4,6-Dimethylpyridine-2,3-dicarbonitrile and its reaction with <Emphasis Type="Italic">N</Emphasis>-acylhydrazines

An efficient method has been developed for the synthesis of 4,6-dimethylpyridine-2,3-dicarbonitrile. A study was carried out on the reaction of this compound with N-acylhydrazines to give two structural isomers, namely, N′-(7-amino-2,4-dimethyl-5H-pyrrolo[3,4-b]pyridin-5-ylidene)carbohydrazides and N′-(5-amino-2,4-dimethyl-7H-pyrrolo[3,4-b]pyridin-7-ylidene)carbohydrazides as well as disubstituted N′,N″-(2,4-dimethyl-5H-pyrrolo[3,4-b]pyridine-5,7-diylidene)dicarbohydrazides.     

Single-step synthesis of substituted 7-aminopyrano[2,3-<Emphasis Type="Italic">d</Emphasis>]pyrimidines

A single-step method for the synthesis of substituted 7-aminopyrano[2,3-d]pyrimidines was developed. The method involves a three-component reaction of barbituric acid or 4,6-dihydroxypyrimidine with aromatic aldehydes and malononitrile in DMF in the presence of N-methylmorpholine as a catalyst.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2242–2244, October, 2004.     

1H-pyrrolo[3,2-c]pyridin-4,6(5H,7H)dione(3,7-dideazaxanthine)

A facile chemical synthesis of 1H-pyrrolo[3,2-c]pyridin-4,6(5H,7H)dione (3,7-dideazaxanthine) has been accomplished from ethyl 3-ethoxycarbonylpyrrole-2-acetate.     

Deoxy-nitrosugars 15th communication Synthesis of N-acetylneuraminic acid and N-acetyl-4-epineuraminic Acid

A synthesis of N-acetylneuraminic acid ( 1 ) and of N-acetyl-4-epineuraminic acid ( 2 , R = H) from 2-acetamido-4,6-O-benzylidene-1,2-dideoxy-1-nitro-D -mannopyranose ( 3 ) and 2-acetamido-1,2-dideoxy-4,6-O-isopropylidene-1-nitro-D -mannopyranose ( 4 ), respectively, is described. Michael addition of 3 and 4 to tert-butyl 2-(bromomethyl)prop-2-enoate ( 5 ) and subsequent hydrolytic removal of the NO₂ group gave the 4-nonulosonate tautomers 6 / 7 and 8 / 9 , respectively (Scheme). Stereoselective reduction of 6 / 7 and 8 / 9 with NaBH₄/AcOH in dioxane/H₂O yielded 12/13 (94:6) and 14/15 (92:8), respectively. Reduction of 6 / 7 and 8 / 9 in the absence of AcOH or in EtOH gave 12 / 13 (15:85) and 14 / 15 (15:85), respectively. Ozonolysis of 12 and 13 followed by hydrolysis gave tert-butyl neuraminate 22 and tert-butyl 4-epineuraminate 24 , respectively. Ozonolysis of 14 / 15 , separation of the products 20 and 21 , and hydrolytic removal of the isopropylidene groups gave 22 and 24 , respectively. The tert-butyl ester 22 was saponified to give 1 , which was further characterized as the methyl ester 23 . Saponification of 24 gave the crude 4-epimer of 1 , which was converted into the stable Na salt 2 and also into the methyl ester 25 .     

4,6-Dihydroxysalicylic Acid-Catalyzed Oxidative Olefination of Methyl N-Heteroarenes with Benzyl Amines

Benzyl amines were deaminated for the olefination of methyl N-heteroarenes such as quinolines, benzothiazoles, and quinoxalines catalyzed by 4,6-dihydroxysalicylic acid with only 1 mol % catalyst loading. A wide range of N-heteroaryl stilbenoids were synthesized in yields of 42 to 96 % using oxygen (1 atm) as the sole oxidant. 4,6-dihydroxysalicylic acid not only behaves as an organocatalyst for the oxidation of benzyl amines to the imine intermediates, but also provides an acidic reaction condition for the olefinations. Gram scale reaction and the synthesis of two pharmaceutically relevant conjugated olefins were also successful using this methodology.     

Synthesis,crystal structures,and catalytic activities of palladium imidazole complexes formed by 2-hydroxyethyl group cleavage

N-4,6-dimethyl-2-pyrimidinylimidazole 1 and its hydroxyethyl derivative 1-(2-hydroxyethyl)-3-(4,6-dimethyl-2-pyrimidinyl)imidazolium chloride 2 have been synthesized and characterized. The attempted synthesis of bis(N-heterocyclic carbene)palladium complexes via the direct reaction of 2 with Pd(OAc)₂ results in the unexpected formation of a bis(N-arylimidazole) palladium complex 3. Additionally, the analogous bis(N-methylimidazole) palladium complex 4 has also been synthesized by the above method. Compounds 1–4 were characterized by elemental analysis, IR, and ¹H NMR. Additionally, their crystal structures have been determined by X-ray diffraction. Complexes 3 and 4 were found to be efficient catalysts for the Suzuki reaction.     

