Synthesis of new functionalized imidazo[2,1‐b]thiazoles and thiazolo[3,2‐a]pyrimidines

5‐Oxo‐5H‐[1,3]thiazolo[3,2‐a]pyrimidine‐6‐carboxylic acid ( 4 ), and 6‐methylimidazo[2,1‐b]thiazole‐5‐carboxylic acid ( 17 ) were reacted with amines 6a‐i by the reaction with oxalyl chloride and N, N‐di methyl‐formamide as a catalyst into primary and secondary amide derivatives 7‐14 and 19‐22. From compound 24 N,N'‐disubstituted ureas 26, 27 and perhydroimidazo[1,5‐c]thiazole 29 derivatives of imidazo[2,1‐b]thiazole were prepared. By nmr analysis of compound 29 , the existence of two stereoisomers resulting from both optical, due to centre of chirality at C7′a, and conformational isomerism, due to restricted C5? N6′ bond rotation were proved.     

Efficient synthesis of 5H‐thiazolo[3,2‐a]pyrimidines from reactions of 3,4‐dihydropyrimidine‐thiones with α‐bromoacetone in aqueous media

An efficient and convenient method for thiazolo[3,2‐a]pyrimidines from cyclization reaction of dihydropyrimidine‐thiones with α‐bromoacetone in aqueous media is described. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:149–153, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20386     

A Simple and Efficient One‐Pot Synthesis of Multifunctional 5‐Aryl‐5H‐thiazolo[3,2‐a]pyrimidines

One‐pot economical and efficient synthesis of multifunctional 5H‐thiazolo[3,2‐a]pyrimidines by the reaction of 4‐aryl dihydrothiopyrimidines with propargyl bromide in the presence of inorganic base has been reported in very short time.     

Three‐Component Reaction for Construction of Spiro[indoline‐3,7′‐thiazolo[3,2‐a]pyridines] and Spiro[benzo[4,5]thiazolo[3,2‐a]pyridine‐3,3′‐indolines]

The three‐component reaction of thiazole (benzothiazole), dialkyl but‐2‐ynedioate, and isatinylidene malononitriles in toluene at 110–120°C in a sealed tube afforded a mixture of cis/trans‐isomers of functionalized diastereoisomeric spiro[indoline‐3,7′‐thiazolo[3,2‐a]pyridines] and spiro[benzo[4,5]thiazolo[3,2‐a]pyridine‐3,3′‐indolines] in good yields. Both cis‐isomers and trans‐isomers were successfully separated out and fully characterized with spectroscopy and single crystal determination. Under similar conditions, the three‐component reaction containing 2‐(1,3‐dioxo‐1H‐inden‐2(3H)‐ylidene)malononitrile resulted in spiro[indene‐2,7′‐thiazolo[3,2‐a]pyridine] derivatives.     

A Convenient Synthesis of Some New 1,3,4‐Thiadiazoles,Thiazoles, Pyrazolo[1,5‐a]pyrimidines,Pyrazolo[5,1‐c]triazine,and Thieno[3,2‐d]pyrimidines Containing 5‐Bromobenzofuran Moiety

1,3,4‐Thiadiazoles, pyrazolo[1,5‐a]pyrimidines, pyrazolo[5,1‐c]triazine, and thieno[3,2‐d]pyrimidines were synthesized from 1‐(5‐bromobenzofuran‐2‐yl)ethanone. The structures of the newly synthesized compounds were elucidated by elemental analysis, spectral data, chemical transformation, and alternative synthesis route whenever possible.     

Tricyclic thiazolo[3,2-a]thiapyrano[4,3-d]pyrimidines and related analogs as potential anti-inflammatory agents

A series of novel tricyclic thiazolo[3,2-a]thiapyrano[4,3-d]pyrimidines and related oxa, aza and carbo analogs of general formula 1 were prepared by a convenient addition-cyclization reaction involving 2-amino-2-thiazoline ( 4 ) and bisarylidene ketones of formula 3. Some of these compounds demonstrated antiinflammatory activity.     

