Synthesis of 3‐alkylcarbonyloxymethyl derivatives of 5‐fluorouracil

3‐Alkylcarbonyloxymethyl derivatives of 5‐fluorouracil have been synthesized starting with 1‐ethyloxy‐carbonyl‐5‐fluorouracil. Alkylation of the starting material with alkylcarbonyloxymethyl iodides, generated from the corresponding chlorides by the Finkelstein reaction, in the presence of 1,8‐bis(dimethyl‐amino)naphthalene followed by deprotection with 1,1‐dimethylethylamine gave good yields (50‐60%) of the target derivatives after column chromatography. A 90% yield of 3‐acetyloxymethyl‐5‐fluorouracil was obtained when the corresponding commercially available bromide was used, instead of the in situ generated iodide, and the product could be isolated from the crude reaction by crystallization. An alternate path of sequential alkylation of 5‐fluorouracil with alkylcarbonyloxymethyl chlorides in the presence of tertiary amines, exhibiting different reactivities towards the chlorides, gave an excellent yield of 1‐acetyloxymethyl‐3‐propionyloxymethyl‐5‐fluorouracil in the one instance it was attempted, but subsequent deprotection of the 1‐position with methylamine gave only a 24% yield of 3‐propionyloxymethyl‐5‐fluorouracil.     

Synthesis and biological activity of novel 1‐(2,3,4‐trimethoxyphenyl)‐2‐{[5‐(3,4,5‐trimethoxyphenyl)‐1,3,4‐thiadiazol‐2‐yl]thio}ethanone oxime ester derivatives

In a search for new fungicide and anticancer agent with improved biological properties and different bioactivity spectrum, we designed and synthesized a series of novel oxime esters containing 1,3,4‐thiadiazole group in moderate yield starting from gallic acid. The title compounds were identified by IR, ¹H NMR, ¹³C NMR and elemental analysis. The bioassay tests showed that these title compounds exhibit weak to moderate anticancer activity in vitro by MTT method.     

Synthesis and Crystal Structure of [1‐(η5‐9‐Fluorenyl)‐2‐(η5‐1‐indenyl)ethane]hafnium Dimethyl

The synthesis and characterization of the unsymmetric hafnium dialkyl [1‐(η⁵‐9‐fluorenyl)‐2‐(η⁵‐1‐indenyl)ethane]HfCl₂ ( 2 ) and corresponding dimethyl complex [1‐(η⁵‐9‐fluorenyl)‐2‐(η⁵‐1‐indenyl)ethane]Hf(CH₃)₂ ( 3 ) is described. The dialkyl hafnocene ( 3 ) crystallizes in monoclinic space group P2₁/c (No. 14) with a = 9.458(8), b = 8.541(8), c = 23.733(11) Å, β = 93.16(5) deg., V = 1914(3) ų, Z = 4. Further on, complex 3 was activated with methylaluminiumoxane (MAO) and utilized as a catalyst in ethene polymerization.     

Synthesis and herbicidal activity of 2‐(3‐(trifluoromethyl)‐5‐(alkoxy)‐1H‐pyrazol‐1‐yl)‐4‐aryloxypyrimidine derivatives

A series of 2‐(3‐(trifluoromethyl)‐5‐(alkoxy)‐1H‐pyrazol‐1‐yl)‐4‐aryloxypyrimidine derivatives were designed and synthesized. The structures of all the title compounds were confirmed by ¹H NMR and elementary analysis. These compounds were screened for herbicidal activity against rape and barnyard grass. Compound B13 exhibited moderate herbicidal activity.     

A novel synthesis of α,β-unsaturated phosphonates

A stereoselective synthesis of α,β-unsaturated phosphonates based on the reaction of S-(β-oxoalkyl)-dithiophosphates and Se-(β-oxoalkyl)selenophosphates with sodium dialkyl phosphites is described.     

Regioisomeric 4‐nitroindazole N1‐ and N2‐(β‐d‐ribonucleosides)

The structures of the isomeric nucleosides 4‐nitro‐1‐(β‐d ‐ribo­furan­osyl)‐1H‐indazole, C₁₂H₁₃N₃O₆, (I), and 4‐nitro‐2‐(β‐d ‐ribo­furan­osyl)‐2H‐indazole, C₁₂H₁₃N₃O₆, (II), have been determined. For compound (I), the conformation of the gly­cosylic bond is anti [χ = −93.6 (6)°] and the sugar puckering is C2′‐exo–C3′‐endo. Compound (II) shows two conformations in the crystalline state which differ mainly in the sugar pucker; type 1 adopts the C2′‐endo–C3′‐exo sugar puckering associated with a syn base orientation [χ = 43.7 (6)°] and type 2 shows C2′‐exo–C3′‐endo sugar puckering accompanied by a somewhat different syn base orientation [χ = 13.8 (6)°].     