Lycopodine‐Type Lycopodium Alkaloids from Huperzia serrata

Eleven Lycopodium alkaloids with a lycopodine‐type skeleton were isolated from the basic material of the whole plant of Huperzia serrata (Thunb .) Trev. (Huperziaceae). Among them, 12‐epilycodoline N‐oxide (=(12α,15R)‐12‐hydroxy‐15‐methyllycopodan‐5‐one N‐oxide; 1 ), 7‐hydroxylycopodine (=(15S)‐7‐hydroxy‐15‐methyllycopodan‐5‐one; 2 ), and 4,6α‐dihydroxylycopodine (=(6α,15R)‐4,6‐dihydroxy‐15‐methyllycopodan‐5‐one; 3 ) are new compounds. Their structures were identified spectroscopically, especially by means of 1D‐ and 2D‐NMR.     

Synthesis and Antibacterial Activity of New 2,5‐Diaryl‐3‐styryl‐4H,2,3,3a,5,6,6a‐hexahydropyrrolo[3,4‐d]isoxazole‐4,6‐diones

The synthesis of some biologically interesting pyrrolo‐isoxazolidine derivatives has been accomplished by the 1,3‐dipolar cycloaddition reaction of substituted open chain conjugated azomethine N‐oxides 1 with substituted N‐aryl maleimides 2 leading to the formation of new stereoisomeric 2,5‐diaryl‐3‐styryl‐4H,2,3,3a,5,6,6a‐hexahydropyrrolo[3,4‐d]isoxazole‐4,6‐dione derivatives 3 in excellent yields. These stereoisomers have been characterized as cis‐ 3A and trans‐ 3B on the basis of their ¹H‐NMR spectral measurements. The synthesized compounds have been screened for their antibacterial activities and have been found to be active against the bacteria Escherichia coli and Pseudomonas aeruginosa up to a significant extent.     

Base Pairing of 8‐Aza‐7‐deazapurine‐2,6‐diamine Linked via the N(8)‐Position to the DNA Backbone: Universal Base‐Pairing Properties and Formation of Highly Stable Duplexes when Alternating with dT

The unusually N⁸‐glycosylated pyrazolo[3,4‐d]pyrimidine‐4,6‐diamine 2′‐deoxyribonucleoside ( 3 ) was synthesized and converted to the phosphoramidite 11 . Oligonucleotides were prepared by solid‐phase synthesis, and the base pairing of compound 3 was studied. In non‐self‐complementary duplexes containing compound 3 located opposite to the four canonical DNA constituents, strong base pairs are formed that show ambiguous pairing properties. The self‐complementary duplex d( 3 ‐T)₆ ( 34 ⋅ 34 ) is significantly more stable than d(A‐T)₆.     

Synthesis of 3-substituted 1-aryl-4,6-dinitro-1H-indazoles based on picrylacetaldehyde and their behavior in nucleophilic substitution reactions

A method for the synthesis of 1-aryl-3-formyl-4,6-dinitro-1H-indazoles by the reaction of picrylacetaldehyde with aryldiazonium salts followed by intramolecular cyclization of the resulting picrylglyoxal monoarylhydrazones was developed. Various 4,6-dinitro-1-phenyl-1H-indazoles substituted in position 3 were prepared via transformations involving the formyl group of 3-formyl-4,6-dinitro-1-phenyl-1H-indazole. 3-R-4,6-Dinitro-1-phenyl-1H-indazoles (R = CHO, CN, 1,3-dioxolan-2-yl) react regiospecifically with anionic O-, S-, and N-nucleophiles, in particular, with replacement of only the 4-NO₂ group. Thus previously unknown 3-R-4-Nu-6-nitro-1-phenyl-1H-indazoles were synthesized (Nu is a nucleophile residue).     

New method for the synthesis of β-tropolones: Structures of condensation products of o-quinones with 2-methylquinolines and the mechanism of their formation

A new method was developed for the synthesis of functionalized β-tropolones based on acid-catalyzed condensation of 2-methylquinoline derivatives with 3,5-di(tert-butyl)-1,2-benzoquinone and 4,6-di(tert-butyl)-3-nitro-1,2-benzoquinone (14). The mechanism of the multistep reaction giving rise to β-tropolones and their tautomerism were studied by quantum chemical methods (DFT B3LYP/6-31G**). The reaction of 2-methylquinoline derivatives containing the tertiary amino group at position 4 with quinone 14 is accompanied by the formation of derivatives of a new heterocyclic system, viz., 4,6-dioxo-2-azabicyclo[3.3.0]octa-2,7-diene N-oxide. The molecular and crystal structures of two 5,7-di(tert-butyl)-3-hydroxy-2-(quinolin-2-yl)tropolones and two dioxoazabicyclooctadiene N-oxides, as well as of the preparatively isolated intermediate of the first condensation step and of the by-product of the reaction were established by X-ray diffraction. Dedicated to Academician O. M. Nefedov on the occasion of his 75th birthday. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 1956–1977, November, 2006.     

