Synthesis and Some Chemical Behaviour of Certain Substituted Thiosemicarbazides

Three new thiosemicarbazides (1 a-c ) were prepared from N-[4-phenyl-5-(2-thienyl)-1,2,4-triazol-3-yl]mercaptoacetohydrazide. Reaction of (1 a-c) with the appropriate phenacyl bromide afforded thiazoline derivatives (2 a-i) whereas their reaction with chloroacetic acid or maleic anhydride gave the corresponding thiazolidine derivatives (3 a,b) and (4 a,b) . Cyclodesulfurization of (1 a-c) with DCCD in toluene yielded 5-substituted-amino-1,3,4-oxadiazoles (5 a,b) , while their dehydration with PPA gave the corresponding 5-substituted-amino-1,3,4-thiadiazoles (6 a-c) . Six representative compounds were tested for their in-vitro antimicrobial activity against some pathogenic microorganisms, some of them were proved to be active.     

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.     

Design and synthesis of novel quinoline derivatives bearing oxadiazole,isoxazoline, triazolothiadiazole,triazolothiadiazine, and piperazine moieties

A new series of 2,3-disubstituted quinoline derivatives were synthesized from 2-chloroquinoline-3-carbaldehyde. In the reaction sequence, acetanilide was cyclized to give 2-chloroquinoline-3-carbaldehyde 1 , which was transformed to 2-(4-phenylpiperazin-1-yl)quinolin-3-carbaldehyde 2 by reaction with 4-phenylpiperazine in DMF-containing anhydrous K₂CO₃; then, compound 2 was oxidized by iodine in methanol, and methyl 2-(4-phenylpiperazin-1-yl)quinoline-3-carboxylate 3 was synthesized. The key intermediate 4 , 4-amino-5-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-4H-1,2,4-triazole-3-thiol, was prepared using the ester 3 by a series of step. Reaction of 5 with various aromatic carboxylic acids or phenacyl bromides yielded 1,2,4-triazolo[3,4-b][1,3,4]thiadiazoles 5a-c and 1,2,4-triazolo[3,4-b][1,3,4]thiadiazines 6a-c , respectively. Moreover, compound 2 condensed with o-phenylenediamine to give 2-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-1H-benzimidazole 7 . Interaction of 7 and 2-chloromethyl-5-aryl-1,3,4-oxadiazoles in the presence of K₂CO₃ led to the title compounds 8a-c . Furthermore, 4,5-dihydroisoxazoline derivatives 9a-c were obtained by the reaction of readily accessible starting materials including 2-(4-phenylpiperazin-1-yl)quinolin-3-carbaldehyde 2 , 1-phenyl-2-(triphenylphosphoranylidene)ethanone and hydroximoyl chlorides under mild conditions in the presence of Et₃N. The hydrazone intermediates 10a-c were obtained by the condensation of 2 with aroylhydrazides in ethanol, then, refluxing in acetic anhydride yielded 3-acetyl-5-aryl-2-[2-(4-phenylpiperazin-1-yl)quinolin-3-yl]-2,3-dihydro-1,3,4-oxadiazoles 11a-c . Structures of these compounds were established by their elemental analysis, IR, ¹H NMR, and mass spectral data.     

Cycloaddition of Chlorosulfonyl Isocyanate to 2H-Azirines: Formation of [2+2+2] Cycloadducts

Chlorosulfonyl isocyanata (CSI) reacts with 2H-azirines 1 a-c at -78°C to form [2+2+2] cycloadducts 3a-c and 4a-c. The tricyclic aziridine derivatives 4a-c undergo CSI extrusion reactions and subsequent oxidation to the corresponding pyrazines 5a-c. Structural identifications of 3a-c and 4a-c are based on ir, nmr and mass spectral data.     