Synthesis of novel 1‐substituted [1,3]thiazolo[3,2‐a]‐[1,5]benzodiazepine derivatives from 1,5‐benzodiazepine‐2‐thiones and α‐halogen carbonyl compounds

A number of substituted 4H,5H,6H‐thiazolo[3,2‐a][1,5]benzodiazepinium salts 2a‐h, 5, 9 , which are based on the novel thiazolobenzodiazepine system, were prepared by condensation‐cyclization of 1,5‐benzodiazepine‐2‐thiones 1a‐f, h, 4 with α‐haloketones, as well as with α‐bromoacetaldehyde diethyl acetal. The structure and stereochemistry of the ring system obtained were investigated by ¹H and ¹³C nmr spectroscopy: the additional heterocyclic nucleus was found to appreciably influence the conformational mobility of the heptatomic ring. Upon treatment of salt 2d with alkali the presence of the base enamine structure in solution has been postulated.     

Synthesis,Characterization and Reactions of 4‐Hydrazino‐2‐methylpyrimidino[4′5′:4,5]thiazolo[3,2‐a]benzimidazole

4‐Hydrazino‐2‐methylpyrimidino[4′,5′:4,5]thiazolo[3,2‐a]benzimidazole ( 4 ) was obtained from hydrazinolysis of the 4‐chloro derivative 3 with hydrazine hydrate. The hydrazino derivative 4 was further cyclized to the corresponding pyrazole 5 , pyrazolone 6 and 5‐methyl‐1,2,4‐triazolo[1″,5″:3′,4′]pyrimidino[5′,6′:5,4]‐thiazolo[3,2‐a]benzimidazole ( 9 ) and 5‐methy‐1,2,4‐triazolo[4″,3″:3′,4′]pyrimidino[5′,6′:5,4]thiazolo‐[3,2‐a]benzimidazole ( 10 ), respectively. The triazolo derivative 10 was isomerized to the triazolo derivative 9 under a variety of reaction conditions.     

The synthesis of 5,10-dihydro- and 2,3,5,10-tetrahydrothiazolo-[3,2-b] [2,4]benzodiazepines, 1,2,3,4,7,12-hexahydrobenzothiazolo-[3,2-b] [2,4] benzodiazepine,and 9,14-dihydro-6H-[1]benzothiopyrano-[4′,3′:4,5]thiazolo[3,2-b] [2,4] benzodiazepine via 1,2,4,5-Tetrahydro-3H-2,4-benzodiazepine-3-thione

Catalytic reductive scission of phthalazine (II) utilizing a two-stage palladium-Raney nickel procedure afforded o-xylene-α,α′-diamine (III) in 97% yield. Treatment of III with carbon disulfide gave [o-(aminomethyl)benzyl]dithiocarbamic acid (IV), which upon thermal cyclization furnished 1,2,4,5-tetrahydro-3H-2,4-benzodiazepine-3-thione (V). Reaction of V with 1,2-dibromoethane, chloro-2-propanone, ethyl 2-chloroacetoacetate, ethyl chloroacetate, and ethyl 2-bromohexanoate gave 2,3,5,10-tetrahydrothiazolo[3,2-b][2,4]benzodiazepine (VII) and substituted 5,10-dihydrothiazolo[3,2-b][2,4]benzodiazepines (Villa and b, IX, and X), respectively. Condensation of V with 2-chlorocyclohexanone and 3-bromothiochroman-4-one afforded 1,2,3,4,7,12-hexahydrobenzothiazolo[3,2-b][2,4]benzodiazepine (XII) and 9,14-dihydro-6H-[1]benzothiopyrano[4′,3′:4,5]thiazolo[3,2-b][2,4]benzodiazepine(XIll). None of the compounds possessed appreciable biological activity.     

A new approach to the synthesis of benzofuro[3,2‐b]quinolines,benzothieno[3,2‐b]quinolines and indolo[3,2‐b]quinolines

Treatment of 2‐hydroxy‐, 2‐mercapto‐, and 2‐ethoxycarbonylamino‐benzonitriles 12 with 2‐fluoro‐ or 2‐nitrophenacylbromides 13 under alkaline conditions provided the corresponding benzofuran, benzothiophene, and indole intermediates 10 , respectivelly. Nucleophilic cyclization of these compounds led to the corresponding tetracyclic quinolinones 7a, 7b , and 3. Denitrocyclization reaction of compounds 10 (R = NO₂) was found especially useful. Compounds 7a, 7b , and 3 were converted to their chloro derivatives 14a‐c , which were reduced with hydrogen and a catalyst to the corresponding compounds 8a, 8b , and 2. The presented pathway represents a new method of preparation of quindoline 2 and its O and S analogs 8. Chloro derivatives 14 are reactive enough to provide the corresponding methoxy derivatives 15 and dimethylamino derivatives 16. Methylation of compounds 7a and 7b with iodomethane providing mixtures of major N‐methyl derivatives 17 and minor O‐methyl derivatives 15 were also studied.     

