Synthesis of isochroman-fused pyrazolone and pyrimidine derivatives

Unsubstituted 5 , and 2-aryl- 6a-c , or 2-(2-benzothiazolyl)-substituted 1,3-dihydroisochromano[4,3-c]pyrazol-3(2H)-ones 7a-f were prepared by the reactions of 3-ethoxyoxalyl- 2 , or 3-ethoxycarbonylisochroman-4-one 3 with hydrazine derivatives. The reactions with amidines gave 2-substituted 4-hydroxyisochromano[4,3-d]-pyrimidines 8a-c .     

BtCH(2)TMS-assisted homologation of carboxylic acids: A safe alternative to the arndt-eistert reaction

One-carbon homologation of carboxylic acids is achieved by (i) treatment of an acyl chloride with 1-[(trimethylsilyl)methyl]-1H-1,2, 3-benzotriazole (BtCH(2)TMS) (1) to afford N-(acylmethyl)benzotriazoles 3a-f, followed by (ii) conversion of 3a-f with triflic anhydride into RC(OTf)=CHBt 4a-f, and (iii) the subsequent reaction of 4a-c with NaOCH(3) followed by 1N HCl to afford esters RCH(2)CO(2)R' 7a-c in overall yields of 50-70%. For the aliphatic compounds 5d-f, treatment of 5d-f with p-toluenesulfonic acid followed by TBAF/THF afforded acids RCH(2)COOH 7d-f.     

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.     

A novel synthesis of precocenes. Efficient synthesis and regioselective O-alkylation of dihydroxy-2,2-dimethyl-4-chromanones

The reactions of trihydroxybenzenes 1a-c and 3-methylbut-2-enoic acid ( 2 ) in a zinc chloride/water/phosphoryl chloride system afford either the new trihydroxyphenylbutenone derivatives 3b,c or dihydroxy-2,2-dimethyl-4-chromanones 4a-c in good yields. Compounds 3b,c can be cyclized in high yields to 4b,c in 5% sodium hydroxide solution. Regioselective O-alkylation of 4a-c leads to 5a-f in good yields. O-Alkylation of 5a-f , followed by reduction and dehydration, results in the formation of precocene 3 ( 7d ) and its regioisomer 7a-c,e,f . Methylation of 4a-c gives 6g-i . Subsequent reduction and dehydration affords precocene 2 ( 7h ) and its regioisomers 7g,i .     

Cyclization of alpha-Oxo-oximes to 2-substituted benzoxazoles

Reactions of oximes 9, 17, and 19 with electrophiles 15a-f and 24 in the presence of anhydrous potassium carbonate or triethylamine give 2-substituted condensed ring oxazoles 10, 16a-c, 18a-d, 20a-c, and 25 in a new general route to these compounds.     

Novel syntheses of 2,3-dihydro-1,5-benzothiazepin-4(5h)-ones and 2h-1,4-benzothiazin-3(4h)-ones

Nucleophilic additions of alpha-mercaptoalkanoate esters and beta-mercaptoalkanoate acids to benzoquinone diimines, followed by cyclization with trifluoroacetic acid or 1,3-dicyclohexylcarbodiimide (DCC), provide novel, high-yielding syntheses of 2H-1,4-benzothiazin-3(4H)-ones (3a-f) and 2,3-dihydro-1,5-benzothiazepin-4(5H)-ones (5a-c), respectively.     

Synthesis of Novel Bis-2-(1,3,4-thiadiazolin-3-ylphenoxy) Alkane Derivatives

A novel synthesis of bis(thiadiazolin-3-yl)ethers 6a-f and bis(thiadiazolin-2-on-3-yl)ethers 10a-f via the reaction of the bis (diazonium) salts 2a-c with the appropriate y -thiocyanatoacetophenone derivatives 4a-c .     

A novel approach to substituted 2H-azirines

2-(Benzotriazol-1-yl)-2H-azirines 4a-c, obtained by treatment of oximes 2a-c with tosyl chloride and aqueous KOH, were reacted with benzylmagnesium bromide or 4-methylbenzylmagnesium bromide in the presence of zinc chloride to give 2-benzyl-2H-azirines 5a-f. Potassium phthalimide and sodium salt of benzenethiol converted 2-(benzotriazol-1-yl)-2H-azirines 4a-c into novel 2H-azirines 6a-c and 7 in good yields.     