1‐(β‐d‐Erythrofuranos­yl)cytidine (β‐erythrocytidine)

1‐(β‐d ‐Erythrofuranosyl)cytidine, C₈H₁₁N₃O₄, (I), a derivative of β‐cytidine, (II), lacks an exocyclic hydroxy­methyl (–CH₂OH) substituent at C4′ and crystallizes in a global conformation different from that observed for (II). In (I), the β‐d ‐erythrofuranosyl ring assumes an E₃ conformation (C3′‐exo; S, i.e. south), and the N‐glycoside bond conformation is syn. In contrast, (II) contains a β‐d ‐ribofuranosyl ring in a ³T₂ conformation (N, i.e. north) and an anti‐N‐glycoside linkage. These crystallographic properties mimic those found in aqueous solution by NMR with respect to furan­ose conformation. Removal of the –CH₂OH group thus affects the global conformation of the aldofuranosyl ring. These results provide further support for S/syn–anti and N/anti correlations in pyrimidine nucleosides. The crystal structure of (I) was determined at 200 K.     

Synthesis and properties of novel α‐(1,2,4‐triazolo[1,5‐a]pyrimidine‐2‐oxyl)phosphonate derivatives

In an attempt to discover novel compounds with high activity and low toxicity, a series of new phosphonate derivatives containing triazolo[1,5‐a]pyrimidine moieties have been designed and synthesized by a nucleophilic substitution between α‐hydroxyphosphonates and 2‐methanesulfonyl‐1,2,4‐triazolo[1,5‐a]pyrimidines. The structures of all compounds prepared were confirmed by elemental analyses and by NMR and MS spectroscopy. The results of preliminary bioassay indicate that the title compounds possess certain selective herbicidal activity against rape and also, to some extent, inhibit of acetolactase synthase activity. © 2000 John Wiley & Sons, Inc. Heteroatom Chem 11:313–316, 2000     

N1‐(4‐tert‐Butyl­phenyl)‐N2‐hydroxy‐α‐oxo‐α‐phenyl­acet­amidine and N2‐hydroxy‐N1‐(4‐nitro­phenyl)‐α‐oxo‐α‐phenyl­acet­amidine hemihydrate

In the title compounds, C₁₈H₂₀N₂O₂, (I), and C₁₄H₁₁N₃O₄·0.5H₂O, (II), respectively, the oxime groups have an E configuration. In (I), the mol­ecules exist as polymers bound by intermolecular C—H⋯O and O—H⋯N hydrogen bonds around inversion centres. In (II), intermolecular OW—H⋯N, OW—H⋯O and O—H⋯OW interactions stabilize the molecular packing.     

3β‐(1‐Allyl‐1‐pyrrolidinio)‐16‐(2‐pyridylmethylene)androst‐5‐en‐17β‐ol bromide hemihydrate

The title compound, C₃₂H₄₅N₂O⁺·Br^?·0.5H₂O, has the outer two six‐membered rings in chair conformations, while the central ring is in an 8β,9α‐half‐chair conformation. The five‐mem­bered ring of the steroid nucleus adopts a slightly deformed 14α‐envelope conformation. The pyridyl­methyl­ene moiety has an E configuration with respect to the hydroxyl group at position 17. The structure is stabilized by a network of O—H?Br‐type intermolecular hydrogen bonds.     

Synthesis,structure and biological activities of [α‐(alkylcarbonyl)‐2‐(1,2,4‐triazol‐1‐yl)]ethyl‐N,N‐dialkydithiocarbamate derivatives

Seven 1,2,4‐triazole compounds containing the N,N‐dialkyldithiocarbamate group were designed and synthesized. Their structures were identified using infrared spectroscopy, element analysis, ¹H NMR spectroscopy and mass spectrometry, and in two cases by single crystal X‐ray diffraction. The result of the biological test showed that the seven compounds all have fungicidal and plant growth‐regulating activities.     

