Herbicidal Activity of Some Pyridazine Derivatives

Herbicidal activity of some 50 pyridazyl ethers was evaluated. Among them, 3-chloro-6-(2-phenylphenoxy)-, 3-chloro-6-(2,6-dichlorophenoxy)-, 3-chloro-6-(3-methoxyphenoxy)- and 3-chloro-6-(4-methoxyphenoxy)-pyridazines showed conspicuous effectiveness on radish and millet in pre-emergence test, whereas postemergent activity of the compounds tested was not so remarkable in general. Relationships between herbicidal activity and chemical structure are discussed.     

Syntheses of Pyridazine Derivatives as Herbicides

Various 3-halo-6-phenoxypyridazines, with or without nitro groups on their benzene rings, and 3-anilino-6-phenoxypyridazines were prepared together with some related compounds to be evaluated as herbicides. Ultraviolet spectra of some nitrophenoxypyridazines thus obtained were also examined.     

Synthesis and Herbicidal Activity of Phenoxypropionic Acid Derivatives with Imidazo[1,2-α]pyridine Moiety

Phenoxypropionic acid derivatives (Ia-s) with an imidazo[1,2-a]pyridine moiety were synthesized and their herbicidal activities were examined. The activities were affected dramatically by the substituents on the imidazo[1,2-a]pyridine ring, and good substituents to enhance the herbicidal activity were a cyano group at the 3-position and a chlorine atom at the 6-position. Among the compounds, n-propyl 2-[4-(6-chloro-3-cyano-2-imidazo[1,2-a]pyridinyloxy)phenoxy]propionate(Iq) was most active against gramineous weeds and the activity was comparable to that of the commercial herbicide fluazifop-butyl.     

Synthesis of Chlorodideoxynucleosides Using Tris(2,4,6-tribromophenoxy)-dichlorophosphorane (BDCP)

Abstract

5′-Chloro-5′-deoxy-N,3′-O-dibenzoylthymidine (3a), 5′-chloro-5′-deoxy-N⁴, 3′-O-dibenzoyldeoxycytidine(3b), 5′-chloro-5′-deoxy-N⁶,3′-O-dibenzoyldeoxyadenosine(3c), N-benzoyl-1-(3-chloro-2,3-dideoxy-5-O-trityl-ß-D-xylofuranosyl)thymine (5a) and N⁶-benzoyl-9-(3-chloro-2,3-dideoxy-5-O-trityl-ß-D-xylofuranosyl)adenine (5b) have been synthesized in very high yields using a new efficient reagent, tris(2,4,6-tribrom-ophenoxy)dichlorophosphorane (BDCP). The reaction time was greatly reduced to 5–8 min. NOE data suggested an inversion of configuration at C₃-position and thus an SN2 mechanism has been proposed for the chlorination reaction.

     

Syntheses of Pyridazine Derivatives as Herbicides

Various 3-phenoxypyridazines were prepared by either catalytic dehalogenation of corresponding 3-phenoxy-6-chloropyridazines or reaction of 3-chloropyridazine with phenols in the presence of base. Syntheses of certain 4-phenoxypyridazines are also described.     

Nucleosides. 145. Synthesis of 2,5′-Anhydro-2-Thiouridine and its Conversion to 3′-O-Acetyl-2,2′-Anhydro-5′-Chloro-5′-Deoxy-2-Thiouridine. Studies Directed Toward the Synthesis of 2′-Deoxy-2′-Substituted arabino Nucleosides (7)

Abstract

In an attempt to introduce a substituent at C-2′ in the “up” arabino configuration directly by nucleophilic displacement reaction of a preformed pyrimidine ribonucleoside, we synthesized 2,5′-anhydro-5′-deoxy-2-thiouridine (6) in three steps from uridine. Compound 6 was converted into the 3′-O-acetyl derivative 7. Upon treatment of 7 with triflyl chloride in methylene chloride in the presence of triethylamine and p-dimethylaminopyridine, 2,2′-anhydro-1-(3-O-acetyl-5-chloro-2,5-dideoxy-β-D-arabinofuranosyl)-2-thiouracil (9) was obtained as the only isolable product. Obviously, the intermediate 3′-O-acetyl-2,5′-anhydro-2′-O-triflyl-2-thiouridine (8) was attacked by the chloride nucleophile at C-5′ first giving the 2′-O-triflyl-2-thiouridine intermediate from which 9 was formed by intramolecular nucleopilic reaction.     