Synthesis of New Quinolone Antibiotics Utilizing Azetidine Derivatives Obtained from 1-Azabicyclo[1.1.0]butane

A series of 3-sulfenylazetidine derivatives 5a-f were synthesized via the ring-opening reactions of 1-azabicyclo[1.1.0]butane (ABB, 3) with thiols 4a-f in 50-92% yields. Treatment of ABB (3) with aromatic amines 9a-e and dibenzylamine (9f) in the presence of Mg(ClO4)2 afforded the corresponding 3-aminoazetidine derivatives 10a-f in 24-65% yields. N-Benzyl-3-bromoazetidine (13), which was obtained by the reaction of ABB (3) with benzyl bromide, gave 3-aliphatic amino-substituted azetidine derivatives 15a, b. Novel fluoroquinolones 7a-f, 11a-f, 16a, b and 25a-c were obtained by the introduction of these azetidine derivatives into the C7 position of a quinolone nucleus 6 and N1-heterocyclic quinolones 21a-c in 21-83% yields. Some of them exhibited a greater antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) in comparison with that of clinically used fluoroquinolone, levofloxacin (LVFX).     

Diastereoselective synthesis of delta-aminoacids through domino Ireland-Claisen rearrangement and Michael addition

A novel domino reaction--stereoselective Ireland-Claisen rearrangement and asymmetric Michael addition--is described. A protocol starting from Baylis-Hillman adducts 3a-f using chiral lithium amide affords optically active gamma-substituted delta-amino acids 4a-f with high diastereoselectivities and enantioselectivities. The acid can be isolated easily from large-scale reactions and transformed to 2,3-disubstituted piperidines 11 or 2-substituted nipecotic acid derivates 12.     

Efficient conversion of sulfones into beta-keto sulfones by N-acylbenzotriazoles

Acyclic sulfones 4a-f and alicyclic sulfone 7 react with readily available N-acylbenzotriazoles 3a-g (derived from aliphatic, aromatic, and heteroaromatic carboxylic acids) to provide the corresponding beta-keto sulfones 5a-n and 8a-c, respectively, in good to excellent yields.     

Synthetic organic chemistry with 2-ethoxy-2-(phenylselenenyl)perfluoroalk-2-enenitrile: application to alpha-cyanoperfluoroacylation of aldehydes

(Z)- and (E)-2-Ethoxyperfluoro-2-(phenylselenenyl)alk-2-enenitriles 2-4 prepared by our original method underwent transmetalation on treatment with n-BuLi or EtMgBr, and the successive reaction with aldehyde and ketones afforded the corresponding allylic alcohols 10a-f, 9a, and 11a,b in good to high yields. Hydrolysis of the alcohols gave alpha-cyano-alpha,beta-unsaturated perfluoroalkyl ketones 13a-c, 13e, 12a, and 15a. alpha-Cyanoperfluoroalkyl ketones were easily converted to alpha,beta-unsaturated 3-aryl-2-cyanoallylic alcohols 18-22 having interesting biological activities and chemical reactivities.     

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 .     

Radiosensitizing hypoxic cells with new 3-nitro-1,2,4-triazole derivatives in vitro and in vivo

The new regioisomer derivatives 4a-f and 5a-f of 3-nitro-1,2,4-triazole (3-NTR) were synthesized for the development of new radiosensitizers of hypoxic cancer cells for radiotherapy. N(2)-Substituted 3-NTR derivatives 5a-f were stronger radiosensitizers of hypoxic cells in vitro (Chinese hamster V79 cells) than N(1)-substituted 3-NTR derivatives 4a-f, but in vivo they were weaker (SCCVII carcinoma cells inoculated into C3H/He mouse).     

REACTIONS WITH 2-THIOHYDANTOIN DERIVATIVES: SYNTHESIS OF MANNICH BASES AND IMIDAZOTHIAZOLE DERIVATIVES

Abstract

5-Arylidene-2-thiohydantoins (la-c) and 5-arylazo-1-phenyl-2-thiohydantoins (7a, b) were condensed with formaldehyde and primary or secondary aromatic amines to give the corresponding Mannich bases (2a-f) and (8a, b) respectively, which could also be converted into the educts (la-c) and (7a, b) by boiling in ethanolic HCI. On treatment of (2a-f), (5a-c) and (8a, b) with an ethereal diazomethane the colourless cyclopropane products (3a-c) and yellow N-methyl substituted compounds (9, b) were isolated respectively. Alkylation of (2d-f) with methyl iodide and (la-e) with 3-chloropentane-2,4 dione gave the corresponding 2-alkylmercapto derivatives (5a-c) and (2a-c) respectively, the former of which on hydrolysis by boiling ethanolic HCI afforded the hydantoin derivatives (6a-c). Cyclization of (12a-c) using polyphosphoric acid resulted in the formation of imidazothiazole derivatives (13a-c). The structure of the isolated products were established by elemental analyses and spectral data studies.     

