Synthesis of Oncinotin-11-one,a Macrocyclic Polyamine Alkaloid from Oncinotis tenuiloba

This paper presents a short synthesis of oncinotin-11-one ( 11 ), a minor alkaloid of Oncinotis tenuiloba (Apocynaceae). Based on a disconnection approach, the spermidine portion of the key intermediate 6 was constructed consecutively by simple N-alkylations starting from ethyl piperidine-2-carboxylate ( 1 ). Treatment of 6 with in situ lithiated 2-[(10-bromodecyl)oxy]tetrahydropyran resulted in the formation of the keto moiety under simultanous deprotection of the lactam N-atom to give the amino ketone 7 in 71% yield. Cleavage of the tetrahydro-2H-pyran-2-yl(Thp) portion and Jones oxidation of the resulting alcohol 8 gave the amino acid 9 which was cyclized. Final N-debenzylation of 10 provided the natural alkaloid 11 . Only two protective groups were needed in this synthesis. The reaction of N-alkyl-lactams with organometallic reagents is discussed.     

A Novel and Efficient Reaction of Imidazolidin-2-one and N-Acylbenzotriazoles: A Facile Synthesis of 1-Acylimidazolidin-2-one

Acylation of imidazolidin-2-one with readily available N-acylbenzotriazoles, in the presence of K₂CO₃, produced 1-acylimidazolidin-2-ones and N,N′-diacyl-imidazolidin-2-one in moderate to good yields. The utilization of N-acylbenzotriazoles which make the reaction simple and mild, may be especially advantageous when the corresponding acid chlorides are not stable or not easily prepared. It's also an example of the reaction of N-acylbenzotriazoles and amide.     

Synthesis of pyrido[2,3-d]pyrimidin-4-one derivatives

This paper describes one-pot synthesis of 5H-[1,3]thiazolo[3,2-a]pyrido[3,2-e]pyrimidin-5-one 4 , 5H-dipyri-do[1,2-a:3′,2′-e]pyrimidin-5-one 10 and 5H-pyrido[3,2-e]pyrimido[1,2-a]pyrimidin-5-one 15 and some of their derivatives, starting with 2-chloro-3-pyridine carboxilic acid 1. Compounds 4 and 10 reacted with phosphorus pentasulfide to give the respective 5-thione analogues, 5 from 4 and 11 from 10 . Boiling the 5-thione derivatives with hydrazine hydrate, the respective 5-hydrazono derivatives 6 from 5 and 12 from 11 were obtained. The 5-acetyl hydrazono, 7 , and the 5-isopropylidenehydrazono, 8 , derivatives were also prepared from 6 , and the 5-propionylhydrazono derivatives, 13 , from 12 . Compound 4 reacted with hydrazine to give an adduct with two molecules of hydrazine and the probable structure 16 . Treating this adduct with acetone a monohydrazone 17 was obtained. Boiling a suspension of this adduct in DMF, it gave 6,10-dihydro-6H-pyrido[3′,2′:5,6]pyrimido[2,1-c][1,2,4]triazin-5-one 20 .     

Synthesis of some 5-arylidene-2-(4-acetamidophenylimino)-thiazolidin-4-one derivatives and exploring their breast anticancer activity

Ten 2-(4-acetamidophenylimino)-5-arylidenethiazolidin-4-one derivatives 6a-k were synthesized and evaluated for their anticancer activity against MCF-7 cell line (breast adenocarcinoma). The synthetic approach involves cyclocondensation of N,N′-bis(4-acetamidophenyl)-thiourea (3) with ethyl bromoacetate in ethanol and sodium acetate to furnish the 2-(4-acetamidophenylimino)-4-thiazolidinone derivative 4 , which underwent Knoevenagel condensation reaction with some substituted aldehydes to afford the targeted 2-(4-acetamidophenylimino)-5-arylidenethiazolidin-4-ones 6a - k . The 4-chlorobenzylidene-thiazolidin-4-one compound 6h exhibited strong inhibitory effect on the growth of breast cancer cell with IC₅₀ (58.33 ± 1.74μM), very close to that of the reference drug doxorubicin (IC₅₀ 48.06 ± 0.36μM).     