Highly Efficient Regio- and Stereoselective Synthesis of β-（1 →6）-Branched β-（1 →3）-Linked Glucohexaose and Its Analogue

A β-（1→）6）-branched β-（1→）3）-linked glucohexaose （1） and its lauryl glycoside （2）, present in many biologically active polysaccharides from traditional herbal medicines such as Ganoderma lucidum, Schizophyllum commune and Lentinus edodes, were highly efficiently synthesized. Coupling of 2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl- （1--）3）-2-O-benzoyl-4,6-O-benzylidene-a-D-glucopyranosyl trichloroacetimidate （7） with 3,6-branched acceptors 8 and 12 gave β-（1→）3）-linked pentasaccharides （9） and （13）, then via simple chemical transformation 4＇,6＇-OH pentasaccharide acceptors 10 and 14 were obtained. Regio- and stereoselective coupling of 3 with 10 and 14 gave β-（1→）3）-linked hexasaccharides （11） and （15） as the major products. Deprotection of 11 and 15 provided the target sugar 1 and 2. Thus, a new method for the preparation of this kind of compounds was developed.     

Synthesis of β-（ 1→6）-Branched （ 1→3）-Glucononaoside with Alter-nate β- and α-Bonds in the Backbone

Lauryl glycoside of β-D-Glcp-(1→3)-[β-D-Glcp-(1→6)-]α-D-Glcp-(1→3)-β-D-Glcp-(1→3)-[β-D-Glcp-(1→6)-]α-D-Glcp-(1→3)-β-D-Glcp-(1→3)-[β-D-Glcp-(1→6)-]β-D-Glcp was synthesized through 3 3 3 strategy. 3-O-Allyl-2,4,6-tri-O-benzoyl-β-D-glucopyranosyl-(1→3)- -[2, 3, 4, 6-tetra-O-benzoyl-β-D-glucopyranosyl-(1→6)-] 1,2-O-isopropylidene-α-D-glucofuranose was used as the key intermediate which was converted to the corresponding trisaccharide donor and acceptor readily.     

1‐(β‐d‐Erythrofuranosyl)adenosine

The title compound, also known as β‐erythroadenosine, C₉H₁₁N₅O₃, (I), a derivative of β‐adenosine, (II), that lacks the C5′ exocyclic hydroxymethyl (–CH₂OH) substituent, crystallizes from hot ethanol with two independent molecules having different conformations, denoted (IA) and (IB). In (IA), the furanose conformation is ^OT₁–E₁ (C1′‐exo, east), with pseudorotational parameters P and τ_m of 114.4 and 42°, respectively. In contrast, the P and τ_m values are 170.1 and 46°, respectively, in (IB), consistent with a ²E–²T₃ (C2′‐endo, south) conformation. The N‐glycoside conformation is syn (+sc) in (IA) and anti (−ac) in (IB). The crystal structure, determined to a resolution of 2.0 Å, of a cocrystal of (I) bound to the enzyme 5′‐fluorodeoxyadenosine synthase from Streptomyces cattleya shows the furanose ring in a near‐ideal ^OE (east) conformation (P = 90° and τ_m = 42°) and the base in an anti (−ac) conformation.     

Synthesis of 5‐Hydroxy‐2‐(naphth‐2‐yl)chromone derivatives

The Diels‐Alder reaction of 5‐hydroxy‐2‐styrylchromones with ortho‐benzoquinodimethane, generated “in situ” by thermal extrusion of sulfur dioxide from 1,3‐dihydrobenzo[c]thiophene 2,2‐dioxide, leads to 2‐(3‐aryl‐1,2,3,4‐tetrahydronaphth‐2‐yl)‐5‐hydroxychromones. These cycloadducts were dehydrogenated with DDQ, using classical thermal reflux conditions and microwave irradiation, affording the corresponding 2‐(3‐arylnaphth‐2‐yl)‐5‐hydroxychromones in high yields (48‐96%).     

Synthesis of 5‐(Arylselanyl)‐2‐(arylsulfanyl)benzoates by [3+3] Cyclocondensation of 3‐(Arylsulfanyl)‐1‐(silyloxy)buta‐1,3‐dienes with 2‐(Arylselanyl)‐3‐(silyloxy)alk‐2‐en‐1‐ones

Functionalized 5‐(arylselanyl)‐2‐(arylsulfanyl)benzoates were prepared by [3+3] cyclocondensation of 3‐(arylsulfanyl)‐1‐(silyloxy)buta‐1,3‐dienes with 2‐(arylselanyl)‐3‐(silyloxy)‐alk‐2‐en‐1‐ones.     

