Synthesis and reactions of 1-[1-oxido-2-(3,4)-pyridinyl]-2-methyloxiranes with nitrogen nucleophiles

Reaction of 2(3,4)-pyridinecarboxaldehydes (5) with ethylidenetriphenylphosphorane afford a mixture of stereoisomers Z-( 6 ) and E-1-[2(3,4)-pyridinyl]-1-propenes ( 7 ). m-Chloroperbenzoic acid oxidation of 6 and 7 yields a 60:40 mixture of Z-( 8 ) and E-1-[1-oxido-2(3,4)-pyridinyl]-2-methyloxiranes ( 9 ). The regiospecific reaction of Z-isomers 8a-c with cyclic amines as piperidine give rise to threo-1-hydroxy-1-[1-oxido-2(3,4)-pyridinyl]-2-(1-piperidino)propanes ( 10 ) while the E-isomer 9a yields erythro- 11 . On tho other hand, the E-isomers 9b and 9c having 1-oxido-3(4)-pyridinyl substituents afford erythro- 12 resulting from attack by piperidine at C-1 of the oxirane. Reductive deoxygenation using 10% palladium on charcoal and hydrogen gas effectively removed the N-oxide substituent from the threo- 10 and erythro- 11 β-aminoalcohols. Dilute solution ir spectroscopy indicated the existance of strong intramolecular hydrogen bonding in the β-aminoalcohols 10 and 11 . The assignment of relative configuration of diastereoisomers 10 and 11 was based on the magnitude of the vicinal coupling constant J where J threo is greater than J erythro.     

Synthesis and antimicrobial activity of new 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole,thiopyrane, thiazolidinone,and azepine derivatives

4-oxo-4-phenylbutanehydrazide 3 was reacted with aryl or alkyl isothiocyanates to give the corresponding N-substituted-2-(4-oxo-4-phenylbutanoyl) hydrazine-1-carbothioamide 4a-c . Cyclization of thiosemicarbazides 4a-c with sodium hydroxide led to the formation of 3-(4-sub-5-thioxo-1,2,4-triazol-3-yl)-propanone 5a-c . Desulfurization of thiosemicarbazides 4a-c by mercuric oxide afforded 3-(5-(sub-amino)-1,3,4-oxadiazol-2-yl)-propanone 6a-c . The reaction of 4a-c with phosphorus oxychloride gave 3-(5-(sub-amino)-1,3,4-thiadiazol-2-yl)-propanone 7a-c . Treatment of 4a-c with ethyl-bromoacetate or α-bromopropionic acid gave N′-(3-sub-thiazolidin-2-ylidene)-butanehydrazide 8a-c and (N′-(3-sub-oxothiazolidin-2-ylidene)-butanehydrazide 9a-c . Chlorination of oxothiazolidine-hydrazide 9a-c by phosphorus oxychloride afforded N-(3-sub-4-oxothiazolidine)-butane-hydrazonoyl-chloride 10a-c . The reaction of 10a-c with mercaptoacetyl-chloride yielded 2-((4-benzoyl-thiopyrane) hydrazono)-3-sub-thiazolidinone 11a-c . Also, reacted of 10a-c with hydrazine hydrate afforded N″-(3-sub-oxothiazolidine)-butane-hydrazon-hydrazide 12a-c . The 3-sub-2-((pyridazine) hydrazono) thiazolidinone 13a-c was obtained by cyclization of 12a-c via refluxing in DMF. The reaction and cyclized of 9a-c with chloroacetyl-chloride in ethanolic KOH afforded 1-((3-sub-4-oxothiazolidine) amino)-azepine-dione 14a-c . The chemical structures of the new compounds have been confirmed by diverse spectroscopy analyses such as IR, NMR, MS, and elemental analysis. The synthesized compounds were tested for their antimicrobial activity and these compounds were considered (Pyridazin-hydrazono-thiazolidinone 13a-c , oxothiazolidin-azepinedione 14a-c , N-thiazolidin-hydrazon-hydrazide 12a-c , and thiopyran-hydrazono-thiazolidinone 11a-c ) the most effective as antimicrobial activity.     