Synthesis of 4(pyrazol-3-yl)[1,2,4]triazolo[4,3-a]quinoxalines and tetrazolo analog

The transformation of 2-chloro-3-[5-(acetoxymethyl)-1-phenylpyrazol-3-yl]quinoxaline 3 to 1-aryl-4-[5-(hydroxymethyl-1-phenylpyrazol-3-yl][1,2,4]triazolo[4,3-a]quinoxalines 4a-c has been achieved upon treatment with aroylhydrazines in boiling butanol. Compounds 4a-c were smoothly acetylated by acetic anhydride to give their acetyl derivatives 5a-c in good yield. 4-[5-(Acetoxymethyl)-1-phenylpyrazol-3-yl]-1-methyl[1,2,4]triazolo[4,3-a]quinoxaline was prepared by ring closure of 2-hydrazino-3-[5-(hydroxymethyl)-1-phenylpyrazol-3-yl]quinoxaline 6 by the action of acetic anhydride. The reaction of 6 with acetylacetone afforded 3-[5-(hydroxymethyl)-1-phenylpyrazol-3-yl]-2-(3,5-dimethylpyrazol-1-yl)quinoxaline 8 . In addition, the reaction of 3 with sodium azide in boiling N, N-dimethylformamide yielded the fused tetrazolo[1,5-a]quinoxaline 9 .     

New tetradentate N,N,N,N-chelating α-diimine ligands and their corresponding zinc and nickel complexes: synthesis, characterisation and testing as olefin polymerisation catalysts

A series of zinc complexes of the general formula {[ZnCl(ArN=C(An)-C(An)=NAr)](+)}(2)[Zn(2)Cl(6)](2-) (where Ar = 2-(1-benzyl-1H-1,2,3-triazol-4-yl)phenyl 2a, 2-(1-(1-phenylethyl)-1H-1,2,3-triazol-4-yl)phenyl 2b, 2-(1-phenyl-1H-1,2,3-triazol-4-yl)phenyl 2c; An = acenaphthene backbone) were prepared by the condensation of acenaphthenequinone with the corresponding o-triazolyl-substituted anilines (2-(1-benzyl-1H-1,2,3-triazol-4-yl)aniline 1a, 2-(1-(1-phenylethyl)-1H-1,2,3-triazol-4-yl)aniline 1b, 2-(1-phenyl-1H-1,2,3-triazol-4-yl)aniline 1c) which were formed by the copper(I)-catalyzed Huisgen[3+2] dipolar cycloaddition between 2-ethynylaniline and the corresponding azides in high yields, using anhydrous ZnCl(2) as the metal template, in boiling glacial acetic acid. Zinc complexes of the type [ZnCl(ArN=C(An)-C(An)=NAr)](+)[ZnCl(3)(NCCH(3))](-) (4a-c) were synthesized by crystallisation of the corresponding complexes 2a-c in acetonitrile, at -20 °C. After removal of zinc dichloride from complexes 2a-c by the addition of potassium oxalate, in dichloromethane, the tetradentate N,N,N,N-chelating α-diimine ligands of the type ArN=C(An)-C(An)=NAr (5a-c) were obtained. The new ligand precursors and zinc complexes were characterised by elemental analysis, (1)H and (13)C{(1)H} NMR spectroscopy, two-dimensional NMR spectroscopy, and X-ray diffraction. Reaction of the ligand precursors 5a-c with [NiBr(2)(DME)], in dichloromethane, gave nickel complexes of the type [NiBr(2)(ArN=C(An)-C(An)=NAr)] (6a-c). The results of single crystal X-ray diffraction characterisation and magnetic susceptibility measurements demonstrated that nickel complexes 6a-c possess octahedral geometries around the nickel atoms with variable configurations, the Br atoms of which can be ionized when dissolved in methanol. In preliminary catalytic tests, complexes 6a-c revealed to be active as catalysts for the polymerisation of norbornene and styrene, when activated by cocatalyst MAO. The characterisation of the polymers by (1)H and (13)C{(1)H} NMR spectroscopy, gel permeation chromatography/size-exclusion chromatography (GPC/SEC) revealed that these polymers were formed by a coordination addition mechanism.     

