Synthesis and anticancer evaluation of some novel N,O,S heterocyclic compounds pendant to 3-methyl-5-cyano-6-(3,4-dimethoxyphenyl)pyrimidine and other related fused pyrimidines

The key starting compound 5-cyano-6-(3,4-dimethoxyphenyl)-2-thiouracil ( 1 ) was synthesized and allowed to undergo electrophilic substitution with methyl iodide to give the corresponding 6-(3,4-dimethoxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydro-pyrimidine-5-carbonitrile ( 2 ). Nucleophilic substitution on compound 2 with hydrazine hydrate led to the corresponding 2-hyrazinopyrimidone intermediate 3 . Compound 3 underwent several substitution and cyclization reactions with β-ketoester, β-ketone, alkyl halides, arylisothiocyanate, or aromatic aldehydes followed by cyclization reactions to give the corresponding N,O,S heterocyclic compounds incorporated into pyrimidine moiety and/or the related S-triazino[3,4-b]pyrimidine derivatives 4 - 18 . Anticancer evaluation of some representative examples of newly synthesized compounds was carried out against MCF-7, HCT116 cell lines. Some of the newly synthesized compounds showed significant activity.     

Addition von Aldehyden an aktivierte Doppelbindungen,XXXIV1). Addition von Aldehyden an cyclische α-Methylenketone

Addition of Aldehydes to Activated Double Bonds, XXXIV¹⁾. Addition of Aldehydes to Cyclic α-Methylene Ketones The thiazolium salt-catalyzed addition of aldehydes to the cyclic α-methylene ketones 3, 4, 7, 8, 48 , and 49 leads to γ-diketones 9 – 22, 50 – 53 ; some of them were converted into unsaturated ketones 23 – 28 , pyrroles 29 – 34, 37 – 43 , and furans 35, 36, 44 – 46 . The α-methylene ketones were synthesized by retro Diels-Alder reaction of the corresponding norbornene compounds 1, 2, 5, 6, 47 .     

New trimethylaluminum-induced mannich-type reaction of hydrazones

Trimethylaluminum addition to N-monoalkyl or N-monoaryl hydrazones followed by aldehyde addition leads to the formation of N-alkylated hydrazones in a new formal Mannich-type process. Addition compounds were also obtained in moderate yields with ketones. The mechanism as well as possible intermediates involved in the reaction are discussed.     

Acetylene mit Elektronendonator und Elektronenakzeptorgruppen

Acetylenes having both electrondonating and electronaccepting groups ( 1 ) may be obtained in good yield from the correspondingly substituted olefines via bromination and elimination of HBr. The reaction of the acetylene aldehyde 1a with proton acids yields, after rearrangement of the primary adducts, the β-substituted acrylamides. Addition of nucleophiles leads to the β-disubstituted α.β-unsaturated carbonyl compounds. With hydrazines one obtains pyrazoles and pyrazolones. The acetylenes 1 undergo [2+2]-, [2+3]- and [2+4]-cycloaddition reactions.     

Quinazolines and 1,4-benzodiazepines LVII. 1H-1,4-benzodiazepines

The preparation of the title compounds 3 and 4 using two different methods of synthesis is described. These compounds are readily reduced to 2,3-dihydro-1H-derivatives 5 . Oxidation of 2-alkylthio-1H-1,4-benzodiazepines leads to the corresponding sulfoxides and sulfones. The oxidative rearrangement of sulfones 9 to a 2H-1,4-benzodiazepin-2-one derivative 10 is also given. The “normal” addition of azodicarboxylate together with an unusual addition of two moles of acetylenedicarboxylate to the enamine double bond of 1H compounds is discussed.     

Cycloadditions of 1H-1,3-Benzazaphospholes with o-Chloranil

NH-Functional 1H-1,3-benzazaphospholes 1a–1c and o-chloranil (tetrachloro-o-benzoquinone - TCBQ) undergo rapid [1+4]-cycloaddition in a 1:2 molar ratio to give 2a – 2c as high-melting zwitterionic σ⁶λ⁵-phosphorus compounds. In the case of 2a the yield is high (rel. to TCBQ) even if the reactants were used in a 1:0.5 molar ratio. For the 2-tert-butyl-substituted compounds 2b and 2c the yields were significantly lower, in part by unidentified byproducts. Addition of excess TCBQ to crude 2c containing unconverted 1c did not increase but strongly decrease the amount of 2c . Crystallization and XRD analysis led to detection of a minor side or consecutive product 3c , formally corresponding to P=C bond cleavage and [1+4] cycloaddition of three equivalents TCBQ, two at the phosphinidene and one at the carbene end. NMR spectroscopic data of 2a – 2c including conclusive ¹³C data for 2a give evidence of the structures of the new compounds.     

