Synthesis of Novel Spiro Thiazolo[3,2-a][1,3,5]triazines via 1,3-Dipolar Cycloaddition of Azomethine Ylide

The 1,3‐dipolar cycloaddition of an azomethine ylide generated by a decarboxylative route from sarcosine and acenaphthenequinone to 7‐arylmethylidene‐3‐aryl‐3,4‐dihydro‐2H‐thiazolo[3,2‐a][1,3,5]triazin‐6(7H)‐ones afforded novel dispiro[acenaphthylene‐1,2′‐pyrrolidine]‐3′,7′ ′‐[1,3]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, elemental analysis and X‐ray crystallographic analysis. The results of experiment indicated that this 1,3‐dipolar cycloaddition proceeded with high stereoselectivity and regioselectivity.     

Unexpected 1,3‐Dipolar Cycloaddition Reaction of Thiazolo[3,2‐a]pyrimidine Derivatives and Nitrilimine

The 1,3‐dipolar cycloaddition reactions of nitrilimine with thiazolo[3,2‐a]pyrimidine derivatives was investigated. Bis‐cycloadducts were obtained through a domino 1,3‐dipolar cycloaddition/ring‐opening/ring‐opening/1,3‐dipolar cycloaddition processes. The structures of the products were characterized thoroughly by NMR, IR, MS, elemental analysis together with X‐ray crystallographic analysis.     

Synthesis of spiro thiazolo[3,2‐a]pyrimidine compounds by one‐pot sequential 1,3‐dipolar cycloadditions

A new class of spiro thiazolo[3,2‐a]pyrimidine compounds were synthesized by the one‐pot sequential 1,3‐dipolar cycloaddition of azomethine ylide (generated from isatin and sarcosine)–nitrile oxide to 2‐arylmethylidene‐6,7‐dihydro‐5H‐thiazolo[3,2‐a]pyrimidin‐3‐ones in moderate yields. The structures of all the products were characterized thoroughly by NMR, MS, IR, elemental analysis, and NMR together with X‐ray crystallographic analysis. J. Heterocyclic Chem., (2011).     

Synthesis of Novel Spiro Pyrano[2,3‐d]thiazolo[3,2‐a]pyrimidine via 1,3‐Dipolar Cycloaddition of Azomethine Ylide

The reaction involving 4‐phenyl‐octahydro‐pyrano[2,3‐d]pyrimidine‐2‐thione, ethyl chloroacetate and the appropriate aromatic aldehyde yielded 2‐arylmethylidene‐5‐phenyl‐5a,7,8,9a‐tetrahydro‐5H,6H‐pyrano[2,3‐d][1,3]thiazolo[3,2‐a]pyrimidin‐3(2H)‐ones. The 1,3‐dipolar cycloaddition of 2‐arylmethylidene‐5‐phenyl‐5a,7,8,9a‐tetrahydro‐5H,6H‐pyrano[2,3‐d][1,3]thiazolo[3,2‐a]pyrimidin‐3(2H)‐ones with azomethine ylide generated by a decarboxylative route from sarcosine and acenaphthenequinone afforded 4′‐aryl‐1′‐methyl‐5″‐phenyl‐5a″,7″,8″,9a″‐tetrahydro‐2H,5″H,6″H‐dispiro[acenaphthylene‐1,2′‐pyrrolidine‐3′,2″‐pyrano[2,3‐d][1,3]thiazolo[3,2‐a]pyrimidine]‐2,3″‐diones in moderate yields. The structures of the products were determined and characterized thoroughly by NMR, MS, IR, elemental analysis, and X‐ray crystallographic analysis.     

Synthesis of bis-spirocoupled pyrrolidinooxindoles derived from isatinylidene derivatives of thiazolotriazinones by [3+2] dipolar cycloaddition

Isatines react with 3,4-dihydro-2H-[1,3]thiazolo[3,2-a][1,3,5]triazin-6(7H)-ones to give their isatinylidene derivatives, which add azomethinylide, generated in situ from paraformaldehide and sarcosine, to yield bis-spirocoupled derivatives of pyrrolidine. The [3+2] dipolar cycloaddition reactions studied proceed absolutely diastereoselectively.     

Synthesis of Novel Spiro Thiazolotriazole Derivatives via 1,3‐Dipolar Cycloaddition of Azomethine Ylide

The 1,3‐dipolar cycloaddition of azomethine ylide generated in situ from isatin and sarcosine to 5‐arylmethylidene thiazolo[3,2‐b][1,2,4]triazol‐6(5H)‐ones afforded novel 1′‐methyl‐4′‐aryldispiro[indole‐3,2′‐pyrrolidine‐3′,5″‐[1,3]thiazolo[3,2‐b][1,2,4]triazole]‐2,6″ (1H)‐diones in moderate yields. The structures of all the products were characterized thoroughly by NMR, infrared spectroscopy (IR), mass spectroscopy (MS) elemental analysis together with X‐ray crystallographic analysis.     