1,3-Dipolar cycloadditions of diazoalkanes to pyridazine derivatives. Thermal 1,5-sigmatropic rearrangement of methyl groups in 3,3-dimethyl-3H-pyrazolo[3,4-d]pyridazine derivatives

Thermal 1,5-sigmatropic rearrangements of one of the methyl group attached at position 3 of 3,3-dimethyl-3H-pyrazolo[3,4-d]pyridazin-4(5H)-ones 1–3 taking place either in a clock-wise or anti-clockwise direction gave N₂-methylated products 4–6 and C_3a-methylated products 7– 9 . The -7(6)-one derivative 10 and -4,7(5H,6H)-dione derivative 12 gave only N₂-methylated products 11 and 13 respectively, and 1,2-dihydro derivative 14 produced after elimination of methane, 15 .     

Synthesis of nitrogen-containing drimane sesquiterpenoids from 11-dihomodrim-8(9)-en-12-one

Products from the reaction of 11-dihomodriman-8α-ol-12-one with several reagents such as MeSO₃SiMe₃, CF₃SO₃SiMe₃, Sc(CF₃SO₃)₃, conc. H₂SO₄ in EtOH (30% solution), and Amberlist-15 ion-exchange resin were studied. 11-Dihomodrim-8(9)-en-12-one and its oxime were synthesized. The reaction of its oxime with H₃PO₄ (86%) or CF₃CO₂H produced (1S,2S,4aS,8aS)-2,5,5,8a-tetramethyldecahydro-1H-naphtho [1,2-e]-3-methyl-4,5-dihydro-[1,2,6]-oxazine; with p-TsCl in Py, (1S,2S,4aS,8aS)-2,5,5,8a-tetramethyldecahydro-1H-naphtho[1,2-d]-2-methylpyrroline-N-oxide; and with PCl₅ in Et₂O, 11-acetylaminodrim-8(9)-ene and 11-methylaminooxodrim-8(9)-ene.     

Novel polycyclic heterocycles. X. Synthesis of 3-amino derivatives derived from 1,2-dihydro-l 1 (trifluoromethyl)-3H,7H-quino [8,1-cd][ 1,5]benzoxazepin-3-one

The reactions of the tetracyclic ketone, 1,2-dihydro-11-(trifluoromethyl)-3H,7H-quino[8,1-cd] [1,5]benzoxazepin-3-one ( 1 ) with pyrrolidine, piperazine, N-methylpiperazine, and dimethyl-amine gave the enamines 2, 13, 11 , and 4 . These were reduced with sodium borohydride to the corresponding 3-amino derivatives 3, 14, 12 , and 5 . The 3-(2-hydroxyethylpiperazino) derivative ( 8 ) was obtained from the 3-chloro compound ( 7 ); 7 was prepared from the carbinol ( 6 ). The 3-NH₂ derivative ( 10 ) was obtained by reduction of the oxime ( 9 ). In 3, 5, 6, 7, 8, 10, 12 , and 14 , the -OCH₂ protons were non-equivalent, since in the pmr spectrum of each of these compounds there was seen a symmetrical, perturbed AB quartet, with a common JAB of 12 cps, that must be attributed to geminal interproton coupling. This phenomenon had not previously been observed with 1, 9 , or the enamines, since in their pmr spectra, the -OCH₂ protons had invariably been seen as singlets.     

Syntheses of 1,3,6,8,10,11,14-heptaazapentaphene-2,4,7,9(14H,3H,8H, -11H)-tetrones (angular mixed flavins), 1,3,5,6,8,10,11,14-octaazapentaphene-2,4,7,9(14H,3H,8H,11H)-tetrones (angular doubled flavins), and their related compounds

Cyclization of N, N′-dialkyl-N-(3-methyluracil-6-yl)-N′-(5-nitro-3-methyluracil-6-yl)- p-phenylenediamines with the Vilsmeier reagent gives the corresponding 1,3,6,8,10,11,14-heptaazapentaphene-2,4,7,9-(14H,3H,8H,-11H) -tetrones (angular mixed flavins) 2. Cyclization of N, N′-di(5-nitro-3-methyluracil-6-yl)-p-phenylenedi-amines with the Vilsmeier reagent gives the corresponding 1,3,5,6,8,10,11,14-octaazapentaphene-2,4,7,9-(14H,3H,8H,11H)-tetrones (angular doubled flavins) 11 along with the angular mixed flavins 2.     