Novel stereoselective synthesis of functionalized oxazolidinones from chiral aziridines

Enantiomerically pure N-(R)-alpha-methylbenzyl-4(R)-(chloromethyl)oxazolidinones (4R)-5a-k were synthesized in one step and high yields from various aziridine-2-methanols (S)-2a-k by intramolecular cyclization with phosgene. The alpha-methylbenzyl substituent on the nitrogen was easily cleaved to give both enanatiomers of 4-(chloromethyl)oxazolidinones (R)-7a and (S)-7a. (R)-7a was used for the efficient syntheses of (L)-homophenylalaninol analogues (S)-12a-j. We also applied the same methodology to prepare oxazolidinones 9a-c containing a heteroatom-substituted alkyl group at C-4 in high yields.     

Trifluoroacetylation of pyrrolo[1,2-<Emphasis Type="Italic">a</Emphasis>]pyrazines

A study was carried out on the reaction of pyrrolo[1,2-a]pyrazines containing an alkyl, aryl, or aralkyl substituent at C-1 with trifluoroacetic anhydride. Trifluoroacetylation products may be formed either by reaction in the pyrrole ring or at the aryl or aralkyl groups at C-1. Products of electrophilic substitution at C-6 are formed in the trifluoroacetylation of pyrrolo[1,2-a]pyrazines containing at C-1 a substituent bulkier than a methyl group but lacking substituents at C-6 (the α-position of the pyrrole ring). __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1226–1233, August, 2007.     

Reaction of lumichrome or 2-thiolumichrome with alkylamines

The reaction of lumichrome ( 2 ) with alkyl (or allyl)amines such as n-butylamine, n-hexylamine and allylamine gave 2,3-disubstituted 6,7-dimethylquinoxalines 4a-d, 5a-d, 6a-d, 7a-d and 8a-d . Similar reaction of 2-thiolumichrome ( 3 ) with alkyl (or allyl)amines gave 2,3-disubstituted 6,7-dimethylquinoxalines 6a-c, 9a-c and 10a-c , 2-alkyl (or allyl)amino-6,7-dimethyl-3,4-dihydrobenzo[g]pteridine-4-ones 11a-c and 2,4-dialkyl (or allyl)amino-6,7-dimethylbenzo[g]pteridines 12a-c .     

Pincer-like amido complexes of platinum, palladium, and nickel

The ligands bis(8-quinolinyl)amine (BQAH, 1), (2-pyridin-2-yl-ethyl)-(8-quinolinyl)amine (2-pyridin-2-yl-ethyl-QAH, 2), o-dimethylaminophenyl(8-quinolinyl)amine (o-(NMe2)Ph-QAH, 3), and 3,5-dimethylphenyl(8-quinolinyl)amine (3,5-Me2Ph-QAH, 4) have been prepared in high yield from aryl halide and amine precursors by palladium-catalyzed coupling reactions. Deprotonation of 1 with nBuLi in toluene affords the lithium amide complex [Li][BQA] (5), whose dimeric solid-state crystal structure is presented. Lithium amide 5 was transmetalated by TlOTf to afford the thallium(I) amido complex [Tl][BQA] (6). An X-ray structural study of 6 shows it to be a 1:1 complex of the BQA ligand and Tl. Entry into the group 10 chemistry of the parent ligand 1 was effected by both protolytic and metathetical strategies. Thus, the divalent chloride complexes (BQA)PtCl (7), (BQA)PdCl (8), and (BQA)NiCl (9) were prepared and fully characterized. An X-ray structural study for each of these three complexes shows them to be well-defined, square-planar complexes in which the auxiliary BQA ligand binds in a planar, eta(3)-fashion. For comparison, the reactivity of ligands 2-4 with (COD)PtCl2 was studied. While reaction with ligand 2 afforded an ill-defined product mixture, ligands 3 and 4 reacted with (COD)PtCl2 to generate the unusual alkyl complexes (o-(NMe2)Ph-QA)Pt(1,2-eta(2)-6-sigma-cycloocta-1,4-dienyl) (10) and (3,5-Me2Ph-QA)Pt(1,2-eta(2)-6-sigma-cycloocta-1,4-dienyl) (11), both of which have been structurally characterized.     