Novel 2′-Deoxy Pyrazine C-Nucleosides Synthesized VIA Palladium-Catalyzed Cross-Couplings

Abstract

The palladium-catalyzed cross-couplings of 2-chloro-3,5-diamino-6-iodopyrazine (1a) and methyl 3-amino-6-iodopyrazine-2-carboxylate (1b) with 1,4-anhydro-3,5-O-bis[(tert-butyl)dimethylsilyl]-2-deoxy-D-erythro-pent-1-enitol (2) followed by desilylation and stereospecific reduction of the 2′-deoxy-3′-keto adduct leads to the formation of 2-chloro-6-(2-deoxy-ß-D-ribofuranosyl)-3,5-diaminopyrazine (4a) and methyl 3-amino-6-(2-deoxy-ß-D-ribofuranosyl)pyrazine-2-carboxylate (4b) in 58% yield and 21% yield, respectively. These are the first syntheses of the heretofore unknown 2′-deoxy pyrazine C-nucleosides and demonstrate the utility of a convergent approach for the synthesis of pyrazine C-nucleosides.     

6′-substituted and 6′,6″-disubstituted derivatives of raffinose

The reaction of 6′-chloro-6′-deoxyraffinose deca-acetate with a variety of nucleophilic anions (Br^-,I^-,N^-₃) gave the corresponding 6′-substituted raffinoses. The 6′-azide was further converted into 6′-amino-6′-deoxyraffinose, isolated as its N-acetyl derivative, and silver fluoride-induced elimination of hydrogen iodide from the 6′-iodide gave the 6′-deoxy-5′-ene. Treatment of 6′-chloro-6′-deoxyraffinose and 6′,6″-dichloro-6′,6″-dideoxyraffinose with base afforded, respectively, 3′,6′-anhydro-and 3′,6′;3″,6″-dianhydro-raffinose in high yields. In addition, the dichloride was converted into 6′,6″-diazido-6′,6″-dideoxyraffinose.     

Enantioselective effects of optically active alpha-methylbenzyl-s-triazine on the root growth of rice and Echinochloa plants and their herbicidal activity

The chiral requirement on the alpha-methylbenzyl moiety of 2,4-diamino-6-chloro-s-triazine for sufficient inhibition of root growth was similar towards both rice and barnyard millet. With the monoalkylamino series, the most suitable configuration was markedly changed by the substituent on the other amino moiety. However, for the dialkylamino series, the (S)-enantiomer was an active inhibitor. Clear species selectivity between rice and barnyard millet was observed in the series for the (R)-enantiomers, providing high herbicidal activity toward Echinochloa plants and safety toward rice. The enantioselectivity against barnyard millet increased with increasing inhibitory activity of the active enantiomers, following Pfeiffer's rule. R-EtNH (3) controlled the growth of barnyardgrass with leaf-burning (LB) under paddy conditions, and S-EtNH (4) and S-Et2N (20) controlled the growth without LB. The RS-EtNH derivative is an interesting inhibitor controlling the growth of barnyardgrass from the just-germinated stage (by the (R)-enantiomer) to early-middle growth stage (by the (S)-enantiomer).     

Synthesis of 6-Arylthio Analogs of 2′,3′-Dideoxy-3′-Fluoroguanosine and Their Effect against Hepatitis B Virus Replication

A key compound, 2-amino-6-chloro-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)purine, was prepared from 2-amino-6-chloropurine riboside in 5 steps, then subjected to the nucleophilic displacement with benzenethiols to afford 6-arylthio congeners. These compounds showed a similar anti-HBV effect to that of 2′,3′-dideoxy-3′-fluoroguanosine.     

Synthesis and antimicrobial activity of some new substituted pyrido[3′,2′:4,5]thieno[3,2-d]-pyrimidinone derivatives

A series of new 3-substituted-7-(2-chloro-6-ethoxypyridin-4-yl)-9-(2,4-dichlorophenyl)-2-methylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4(3H)-one derivatives were synthesized as antimicrobial agents using 7-(2-chloro-6-ethoxypyridin-4-yl)-9-(2,4-dichlorophenyl)-2-methyl-4H-pyrido[3′,2′:4,5]thieno[3,2-d]-[1,3]oxazin-4-one as a starting compound. Its condensation with substituted aniline derivatives or phenyl hydrazine gave the corresponding N-substituted derivatives. Treatment of the starting compound with hydrazine hydrate afforded the corresponding N-amino derivative, which was reacted with substituted phenylisocyanate and phenylisothiocyanate derivatives to give the corresponding semicarbazides and thiosemicarbazide derivatives. All the newly synthesized compounds were evaluated for their antimicrobial activities in comparison to streptomycin and fusidic acid as positive controls. The structure assignments of the new compounds are based on chemical and spectroscopic evidence.     