Synthesis,Structure and Cytotoxic Properties of Copper(II) Complexes of 2-Iminocoumarins Bearing a 1,3,5-Triazine or Benzoxazole/Benzothiazole Moiety

A series of copper(II) complexes of 2-imino-2H-chromen-3-yl-1,3,5-triazines 2a-h, 3-(benzoxazol-2-yl)-2H-chromen-2-imines 4a-b, and 3-(benzothiazol-2-yl)-2H-chromen-2-imines 6a-c were obtained by reacting of appropriate 2-iminocoumarin ligands L1a-h, L3a-b, and L5a-c with 3-fold molar excess of copper(II) chloride. The structure of these compounds was confirmed by IR spectroscopy, elemental analysis, and single-crystal X-ray diffraction data (2f, 2g, 2h, and 6c). All the synthesized complexes were screened for their activity against five human cancer cell lines: DAN-G, A-427, LCLC-103H, SISO, and RT-4 by using a crystal violet microtiter plate assay and relationships between structure and in vitro cytotoxic activity are discussed. The coordination of 2-iminocoumarins with copper(II) ions resulted in complexes 2a-h, 4a-b, and 6a-c with significant inhibitory properties toward tested tumor cell lines with IC₅₀ values ranging from 0.04 μM to 15.66 μM. In comparison to the free ligands L1a-h, L3a-b, and L5a-c, the newly prepared Cu(II) complexes often displayed increased activity. In the series of copper(II) complexes of 2-imino-2H-chromen-3-yl-1,3,5-triazines 2a-h the most potent compound 2g contained a 4-phenylpiperazine moiety at position 6 of the 1,3,5-triazine ring and an electron-donating diethylamino group at position 7′ of the 2-iminocoumarin scaffold. Among the Cu(II) complexes of 3-(benzoxazol-2-yl)-2H-chromen-2-imines 4a-b and 3-(benzothiazol-2-yl)-2H-chromen-2-imines 6a-c the most active was benzoxazole-2-iminocoumarin 4b that also possessed a diethylamino group at position 7′ of the 2-iminocoumarin moiety. Moreover, compound 4b was found to be the most prominent agent and displayed the higher potency than cisplatin against tested cell lines.     

Condensation of 2-naphthol and naphthalenediols with o-dichlorobenzene in the presence of aluminum halides

It is known that 1-naphthol, as a result of superelectrophilic (dicationic) activation in superacid media, is able to react with such deactivated aromatic compound as o-dichlorobenzene to give 4-(3,4-dichlorophenyl)-1-tetralone (2), which is a highly valuable intermediate in the synthesis of the antidepressant, sertraline (1) and other useful derivatives. However, the analogous reactivity of 2-naphthol and a variety of naphthalenediols towards o-dichlorobenzene has not been investigated thus far, although the corresponding tetralones, bearing dichlorophenyl moiety, could be of great pharmacochemical interest. In present work, we disclose that 1,5-, 1,6-, and 1,7- naphthalenediols (6a-c) react smoothly with o-dichlorobenzene in the presence of an excess of aluminum chloride or aluminum bromide to give the pairs of isomeric 4-(3,4-dichlorophenyl)- and 4-(2,3-dichlorophenyl)- 5-, 6-, and 7-hydroxy-1-tetralones (10a-c and 11a-c) in high overall yields. 2-Naphthol and 2,7-naphthalenediol (6d) exhibited comparatively lower reactivity, which however was sufficient to obtain the corresponding dichlorophenyl-2-tetralones in moderate yields. The mechanism of these reactions involving superelectrophilic dicationic or even tricationic intermediates, is discussed.     

α,β-Unsaturated γ-Oxo Carboxylic Acids in Heterocylic Synthesis II. Behavior of 4-(5,5-Dioxodibenzothiophen-2-yl)-4-oxo-2-butenoic Acid Towards Carbon Nucleophiles under Michael Reaction Condition

4-(5,5-Dioxodibenzothiophen-2-yl)-4-oxo-2-butenoic acid ( 1 ) was condensed with compounds containing active methylene groups under Michael reaction conditions to form the Michael adducts 2a-c , 3a-c , and 4a-b . The behavior of Michael adduct towards the action of hydrazine hydrate was investigated. The compounds were tested for biological properties.     