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.     

Efficient Synthesis of [1,3]Oxazino[3,2‐f]phenanthridine Derivatives by a Novel 1,4‐Dipolar Cycloaddition Involving a Phenanthridine–Dimethyl Acetylenedicarboxylate Zwitterion and Aromatic Aldehydes

An efficient synthesis of [1,3]oxazino[3,2‐f]phenanthridine derivatives via a three‐component reaction of phenanthridine, dimethyl acetylenedicarboxylate (DMAD), and aromatic aldehydes is described. This novel method is complementary to the classical Huisgen 1,4‐dipolar cycloaddition in that it is well‐suited to the preparation of [1,3]oxazino[3,2‐f]phenanthridines.     

Synthesis of N1-Substituted 1,2,3,6-Tetrahydropyrimidin-2-ones via an Unexpected Reaction of Thiazolo[3,2-a]-pyrimidine Derivatives and Nitrile Oxide

A new class of N1‐substituted 1,2,3,6‐tetrahydropyrimidin‐2‐ones was prepared in moderate yields by the reaction of nitrile oxide with thiazolo[3,2‐a]pyrimidine derivatives via a domino 1,3‐dipolar cycloaddition/ring‐opening/ substitution process. The structures of the products were characterized thoroughly by IR, elemental analysis, MS, NMR together with X‐ray crystallographic analysis.     

Synthesis of 3‐substituted pyrido[4′,3′:4,5]thieno[2,3‐d]pyrimidines and related fused thiazolo derivatives

Convenient syntheses of 3‐substituted ethyl 4‐oxo‐2‐thioxo‐1,2,3,4,5,6,7,8‐octahydropyrid[4′,3′:4,5]thieno[2,3‐d]pyrimidine‐7‐carboxylates 3a, b, 6, 11–13 , ethyl 3‐methyl‐5‐oxo‐2,3,6,9‐tetrahydro‐5 H‐pyrido[4′,3′:4,5]thieno[2,3‐d][1,3]thiazolo[3,2‐a]pyrimidine‐8‐7H‐carboxylate ( 4 ), and ethyl 2‐methyl‐5‐oxo‐2,3,6,9‐tetrahydro‐5H‐pyrido[4′,3′:4,5]thieno[2, 3‐d][1,3]thiazolo[3,2‐a]pyrimidine‐8[7H]carboxylate ( 8 ) from diethyl 2‐isothiocyanato‐4,5,6,7‐tetrahythieno[2,3‐c]pyridine‐3,6‐dicarboxylate ( 1 ) are reported. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:201–207, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10131     

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.     

Facile Access to Benzothiazole‐Containing Pyrrolo[1,2‐a]quinolines and Pyrrolo[2,1‐a]isoquinolines via Nitrogen Ylides

Quinoline and isoquinoline react with 2‐(bromoacetyl)benzothiazole ( 1 ) in dry benzene to give the corresponding quinolinium and isoquinolinium salts 2 and 10 which undergo base‐mediated [3+2] 1,3‐dipolar cycloaddition with some acetylene and ethylene derivatives to give the corresponding benzothiazole‐containing pyrrolo[1,2‐a]quinoline and pyrrolo[2,1‐a]isoquinoline derivatives.     

Synthesis of pyrrolo[2,1‐a]phthalazines by 1,3‐dipolar cycloaddition of phthalazinium N‐ylides with alkenes in the presence of tetrakis‐pyridine cobalt (II) dichromate

We describe here, for the first time, that 1‐cyano‐3‐benzoyl‐1,2,3,10b‐tetrahydropyrrolo[2,1‐a]phthalazine (8), prepared by 1,3‐dipolar cycloaddition of 2‐phenacyl phthalazinium bromide ( 6a ) with acrylonitrile ( 7a ), can be aromatized by tetrakis‐pyridine cobalt (II) dichromate (TPCD) to give 1‐cyano‐3‐benzoylpyrrolo[2,1‐α]phthalazine ( 9a ) in good yield. Furthermore, a general and convenient one‐pot procedure for preparation of pyrrolo[2,1‐α]phthalazines ( 9a‐p ) was developed by 1,3‐dipolar cycloaddition of phthala zinium N‐ylides ( 6a‐c ) with alkenes ( 7a‐g ) in the presence of TPCD.     

