation pathways of highly active [Cp*Ir(κ²-N,N-R-pica)Cl] catalysts (pica=picolinamidate; 1 R=H, 2 R=Me) for formic acid (FA) dehydrogenation were investigated by NMR spectroscopy and DFT calculations. Under acidic conditions (1 equiv. of HNO₃), 2 undergoes partial protonation of the amide moiety, inducing rapid κ²-N,N to κ²-N,O ligand isomerization. Consistently, DFT modeling on the simpler complex 1 showed that the κ²-N,N key intermediate of FA dehydrogenation ( I_NH ), bearing a N-protonated pica, can easily transform into the κ²-N,O analogue ( I_NH2 ; ΔG^≠≈11 kcal mol⁻¹, ΔG ≈−5 kcal mol⁻¹). Intramolecular hydrogen liberation from I_NH2 is predicted to be rather prohibitive (ΔG^≠≈26 kcal mol⁻¹, ΔG≈23 kcal mol⁻¹), indicating that FA dehydrogenation should involve mostly κ²-N,N intermediates, at least at relatively high pH. Under FA dehydrogenation conditions, 2 was progressively consumed, and the vast majority of the Ir centers (58 %) were eventually found in the form of Cp*-complexes with a pyridine-amine ligand. This likely derived from hydrogenation of the pyridine-carboxiamide via a hemiaminal intermediate, which could also be detected. Clear evidence for ligand hydrogenation being the main degradation pathway also for 1 was obtained, as further confirmed by spectroscopic and catalytic tests on the independently synthesized degradation product 1 c . DFT calculations confirmed that this side reaction is kinetically and thermodynamically accessible.     

Alkaline Earth Diazapentadienyl Compounds: Structure of [Ba2{(C6H11)NC(Me)CHC(Me)N(C6H11)}3{(SiMe3)2N}]

Three different bonding modes in one molecule! The diazapentadienyl ligands in the title compound 1 adopt η¹,η¹-N,N-chelating plus η⁵-terminal, η¹η¹-N,N chelating plus η⁵-bridging, and novel η¹-N plus η³-1-aza-allyl bonding modes. R=cyclohexyl.     

Synthesis and X-ray structures of cyclorhodated indole-tert-thiocarboxamides

Indole-1(and 3)-N,N-dimethylthiocarboxamide, 3-(1-pyrrolidinothiocarbonyl)indole and -1-methylindole (HL) react with hexachlorotetrakis(tri-n-butylphosphine)dirhodium(III) to give cyclorhodated complexes, [Rh(L)Cl₂(PBu₃)₂] with L acting as a C—S chelate ligand (PBu₃ = tri-n-butylphosphine) and indole-2-N,N-dimethylthiocarboxamide forms [Rh(L)Cl₂(PBu₃)₂] with L acting as an N—S chelate. 1-Methylindole-2-N,N-dimethylthiocarboxamide and 2-(1-pyrrolidinothiocarbonyl)-1-methylindole did, however, not react under similar conditions. The complexes were characterized by spectroscopic methods and the structures of the four complexes with HL = indole-1- and 3-N,N-dimethylthiocarboxamide, and 3-(1-pyrrolidinothiocarbonyl)indole and -1-methyl-indole were confirmed by X-ray analysis. The octahedral complex [Rh(L)Cl₂(PBu₃)₂] had trans-(PBu₃)₂ and cis-(Cl)₂ arrangements and L was coordinated through the S and indole ring C2 atoms to form a five-membered chelate ring. The unreactivity of 1-methylindole-2-N,N-dimethylthiocarboxamide and 2-(1-pyrrolidino)thiocarbonyl-1-methyl-indole may be due to steric hindrance caused by the additional 1-methyl substituent.     

Acetylenchemie. 9. Mitt. Anellierte imidazole aus N-propinylamid-vorstufen

The Compound 2-(N-Formyl-N-prop-2′-inyl)aminopyridine was cyclised in boiling formic acid to 3-methylimidazo[1,2-a]pyridine, with 3-methylene-2H-imidazo[1,2-a]pyridine as the intermediate. Under similar conditions the 1,3-diprop-2-inylpyrimido[4,5-b]quinoline-2,4-dione resulted from 1-methylimidazo[1,2-a]quinoline-4-carbonic acid-N-2-prop-2′-inylamide and from the 1-prop-2′-inylbenzo[b][1,8]naphthyridin-2-one the 1-methylbenzo[b]imidazo[1,2,3-ij]naphthyridine-4,7-dione as a new ring system, was obtained.     

Synthesis and properties of [1,4]diazepino[6,5-b]indoles

1-Aryl-2-oxo-1,2,3,6-tetrahydro[1,4]diazepino[6,5-b]indole N-oxides were synthesized based on 3-(N"-aryl-N"-chloroacetyl)amino-2-formylindoles. Deoxidation of 2-oxo-1-phenyl-1,2,3,6-tetrahydro[1,4]diazepino[6,5-b]indole N-oxide afforded 1,2,3,6-tetrahydro- and 1,2,3,4,5,6-hexahydro[1,4]diazepino[6,5-b]indole derivatives. A new approach to the synthesis of pyrido[3,2-b]indole and pyrimido[5,4-b]indole derivatives was developed.     

