On the reactivity of N-benzylpyrimidinium salts with nitrogen nucleophiles

Treatment of the l-benzyl salts of pyrimidine, 4,6-dimethylpyrimidine, and 4-t-butylpyrimidine with liquid ammonia leads to debenzylation. The ¹H-nmr spectroscopic evidence is presented that the initial step in the debenzylation of l-benzyl-4,6-dimethylpyrimidinium bromide is the addition of the ammonia at C-2, while with l-benzyl-4-t-butylpyrimidinium bromide the addition takes place at C-6. It is proved by ¹⁵N labelling that the debenzylation occurs according to the ANRORC mechanism. The above-mentioned l-benzylpyrimidinium bromides give with hydrazine, pyrazole, 3,5-dimethylpyrazole and 3-t-butylpyrazole, respectively.     

The molecular structure and chemical reactivities of the condensation products of o-substituted benzylidenacetylacetone with hydrazine dihydrochloride

Reaction of o-nitrobenzylideneacetylacetone ( 1a ) with hydrazine dihydrochloride in methanol gave 4-(α-methoxy-o-nitrobenzyl)-3,5-dimethylpyrazole hydrochloride ( 4a ), whose structure was unambigously confirmed by an X-ray crystallographic analysis, via 4-(o-nitrobenzylidene)-3,5-dimethylisopyrazole ( 2a ). Compound 2a was synthesized by condensation of 1a with hydrazine dihydrochloride in acetonitrile. Analogously the corresponding o-chloro derivatives ( 2b, 4b ) were obtained. These were converted to N-methyl ( 6b ) and N-acetyl ( 7a,b ) derivatives and the behaviors on bromination and pyrolysis were investigated.     

Cellulose organic solutions: A nuclear magnetic resonance investigation

Four solvents of cellulose have been studied by using ¹³C-NMR spectroscopy. All these solvents, N-methyl morpholine-N-oxide, methylamine, hydrazine, and paraformaldehyde (PF), contained dimethyl sulfoxide (DMSO) as a cosolvent. Oligomers of cellulose of DP = 10 soluble in hot DMSO have been used as model compounds. ¹³C chemical shifts and line shapes show that three of the mentioned solvents are “true solvents” of cellulose. On the other hand, dissolution of cellulose in DMSO-PF system occurs by the formation of a statistical derivative of cellulose. Enriched ¹³C bacterial cellulose on C-1 and C-6 positions have been used to identify the ¹³C positions mainly in DMSO-N-methyl morpholine-N-oxide system. This solvent has been found to be degradative for the macromolecule when the solution is kept at 100°C over a long period. Viscosity measurements show a reduction of the molecular weight in these conditions. Polarimetry indicates that no glucose is present in solution and hence there is a statistical break of the chain. Enriched cellulose solution in DMSO–N-methyl morpholine-N-oxide has been also used for relaxation time (T₁) determination both of the solvent and of the enriched carbons of the polymer. Nuclear Overhauser enhancement (NOE) was found to be 1.8 for C-1 and 2.1 for C-6 showing that relaxation phenomenon is not purely dipolar. T₁ values of 97 and 65 msec are found for C-1 and C-6 of cellulose, in good agreement with the values known for polysaccharides. Determination of T₁ for the different carbon atoms of the solvent DMSO-N-methyl morpholine-N-oxide with and without cellulose shows a large reduction of T₁ for N-methyl morpholine-N-oxide molecule. This denotes a slower molecular motion of this molecule and a preferential interaction with the cellulose macromolecule.     