Synthesis of 5-alkoxymethyl derivatives of 3'-amino-2',3'-dideoxyuridine and evaluation of their activity against HIV and cancer.

5-Alkoxymethyluracils 2a-c have been prepared by acid-catalyzed etherification of 5-hydroxymethyluracil (1). Compounds 1, 2a-c, 5-methoxymethyl- and 5-benzyloxymethyl-uracil were silylated and coupled with 1,5-di-O-acetyl-3-phthalimido-2,3-dideoxy-beta- D-erythro-pentofuranose (3), in the presence of trimethylsilyl triflate as a catalyst, to give the corresponding 3'-phthalimido-2',3'-dideoxynucleosides 5a-f and 6 which on treatment with 33% methylamine-ethanol afforded the corresponding 3'-amino-2',3'-dideoxynucleosides 7a-f and 8 in high yields. Compound 7d showed colony inhibition when tested against human epidermoid cervical cancer cells. Nucleosides 5a-e, 7a-f and 8 did not show any significant activity against HIV-1.     

Direct synthesis of esters and amides from unprotected hydroxyaromatic and -aliphatic carboxylic acids

A facile method for the activation of hydroxy-substituted carboxylic acids using benzotriazole chemistry without prior protection of the hydroxy substituents is presented. The N-acylbenzotriazole intermediates 2a-g, 6a-d, and 9a-c have been used for high-yielding synthesis of both aliphatic (3a-l) and aromatic (7a-h, 10a-f) hydroxy carboxamides. High yields of aromatic hydroxy esters 12a-h and 13a-i were obtained using either neat alcohols in neutral microwave conditions or nucleophilic alkoxides and the intermediate N-(arylacyl)benzotriazoles. Moderate yields were obtained in the case of aliphatic hydroxy esters 11a,b and thiolesters 11e-g from the intermediates 2a-c.     

An effective synthesis of fused cyclic thiopyrans and pyrans by molybdenum(VI) sulfide catalyzed reduction of the corresponding thiopyranones and pyranones

The synthesis of fused cyclic dihydrothiopyrans 2a-c from dihydrothiopyranones 1a-c and thiopyrans 2d-f from thiopyranones 1d-f by catalytic reduction over molybdenum(VI) sulfide (MoS₃) has been studied. The hydrogenolysis of the carbonyl group of 1a-f over MoS₃ catalyst proceeded selectively to give the corresponding 2a-f in high yields. Neither alcohols nor olefins were not detected in the products. The method was also applied successfully to the synthesis of dihydropyran 2h and pyran 2g from dihydro-pyranone 1h and pyranone 1g.     

The first synthesis of phosphonoacrolein. Application to Diels-Alder reaction as heterodiene

The first synthesis of phosphonoacrolein 3 was made in quantitative yield by acidic treatment of beta-ethoxy-alpha-(methoxymethyl)vinylphosphonate 2, derived from a beta-ethoxy-alpha-phosphonovinyl anion and MOMCl. The phosphonoacrolein 3 easily underwent a hetero-Diels-Alder reaction with electron-rich alkenes 4a-f or alkynes 9a-c under mild conditions, and phosphono-substituted pyrans 5a-d, 6e,f or pyranopyrans 11a-c were obtained in good to excellent yields. The reaction of 3 with cyclopentadiene and cyclohexadiene led to mixtures of [2 + 4] and [4 + 2] cycloadducts 7a, 8a and 7b, 8b in modest yields. The cycloaddition reaction between 3 and pyranopyran 13 or dibromocarbene and 13 resulted in [4 + 2] or [2 + 1] cycloadducts 14 or 15 in good yields.     

Reaction of E-2-arylidene-1-indanones,Z-aurones,Z-1-thioaurones and Z-2-arylidene-2,3-dihydro-1H-indol-3-ones with diazomethane

1,3-Dipolar cycloaddition of E-2-arylidene-1-indanones 1a-h and Z-aurones 3a-c with diazomethane provided trans-spiro-1-pyrazolines 2a-h and 4a-c , respectively, as sole products. However, the same cycloaddition of Z-1-thioaurones 5a-f afforded a mixture of Z-α-methyl-1-thioaurones 6a-f and trans-cyclopropane derivatives 7a-f as a result of the spontaneous denitrogenation of the initially formed 1-pyrazolines. Similar reaction of Z-2-arylidene-2,3-dihydro-1H-indol-3-ones 8a,b and diazomethane yielded trans-cyclopropanes 9a,b . Structure and stereochemistry of the compounds synthesized have been elucidated by nmr spectroscopic measurements.