Synthesis and transformations of 1-(1,3-butadien-1-yl)benzotriazoles

1-[α-(Phenylthio)alkyl]benzotriazoles were converted into the corresponding 1-(1,3-butadien-1-yl)benzotriazoles in good yields by one-pot sequential reactions with (i) lithium diisopropylamide, (ii) allyl bromide or cinnamyl chloride, and (iii) potassium t-butoxide. Diels-Alder and hetero [4 + 2] cycloadditions of 1-(1,3-butadien-1-yl)benzotriazoles and some transformations of their α-lithio derivatives were studied.     

Microwave assisted synthesis of novel functionalized hydantoin derivatives and their conversion to 5-(Z) arylidene-4H-imidazoles

2-(Alkyl-1-yl)-1H-imidazol-5(4H)-ones 5a-n were synthesized via nucleophilic substitution of the methylsulfanyl group of the corresponding 2-(methylthio)-1H-imidazol-5(4H)-ones 3a-c with suitably substituted secondary amines. The starting 2-thioxo- imidazolidin-4-ones 2a,2b were prepared by condensation of thiohydantoin and benzo[b]-thiophene-3-carbaldehyde or benzofuran-3-carbaldehyde under microwave irracdiation (MW) conditions. 2-Methylthio derivatives 3a-c were prepared by treatment of 2a-b with methyl iodide in the presence of aqueous sodium hydroxide.     

Regioselectively nucleus and/or side-chain fluorinated 2-(Phenanthryl)propionic acids by an effective combination of radical and organometallic chemistry

Regioselectively nucleus and/or side-chain fluorinated 2-(phenanthr-1-yl)- and 2-(phenanthr-2-yl)propionic acids 1-5 were prepared using phenanthren-1(2H)-ones 6a-c as key intermediates. Thus, ethyl 2-(fluorophenanthryl)propionates 11 were obtained in good yields by Reformatsky reaction of 6a-c with ethyl 2-bromopropionate followed by dehydratation and DDQ-promoted aromatization of the resulting beta-hydroxyesters. Side-chain alkyl 2-hydroxy-2-(phenanthr-1-yl)propionates 14 were obtained by bromine/lithium permutation of dihydrophenanthryl bromides 12a-c with butyllithium followed by quenching of the lithiated intermediates with methyl pyruvate or ethyl 3,3,3-trifluoropyruvate and subsequent DDQ-promoted aromatization. The alkyl 2-hydroxy-2-(phenanthr-1-yl)propionates 25 were prepared by reacting 8-bromo-1,3-difluorophenanthrene 24 with butyllithium for 10 seconds at -110 degrees C and subsequent addition of the suitable pyruvate to the lithiated intermediates. Alkyl 2-hydroxy-2-(phenanthr-2-yl)propionates 26 and 29 were suitably obtained by site-selective metalation of 1,3-difluorophenanthrene 28 and the bromophenanthrene 24, respectively, with LDA followed by quenching of the metalated intermediates with the suitable alkyl pyruvate. Fluorination of the above alpha-hydroxypropionates with DAST, followed by the alkaline hydrolysis, allowed the expected 2-(phenanthryl)propionic acids 1-5 to be obtained in satisfactory overall yields.     

Synthesis and anti-inflammatory activity of some benzofuran and benzopyran-4-one derivatives

New series of furosalicylic acids 3a-c, furosalicylanilides 6a-n, furobenzoxazines 8a-f, 1-benzofuran-3-arylprop-2-en-1-ones 12a,b, 6-(aryl-3-oxoprop-1-enyl)-4H-chromen-4-ones 16a-c and 6-[6-aryl-2-thioxo-2,5-dihydropyrimidin-4-yl]-4H-chromen-4-ones 17a-c were synthesized. Anti-inflammatory activity evaluation was performed using carrageenan-induced paw edema model in rats and prostaglandin E(2) (PGE(2)) synthesis inhibition activity. Some of the tested compounds revealed comparable activity with less ulcerogenic effect than Diclofenac at a dose 100 mg/kg. All the synthesized compounds were docked on the active site of cyclooxygenase-2 (COX-2) enzyme and most of them showed good interactions with the amino acids of the active site comparable to the interactions exhibited by Diclofenac.     