Heterocyclic synthesis via enaminones: Novel synthesis of (1H)‐pyridin‐2‐one,pyrazolo[1,5‐a]pyrimidine and isoxazole derivatives incorporating a N‐methylphthalimide and their biological evaluation

Novel synthesis of (1H)‐pyridin‐2‐one, pyrazolo[1,5‐a]pyrimidine and isoxazole derivatives incorporating N‐methylphthalimide moiety are reported. Reaction of enaminone 2 with malononitrile affords 4. Condensation of 2 with cyanothioacetamide or benzoylacetonitrile affords compounds 6 and 7 respectively. Reaction of 2 with hydrazine hydrate afford 2,3‐dihydrophthalazine‐1,4‐dione ( 10 ). Condensation of 2 with hydroxylamine and 3‐aminopyrazole derivatives affords compounds 12 and 15a,b respectively. Antimicrobial and antifungal activity were determined for representative compounds and most of them showed moderate activity as antimicrobial agents, while compounds 2 and 7 show strong activity against Aspergillus niger. The structure of the newly synthesized compounds was elucidated by elemental analyses and ¹H nmr spectra and some cases by ¹³C nmr investigation.     

Reaction of 9-substituted 1-aminoadenine with hydrazine

Reaction of 9-substituted (methyl or benzyl) 1-aminoadenines 1 with hydrazine afforded 9-substituted 6-hydrazinopurines 2 and 1-substituted 5-ammo-4-(4-amino-1,2,4-triazol-3-yl)imidazole ( 4 ). The product ratio of 2 to 4 rose with increasing amounts of methanol used as the solvent. When the same reaction was carried out using 1,9-dimethyladenine instead of 1 , compounds 2 and 4 were also obtained with N⁶,9-dimethyladenine. A possible mechanism for formation of 2 and 4 is discussed.     

Synthesis of Some Novel 2‐Anilinothiophene, 2,3′‐Bithienyl and Thienylthiopyridine Derivatives Resistance to Penicillium Digitatum Effect the Fruit

Reaction of benzotriazol‐1‐yl acetone 1 with phenyl isothiocyanate followed with α‐chloroacetone or ethyl‐α‐chloroacetate afforded 2‐anilinothiophenes 3 or 4 , respectively. Treatment of 3 with malononitrile at different reaction conditions afforded 6 or 7 . Reaction of 1 with CS₂ in DMF and phenacylbromide afforded S‐alkylated thiophene 10 . Reactions of the latter compound with different active methylene nitriles afforded thienylthiopyridine derivatives 14 and 15 . Condensation of 10 with hydrazine hydrate afforded hydrazon derivative 16 . Reaction of thiophene 17 with formamide in DMF afforded 19 which converted to N‐thienylpyrimidine 20 when treated with malononitrile. The structure of the newly synthesized compounds has been established on the basis of their analytical and spectral data. The compounds were also investigated for antibacterial and antifungal activities.     

Ring transformation of 6-methyl-3,4-dihydro-2H-1,3-oxazine-2,4-diones

Ring transformation of 6-methyl-3,4-dihydro-2H-1,3-oxazine-2,4-dione (Ia) and its N-sub-stituted derivatives, such as 3-methyl (Ib), 3-ethyl (Ic), and 3-benzyl (Id) derivatives is described. Reaction of Ia with hydrazine hydrate gave 1-amino-6-methyluracil (II), while Id reacted with hydrazine hydrate to give 3-hydroxy-5-methylpyrazole (III). Reaction of Ia,b,d with ethyl acetoacetate in ethanol in the presence of sodium ethoxide afforded ethyl 3-acetyl-6-hydroxy-4-methyl-2(1H) pyridone-5-carboxylate derivatives (IVa,b,d). On the other hand, reaction of Ib,c,d with ethyl acetoacetate in tetrahydrofuran in the presence of sodium hydride did not give IV, but gave 3-acetyl-1-alkyl-5-(N-alkylcarbamoyl)-6-hydroxy4-methyl-2(1H) pyridone (VIb,c,d). Mechanisms for the formation of compounds IV and VI are discussed.     