Synthesis,photochemical synthesis and antitumor evaluation of novel derivatives of thieno[3',2':4,5]thieno[2,3-c]quinolones

The novel derivatives of thieno[3',2':4,5]thieno[2,3-c]quinolones 6a, 6b, 7, 10a and 10b were synthesized in multistep synthesis starting from thiophene-3-carboxaldehyde and malonic acid reacting in aldol condensation or from 3-bromothiophenes or methyl 4-bromothiophene-2-carboxylate reacting in Heck reaction. They resulted in corresponding substituted thienylacrylic acids 3a-c, which were cyclized into thieno[2,3-c]thiophene-2-carbonyl chlorides 4a-c and converted into thieno[2,3-c]thiophene-2-carboxamides 5a-d. Prepared carboxamides were photochemically dehydrohalogenated into corresponding substituted thieno[3',2':4,5]thieno[2,3-c]quinolones 6a-d. Compound 7 was prepared from 6d by alkylation with N-[3-(dimethylamino)propyl]chloride hydrochloride in the presence of NaH. Compounds 10a and 10b were prepared from 6c in the multistep synthesis over acid 8 and acid chloride 9. Compounds 6a, 6b, 7, 10a and 10b were found to exert cytostatic activities against malignant cell lines: pancreatic carcinoma (MiaPaCa2), breast carcinoma (MCF7), cervical carcinoma (HeLa), laryngeal carcinoma (Hep2), colon carcinoma (CaCo-2), melanoma (HBL), and human fibroblast cell lines (WI-38). The compound 6b, which bears the 3-dimethylaminopropyl substituent on quinolone nitrogen and methoxycarbonyl substituent on position 9, exhibited marked antitumor activity. On the contrary, compound 7, which also bears the 3-dimethylaminopropyl substituent on the quinolone nitrogen but anilido substituent on position 9, exhibited less antitumor activity than the others.     

Thermal reactions of 2-(2-oxo-3-nitro-4-quinolinyl)malonates

Depending on the ester substituent, diethyl 2-(3-nitro-2-oxo-4-quinolinyl)malonates 2 give upon thermolysis ethyl 2-(3-nitro-2-oxo-4-quinolinyl)acetates 4, whereas dimethyl 2-(3-nitro-2-oxo-4-quinolinyl)-malonates 3 cyclize to give 1-methoxycarbonylisoxazolo[3,4-c]quinolin-4(5H)-ones 5. The necessary reaction conditions can be obtained easily with the help of differential scanning calorimetry.     

Synthesis and NMR spectral studies of N-chloroacetyl-2,6-diarylpiperidin-4-ones

A series of 2,6-diarylpiperidin-4-ones having electron withdrawing chloroacetyl group at the heterocyclic nitrogen were synthesized. Unambiguous characterizations of the synthesized compounds were achieved by one-dimensional ((1)H NMR and (13)C NMR) and two-dimensional (HOMOCOSY, NOESY and HSQC spectra for compounds 8 and 9 and HOMOCOSY spectrum only for 10) NMR spectroscopic data. The conformational preferences of N-chloroacetyl-2,6-diarylpiperidin-4-ones with and without alkyl substituent at C-3 and C-5 (8-14) have also been discussed using the spectral studies. The spectral data and extracted coupling constant values suggest that the compounds 8, 12 and 14 adopt flattened boat conformation whereas the remaining compounds exist in twist-boat conformations in solution with coplanar orientation of the chloroacetyl moiety present at the heterocyclic nitrogen. The substituent parameters for the chloroacetyl moiety on the heterocyclic ring carbons have also been derived and discussed elaborately on the basis of their steric, electronic and gamma-eclipsing interaction. This substituent at the nitrogen causes a substantial change on the chemical shifts of ring carbons and the associated protons.     