Absolute Configuration of a Diterpene Lactone from Parinari capensis

Phytochemical investigation of Parinari capensis (Chrysobalanaceae) led to the isolation of three diterpene lactones 1–3. The structures of these compounds have been established by NMR spectroscopy and X-ray crystal-structure analysis. Addition of bromine onto the exocyclic methylidene group of 1 yielded the brominated derivative 1-Br . X-Ray analysis of 1-Br established unambiguously the absolute configuration, and 1 was then identified as the (4R, 9R)-10-hydroxy-13-methoxy-9-methyl-15-oxo-20-norkaur-16-en-18-oic acid γ-lactone. Diterpenes 2 and 3 were identified as the C(13)-demethoxylated and the C(13)-demethylated derivatives of diterpene 1 , respectively. Antifungal activity against Cladosporium cucumerinum was determined for 1–3 .     

Additionsreaktionen von 3-Dimethylamino-2,2-dimethyl-2H-azirin an Isothiocyanate

Addition Reactions of 3-Dimethylamino-2, 2-dimethyl- 2 H-azirine and Isothiocyanates. The title azirine readily reacts with two molecules of benzyl- or methylisothiocyanate to form the zwitterionic 1:2 addition compounds 4 and 13 , respectively (Scheme 2). The presumed 1:1 addition products, which are intermediates in the formation of 4 and 13 , cannot be detected. The structure of 4 and 13 follows from their spectroscopic and chemical properties. With water they give the thiourea derivates 5 and 14 , respectively; treatment with aqueous acid leads to the Δ²-1, 3-thiazolin-5-on-derivates 7 and 15 , respectively. With sodium borohydride compounds 8 and 16 , respectively, are obtained (Scheme 2). The zwitterionic compounds 4 and 13 are able to react further with one molecule of the isothiocyanates to give, in high-yield, triazines 9 and 18 , respectively (Scheme 3). The structure of these compounds was again derived from their spectroscopic data. The mechanism for the formation of 9 and 18 is given in Scheme 3. Acid catalysed hydrolysis of 9 and 18 lead to the trithiocyanuric acid derivates 12 and 20 , and to the spiro compounds 11 and 19 , respectively (Sceme 6). Reaction of 4 with one molecule of phenylisocyanate gives triazine 10 (Scheme 5). According to the X-ray analysis of the methyl compound 18 , there are strong steric interactions in this molecule which are due to the side chain. This is demonstrated by the small distances between C(2) … C(13), N(7) … C(11), and C(8) … C(11) (Table 4). These steric interactions, in addition, cause widening of the bond angles N(1)? C(2)? N(7) and C(9)? N(10)? C(11) (Fig.2). Furthermore, the triazine ring is no longer planar. This deformation of the ring diminishes repulsion between the methyl groups C(13) and C(15).     

Stereospecific synthesis of P-epimeric (Rp1, Rp2)-bis-[O-l-menthylphenylphosphonothionyl] diselenide. A new variant of the stereoselective Staudinger reaction

An efficient procedure is described that leads to pure (S_P)- O -l-menthylphenylthiophosphinate. The absolute configuration of this diastereomer was assigned by chemical correlation and confirmed by X-ray crystallography. The reaction of the isomer with phenyl azide, leading to amidate, is a new variant of the stereoselective Staudinger reaction. Addition of elemental selenium to the (S_P)-thiophosphinate led to diastereomeric O-l-menthylphenylselenophosphonothioic acid, which was finally oxidized to the diastereomeric (R_P1,R_P2)-bis-[O-l-menthylphenylphosphonothionyl] diselenide. The diselenide structure was unambiguously confirmed by ³¹P NMR spectroscopy.     

Addition polymerization of nitrile compounds by organotin catalysts

A study was made of the polymerization of NC(CH₂)_nCN (n = 1?4), fumaronitrile and tetracyanoethylene (TCNE) by organotin compounds such as, oxides and alkoxides, as catalysts. It was found that polymerization occurred with malononitrile, succinonitrile, fumaronitrile and TCNE, but not with glutaronitrile and adiponitrile. Initiation of the polymerization is by addition of the tin compounds to the CN bond leading to the formation of a SnN bond, and propagation is probably by insertion of this bond to CN bonds. Addition of the tin compounds occurred only to nitrile groups that were sufficiently activated by proximity to electron withdrawing groups. The mutual electron withdrawing effect of one nitrile on the other is sufficient to permit this addition if the nitriles are geminal or vicinal, otherwise no reasonable polymerization occurred. The polymerization of the nitrile bond leads to the formation of highly conjugated systems, which give a black colour to the polymers.     