On the chichibabin amination of pyrimidine and N-alkylpyrimidinium salts using liquid ammonia/potassium permanganate

Treatment of the 2-R-pyrimidines ( 1 , R = methyl, ethyl, i-propyl and t-butyl) with potassium amide/liquid ammonia/potassium permanganate leads to amination at C-4(6). The yields of the 4(6)-amino compounds 3 in-crease in the order 2-methyl (10%), 2-ethyl (30%), 2-i-propyl (45%) and 2-t-butyl (60%). Treatment of the 2-R-N-methylpyrimidinium salts ( 4 , R = hydrogen, methyl) with liquid ammonia/potassium permanganate leads to a regiospecific imination at C-6, the corresponding 2-R-1,6-dihydro-6-imino-1-methylpyrimidines 6 being obtained in 80-85% yield. It is proved by ¹⁵N-labelling that no ring opening is involved in these imination reactions. Treatment of the imino compounds with base leads to the corresponding 2.R-6-methylamino-pyrimidines 8 , involving, as proved by ¹⁵N-labelling, an ANRORC-mechanism. 2-t-Butyl-1-ethylpyrimidinium tetrafluoroborate ( 9b ) when treated with liquid ammonia/potassium permanganate undergoes N-deethylation, 2-t-butylpyrimidine being exclusively formed.     

1-(Cyanoacetyl)-3,5-dimethylpyrazole as Active Methylene Compound in Hantzsch-type Pyridine Synthesis: A Convenient and Highly Effective Approach to 3,5-Dicyano-4-(het)aryl-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates

Summary. Reaction of 1-(cyanoacetyl)-3,5-dimethylpyrazole with (E)-2-cyano-3-(het)arylprop-2-enethioamides was used for the synthesis of N-methylmorpholinium 3,5-dicyano-4-(het)aryl-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolates for the first time. The latter were also obtained in a multicomponent one-pot mode via the condensation of cyanothioacetamide with corresponding aldehydes and above 1-cyanoacetylpyrazole in the presence of N-methylmorpholine under mild conditions. Thiolates 1 exist as a pair of cis/trans-diastereomers in different ratios (from 3:4 to 2:1). Last author was Deceased on February 26, 2007     

Carbon-13 NMR spectra of a series of para-substituted N,N-dimethylbenzamides. Comparisons of linear free energy relationships for carbon-13 and nitrogen-15 chemical shifts and rotation barriers

All carbon-13 chemical shifts for 11 para-substituted N,N-dimethylbenzamides in 1 mole % chloroform solution are reported, with assignments based upon double resonance experiments, analogy to chemical shifts of benzamide, and self-consistency between experimental and calculated values using recognized substituent parameters. In contrast to earlier reports, the aryl carbon chemical shift assignments for N,N-dimethylbenzamide are C-2, 127.0; C-3, 128.7; C-4, 129.4, and for p-chloro-N,N-dimethylbenzamide are C-1, 134.6; C-4, 135.5 ppm, relative to internal TMS. Good Hammett correlations (σ_p) are reported for ¹³C chemical shifts of C-1 (σ = 11.9 ppm) and even for the carbonyl group (σ = ?2.3 ppm) but are markedly improved if correlated with σ_p+ (σ = 9.5 ppm) and Dewar's F (σ = ?1.9 ppm), respectively. Excellent Swain–Lupton F and R correlations were found for some of the ¹³C chemical shifts and yielded values for percent resonance contributions to transmission of substituent effects as follows, C-1, 75 ± 4%; C-2, 51 ± 3%; C?O, 31±2%. These are compared to similar values calculated from the C?O of benzoic acids of 34±10%, and from the nitrogen-15 chemical shifts of benzamides of 56±2%. Correlations of these ¹³C δ values and ¹⁵N δ values with rotation barriers (ΔG) for N,N-dimethylbenzamides were examined, and it was found that while C?O δ values correlated only poorly the C-1 δ values correlated very well, but the best correlation was for ¹⁵N δ values of benzamides. It is suggested that Δ G and δ ¹⁵N are intrinsically related due to their numerical correlation, and the close similarity in percent resonance contribution of substituent influence on these parameters.     