Synthesis of 1-substituted 3-nitroquinolin-4(1H)-ones

A versatile synthetic method for preparing 1-substituted 3-nitroquinolin-4(1H)-ones from corresponding 2-fluoro-α-nitroacetophenones is demonstrated by the synthesis of 6,7-difluoro derivatives 7a-c . The method involves sequential treatment of the starting nitroacetophenone with triethyl orthoformate and the appropriate amine, followed by a nucleophilic cyclization reaction under mild conditions. The C-7 fluorine atom of 7 can be displaced by cyclic amines. Substituted 6-fluoro-7-(4-methyl-1-piperazinyl)-3-nitroquinolin-4(1H)-ones 8a-c were prepared in this way.     

Reaction of octafluorotoluene, 3,5-dichlorotrifluoropyridine, 3-chlorotetrafluoro-yridine and tetrafluoropyrimidine with alkali-metal oximates

Treatment of octafluorotoluene (2) with approximately one-molar equivalents of the oximates R¹R²C = NO~ M⁺ (R¹ = R²=Me;R¹ = R² = Ph; R¹ = Me, R² = Ph;M = Na) (6a-c) in diethyl ether gives 4-(R¹R²C = NO)C₆F₄CF₃ (7a-c) as the only isolated products. Corresponding reaction of 3,5-dichlorotrifluoropyridine (3) with the oximates 6a-c affords 4-and 2-(R¹R²C = NO)C5F₂C12N (8a-c) and (9a-c), respectively (4-/2ratios at −35 °C: 65:35; 30:70; 12:88) ; the lithium oximates (R¹ = R² =Ph ; R¹ = Me, R² = Ph; M = Li) (6d) and (6e) give comparable results. With 3-chlorotetrafluoropyridine (4), treatment with sodium oximate 6c gives 4-(PhCMe = NO)-3-ClC₅F₃N (10) and 2-(PhCMe = NO)-5ClC₅F₃N (11) (ratio 44:56 at −35 °C). Such competition between S_NAr attack of these alkali-metal oximates at the C-4 and C-2 positions of chlorofluoropyridines 3 and 4 can be rationalized by invoking chelation of an alkali-metal cation with ring nitrogen in the transition state leading to formation of an orthio-quinonoidal σ-complex. Exclusive initial attack at the C-4 ring site appears to occur in the reaction of tetrafluoropyrimidine (5) with oximates 6a and 6c to afford 4-(MeC = NO)C₄F₃N₂ (12a) and 4-(PhCMe=NO)C₄F₃NN₂ (12b), respectively; Some further attack on product 12b by oximate 6c at the C-6 site takes place to give the disubstituted derivative 4,6-(PhCMe=NO)₂C₄F₂N₂ (13).     

Alpha,beta-unsaturated ketoximes carrying a terminal pyridine or quinoline subunit as building blocks for supramolecular syntheses

[Structure: see text]. The crystal structures of a new series of alpha,beta-unsaturated ketoximes, 8-14, carrying the terminal 4-pyridinyl, 3-pyridinyl, or 4-quinolinyl subunit have been investigated by X-ray structural analysis. The dominating intermolecular interaction in all structures, except 11, is the head-tail OH...N hydrogen bond between the oxime moiety and the nitrogen atom of the heterocyclic unit. This intermolecular interaction generates infinite chains, which are cross-linked by CH...O/N/Cl or CH...pi interactions. Compound 10 has been shown to adopt a double-helical structure in the crystalline state. Compound 11 represents the only case where the unexpected head-head NOH...N(OH) hydrogen bonds determine the crystal packing. Both hydrogen-bonding and aromatic interactions stabilize the crystal structures of 8-14.     