Supramolecular Complexes of Calix[4]resorcinolarene Tetramethylsulfonate with Organophosphorus Compounds

Supramolecular complexes of calix[4]resorcinolarene tetramethylsulfonate with certain organophosphorus compounds, such as dimethyl (1,1-dimethyl-3-oxobutyl)phosphonate, 1-O-[bis(N,N-diethylamino)thiophosphinoyl]-3,5-O-[(N,N-diethylamino)thiophosphonoyl)-2,4-O-methylenexylitol, and 2-O-[bis(N,N-diethylamino)thiophosphinoyl]-3,5-O-[(N,N-diethylamino)thiophosphonoyl)-1,4-anhydroxylitol, were prepared in aqueous and organic media. The complexes were isolated and characterized by elemental analysis and ¹H and ¹³C NMR spectroscopy.     

1,2-fused pyrimidines. V. Synthesis of 1-alkyl or phenyl-2H-dipyrido-[1,2-a:2′,3′-d]pyrimidine-2,5(1H)-diones

The reaction of 2-[(N-acyl, N-alkyl or phenyl)amino]-4H-pyrido[1,2-a]pyrimidin-4-ones 8a-g with the N,N-dimethylformamide/phosphorus oxychloride Vilsmeier reagent 1 (95°, 90 minutes) afforded 1-alkyl or phenyl-2H-dipyrido[1,2-a:2′,3′-d]pyrimidine-2,5(1H)^?diones, 3-alkyl substituted or not, 10a-g . The starting compounds 8 were prepared by treating 2-amino-4H-pyrido[1,2-a]pyrimidin-4-ones N-alkyl substituted 7a,b or N-phenyl substituted 4 with excess anhydrides (130°, 7 hours) when the 2-(alkylamino) derivatives 7 were used in the reaction, compounds 8 were obtained along with very small amounts of 3-acyl-2-(alkylamino)-4H-pyrido[1,2-a]pyrimidin-4-ones 9 .     

Synthesis of (1′S*,2R*,3R*)- and (1′S*,2R*,3S*)-N-arylsulfonyl-2-(1′-halogenethyl)-3-methylindolines and their selective toxicity against SH-SY5Y cell line

N-tosyl-2- and N-tosyl-4-halogen-substituted derivatives of 2-(1-methylbut-2-en-1-yl)aniline were synthesized and their molecular iodine-mediated cyclization was investigated. The cyclization upon interaction of N-tosyl-6-methyl-2-(1-methylbut-2-en-1-yl)aniline with molecular iodine in methyl tert-butyl ether or acetonitrile was studied, as well as the interaction of this sulfonamide with N-bromosucinimide in dichloromethane. Synthesized (2R*,3R*)- and (2R*,3S*)-N-arylsulfonyl-2-(1-halogenoethyl)-3-methylindoline derivatives showed cytotoxic activity against HEK293 cells, SH-SY5Y, Jurkat, and HepG2 cell lines. The compounds (2R*,3S*)-N-arylsulfonyl-7-bromo-2-(1-halogenoethyl)-3-methylindoline cis- 4a , stereoisomeric (2R*,3R*)-trans- 4h and (2R*,3S*)-N-tosyl-7-chloro-2-(1-halogenoethyl)-3-methylindoline cis- 4h demonstrated selective toxicity against SH-SY5Y cell line (IC₅₀ ≈ 3 ÷ 5 μM), and did not affect HEK293, Jurkat, and HepG2 cells.     

Oxidation of 3-hydroxykynurenine. A reexamination

The oxidation mixture of 3-hydroxykynurenine ( 1 ), treated with aqueous acetic anhydride and, subsequently, with acidic methanol, yields the 1-hydroxy-3-carbomethoxy-5-methoxy-11-(β-aspartoyl-N-acetyl-methyl ester)pyrido[3,2-a]phenoxazine ( 5 ), the 1-hydroxy-11-(β-aspartoyl-N-acetyl-methyl ester)-5.H-pyrido[3,2-a]-phenoxazin-5-one ( 6 ), the 1-methoxy-11-(β-aspartoyl-N-acetyl-methyl ester)-5H-pyrido[3,2-a]phenoxazin-5-one ( 6a ), the l,5-dimethoxy-11-(β-aspartoyl-N-acetyl-methyl ester)pyrido[3,2-a]phenoxazine ( 7 ) and the 1-methyl-1(1′-[11-(β-aspartoyl-methyl esterimino)]ethenyl)ketal-1H,5H-pyrido[3,2-a]phenoxazin-5-one ( 8 ). A probable scheme, for the compound formation, is reported.     

Synthesis and Anti-HIV Activity of Further Examples of 1-[3-Deoxy-3-(N-hydroxyamino)-β-d-threo-(and β-d-erythro)-pentofuranosyl]thymine Derivatives1

Abstract

Upon sodium cyanoborohydride reduction followed by de-O-silylation, the O-methyloxime and N-benzylnitrone of 5′-TBDMS-3′-ketothymidine gave resolvable epimeric mixtures of 1-[2,3-dideoxy-3-(N-methoxyamino)-β-d-threo-and β-d-erythro-pentofuranosyl]thymine and 1-[3-(N-benzyl-N-hydroxyamino)-2,3-dideoxy-β-d-threo- and β-d-erythro-pentofuranosyl]thymine respectively. These compounds were inactive against HIV. On the other hand, 1-[2,3-dideoxy-3-(N-hydroxyamino)-5-O-TBDMS-β-d-threo-pentofuranosyl]thymine, upon treatment with acetone, then de-O-silylation, gave the bicyclonucleoside analogue 15, slightly more active against HIV in vitro than DDI.