Synthesis of polyamides from active N,N′-diacylbis [1,2-benzisothiazol-3(2h)-one]s and 4,4′-oxydianiline under mild conditions

The aminolysis of 3-benzoyloxy-1,2-benzisothiazole and N-benzoyl[1,2-benzisothiazol-3(2H)-one] derived from 1,2-benzisothiazol-3-ol was studied in model systems and was found to give good yields of N-substituted benzamides at room temperature. Solution polycondensation of new bisamides, N,N′-isophthaloyldi[1,2-benzisothiazol-3(2H)-one], and N,N′-adipoyldi[1,2-benzisothiazol-3(2H)-one], proceeded slowly to give polyamides with moderate molecular weights. The chloroform–triethylamine · hydrochloride system was the best polycondensation medium compared with some polar aprotic solvents for the formation of higher-molecular-weight polyamides.     

Influence of N,N′-Substituents on the FeCl3-Catalyzed Photo-oxidation of 2,5-Dibenzylpiperazine-3,6-Diones

Reactions carried out on benzoyl ( 2 ) and hydroxybenzyl ( 10 ) derivatives of L -phenylalanine-cycloanhydride 1 lead to the conclusion that the structure 3 , previously proposed for picroroccellin (a metabolite from the lichen Roccella fuciformis), should be revised to 6 , While the FeCl₃-catalyzed photo-oxidation of 1 gives 2 , the N,N′-dimethyl derivative 7 leads to N,N′-dimethyl-2-benzylpiperazine-3,5,6-trione ( 9 ). N,N′ -diacetyl-L -phenylalanine-cycloanhydride 11 remains unchanged. It is established that N,N′ -substitutions of 2,5-dibenzylpiperazines-3,6-diones considerably influence their photo-oxidations under the reported conditions.     

The Synthesis of Bicyclic N4-Amino-2′-deoxycytidine Derivatives

Nucleosides which have ambivalent tautomeric properties have value in a variety of nucleic acid hybridization applications, and as mutagenic agents. We describe here synthetic studies directed to stable derivatives of this kind of nucleoside based on N⁴-aminocytosine. Treatment of the 4-(1H-1,2,4-triazol-1-yl)-5-(chloroethyl)pyrimidinone nucleoside derivative 5 with hydrazine leads to formation of the 6,6-bicyclic pyrimido-pyridazin-7-one 3 , and with methylhydrazine to the corresponding fixed tautomeric 1-methyl derivative 7 (Scheme 1). If these cyclization reactions are carried out in the presence of a base, the 6-ring bicyclic derivatives undergo rearrangement to their corresponding 5-ring pyrrolo-pyrimidin-2-one analogues 8 (Scheme 2). In the reaction of the triazolyl derivative 5 with 1-[(benzyloxy)carbonyl]-1-methylhydrazine, spontaneous cyclization gives the 5-ring derivative 13 related to 8 rather than the open-chain product 12 (Scheme 4). Reaction of an acetylated analogue of triazolyl derivative 5 with 1,1-dimethylhydrazine gives rise to some of the open-chain product 9 , but it too cyclizes to a product that we have assigned the structure of the 6,6-ring quaternary ammonium salt 11 (Scheme 3).     

The synthesis of 5-substituted 3-benzoylamino-6-(2-substituted amino-1-ethenyl)-2H-pyran-2-ones and their transformations into 2H-pyrano[3,2-c]pyridine derivatives

A new approach to the 2H-pyrano[3,2-c]pyridine system is described. 5,6-Disubstituted 3-benzoylamino-2H-pyran-2-ones 3a,b , prepared from the corresponding 1,3-dicarbonyl compounds 1a,b and methyl (Z)-2-benzoylamino-3-dimethylaminopropenoate ( 2 ), were converted into 3-benzoylamino-6-(2-dimethylamino-1-ethenyl)-5-ethoxycarbonyl-2H-pyran-2-one ( 4a ) and 5-acetyl derivative 4b . The exchange of the dimethylamino group in 4a,b with aromatic amines 5a-f,m , héteroaromatic amines 5g-i , and benzylamines 5j-l produced 5-ethoxycarbonyl-3-benzoylamino-6-(2-arylamino- or heteroarylamino-or benzylamino-1-ethenyl)-2H-pyran-2-ones 6a-l , and its 5-acetyl analog 6m . The compounds 6 were cyclized in basic media into 2H-pyrano[3,2-c]pyridine derivatives 7a-h . Analogously react also α-amino acid derivatives 8a-c and 11 as nitrogen nucleophiles producing 9a-c, 10 and 12 .     