Asymmetric Synthesis. 39.(1) Synthesis of 2-(1-Aminoalkyl)piperidines via 2-Cyano-6-phenyl Oxazolopiperidine

The asymmetric synthesis of a series of 2-(1-aminoalkyl) piperidines using (-)-2-cyano-6-phenyloxazolopiperidine 1 is described. LiAlH(4) reduction of 1 followed by hydrogenolysis led to the diamine 3. The same strategy applied to C-2-methylated compound 7 afforded [(2S)-2-methylpiperidin-2-yl]methanamine (9). Addition of lithium derivatives to the cyano group of 1 resulted in the formation of an intermediate imino bicyclic system (11a-c) which could be diastereoselectively reduced to substituted diamino alcohols 13a-c. The addition of an excess of PhLi to 1 in the presence of LiBr furnished disubstituted amine 19, the precursor of diphenyl[(2S)-piperidin-2-yl]methanamine (22).     

Syntheses of optically active tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones and hexahydroimidazo[1,2-a]pyridin-2(3H)-ones

The reactions of (2S)-2-amino-2-substituted-N-(4-nitrophenyl)acetamides 16a-c, succindialdehyde (13), and benzotriazole afforded enantiopure (3S,5R,7aR)-5-(1H-1,2,3-benzotriazol-1-yl)-3-substituted-1-(4-nitrophenyl)tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones 17a-c, which were converted by sodium borohydride into (3S,7aR)-3-substituted-1-(4-nitrophenyl)tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones 18a-c. Chiral (2S)-2-amino-2-substituted-N-(4-methylphenyl)acetamides 12a-d, easily prepared in two steps from N-Boc-alpha-amino acids 10a-d, similarly reacted with glutaraldehyde (20) and benzotriazole to generate 5-benzotriazolyl-3-substituted-hexahydroimidazo[1,2-a]pyridin-2(3H)-ones 21a-d, which were converted by sodium borohydride directly into optically active 3-substituted-hexahydroimidazo[1,2-a]pyridin-2(3H)-ones 22a-d.     

Features of the reaction of 4-bromobut-2-enylphosphonium salts with monosubstituted hydrazines

(4-Bromobut-2-en-1-yl)triphenylphosphonium bromide reacted with phenylhydrazine at 2°C in the presence of sodium carbonate to form triphenyl[4-(2-phenylhydrazinylidene)but-2-en-1-yl]phosphonium bromide in 62% yield. The obtained N-phenylhydrazine derivatives cyclized into the corresponding pyrazoline derivatives of phosphonium salts. Unlike phenylhydrazine, ethylhydrazine reacted with (4-bromobut-2-ene-1-yl)triphenylphosphonium bromide under the same conditions to afford triphenyl[(1-ethyl-4,5-dihydro-1Hpyrazol-3-yl)methyl]- and -[(1-ethyl-1H-pyrazol-3-yl)methyl]phosphonium bromides in yields of 60 and 40%.     