Activation of Small Molecules by Phosphorus Biradicaloids

The reactivity of biradicaloid [P(μ‐NTer)]₂ was employed to activate small molecules bearing single, double, and triple bonds. Addition of chalcogens (O₂, S₈, Se_x and Te_x) led to the formation of dichalcogen‐bridged P₂N₂ heterocycles, except from the reaction with molecular oxygen, which gave a P₂N₂ ring featuring a dicoordinated P^III and a four‐coordinated P^V center. In formal [2πe+2πe] addition reactions, small unsaturated compounds such as ethylene, acetylene, acetone, acetonitrile, tolane, diphenylcarbodiimide, and bis(trimethylsilyl)sulfurdiimide are readily added to the P₂N₂ heterocycle of the biradicaloid [P(μ‐NTer)]₂, yielding novel heteroatom cage compounds. The synthesis, reactivity, and bonding of the biradicaloid [P(μ‐NTer)]₂ were studied in detail as well as the synthesis, properties, and structural features of all addition products.     

Kinetics,catalysis, and mechanism of isomerization of N-[(benzotriazol-1-yl)methyl]anilines into the benzotriazol-2-yl derivatives

The ¹H NMR technique was applied for the measurement of the isomerization rates of N-ethyl-N-[(benzotriazol-1-yl)methyl]aniline ( 4 ) and 4-butyl-N-[(benzotriazol-1-yl)methyl]aniline ( 7 ) to the corresponding benzotriazol-2-yl isomers in dioxane-d₈ at 35°C. The rate constants obtained for pure dioxane-d₈ were 1.62 and 0.28 h^?1 for 4 and 7 , respectively. For both compounds, addition to acetic acid to the dioxane solutions accelerated the isomerizations whereas addition of triethylamine retarded it strongly. Addition of water slowed the isomerization of 4 but accelerated that of 7 : the different effects operating in the two cases are discussed and rationalized. © 1995 John Wiley & Sons, Inc.     

Synthesis of 4-hydroxy-6,9-difluorobenz[g]isoquinoline-5,10-diones and conversions to 4-hydroxy-6,9-bis[(aminoalkyl)amino]-benz[g]isoquinoline-5,10-diones

Synthetic procedures have been developed which lead to 4-hydroxy-6,9-difluorobenz[g]isoquinoline-5,10-dione ( 4a ) and its 3-methyl analogue 4b . Attempts to displace the fluorides from 4a with N,N-dimethylethylenediamine were unsuccessful. Analogue 4a on treatment with N-(t-butoxycarbonyl)ethylene diamine led to 15 , formed from addition of the nucleophilic amine to C-3. On the other hand, analogue 4b , on treatment with N,N-dimethylethylenediamine led to the anticipated difluoride displacement product 3c . The protection of the hydroxy group of 4a by benzylation with phenyldiazomethane led to 4c which on treatment with N-(t-butoxycarbonyl)ethylene diamine or N,N-dimethylethylenediamine led to the corresponding 6,9-bis-substituted analogues 18a and 18b , respectively. Reductive debenzylations of 18a and 18b by hydrogenation over Pearlman's catalyst also effected partial reductions of the quinone. However, air oxidation of the over reduced products led to 3a and 3b , respectively. Treatment of 3a with hydrogen chloride gas led to the hydrochloride salt of 3d . Addition of O-p-Methoxybenzyl-N,N'-diisopropylurea to 4a led to the p-methoxybenzyl analogue 4d . Treatment of 4d with N,N-dimethylethylene diamine or N-(t-butoxycarbonyl)ethylene diamine led to displacements of the fluorides to yield 18c and 18d , respectively. Deprotection of 18c to 3b was accomplished using methanesulfonic acid. Treatment of 18d with trifluoroacetic acid followed by addition of maleic acid led to dimaleate salt of 3d .     