Syntheses of substituted 1-(2-phenethyl)pyrazoles

Alkylation of 3-methylpyrazole with 2-phenethyl p-toluenesulfonate gave 3-methyl-1-(2-phenethyl)pyrazole ( 2a ) and 5-methyl-1-(2-phenethyl)pyrazole ( 3a ) in low yield. Reaction of 5-chloro-1,3-dimethylpyrazole ( 5 ) with substituted-benzaldehydes afforded compounds 7 . Reduction of the latter afforded compound 2 in high yield. Compound 3 could be obtained from the reaction of substituted-2-(phenethyl)hydrazine hydrochloride 9 with acetoacetaldehyde dimethylacetal in moderate yield.     

Reaction of N1, N2-diarylamidines with chloranil and 2,3-dichloro-1,4-naphthoquinone

Nucleophilic attack by N² of N¹ N²-diarylformamides 1a-c on C-2 of chloranil (2) and subsequently by N¹ on C-1 of 2 initiates the formation of benzimidazolinones 8a-c. In contrast, when 1b-e is reacted with 2,3-dichloro-1,4-naphthoquinone (9) , both chlorine atoms are successively substituted by the two nitrogen atoms and 2-(arylamino)-3-(N-formylarylamino)-1,4-naphthoquinones 13b-e result, which (probably via their cyclic tautomers 12b-e ) may be cyclodehydrogenated to form N¹,N³-diarylnaphtho[2,3-d] imidazoline-2,4,9-triones (as 14b,c ). On the other hand, N¹,N²diarylacetamidines 15a-d attack 2 and 9 at C-2 with N² but subsequently exert nucleophilic character at the acetamidine α-carbon attacking C-1 of 2 and 9 , respectively, thus forming 1-aryl-2-(arylimino)-3a-hydroxy-2,3,3a,6-tetrahydro-1N-indol-6-ones 18a-d and 3-aryl-2-(arylimino)-9b-hydroxy-2,3,5,9b-tetrahydro-1-H-benz[e]indol-5-ones 19b,c , respectively. The latter may be thermally dehydrated to the fully conjugated 2,5-dihydro-3H-benz[e]indol-5-ones 20b,c. Unambiguous structural assignments for 18b and 20c are made on the basis of X-ray crystal structure analyses.     

Functionalized 2‐Hydrazinobenzothiazole with Isatin and Some Carbohydrates under Conventional and Ultrasound Methods and Their Biological Activities

Several chemical reactions were carried out on 3‐(benzothiazol‐2‐yl‐hydrazono)‐1,3‐dihydro‐indol‐2‐one ( 2 ). 3‐(Benzothiazol‐2‐yl‐hydrazono)‐1‐alkyl‐1,3‐dihydro‐indol‐2‐one 3a , 3b , 3c have been achieved. Reaction of compound 2 with ethyl bromoacetate in the presence of K₂CO₃ resulted the uncyclized product 4 . Reaction of compound 2 with benzoyl chloride afforded dibenzoyl derivative 5 . Compound 2 was smoothly acetylated by acetic anhydride in pyridine to give diacetyl derivative 6b . Moreover, when compound 4 reacted with methyl hydrazine, it yielded dihydrazide derivative 7 , whereas the hydrazinolysis of this compound with hydrazine hydrate gave the monohydrazide derivative 8 . {N‐(Benzothiazol‐2‐yl‐N′‐(3‐oxo‐3,4‐dihydro‐2H‐1,2,4‐triaza‐fluoren‐9‐ylidene)hydrazino]‐acetic acid ethyl ester ( 9 ) was prepared by ring closure of compound 8 by the action of glacial acetic acid. In addition, the reaction of 2‐hydrazinobenzothiazole ( 1 ) with d ‐glucose and d ‐arabinose in the presence of acetic acid yielded the hydrazones 10a , 10b , respectively. Acetylation of compound 10b gave compound 11b . On the other hand, compound 13 was obtained by the reaction of compound 1 with gama‐d ‐galactolactone ( 12 ). Acetylation of compound 13 with acetic anhydride in pyridin gave the corresponding N¹‐acetyl‐N²‐(benzothiazolyl)‐2‐yl)‐2,3,4,5,6‐penta‐O‐acetyl‐d ‐galacto‐hydrazide ( 14 ). Better yields and shorter reaction times were achieved using ultrasound irradiation. The structural investigation of the new compounds is based on chemical and spectroscopic evidence. Some selected derivatives were studied for their antimicrobial and antiviral activities.     