A new triterpene from Barringtonia asiatica

The freeze-dried bark of Barringtonia asiatica afforded a new triterpene: (3β,11α)-11-hydroxyolean-12-en-3-yl palmitate (1). The bark also yielded mixtures of (3β)-olean-12-en-3-yl palmitate (2a), (3β)-urs-12-en-3-yl palmitate (2b) and (3β)-olean-18-en-3-yl palmitate (2c) in a 2?:?1?:?4 ratio; β-amyrin (3a), α-amyrin (3b) and germanicol (3c) in a 3?:?1?:?4 ratio; 22-O-tigloylcamelliagenin A (4a) and betulinic acid (4b) in a 2?:?1 ratio; olean-12-en-3β,16β,22α-triol (5), β-sitosterol, spinasterol, squalene and trilinolein. The roots yielded 2a-c and 3a-c as well as trilinolein, spinasterol and squalene, while the flowers afforded verimol k (6), linoleic acid, spinasterol, squalene, phytyl fatty acid ester and trilinolein. Compounds 1-4 and 6 were tested for antimicrobial property against seven microorganisms. All compounds tested exhibited slight activity against Candida albicans and were found inactive against Escherichia coli, Bacillus subtilis, Trichophyton mentagrophytes and Aspergillus niger. Except for the mixture of 4a and 4b that proved to be inactive, all the compounds were slightly active against the bacterium Staphylococcus aureus, while 3a-c were slightly active against Pseudomonas aeruginosa.     

Reactions of 1,1,4,4-tetramethylsemicarbazide with prop-2-ynyl bromide, allyl bromide, and 1,3-dibromoprop-1-yne

1,1,4,4-Tetramethylsemicarbazide readily undergoes alkylation with prop-2-ynyl bromide and allyl bromide at the tertiary nitrogen atom of the hydrazine fragment to give 1-(prop-2-yn-1-yl)-and 1-(prop-2-en-1-yl)-1,1-dimethyl-2-(dimethylaminocarbonyl)hydrazinium bromides, respectively. A new procedure was proposed for the synthesis of 6-bromomethylidene-2-dimethylamino-4,4-dimethyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-ium bromide by reaction of 1,1,4,4-tetramethylsemicarbazide with 1,3-dibromoprop-1-yne in acetonitrile.     

Synthesis of NSC-341,964: An unexpected study on the stability of 2-aryl-4H-3,1-benzoxazin-4-ones

Resynthesis of NSC 341,964, which had been assigned structure 1 (1-[[3-(7-chloro-4-oxo-4H-3,1-benzoxazin-2-yl)phenyl]methyl]pyridinium chloride) was approached via 7-chloro-2-(3-methylphenyl)-4H-3,1-benzoxazin-4-one ( 5 ) obtained from 3-methylbenzoyl chloride ( 2 ) and 2-amino-4-chlorobenzoic acid ( 3 ) followed by dehydration in acetic anhydride. Radical bromination provided 6 which with pyridine afforded the bromide analog 7 of 1 . Ion exchange, however, gave ring-opened benzoic acid 8 rather than 1 . The original sample of NSC 341,964 also proved to be ring-opened material. However, 7 upon standing exhibited slow hydrolysis to 8 so that the structure of the original NSC 341,964 remains uncertain. A more direct route to compound 8 is also described.     

Halogenated 7-deazapurine nucleosides: stereoselective synthesis and conformation of 2'-deoxy-2'-fluoro-beta-D-arabinonucleosides

The stereoselective syntheses of 5-halogenated 7-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine nucleosides 3b-d, 4a-c as well as 7-deaza-2'-deoxyisoguanosine are described. Nucleobase anion glycosylation of 2-amino-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5) with 3,5-di-O-benzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranosyl bromide (6) exclusively gave the beta-D-anomer, which was deblocked (--> 8), aminated at C4 (--> 3a) and selectively deaminated at C2 to yield 2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl 7-deazaisoguanine (2). Condensation of the 5-halogenated 4-chloro-2-pivaloylamino-7H-pyrrolo[2,3-d]pyrimidines 9a-c with 6 furnished the N7-nucleosides 10a-c together with N2,N7-bisglycosylated compounds 11a-c. The former was converted to the corresponding 2,4-diamino-compounds 3b-d, and the latter was deblocked by NaOMe/MeOH to yield the 4-methoxy-nucleosides 4a-c. Conformational analysis of the sugar moiety of the nucleosides 2 and 3a-d was performed on the basis of vicinal [1H,1H] coupling constants. The fluorine atom in the sugar moiety shifts the sugar conformation from S towards N by about 10%, while the halogen substituents in the base moiety increase the hydrophobicity and polarizability of the nucleobases.