Umsetzung von 3-Amino-2H-azirinen mit Salicylohydrazid

Reaction of 3-Amino-2H-azirines with Salicylohydrazide 3-Amino-2H-azirines 1a–g react with salicylohydrazide ( 7 ) in MeCN at 80° to give 2H, 5H-1,2,4-triazines 10 , 1,3,4-oxadiazoles 12 and, in the case of 1d , 1,2,4-triazin-6-one 11a (Scheme 3). The precursor of these heterocycles, the amidrazone of type 9 , except for 9c and 9g , which could not be isolated, has been found as the main product after reaction of 1 and 7 in MeCN at room temperature. 3-(N-Methyl-N-phenylamino)-2-phenyl-2H-azirin ( 1g ) reacts with 7 to give mainly the aromatic triazines 15b₁ and 15b₂ . In this case, two unexpected by-products, 16 and salicylamide ( 17 ), occurred, probably by disproportionation of a 1:1 adduct from 1g and 7 (Scheme 8). Oxidation of 10f with DDQ leads to the triazine 15a . The structure of 10c, 11a, 12c, 13 (by-product in the reaction of 1b and 7 ), the N′-phenylureido derivative 14 of 9d (Scheme 4) as well as 15b₂ has been established by X-ray crystallography. The ratio of 10/12 as a function of substitution pattern in 1 and solvent has been investigated (Tables 1, 3, 4, and 7). A mechanism for the formation of 10 and 12 is proposed in Scheme 7.     

Studies on Pyrazine Derivatives,XLV: Synthesis,Reactions, and Tuberculostatic Activity of N-Methyl-N′-(pyrazine-2-carbonyl)-hydrazinecarbodithioic Acid Methyl Ester

Methyldithiocarbonyl derivative 2 of pyrazine-2-carboxylic acid N′-methyl-hydrazide 1 was synthesized by methylation of CS₂ adduct. Benzylamine caused the decomposition of compound 2 to pyrazine-2-carboxylic acid benzylamide 5 and 1,3-dibenzylthiourea 6. N-methyl-N′-(pyrazine-2-carbonyl)-hydrazinecarbodithioic acid methyl ester 2 were evidenced to cyclize to 3-methyl-5-pyrazin-2-yl-3H-[1, 3, 4]oxadiazole-2-thione 8 in the presence of triethylamine. In the reactions with secondary amines such as morpholine, pyrrolidine and phenylpiperazine pyrazinoyl derivatives (9–11) of thiosemicarbazide were obtained. Hydrazine, methylhydrazine, aminoalcohols, and N-alkylamino-substituted cyclic amines reacted with cyclization to 4-substituted 1,2,4-triazole-3-thiones 12, 13, and 18–22. Synthesized compounds exhibited low tuberculostatic activity in vitro (MIC 50–100 μg/mL).     

A Total Synthesis of (±)- Aphidicolin: Regio- and stereoselective conversion of 3α,18-Di-O-benzyl-17-nor-14-aphidicolen-16-one into (±)-aphidicolin

A regio- and steroselective conversion of the totally synthetic 3α, 18-di-O-benzyl-17-nor-14-aphidicolen-16-one (5), into (±)-aphidicolin 1 , by hydroxylation of the 2-methylidenebicyclo[3.2.1] oct-3-ene derivative 6 is described. Compound 5 was a key intermediate in our previously described total synthesis of 2 , which represented a formal synthesis of 1 .     

Stoffwechselprodukte von Mikroorganismen 215. Mitteilung Röntgenstrukturanalyse von Di-O-acetyl-aspochalasin C

The X-ray crystal structure analysis of the 17,18-di-O-acetyl derivative of the antibiotic aspochalasin C (monoclinic, a = 26.377, b = 10.840, c = 11.937 Å, β = 102.08°, space group C 2) confirms the constitution elucidated by spectroscopic methods and chemical degradation, and establishes the relative configuration.     