An Efficient Synthesis of Some Novel 3‐Cyano‐4‐imino‐2‐(methylthio)4H‐pyrido[1,2‐a]pyrimidine and Their Derivatives

Pyrazolo pyrimido pyrimidine ( 4a–k ) was prepared by the reaction of compound 3‐cyano‐4‐imino‐2‐(methylthio)4H‐pyrido[1,2‐a]pyrimidine ( 3 ) with hydrazine hydrate, phenyl hydrazine, 2‐hydrazino benzothiazole, and 6‐substituted hydrazine benzothiazole in N,N‐dimethylformamide and anhydrous potassium carbonate. These synthesized compounds were characterized by elemental analysis IR, ¹H NMR, and mass spectral data.     

Reaction of N-(4-Pyridylrnethyl)benzamide N-oxides and N-[(α-acetoxy)-4-pyridylmethyl]benzamides with 1,3-diphenyl-1,3-propanedione

Reaction of N-(4-pyridylmethyl)benzamide N-oxides 2 with 1,3-diphenyl-1,3-propanedione in the presence of acetic anhydride afforded 1,1-dibenzoyl-2-(4-pyridyl)-2-(benzoylamino)ethanes 4 in low yield. Treatment of N-[(α-acetoxy)4-pyridylmethyl]benzamides 3 with 1,3-diphenyl-1,3-propanedione in the presence of triethylamine and chloroform as a solvent provided 4 in high yield. Reaction of 4 with nucleophiles as hydrazine, methyl and phenylhydrazine gave the corresponding pyrazoles 5 .     

Synthesis and reactions of 3‐amino‐2‐methyl‐3H‐[1,2,4]triazolo[5,1‐b]‐quinazolin‐9‐one and 2‐hydrazino‐3‐phenylamino‐3H‐quinazolin‐4‐one

The reaction of 3‐N‐(2‐mercapto‐4‐oxo‐4H‐quinazolin‐3‐yl)acetamide ( 1 ) with hydrazine hydrate yielded 3‐amino‐2‐methyl‐3H‐[1,2,4]triazolo[5,1‐b]quinazolin‐9‐one ( 2 ). The reaction of 2 with o‐chlorobenzaldehyde and 2‐hydroxy‐naphthaldehyde gave the corresponding 3‐arylidene amino derivatives 3 and 4 , respectively. Condensation of 2 with 1‐nitroso‐2‐naphthol afforded the corresponding 3‐(2‐hydroxy‐naphthalen‐1‐yl‐diazenyl)‐2‐methyl‐3H‐[1,2,4]triazolo[5,1‐b]quinazolin‐9‐one ( 5 ), which on subsequent reduction by SnCl₂ and HCl gave the hydrazino derivative 6. Reaction of 2 with phenyl isothiocyanate in refluxing ethanol yielded thiourea derivative 7. Ring closure of 7 subsequently cyclized on refluxing with phencyl bromide, oxalyl dichloride and chloroacetic acid afforded the corresponding thiazolidine derivatives 8, 9 and 10 , respectively. Reaction of 2‐mercapto‐3‐phenylamino‐3H‐quinazolin‐4‐one ( 11 ) with hydrazine hydrate afforded 2‐hydrazino‐3‐phenylamino‐3H‐quinazolin‐4‐one ( 12 ). The reactivity 12 towards carbon disulphide, acetyl acetone and ethyl acetoacetate gave 13, 14 and 15 , respectively. Condensation of 12 with isatin afforded 2‐[N‐(2‐oxo‐1,2‐dihydroindol‐3‐ylidene)hydrazino]‐3‐phenylamino‐3H‐quinazolin‐4‐one ( 16 ). 2‐(4‐Oxo‐3‐phenylamino‐3,4‐dihydroquinazolin‐2‐ylamino)isoindole‐1,3‐dione ( 17 ) was synthesized by the reaction of 12 with phthalic anhydride. All isolated products were confirmed by their ir, ¹H nmr, ¹³C nmr and mass spectra.     