One‐pot Multicomponent Synthesis of Isoxazolyl Spiro[indoline‐3,2′‐pyrrolidine]‐2,4′‐diones Catalyzed by CAN

An efficient CAN‐catalyzed synthesis of isoxazolyl spiro[indoline‐3,2′‐pyrrolidine]‐2,4′‐diones has been developed via one‐pot three‐component reaction of isoxazole amine, differently substituted isatins, and acetone at room temperature. Several catalysts and solvents have been screened for the efficiency, but the optimum results were obtained with CAN in THF.     

Direct Synthesis of Trichloro‐thiazolo[3,2‐a]pyrimidine and Thiazolo[2,3‐b]quinazoline Derivatives

An efficient one‐pot method for synthesis of new biologically active thiazolo[3,2‐a ]pyrimidine and thiazolo[2,3‐b ]quinazoline derivatives is described via reaction of pentachloropyridine with fused pyrimidine‐2(5H )‐thiones or quinazoline‐2(1H )‐thiones. These reactions were carried out in the presence of potassium carbonate as a base in acetonitrile as a solvent to produce products 3a – n in good‐to‐excellent yield. Pentachloropyridine is doubly electrophilic building blocks for the formation of ring annulated thiazolo[3,2‐a ]pyrimidine and thiazolo[2,3‐b ]quinazoline products.     

Synthesis of new thieno[2,3‐d]pyrimidines,thieno[3,2‐e]pyridines,and thieno[2,3‐d][1,3]oxazines

o‐Aminothiophene dicarbonitrile 1 on neat reaction with cyclic ketones in anhydrous ZnCl₂ yielded mixture of fused aminopyridine 3 and iminospirooxazine 4 derivatives. Similarly, pyrimidine derivatives 5 and 8 were obtained by the reaction of this intermediate 1 with formic acid and DMF‐DMA followed by hydrazine hydrate, respectively. The reaction of o‐amino‐thiophene dicarboxamide 2 at ambient temperature with cyclic ketones yielded spiropyrimidine 10 as a sole product in quantitative yield. The regioselective anellated pyrimidine 9 , 11 , and dihydropyrimidine 12 derivatives were also obtained by the reaction with aromatic aldehydes in presence of piperidine and iodine respectively. J. Heterocyclic Chem., (2012).     

Synthesis of dispiro[oxindole‐pyrrolidine]‐thiazolo[3,2‐a][1,3,5]triazines by 1,3‐dipolar cycloaddition

The 1,3‐dipolar cycloaddition of an azomethine ylide generated by a decarboxylative route from sarcosine and isatin to 7‐arylmethylidene‐3‐aryl‐3,4‐dihydro‐2H‐thiazolo[3,2‐a][1,3,5]triazin‐6(7H)‐ones afforded novel dispiro[oxindole‐pyrrolidine]‐thiazolo[3,2‐a][1,3,5]triazines in moderate yields. The structures of the products were determined and characterized thoroughly by NMR, MS, IR, and elemental analysis. The results of experiment indicated that this 1,3‐dipolar cycloaddition proceeded with high stereoselectivity and regioselectivity. J. Heterocyclic Chem., (2011).     