Syntheses of 3-substituted 2,3-dihydrobenzofuranes, 1,2-dihydronaphtho(2,1-b)furanes,and 2,3-dihydro-1H-indoles by tandem ring closure-S(RN)1 reactions

3-Substituted 2,3-dihydrobenzofuranes (7a-c), 1,2-dihydronaphtho(2,1-b)furanes (10a-c), and N-substituted 2,3-dihydro-1H-indoles (8a-c, 9a,b) are obtained in very good yields by S(RN)1 photostimulated reactions in liquid ammonia from adequate haloaromatic compounds ortho-substituted with a suitable double bond (3a,b; 4a,b; 5a; 6a,b) and Me3Sn-, Ph2P-, and -CH2NO2 anions. The novelty of the work involves the versatile application of a 5-exo ring closure process during the propagation cycle of the S(RN)1 reaction; the alkyl radical intermediates formed react with the nucleophiles to afford the ring closure-substituted heterocycles. The factors governing the observed product distribution are discussed.     

Synthesis and antimicrobial activity of some novel 5-alkyl-6-substituted uracils and related derivatives

6-chloro-5-ethyl-, n-propyl- and isopropyluracils 5a-c were efficiently prepared from the corresponding 5-alkybarbituric acids 3a-c via treatment with phosphorus oxychloride and N,N-dimethylaniline to yield the corresponding 5-alkyl-2,4,6-trichloro-pyrimidines 4a-c, which were selectively hydrolyzed by heating in 10% aqueous sodium hydroxide for 30 minutes. The reaction of compounds 5a-c with 1-substituted piperazines yielded the corresponding 5-alkyl-6-(4-substituted-1-piperazinyl)uracils 6a-j. The target 8-alkyltetrazolo[1,5-f]pyrimidine-5,7(3H,6H)-diones 7a-c were prepared via the reaction of 5a-c with sodium azide. Compounds 6a-j and 7a-c were tested for in vitro activities against a panel of Gram-positive and Gram-negative bacteria and the yeast-like pathogenic fungus Candida albicans. Compound 6h displayed potent broad-spectrum antibacterial activity, while compound 6b showed moderate activity against the Gram-positive bacteria. All the tested compounds were practically inactive against Candida albicans.     

Novel 6-(trifiuoromethyl)cytosines and 6-(trifluoromethyl)uracils

Ethyl 3-amino-4,4,4-trifluorocrotonate ( 3 ) has been converted by a one step reaction with alkyl and aryl isocyanates to novel 3-substituted-6-(trifluoromethyI)uracils. Also several 3-amino-4,4,4-trifluorocrotonitriles ( 11a-c ) have been cyclized to novel 6-(trifluoromethyI)cytosines ( 13a-c ) and then hydrolyzed to the corresponding uracils ( 4, 14b-c ). Alkylation studies with isopropyl bromide of three 6-(trifluoromethyl)uracils ( 1, 4, 5 ) are described.     

Synthesis of 3-dialkylaminomethyl-5-methyl-4-substituted-1H-pyrazoles. Selective functionalization of one methyl group via n-nitration of 3,5-dimethyl-4-substituted-1H-pyrazoles

Treatment of 4-substituted 3,5-dimethyl-1-nitro-1H-pyrazoles 1 and 10a-c with secondary amines in acetonitrile, in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), affords the novel dialkyl-aminomethyl-1H-pyrazoles 5, 6, 7, 8, 11a-c, 12a-c and 13a-c in good to excellent yields. In this way one of the, in general, inert methyl groups of 3,5-dimethyl-4-substituted-1H-pyrazoles is functionalized creating a new synthetic route to azoles containing a coordinating substituent.     