Alkylating nucleosides. 3. The reaction of 3,5-dimethylpyrazole nucleosides with N-bromosuccinimide

Bromination of 3,5-dimethylpyrazole nucleosides with N-bromosuccinimide gave the corresponding 4-bromo-3,5-dimethylpyrazole, 3-methyl-5-(bromomethyl)pyrazole and 4-bromo-3-methyl-5-(bromomethyl)pyrazole nucleosides. Structural assignments were made on basis of analytical and ¹ H nmr spectral data. All of the bromomethylpyrazole nucleosides described showed cytostatic activity against HeLa cell sultures.     

The synthesis of 6-C-substituted 9-methoxymethylpurine derivatives

6-Cyanomethylene ( 2 ), which was prepared via 1 by substitution with malononitrile, has been catalytically hydrogenated to the α-(aminomethylene)-9-(methoxymethyl)-9H-purine-6-acetonitrile ( 3 ) in good yield using N,N-dimethylformamide-benzene as solvent over Pd-C under medium pressure. Intermediate 3 was derived to aldehyde 5 by hydrolysis with acid or base. Substitution of 3 with amines gave the corresponding alkylamines 6 and 7 . Reaction of 3 with hydrazine and acetamidine hydrochloride gave pyrazole derivative 8 and pyrimidine derivative 9 , respectively.     

SN(ANRORC) mechanism XX. Degenerate ring transformations in reactions of 1,2,4,5-tetrazines with hydrazine

Evidence is presented that the hydrazinolysis of 3-amino- (5) and 3-bromo-6-methyl-1,2,4,5-tetrazine ( 7 ) into the 3-hydrazino-6-methyl-1,2,4,5-tetrazine ( 6* ) with ¹⁵N-labelled hydrazine leads to incorporation of ¹⁵N in the 1,2,4,5-tetrazine ring. Thus in the hydrazino-deamination and hydrazino-debromination a S_N(ANRORC) mechanism is operative. Based on quantitative mass spectrometry it was found that 20-25% of both 5 and 7 reacts according to this S_N-(ANRORC) mechanism. The mechanism of these degenerate ring transformations is discussed.     

The Syntheses of Pyrimido‐pyridazinone and Pyrrolidino‐pyrimidinone 2′‐Deoxynucleoside Derivatives

Nucleosides that have ambivalent tautomeric properties have value in a variety of nucleic‐acid hybridisation applications and as mutagenic agents. We describe here synthetic studies directed to stable derivatives based on N⁴‐aminocytosine. Treatment of the 5‐(chloroethyl)‐4‐(triazol‐1‐yl)pyrimidine‐nucleoside derivative 1 with benzylhydrazine leads to the formation of the 6,6‐bicyclic pyrimido‐pyridazin‐7‐one 6 , in addition to the 5,6‐bicyclic derivative 7 . The 6,6‐bicyclic benzyl derivative 6 was converted to its 5′‐triphosphate for studies with DNA polymerases. Reaction of the triazole 1 with hydrazine, followed by acetylation, led to the desired acetylated 6,6‐bicyclic derivative 12 . However, the latter compound undergoes acyl migration followed by ring contraction to the 5,6‐bicyclic compound 13 on treatment with base.