The synthesis of new 2,4‐diaminofuro[2,3‐d]pyrimidines with 5‐biphenyl,phenoxyphenyl and tricyclic substitutions as dihydrofolate reductase inhibitors

Nonclassical 2,4‐diamino‐5‐substituted furo[2,3‐d]pyrimidines 4a‐i, 5a‐b and 7a‐f were synthesized as extended aromatic ring appended analogs of previously reported antifolates 1a‐b. The extended aromatic system was designed to better interact with a phenylalanine residue (Phe69) of dihydrofolate reductase from the opportunistic pathogen Pneumocystis carinii to afford potent and selective inhibitors of Pneumocystis carinii dihydrofolate reductase. The target compounds were synthesized by nucleophilic displacement of 2,4‐diamino‐5‐(chloromethyl)furo[2,3‐d]pyrimidine 3 with the appropriate aromatic amine or thiol. The compounds were evaluated as inhibitors of dihydrofolate reductase from Pneumocystis carinii and Toxoplasma gondii, and their selectivity was determined using rat liver dihydrofolate reductase as the mammalian reference. In the C8‐N9 bridged series, compound 4e , with a 3‐(2‐methoxydibenzofuran)‐ side chain, exhibited greatest potency and was more than 3 times as selective for Pneumocystis carinii dihydrofolate reductase compared to rat liver dihydrofolate reductase. Compounds 4b and 4c also exhibited selectivity. Compounds in the C8‐S9 bridged series showed comparable potencies, and each showed higher selectivity for Pneumocystis carinii dihydrofolate reductase compared to rat liver dihydrofolate reductase.     

A convenient synthesis of 2‐Arylidene‐5H‐thiazolo[2,3‐b]quinazo‐line‐3,5[2H]‐diones and their benzoquinazoline derivatives

Various 5H‐thiazolo[2,3‐b]quinazoline‐3,5[2H]‐diones (7a,b), 2‐arylidene‐5H‐thiazolo[2,3–b]quin‐azoline‐3,5[2H]‐diones ( 9a‐o ) and 2‐arylidene‐5H‐thiazolo[2,3‐b]benzoquinazoline‐3,5[2H]‐diones ( 12a,b ) have been synthesized via simple and efficient methods.     

Design,synthesis and biological evaluation of 2,4‐diamino‐6‐methyl‐5‐substitutedpyrrolo[2,3‐d]pyrimidines as dihydrofolate reductase inhibitors

Nine novel nonclassical 2,4‐diamino‐6‐methyl‐5‐mioarylsubstituted‐ 7H ‐pyrrolo[2,3‐d]pyrimidines 2‐10 were synthesized as potential inhibitors of dihydrofolate reductase and as antitumor agents. The analogues contain various electron donating and electron withdrawing substituents on the phenylsulfanyl ring of the side chains and were synthesized from the key intermediate 2,6‐diamino‐6‐methyl‐7H‐pyrrolo[2,3‐d]‐pyrimidine, 14 . Compound 14 , was in turn obtained by chlorination of 4‐position of 2‐amino‐6‐methylpyrrolo[2,3‐d]pyrimidin‐4(3H)‐one, 16 followed by displacement with ammonia. Appropriately substituted phenyl thiols were appended to the 5‐position of 14 via an oxidative addition reaction using iodine, ethanol and water. The compounds were evaluated against rat liver, rat‐derived Pneumocystis, Mycobacterium avium and Toxoplasma gondii dihydrofolate reductase. The most potent and selective inhibitor, (2) has a 1‐naphthyl side chain. In this series of compounds electron‐withdrawing and bulky substituents in the side chain afford marginally active dihydrofolate reductase inhibitors. The single atom sulfur bridge in the side chain of these compounds is not conducive to potent dihydrofolate reductase inhibition.     

Synthesis of trifluoromethylated pyrido[2,3‐d]pyrimidine‐2,4‐diones from 6‐aminouracils and trifluoromethylated pyrazolo[3,4‐b]‐pyridines from 5‐aminopyrazoles

5 or 7‐Trifluoromethyl‐1,2,3,4‐tetrahydropyrido[2,3‐d]pyrimidine‐2,4‐diones 3 , 5 , 10 , 13 and 4‐ or 6‐trifluoromethylpyrazolo[3,4‐b]pyridines 15 , 16 , 19 , 21 were prepared from 6‐aminouracils and 5‐aminopyrazoles, respectively, in good yields by the use of building blocks such as 4,4,4‐trifluoro‐1‐phenyl‐1,3‐butanedione, 1,1,1‐trifluoro‐4‐phenyl‐3‐buten‐2‐one, 4‐ethoxy‐1,1,1‐trifluoro‐3‐buten‐2‐one, and ethyl trifluoroacetoacetate.