Covalent amination of 1-alkyl- and 1-aryl-3-carbamoylpyridinium chlorides as “model” for enzymic activity of rabbit liver aldehyde oxidase

The site of animation for 1-alkyl-3-carbamoylpyridinium chlorides in liquid ammonia is dependent on the identity of the 1-alkyl substituent. For the methyl, ethyl and n-propyl derivatives exclusively 6-adducts are found. Adduct formation takes place at C-6 and C-4, when the 1-substituent is an i-propyl or t-butyl group. The adduct ratio for the latter compounds is determined by the size of the substituent. 1-Aryl derivatives exhibit amination at C-2 and C-6 and the adduct ratios are dependent on the temperature. When the aryl substituent is a 2,4,6-trimethylphenyl group the 4-adduct is detected as well. A comparison is made between the sites of oxidation of these compounds by rabbit liver aldehyde oxidase and the covalent amination pattern in liquid ammonia. It is shown that covalent animation as a “model” for the enzymic activity of aldehyde oxide1 is particularly valuable in cases where the enzyme reaction is controlled by steric factors.     

Synthesis and reactions of heterocyclic methyl 2-propenoates and 2,3-epoxypropanoates with nucleophiles

Reaction of 2-(3-,4-)pyridinecarboxaldehydes 5 with carbomethoxymethylene triphenylphosphorane afforded predominantly E-methyl-3-(pyridinyl)-2-propenoates 7. Oxidation of 7a-c with m-chloroperbenzoic acid gave methyl E-3-(1-oxidopyridinyl)-2-propenoates 8a-c in high yield. The Darzen's reaction of 5a-c with methyl bromoacetate yielded a mixture of stereoisomers cis- 9a-c and methyl trans-3-(pyridinyl)-2,3-epoxy-propanoates 10a-c in a ratio of 2:1. Oxidation of cis- 9a-c and trans- 10a-c afforded the corresponding cis- 11a-c and methyl trans-3-(1-oxidopyridinyl)-2,3-epoxypropanoates 12a-c in good yield. The reaction of 11a and 12a with cyclic amines as piperidine gave the respective threo- 13 and methyl erythro-2-(1-piperidino)-3-hydroxy-3-(1-oxido-2-pyridino)propanoate 14. The sodium borohydride reduction of the N-alkoxylcarbonyl pyridinium salts of 9c and 10c afforded the corresponding N-alkoxycarbonyl-1,2-dihydropyridyl derivatives 15 and 16. A number of selected compounds ( 7a-c , 9a-c , 10a , 10c , 11a-c and 12a , 12c ) were found to be inactive in the P388 Lymphocytic screen. Compounds 9-12 did not react with the model nucleophile ethanethiol in phosphate buffer at 37°.     

Synthesis of isocoumarins and alpha-pyrones via tandem Stille reaction/heterocyclization

A general route to alpha-pyrones and 3-substituted isocoumarins from (Z)-iodovinylic acids 1a-f or 2-iodobenzoic acids 4a-c is described, including compounds bearing a substituent on the aromatic ring. Treatment of (Z)-beta-iodovinylic acids 1a-f or 2-iodobenzoic acids 4a-c with various allenyltributyltin reagents in the presence of palladium acetate, triphenylphosphine, and tetrabutylammonium bromide in dimethylformamide provided good yields of the corresponding alpha-pyrones 3a-k or 3-substituted isocoumarins 5a-g via tandem Stille reaction and 6-endo-dig oxacyclization.     

A carbon-13 NMR study of some alkyl-substituted indenes. An experimental study of the baker-nathan order of hyperconjugation in the neutral ground state

Carbon-13 NMR spectra of several alkyl-substituted indenes have been assigned and analysed. For structures having an alkyl substituent in the C-2 position an increased shielding was observed for the remote conjugated positions C-4 and C-6, an alternating trend similar to that found for the 2-cycloaminoindenes. The hyperconjugative behaviour was slightly more pronounced for the methyl group compared with an isopropyl or tert-butyl substituent, a fact which supports a model where C? H σ–π interactions are more efficient than those involving C? C bonds.