Synthetic approaches towards the sulfonamide substituted‐4,5‐diaryl‐4H‐1,2,4‐triazole‐3‐thiones

A new series of 3‐alkylthio‐4,5‐diaryl‐4H‐1,2,4‐triazoles having a SO₂NH₂ substituent in the para‐position on one of the aryl rings ( 19/25 ) were prepared starting from the appropriate benzoic acid hydrazides ( 15/21 ). Reaction of the corresponding hydrazides with the appropriate isothiocyanates yielded 16/22 , which were cyclized in basic media to give 4,5‐diaryl‐2,4‐dihydro‐3H‐1,2,4‐triazole‐3‐thiones 17/23 . Alkylation of 17/23 afforded the alkylthio compounds 18/24 . Final debenzylation was achieved with concentrated sulfuric acid to give the target sulfonamides 19/25 .     

Δ2‐Isoxazolines from β,γ‐unsaturated oximes

3,5‐Disubstituted Δ²‐isoxazolines can be prepared using the palladium‐mediated nucleometalation / methoxycarbonylation of β,γ‐unsaturated oximes. This novel route to this class of compounds is tolerant of a wide variety of functionality in the starting material, and provides a rapid route to highly functionalized isoxazolines.     

Reaction of 4‐substituted thiosemicarbazides with (2,4,7‐trinitro‐9H‐fluoren‐9‐ylidene)propanedinitrile

4‐Substituted thiosemicarbazides 4a‐c reacted with (2,4,7‐trinitro‐9H‐fluoren‐9‐ylidene)‐propanedinitrile ( 2 ) in pyridine with admission of air to form spiro[fluorene‐9,3′‐(1,2,4‐triazole)]derivatives 5a‐c and (4‐substituted thiosemicarbazono)propanedinitriles 6a‐c in modest yields. 2,4,7‐Trinitro‐9‐fluorenone ( 8 ) as well as one reduction product thereof and of 2 , namely compounds 9 and 10 , respectively are also found. A rationale for the conversions observed is presented.     

A novel synthesis of some new benzoyl‐substituted heterocycles from 2‐benzoyl‐3‐phenylpent‐2‐ene‐1,5‐dinitrile

2‐Benzoyl‐3‐phenylpent‐2‐ene‐1,5‐dinitrile 1 undergoes bromination with N‐bromosuccinimide (NBS) to afford the bromo derivative 2a . This bromo derivative undergoes reactions with sodium hydrogen sulfide, ethyl thioglycollate, hydroxylamine hydrochloride, hydrazines, cyanoacetamide, cyanacetohydrazide and urea derivatives to afford the thiophene 4 , 4H‐thiopyran 6 , 4H‐1,2‐oxazine 8 , 4H‐pyridazines 10a,b , the pyridine 15 , pyrrolo[1,2‐b]pyridazine 17 and the N‐substituted‐pyrrole derivatives 19a‐c respectively.     

Synthesis and antimicrobial activity of new benzofuranyl‐1,3‐benzoxazines and 1,3‐benzoxazin‐2‐ones

New benzofuranyl‐1,3‐benzoxazines and 1,3‐benzoxazin‐2‐ones are synthesized in which benzofuran is coupled with 1,3‐benzoxazines and 1,3‐benzoxazin‐2‐ones through ‐CONH‐ and ‐COCH₂‐ bridges, respectively. The antimicrobial activity of these compounds is reported.     

Reactions of 2‐amino‐4h‐1‐benzopyran‐4‐one with 4‐oxo‐4h‐1‐benzopyran‐3‐carbaldehydes

The title aldehyde 1 reacts smoothly with the enamine moiety of 2 ‐aminochromone 2 to produce hitherto unreported 3‐(2‐hydroxybenzoyl)‐5H‐1‐benzopyrano[2,3‐b]pyridin‐5‐one (azaxanthone) 5 . This reaction has been extended for the synthesis of bisazaxanthone 9.     

Synthesis of 5‐substituted 2‐(2,4‐dihydroxyphenyl)‐1,3,4‐thiadiazoles

One‐stage synthesis of 5‐substituted (alkyl, aryl, heteroaryl, arylalkyl, heteroalkyl, alkoxy‐, aryloxy)‐2‐(2,4‐dihydroxyphenyl)‐1,3,4‐thiadiazoles is described. The compounds were prepared by the reaction of sulfinyl‐bis(2,4‐dihydroxythiobenzoyl) (STB) with hydrazides or carbazates. The structure of new compounds was assigned by ir, nmr and ms data.     