η5‐(3)‐1‐Methyl‐1,2‐dicarbollyl‐η5‐2′,5′‐dimethylpyrrolylcobalt(III)

In the title compound, (η⁵‐2,5‐di­methyl­pyrrolyl)[(7,8,9,10,11‐η)‐7‐methyl‐7,8‐dicarba‐nido‐undecaborato]­cobalt(III), [3‐Co{η⁵‐[2,5‐(CH₃)₂‐NC₄H₂]}‐1‐CH₃‐1,2‐C₂B₉H₁₀] or [Co(C₃H₁₃B₉)(C₆H₈N)], the Co^III atom is sandwiched between the pentagonal faces of the pyrrolyl and dicarbollide ligands, resulting in a neutral mol­ecule. The C—C distance in the dicarbollide cage is 1.649 (3) Å.     

Reinvestigation of the Synthesis of Ketanserin (5) and its Hydrochloride Salt (5.HCl) via 3‐(2‐Chloroethyl)‐2,4‐(1H,3H)‐quinazolinedione (2) or Dihydro‐5H‐oxazole(2,3‐b)quinazolin‐5‐one (1)

The synthesis of ketanserin ( 5 ) and its hydrochloride salt ( 5.HCl ) using respectively equimolar amounts of 3‐(2‐chloroethyl)‐2,4‐(1H,3H)‐quinazolinedione ( 2 ) with 4‐(parafluorobenzoyl)piperidine ( 3 ) and dihydro‐5H‐oxazole(2,3‐b)quinazolin‐5‐one ( 1 ) with hydrochloride salt of 4‐(parafluorobenzoyl)piperidine ( 3.HCl ) is reinvestigated. The one‐pot reaction of ethyl‐2‐aminobenzoate with ethyl chloroformate and ethanol amine has afforded 3‐(2‐chloroethyl)‐2,4‐(1H,3H)‐quinazolinedione ( 2 ) (86%) that was then refluxed with 4‐(parafluorobenzoyl)piperidine ( 3 ) in ethyl methyl ketone in the presence of sodium carbonate to obtain free base of ketanserin (87%). In another attempt, a very pure hydrochloride salt of ketanserin ( 5.HCl ) was synthesized using equimolar amounts of dihydro‐5H‐oxazole(2,3‐b)quinazolin‐5‐one ( 1 ) and hydrochloride salt of 4‐(parafluorobenzoyl)piperidine ( 3.HCl ) by a solvent‐less fusion method. Thus, under optimized conditions, 180°C and a reaction time of 30 min, the powder mixture was transformed into glassy crystals that were initially readily soluble in chloroform but were transformed afterwards over time (2 h) to white precipitates ( 5.HCl ) suspended in chloroform with a yield of 72%.     

Synthesis of 4‐(2‐hydroxyphenyl)‐1‐phenyl‐1,2,4‐triazolidine‐3,5‐dione derivatives through cyclic transformations of 3‐(2‐phenylcarbazoyl)‐2(3H)‐benzoxazolone derivatives

Four 3‐(3‐benzylidene‐2‐phenylcarbazoyl)‐2(3H)‐benzoxazolone derivatives 3 have been synthesized from benzoxazolone derivatives 1 and benzaldehyde N‐chloroformylphenylhydrazone 2. By acid hydrolysis, these compounds yielded 3‐(2‐phenylcarbazoyl)‐2(3H)benzoxazolone derivatives 4 which were not isolated and were transformed via an intramolecular reaction into 4‐(2‐hydroxyphenyl)‐1‐phenyl‐1,2,4‐triazolidine‐3,5‐dione derivatives 5 in a good yield. Attempts to cyclize these compounds by intramolecular elimination of water into tricyclic compounds 6 with various dehydrating agents were unsuccessful.     

Synthesis of novel 2‐(2‐methylsulfonyl‐1‐methyl‐1H‐imidazol‐5‐yl)‐5‐(alkylsulfonyl)‐1,3,4‐thiadiazoles

Starting from 5‐hydroxymethyl‐2‐mercapto‐1‐methyl‐1H‐imidazole (1), a series of 2‐(1‐methyl‐2‐methylsulfonyl‐1H‐imidazol‐5‐yl)‐5‐alkylthio and 5‐alkylsulfonyl‐1,3,4‐thiadiazole derivatives ( 9a , 9b , 9c , 9d and 10a , 10b , 10c , 10d ) were prepared as potential antimicrobial agents. The structure of the obtained compounds was confirmed by NMR, IR, Mass spectroscopy, and elemental analysis. J. Heterocyclic Chem., (2010)