A Facile,One-Pot Synthesis of Azoic Compounds and Anthraquinone Derivatives Containing Dialkyl Phosphoryl Moieties in Multicomponent Reactions

Protonation of the reactive 1:1 intermediates produced in the reactions between triphenylphosphine and dialkyl acetylenedicarboxylates by 1-amino-anthraquinone or 1,5-diphenylcarbazone as a core dye leads to vinyl phosphonium salts, which undergo Michael addition with conjugate base of NH compounds to produce stable phosphorus ylides as novel dyes in fairly good yields. These ylides can exist in two geometrical isomers (Z) and (E) for 3, because the negative charge of the ylide moiety of these compounds are strongly conjugated with the adjacent carbonyl group. Rotation around the carbon–carbon double bond is slow in the (Z) and (E) geometrical isomers on the NMR time scale at ambient temperature. These compounds are assigned by their IR, ¹H, ¹³C NMR spectral data as well as their mass spectroscopic data.     

Carbophile Additionen von Organocupraten mit 1,3-Thiazol-5(4H)-thionen

Carbophilic Additions of Organocuprates and 1,3-Thiazole-5(4H)-thiones Organocuprates and 1,3-thiazole-5(4H)-thiones 1 react in THF at 0° via carbophilic addition onto the C? S bond to give 4,5-dihydro-1,3-thiazole-5-thiols 3 (Scheme 3). This observation is in marked contrast to the previously described reaction of organolithium compounds and 1 , which undergo a thiophilic addition onto the exocyclic S-atom. As an exception, treatment of the 1,3-thiazole-5(4H)-thione 1a with tert-butyl cuprate leads to 7a (Scheme 3).     

Triphenylphosphine-Catalyzed Stereoselective Synthesis of Alkyl 3-(2-Naphthylsulfanyl)-2-propenoate from Alkyl Acetylenecarboxylates and 2-Naphthalenethiol

Protonation of the highly reactive 1:1 intermediates, produced in the reaction between triphenylphosphine and alkyl acetylenecarboxylates by 2-naphthalenethiol, leads to vinyltriphenylphosphonium salts, which undergo an addition–elimination reaction to produce the corresponding S-vinyl thioethers. The NMR spectra indicated that the compounds contained two stereoisomers for each S-vinyl thioether; their ratio was determined on the basis of ¹ H NMR spectra. The reaction is fairly stereoselective.     

Degradation of Polycyclic Aromatic Hydrocarbons by <Emphasis Type="Italic">Rigidoporus lignosus</Emphasis> and its Laccase in the Presence of Redox Mediators

The metabolism of polycyclic aromatic hydrocarbons (PAHs) was studied in vivo and in vitro in systems consisting of Rigidoporus lignosus and its laccase, in the presence of so-called “mediator” compounds. The static culture of the native fungal strain was able to metabolize anthracene and 2-methylanthracene, but not 9-nitroanthracene. The addition of redox mediators 2,2’-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 1-hydroxybenzotriazole (HBT) or violuric acid (VA) led to a significant increase in the degradation of substrates. The oxidation of PAHs was not significant when purified laccase was used without the addition of mediators. The addition of these compounds increased the oxidation of all substrates by approximately 70–80% after 72 h of incubation. The degradation rate was highest for 2-methylanthracene in the presence of VA.     

Effect of water on the palladium-catalyzed reaction of styrene with iodobenzene

The effect of the amount of water in teh solvent (DMF) on the rate of the reaction of styrene with iodobenzene in the presence of various palladium compounds has been studied. Addition of water to reaction mixture promotes the reaction. The effect of the addition water depends on the nature of the palladium complexes and temperature. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1401–1404, July, 1997.     

Synthesis and reactions of 4-Hydroxy-2(1H)-pyridones with thienyl and pyridyl substituents in position 6 starting with azomethines and malonates

The reaction of 4 with substituted diethyl malonates 5a , or “magic malonates” (bis-2,4,6-trichlorophenylmalonates 5b ) leads to 4-hydroxy-2(1H)-pyridones 6. The azomethines 4 are prepared via the Strecker compounds 3 starting with methyl ketones 1 , anilines, and potassium cyanide. Chlorination of pyridones 6 with sulfuryl chloride leads to compounds 7 while nitration gives 9.     

Synthesis of chiral N-protected 1,2-dihydro-quinoline-2-carbonitrile and 1,2-dihydro-isoquinoline-1-carbonitrile via an asymmetric Reissert reaction

Addition of cyanide ion to chiral N-acyl-quinolinium and N-acyl-isoquinolinium salts led selectively to 1,2-addition products. Removal of the chiral auxiliary affords the title compounds in pure enantiomeric form.