O6-(4-Nitrophenyl)inosine and -Guanosine as Chromogenic Substrates for Adenosine Deaminase

Abstract

O⁶-(4-Nitrophenyl)inosine (la), O⁶ -(4-nitrophenyl)guanosine (1c) and O⁶ -(4-methylumbelliferonyl)inosine (2) were obtained by reaction of 6-chloro-9-(β-D-ribofuranosyl)purine (3a) or 2-amino-6-chloro-9-(β-D-ribofuranosyl)purine (3c) with sodium salts of 4-nitrophenol or 4-methylumbelliferone in N,N-dimethylformamide. Similarly, 6-chloro-9-(β-D-2,3-isopropylideneribofuranosyl)purine (3b) was transformed to 2′,3′-O-isopropylidene-O⁶-(4-nitrophenyl)inosine (1b). Deprotection of 1b with CF₃COOH gave compound la and O⁶ -(4-nitrophenyl)hypoxanthine (4). Compounds 1a and 1c are substrates for adenosine deaminase releasing 4-nitrophenol which is readily detected visually or spectrophotomemcally. Rate and extent of hydrolysis of la are significantly increased in the presence of purine nucleoside phosphorylase but xanthine oxidase has no influence. A potential fluorogenic analogue 2 is not a substrate for adenosine deaminase.

     

Design, syntheses and 3D-QSAR studies of novel N-phenyl pyrrolidin-2-ones and N-phenyl-1H-pyrrol-2-ones as protoporphyrinogen oxidase inhibitors

The characteristics of low application rates, good crop selectivity, low residue and environmental safety exhibited by Protoporphyrinogen oxidase (PPO, EC 1.3.3.4)-inhibiting herbicides have attracted a world-wide research interests. As continuation of our research work on the development of new PPO inhibitors, a series of mono-carbonyl analogues of cyclic imides, N-phenyl pyrrolidin-2-ones and N-phenyl-1H-pyrrol-2-ones, were designed and synthesized based on previously established DFT-QSAR results. The PPO inhibition activities of 29 newly synthesized compounds were tested and a predictive comparative molecular field analysis (CoMFA) model was established with the conventional correlation coefficient r(2)=0.980 and the cross-validated coefficient q(2)=0.518. According to the CoMFA model, the substituent effects on the PPO inhibition activity were explained reasonably. Further greenhouse assay showed that 2-(4-chloro-2-fluoro-5-propoxy-phenyl)-2,3,4,5,6,7-hexahydro-isoindol-1-one (C(6), k(i)=0.095μM) and 2-(5-allyloxy-4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-isoindol-1-one (C(7), k(i)=0.12μM) displayed excellent post-emergency herbicidal activity at the concentration of 150g.ai/ha against seven tested weeds. Due to their high PPO inhibition effect and broad spectrum herbicidal activity, these two compounds have the potential for further study on crop selectivity and field trial. These results confirmed once again that only one of the carbonyl groups of cyclic imides is essential to the PPO inhibition activity.     

Syntheses and Herbicidai Activities of Phenoxypyrimidines and Phenoxytriazines

Series of phenoxypyrimidines and phenoxytriazines were prepared to be evaluated as herbicides. Among them, 2-(2,6-dichlorophenoxy)-pyrimidine (XV), 2-phenoxy-4,6-dimethyl- pyrimidine (XVII), 2-(3-methyl-4-chlorophenoxy)-4,6-bis(ethylamino)-5-triazine (LIV), 2-(2,4-dichlorophenoxy)-4,6-bis(ethylamino)-s-triazine (LVIII), and 2-(2,6-dichlorophenoxy)-4,6-bis(ethylamino)-s-triazine (LX) showed high pre-emergent herbicidai activity to radish. On the other hand, 2-chloro-4-(2,6-dichlorophenoxy)-6-methylpyrimidine (XXX) revealed high efficiency to millet. Some structure-activity relationship is discussed.     

Synthesis of Some Nucleoside Cyclic Ethylene Phosphothionates

Abstract

This communication describes the synthesis of 5′-deoxy-5′-chloro-3′-(2-thio-1,3,2-dioxaphosphorinanyl)thymidine, N⁴,2′,3′-triacetyl-5′-(2-thio-1,3,2-dioxaphosphorinanyl)-1-β-D-arabinosyl-cytosine and N⁴-acetyl-5′-(2-thio-1,3,2-dioxaphosphorinanyl)-1-β-D-arabinosylcytosine.     