Convergent synthesis of 4,6-unsubstituted 5-acyl-2-aminodihydropyrimidines using Weinreb amide

A method of convergent synthesis of novel 4,6-unsubstituted 5-acyl-2-aminodihydropyrimidines 7 is developed. The synthetic intermediate of 7, 4,6-unsubstituted 2-aminodihydropyrimidines 9 having a Weinreb amide at the 5-position, is prepared by the sequential Staudinger/aza-Wittig/cyclization reactions of (E)-tert-butyl{3-azido-2-[methoxy(methyl)carbamoyl]allyl}carbamate (E)-10. The transformation of the Weinreb amide of 9 to an acyl group proceeds smoothly by a substitution reaction using aryllithiums or alkyllithiums in the presence of a catalytic amount of BF₃ etherate, affording 7 in good to high yield. The N-protecting group of 7 can be easily removed to obtain N-unsubstituted 2-amino-5-acyldihydropyrimidines 8, and the derivatives are observed as a single isomer in ¹H NMR spectroscopy. All dihydropyrimidines in this study were hitherto unavailable and difficult to synthesize by conventional methods.     

Ring transformations of heterocyclic compounds. XV. N-(2-hydroxyphenyl) substituted 2-alkylamino-4,6-diarylbenzophenones by ring transformation of 2,4,6-triarylpyrylium salts with anhydrobases of benzoxazolium salts

The synthesis of hitherto unknown N-(2-hydroxyphenyl) substituted 2-alkylamino-4,6-diarylbenzophenones 3 from 2,4,6-triarylpyrylium salts 1 and 3-alkyl-2-methylbenzoxazolium salts 2 in the presence of triethylamine in ethanol by a 2,5-[C₄+C₂] pyrylium ring transformation is reported. Structure elucidation is performed by an X-ray crystal structure determination of the benzophenone 3a. Spectroscopic data of the transformation products and their mode of formation via anhydrobases of the salts 2 are discussed.     

2-Benzoyl-2-ethoxycarbonylvinyl-1 and 2-benzoylamino-2-methoxy-carbonylvinyl-1 as N-protecting groups in peptide synthesis. Their application in the synthesis of dehydropeptide derivatives containing N-terminal 3-heteroarylamino-2,3-dehydroalanine

Ethyl 2-benzoyl-3-dimethylaminopropenoate ( 6 ) and methyl 2-benzoylamino-3-dimethylaminopropenoate ( 46 ) were used as reagents for the protection of the amino group with 2-benzoyl-2-ethoxycarbonylvinyl-1 and 2-benzoylamino-2-methoxycarbonylvinyl groups in the peptide synthesis. Reactions of ethyl 2-benzoyl-3-dimethylaminopropenoate (6) with α-amino acids gave N-(2-benzoyl-2-ethoxycarbonylvinyl-1)-α-amino acids 13–19. These were coupled with various amino acid esters to form N-(2-benzoyl-2-ethoxycar-bonylvinyl-1)-protected dipeptide esters 20–31. The removal of 2-benzoyl-2-ethoxycarbonylvinyl-1 group, which was achieved by hydrazine monohydrochloride or hydroxylamine hydrochloride, afforded hydrochlo-rides of dipeptide esters 32–41 in high yields. Similarly, the substitution of the dimethylamino group in methyl 2-benzoylamino-3-dimethylaminopropenoate ( 46 ) by glycine gave N-(2-benzoylamino-2-methoxycar-bonylvinyl-1)glycine ( 47 ), which was coupled with glycine ethyl ester to give N-[N-(2-benzoylamino-2-methoxycarbonylvinyl-1)glycyl]glycine ethyl ester ( 48 ). Treatment of 48 with 2-arnino-4,6-dirnethylpyrimi-dine afforded N-[glycyl]glycine ethyl ester hydrochloride (34) in high yield. Amino acid esters and dipeptide esters were employed in the preparation of tri- 58-70, tetra- 71–82, and pentapeptide esters 83–85 containing N-terminal 3-heteroarylamino-2,3-dehydroalanine. 2-Chloro-4,6-dimethoxy-1,3,5-triazine was employed as a coupling reagent for the preparation of peptides 58–85.     