Synthesis and anti‐HIV activity of n‐(3‐amino‐3,4‐dihydro‐4‐oxopyrimidin‐2‐yl)‐4‐chloro‐2‐mercapto‐5‐methylbenzenesulfonamide derivatives

A series of N‐(3‐amino‐3,4‐dihydro‐4‐oxopyrimidin‐2‐yl)‐4‐chloro‐2‐mercapto‐5‐methylbenzenesulfonamide derivatives 10‐17 have been synthesized as potential anti‐HIV agents. The in vitro anti‐HIV‐1 activity of these compounds has been tested at the national Cancer Institute (Bethesda, MD), and the structure‐activity relationships are discussed. The selected N‐[3‐amino‐3,4‐dihydro‐6‐(tert‐butyl)‐4‐oxothieno[2,3‐e]pyrimidin‐2‐yl]‐4‐chloro‐2‐metcapto‐5‐methylbenzenesulfonamide ( 14 ) showed good anti‐HIV‐1 activity with 50% effective concentration (EC₅₀) value of 15 μM and weak cytotoxic effect (IC₅₀ = 106 μM).     

Synthesis of first representatives of 3,3′‐bi(6,8‐dialkyl‐2,4‐dioxa‐6,8‐diazabicyclo[3.3.0]octan‐7‐ones)

The first representatives of 3,3′‐bi(2,4‐dioxa‐6,8‐diazabicyclo[3.3.0]octan‐7‐ones) have been synthesized by a reaction of glyoxal as form of 2,2′‐bi(4,5‐dihydroxy‐1,3‐dioxalane) with N,N′‐dialkylureas. Their structures have been supported by X‐ray analysis. 1,3‐Dialkylimidazolidine‐2,4‐diones (hydantoins) have been isolated as by‐products and their formation mechanism has been experimentally confirmed.     

Synthesis and antimalarial activity of 7‐benzylamino‐1‐isoquinolinamines

Computer modelling suggests that 7‐benzylamino‐1‐isoquinolinamines should mediate antimalarial effects by a mechanism distinct from that employed by existing antimalarial drugs. A series of these compounds was prepared in seven synthetic steps, via reductive amination of 1,7‐isoquinolinediamine. In vitro efficacy testing of the novel compounds against Plasmodium falciparum revealed them to be potent antimalarial agents.     

Reactivity of (2‐methylsulfanyl‐4‐oxo‐6‐phenyl‐4h‐pyrimidin‐3‐yl)‐acetic acid methyl ester towards hydrazine hydrate and benzylamine

The title ester 1 reacted with hydrazine hydrate to give hydrazide 2 , which underwent intramolecular cyclization to yield 1‐amino‐7‐phenyl‐1H‐imidazo[1,2‐a]pyrimidine‐2,5‐dione ( 3 ) or took place in a substitution reaction with benzylamine to form N‐benzyl‐2‐(2‐benzylamino‐4‐oxo‐6‐phenyl‐4H‐pyrimidin‐3‐yl)‐acetamide ( 4 ). The reaction of ester 1 with benzylamine gave corresponding amide 7 , disubstituted derivative 4 or 1‐benzyl‐7‐phenyl‐1H‐imidazo[1,2‐a]pyrimidine‐2,5‐dione ( 8 ) depending on the reaction conditions.     

Synthesis of 1‐acyl‐1,2‐dihydro‐3H‐pyrazol‐3‐ones VIA lewis acid‐mediated rearrangement of 3‐acyloxypyrazoles

The unusual formation of 1‐acyl‐1,2‐dihydro‐3H‐pyrazol‐3‐ones starting from 3‐acyloxypyrazoles by Fries‐type rearrangement is described. Under normal conditions, acylation of 2,4‐dihydro‐3H‐pyrazol‐3‐ones 1 and 2 with acid chlorides or anhydrides in the presence of triethylamine gave the corresponding 3‐acyloxypyrazoles 3a‐f and 4a‐f . Treatment of 3a‐c and 4a‐f with Lewis acid, e.g. titanium(IV) chloride and tin(IV) chloride, caused migration of acyl groups to afford the corresponding 1‐acyl‐1,2‐dihydro‐3H‐pyrazol‐3‐ones 5a‐c and 6a‐f . Interestingly, the reactions of 3‐acyloxypyrazoles 3e and 3f with tin(IV) chloride provided the corresponding tin(IV) complexes 8e and 8f .     