The absolute configuration of the enantiomers of 6-chloro-9-(4′-diethylamino-1′-methylbutyl)-amino-2-methoxyacridine (quinacrine)

Absolute configurations have been assigned to the enantiomers of the antimalarial drug quinacrine dihydrochloride. Condensation of (?)-(R)-4-amino-1-diethylaminopentane (from L -glutamic acid) with 6,9-dichloro-2-methoxyacridine gave (?)-(R)-6-chloro-9-(4′-diethylamino-1′-methylbutyl) amino-2-methoxyacridine [(?)-(R)-quinacrine] while (+)?(S)-quinacrine was obtained from the enantiomeric diamine.     

Synthesis of Derivatives of 3-Methylxantheve and 1-Methyl-3-Isobutylxanthine 7-β-D-Ribofuranosides

Abstract

Methods of synthesis of 7–(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl)-8-chloro-3-methylxanthine (5a) and l-methyl-3-isobutylxanthine (5b) were reported. Further nucleophilic displacement of chlorine has provided the corresponding 8-alkylamino and 8-benzylamino derivatives (6a,b-9a,b). Several 5′-acyl analogues of 3-methylxanthine-7–β-D-ribofuranoside (15–18) were synthesized using 7–(2′,3′-di-O-isopropylidene-β-D-ribofuranosyl)-3-methylxanthine (10) as intermediate.     

Synthesis and Herbicidal Activity of Pyridinyloxyphenoxypropionamides

New derivatives of pyridinyloxyphenoxypropionamide were synthesized, which have an unnatural α-amino acid or its decarboxylated structure as amide moieties. Some compounds such as N-(1-metboxycarbonyl-l-tert-butylamino)methyl, N-methoxymethyl and N-hydroxymethyl 2-[4-(3-chloro-5-trifluoromethyl-2-pyridinyloxy)phenoxy] propionamide were found to show stronger herbicidal activity against grass weeds than that of pyridinyloxyphenoxypropionamides which have already been synthesized.     

Reaction of epichlorohydrin with adenosine, 2'-deoxyadenosine and calf thymus DNA: identification of adducts

Epichlorohydrin (a probable human carcinogen) was allowed to react with adenosine and the adducts were characterized by NMR and UV spectroscopy, and mass spectrometry. The adduct initially formed was 1-(3-chloro-2-hydroxypropyl)-adenosine, which subsequently ring closures to 1,N(6)-(2-hydroxypropyl)-adenosine at neutral and basic conditions. At acid conditions, the N-1 adduct undergoes a slow deamination to yield 1-(3-chloro-2-hydroxypropyl)-inosine. Minor adducts identified were 7-(3-chloro-2-hydroxypropyl)-adenosine and 3-(3-chloro-2-hydroxypropyl)-adenosine which are easily deglycosylated, and an adduct where the epichlorohydrin residue was attached to the sugar moiety of adenosine. A diadduct, 1,N(6)-(2-hydroxypropyl)-N(6)-(3-chloro-2-hydroxypropyl)-adenosine was also identified. The reaction of epichlorohydrin with calf thymus DNA gave 1,N(6)-(2-hydroxypropyl)-deoxyadenosine and 3-(3-chloro-2-hydroxypropyl)-adenine (major adduct).     

CHEMICAL AND ENZYMATIC SYNTHESIS OF 4′-THIO-β-D-ARABINOFURANOSYLCYTOSINE MONOPHOSPHATE AND TRIPHOSPHATE

N⁴-Acetyl-1-(2, 3-di-O-acetyl-4-thio-β-D-arabinofuranosyl)cytosine (2) was synthesized in three steps from 1-(4-thio-β-D-arabinofuranosyl)cytosine (1). The reaction of this partially blocked 4′-thio-ara-C derivative 2 with 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one gave the 5′-phosphitylate derivative 3, which on reaction with pyrophosphate gave the 5′-nucleosidylcyclotriphosphite 4. Product 4 was then oxidized with iodine/pyridine/water and deblocked with concentrated ammonium hydroxide to provide the desired 4′-thio-ara-C-5′-triphosphate 5. This triphosphate 5 was converted to 4′-thio-ara-C -5′-monophosphate 6 by treatment with snake venom phosphodiesterase I. The details of the synthesis, purification, and characterization of both nucleotides are described.