Synthesis of Azo-Sulfa Drugs Based on 2-Pyridinone and 2-Pyridinethione

Some new azo sulfa drugs 3-cyano-4,6-diphenyl-1-[4-(N-substituted)sulfamyl]phenylazo-2-pyridinone dyes (1-6) and 3-cyano-4,6-diphenyl-1-[4-(N-substituted)sulfamyl]phenylazo-2-pyridinethione dyes (1′-6′) were synthesized by coupling of 4-(N-substituted)sulfamylbenzene diazonium salts with 3-cyano-4,6-diphenyl-2-pyridinone and/or with 3-cyano-4,6-diphenyl-2-pyridin-ethione. The corresponding iron (1a-6a, 1′a-6′a), copper (1b-6b, 1′b-6′b) and mercury (1c-6c, 1′c-6′c) chelates wvere also prepared. All synthesized compounds were screened in vitro for antibacterial and antifungal activities.     

New coupling reagents for homogeneous esterification of cellulose

A group of known, but in cellulose chemistry new coupling reagents for homogeneous esterification has been investigated: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride, N-methyl-2-bromopyridinium iodide, N-methyl-2-chloropyridinium iodide, and N-methyl-2-bromopyridinium tosylate. In order to study their ability to activate carboxylic acids in esterifications of cellulose they have been employed in synthesis of cellulose adamantate esters. Their effectiveness has been estimated in terms of degree of substitution of resulting esters and compared to that obtained with the commonly used N,N′-carbonyldiimidazole.     

Synthese von natürlichen Haloindolen via Hetero-Cope-Umlagerung von Vinyl-N-phenylhydroxamaten

Synthesis of Natural, Halogenated Indoles via Hetero-Cope Rearrangement of Vinyl N-Phenylhydroxamates An efficient method for the synthesis of natural 4-chloro-6-methoxyindole (the promutagen from fava beans) and of the two 4,6- dibromo- and 3,4,6-tribromoindoles (produced by acorn worms, Enteropneusta) is presented. The key step is a hetero-Cope rearrangement of the intermediate N-phenyl-O-vinylhydroxylamine derivatives.     

A new synthesis of imidazo[1,2-a]pyridine and imidazo[2,1-a]isoquinoline derivatives

A new synthesis of imidazo[1,2-a]pyridine and imidazo[2,1-a]isoquinoline derivatives 4 and 8 , respectively by 1,5-dipolar cyclization reactions of stabilized pyridinium N-ylides 3a-e or isoquinolinium N-ylide 7 is described. The starting N-ylides 3a-e and 7 are prepared by the reaction of the corresponding pyridinium salts 1a-e or isoquinolinium salts 6 with N-bis(methylthio)methylene-p-toluenesulfonamide (2) .     

2-amino-4,6-lutidineN-oxide complexes formed from various copper(II) salts

Summary Copper(II) complexes of 2-amino-4,6-lutidineN-oxide (4,6DMAH) have been isolated as tetrafluoroborate, nitrate, chloride and bromide salts, and characterized by spectral methods (i.e., i.r., u.v.-vis. and e.s.r.). Variation of the ligand-to-copper(II) ratio yielded solids having the following empirical formulae: [Cu(4,6DMAH)₄]X₂ (X=BF₄), [Cu(4,6DMAH)₂X₂] (X=NO₃, Cl) and [Cu(4,6DMAH)X₂] (X=Br). In addition, a deprotonated ligand complex, Cu(4,6DMA)₂, was prepared using copper(II) acetate. The Sigand usually binds to the copper(II) centresvia theN-oxide oxygen and only the deprotonated ligand coordinatesvia the exocyclic nitrogen as well as the TV-oxide oxygen. The complexes involving coordinated anions and at least two ligands are monomeric while Cu(4,6DMAH)Br₂ is polymeric. The ring substituents affect either the stoichiometry or the stereochemistry of these solids when compared to less sterically demanding 2-aminopyridineN-oxides.     

Facile microwave-assisted synthesis of bis-pyrazol pyrimidine derivatives via an <Emphasis Type="Italic">N</Emphasis>-alkylation reaction

Abstract  

We present herein a new and efficient method for synthesis of bis-pyrazol pyrimidine derivatives by N-alkylation using a microwave-assisted synthetic process. Two new compounds, N-(4,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)methyl nicotinonitrile and 2,6-bis(3,5-dimethyl-1H-pyrazol-1-yl)-4-methyl nicotinonitrile, were synthesized by the N-alkylation reaction. The novel compounds were characterized by Fourier transform infrared spectrometry, ultraviolet spectroscopy, elemental analysis, and nuclear magnetic resonance spectroscopy, etc. The microwave-assisted procedures have noteworthy advantages in terms of thermal efficiency over those carried out by conventional heating methods.