Isothiazolo[5,4‐d]isoxazole S,S‐dioxides and pyrazolo [3,4‐d]‐isothiazole S,S‐dioxides through cycloaddition reaction on 3‐benzylaminoisothiazole S,S‐dioxides

By reacting 4,5‐unsubstituted isothiazole dioxides with diazoalkanes and nitrile oxides bicyclic pyrazolo[3,4‐d]isothiazole and isothiazolo[5,4‐d]isoxazole S,S‐dioxides were obtained in good yield through a regioselective cycloaddition reaction. Through cycloaddition reaction of 3‐benzylamino‐4‐bromo‐isothiazole S,S‐dioxide labile cycloadducts were formed that underwent in situ dehydrobromination affording the corresponding aromatized compounds.     

Cyclocondensation reactions of heterocyclic carbonyl compounds XI . Synthesis and study of cyclocondensation reactions of some 3‐substituted‐5‐(2‐aminobenzyl)‐1H‐[1,2,4]triazine‐6‐ones

A series of 2‐substituted‐4‐(2‐nitrobenzylidene)‐4,5‐dihydrooxazol‐5‐ones ( 2a‐2i ) was prepared by the Erlenmeyer's synthesis of 2‐nitrobenzaldehyde with acylglycines ( 1a‐1i ) and the series of corresponding aminoderivatives ( 3b‐3d and 3g‐3i ) was synthetised by catalytic hydrogenation of ( 2b‐2d and 3g‐3i ). Hydrazinolysis of azlactones ( 2 ) and ( 3 ) gave hydrazides ( 4 ) and ( 5 ). The hydrazides ( 5 ) were also obtained by catalytic hydrogenation of corresponding nitroderivatives ( 4 ). The cyclization reaction of hydrazides ( 4 ) or ( 5 ) proceeded to 3,5‐disubstituted‐1,6‐dihydro‐[1,2,4]triazine‐6‐ones ( 6 ) or ( 7 ). Aminoderivatives ( 7 ) were also obtained by reduction of nitro group of compounds ( 6 ). The aminoderivatives ( 7 ) were then cyclized to 3‐substituted‐1,5‐dihydro‐[1,2,4]triazino[6,5‐b]quinolines ( 9 ), resp. its tautomers ( 10 ).     

Synthesis and Optical Properties of 2‐(Benzo[b]thiophene‐3‐yl)pyrroles and a New BODIPY Fluorophore (BODIPY=4,4‐Difluoro‐4‐bora‐3a,4a‐diaza‐s‐indacene)

The light fantastic : Two new 2‐(benzo[b]thiophene‐3‐yl)pyrroles have been synthesized, and are shown to exhibit optical properties that are promising for optoelectronic materials and devices such as highly efficient fluorescent sensors (see scheme). In addition a new BODIPY fluorophore, derived from 2‐(benzo[b]thiophene‐3‐yl)pyrrole, was also isolated and shows good spectroscopic properties in solution which are fully preserved in the solid state.

     

Some nucleophilic substitutions in 2‐cyano‐3‐nitroimidazo[1,2‐a]pyridine

In some nucleophilic substitution reactions of 2‐cyano‐3‐nitroimidazo[1,2‐a]pyridine, nitrogen (alkylamines, guanidine) and oxygen nucleophiles (alkoxides) underwent substitution of the 2‐cyano group, while sulfur nucleophiles (alkylthiols) underwent substitution of the 3‐nitro group.     

Synthesis of 3‐(2‐hydroxy‐1‐phenylethyl)‐ and 3‐(2‐hydroxy‐2‐phenylethyl)adenine,DNA adducts derived from styrene

3‐(2‐Hydroxy‐2‐phenylethyl)‐ and 3‐(2‐hydroxy‐1‐phenylethyl)adenine, DNA adducts derived from styrene, along with their 9‐substituted analogues were prepared by alkylation of 8‐bromoadenine with corresponding allyl‐protected bromohydrins followed by a new deallylation procedure using tetrakis(triphenylphosphine)palladium catalyzed reductive cleavage by poly(methylhydrosiloxane) in the presence of p‐toluenesulphonic acid. This novel procedure proved to be useful for purine derivatives, which were resistant to other deallylation protocols. Structure of positional isomers was assigned using 2D NMR experiments HMBC and HMQC.     

Synthesis of 1,3‐thiazole and 1,2,4‐oxadiazole substituted spiro[3H‐indole‐3,2′‐thiazolidine]‐2,4′(1H)‐diones

Some new derivatives of spiro[3H‐indole‐3,2′‐thiazolidine]‐2,4′(1H)‐dione with the heterocyclic ring such as substituted thiazole and 1,2,4‐oxadiazole attached to the indolinone ring via CH₂ linkage has been synthesized in moderate yields. The synthesis have been carried out by making use of the reactivity of the NH group of the indolinone moiety present in spiro[3H‐indole‐3,2′‐thiazolidine]‐2,4′(1H)‐dione.