Synthesis and Characterization of N,N‐Di‐substituted Acylthiourea Copper(II) Complexes

A series of six N,N‐di‐substituted acylthiourea ArC(O)NHC(S)NRR′ ligands (denoted as HLⁿ) [Ar = 1‐Naph: NRR′ = NPh₂, HL¹ ( 1 ); N(iPr)Ph, HL² ( 2 ). Ar = Mes: NRR′ = NPh₂, HL⁴ ( 3 ); N(iPr)Ph, HL⁵ ( 4 ); NEt₂, HL⁶ ( 5 ). Ar = Ph: NRR′ = N(iPr)Ph, HL⁸ ( 6 )] were synthesized and characterized. These ligands were deprotonated to form Cu^II complexes through metathesis or combined redox reaction with copper halides. The structures of the complexes were investigated with single‐crystal X‐ray diffraction. The reaction of the 1‐naphthalene derivative HL¹ ( 1 ) with CuBr in the presence of sodium acetate produced cis‐CuL¹₂ ( 7 ), where the deprotonated ligand is bound to the Cu^II atom in a bidentate‐(O, S) coordination mode. Similarly treatment of HL² ( 2 ) with NaOAc and CuCl resulted in the formation of the cis‐arranged product [cis‐CuL²₂ ( 8 )]. The reaction of mesityl derivative HL⁴ ( 3 ) and CuBr with and without the addition of NaOAc gave the cis‐CuL⁴₂ ( 9 ) and cis‐(HL⁴)₂CuBr ( 10 ), respectively. In contrast, reaction of HL⁵ ( 4 ) and CuI in the presence of NaOAc resulted in trans‐CuL⁵₂ ( 11 ). Alternatively trans‐CuL⁶₂ ( 12 ) was obtained by the reaction of diethyl‐substituted HL⁶ ( 5 ) with CuCl₂ in the absence of a base.     

Chiral 1,4-benzodiazepines. IX. Attempts at a preparation of 7-chloro-5-phenyl-3(S)methyl-1,4-benzodiazepin-2-one through C(5)?C(5a) bond formation

During attempts at preparation of 7-chloro-5-phenyl-3(S)methyl-1,4-benzodiazepin-2-one ( 9 ) by cyclisation of N'-α-chlorobenzylidene-(S)alanyl-p-chloroaniline ( 7 ) and the related o,p-dichloroaniline derivative ( 8 ), it was observed that the intermediate products, both N'-benzylidene-(S)alanyl-p-chloroaniline ( 5 ), as well as the related o,p-dichloroaniline derivative ( 6 ), undergo cyclisation to N-(p-chlorophenyl)-2-phenyl-4(S)methylimidazolidin-5-one ( 17 ), and N-(o,p-dichlorophenyl)imidazolidin-5-one ( 18 ), respectively. Isolation and properties of the side products, N'-benzylated-(S)alanyl-p-chloro-, and o,p-dichloroanilines ( 15 and 16 ), as well as of N'-benzoylated-(S)alanyl-p-chloroanilines ( 19 and 20 ) are described.     

Tricyclo[7.2.1.02,7]dodec-2(7)-en-12-one. Synthesis and Some Reactions

Tricyclo[7.2.1.02,7]dodec-2(7)-en-12-one was synthesized by dehydration of the corresponding hydroxy ketone and was brought into the Leuckart reaction. The resulting N-tricyclo[7.2.1.0^2,7]dodec-2(7)-en- 12-ylformamide was hydrolyzed to 12-aminotricyclo[7.2.1.02,7]dodec-2(7)-ene and was converted into 2,7-epoxy derivative. The structure of the latter was determined by X-ray analysis. Hydrolysis of the amide group gave 12-amino-2,7-epoxytricyclo[7.2.1.02,7]dodecane. The stereochemistry of hydroamination of the bridging carbonyl group is discussed.     

SYNTHESIS OF 6-SUBSTITUTED 5-AZAURIDINES AND THEIR PYRANOSE-TYPE NUCLEOSIDES BY CYCLODESULFURIZATION OF GLYCOSYL THIOUREAS

Cyclodesulfurization of N,N,N′-trisubstituted glycosyl thioureas with silver cyanate in acetonitrile for 5 h at 50 °C gave 1-glycosyl 5-azauracil derivatives as nucleoside analogues in good yields. The structures were determined by spectroscopic and X-Ray analyses and the reaction mechanism is discussed.