Synthesis of a Novel Triheterocyclic Framework via 1,3‐Dipolar Cycloaddition of a Nitrile Oxide with Imidazo[2,1‐b][1,3]thiazole‐3(2H)‐ones

A novel series of (9Z)‐9‐arylmethylidene‐3‐(2,6‐dichlorophenyl)‐5,6‐dihydro[1,3]thiazolo[2′,3′:2,3]imidazo [1,2‐d][1,2,4]oxadiazol‐8(9H)‐one derivatives were prepared in moderate yields by the 1,3‐dipolar cycloaddition reaction of a nitrile oxide with (2Z)‐2‐arylmethylidene‐5,6‐dihydroimidazo [2,1‐b][1,3]thiazol‐3(2H)‐ones. The reaction site of the dipolarphile is the C═N of imidazo[2,1‐b][1,3]thiazole rather than the expected C═C of the arylmethylidene. The product structures were characterized thoroughly by IR, MS, NMR spectroscopy, and elemental analysis. The results indicate that this reaction proceeds with chemoselectivity and regioselectivity.     

Diastereoselective Synthesis of (Z)‐6‐(2‐Oxo‐1,2‐dihydro‐3H‐indol‐3‐ylidene)‐3,3a,9,9a‐tetrahydroimidazo[4,5‐e]thiazolo[3,2‐b]‐1,2,4‐triazin‐2,7(1H,6H)‐diones

Two efficient and diastereoselective procedures for the synthesis of (Z)‐6‐(2‐oxo‐1,2‐dihydro‐3H‐indol‐3‐ylidene)‐3,3a,9,9a‐tetrahydroimidazo[4,5‐e]thiazolo[3,2‐b]‐1,2,4‐triazin‐2,7(1H,6H)‐diones by aldol‐crotonic condensation of 1,3‐dimethyl‐3a,9a‐diphenyl‐3,3a,9,9a‐tetrahydroimidazo[4,5‐e]thiazolo[3,2‐b]‐1,2,4‐triazin‐2,7(1H,6H)‐dione with isatins under acidic or basic catalysis are reported. Isomerization in (Z)‐7‐(1‐allyl‐2‐oxo‐1,2‐dihydro‐3H‐indol‐3‐ylidene)‐1,3‐dimethyl‐3a,9a‐diphenyl‐1,3a,4,9a‐tetrahydroimidazo[4,5‐e]thiazolo[2,3‐c]‐1,2,4‐triazin‐2,8(3H,7H)‐dione was observed under basic conditions.     

Synthesis of [1,3,4]thiadiazolo[3,2-a]pyrimidines in the presence of formic acid

Formic acid-phosphorus pentoxide was effective for the preparation of 5,7-dimethyl[1,3,4]thiadiazolo- and -[1,3]thiazolo[3,2-a]pyrimidin-4-ium salts. Further, the pyrimidine ring transformation and the isocyanation of 5imino-6H-[1,3,4]thiadiazolo- and -[1,3]thiazolo[3,2-a]pyrimidin-7-ones were carried out in the presence of formic acid and triethyl orthoformate, respectively.     

The Influence of Condensed Cycle on Regiochemistry of Electrophilic Heterocyclization of 3‐Alkenyl‐2‐Thioxopyrimidin‐4‐One by p‐Alkoxyphenyltellurium Trichloride

Electrophilic heterocyclization of 5‐alkenyl‐1‐methyl‐6‐thioxopyrazolo[3,4‐d]pyrimidin‐4‐ones and 3‐alkenyl‐2‐thioxoquinazoline‐4‐ones under the action of p‐alkoxyphenyltellurium trichloride leads to annulation of thiazoline cycle with formation of 7‐[(p‐alkoxyphenyl)telluromethyl]‐1‐methyl‐6,7‐dihydropyrazolo[3,4‐d][1,3]thiazolo[3,2‐a]pyrimidin‐4(1H)‐ones hydrochlorides and 2‐(p‐alkoxyphenyl)dichlorotelluromethyl‐2,3‐dihydro ‐ 5H‐[1,3]thiazolo[2,3‐b]quinazolin‐5‐ones hydrochlorides. Reduction of salts by the action of excess of sodium sulfite leads to formation of arylhetaryl telluride.     

Regioselective synthesis of novel spiroheterocyclic framework via the 1,3‐dipolar cycloaddition

A series of novel dispiro[oxindole‐fused pyrimidine]pyrrolidine ring systems 4a‐f were synthesized by the regioselective 1,3‐dipolar cycloaddition reaction of the 2‐arylmethylene‐7‐benzyl‐9‐(benzylidene)tetrahydropyrido[4,3‐d]thiazolo[3,2‐a]pyrimidin‐3‐ones 1a‐f with azomethine ylides, generating by the decarboxylative route from isatin 2 and sarcosine 3 , in moderate to good yields. The regiochemistry of designed dispiroheterocyclic compounds 4a‐f was established by single crystal X‐ray structure and spectroscopic techniques.     

Synthesis of Dispiro[indole‐3,2′‐pyrrolidine‐3′,2″‐pyrrolizine]‐1″,2(1H)‐diones via Azomethine Ylide 1,3‐Dipolar Cycloaddition

The 1,3‐dipolar cycloaddition of azomethine ylide generated in situ from isatin and sarcosine to 2‐arylmethylidene‐2,3‐dihydro‐1H‐pyrrolizin‐1‐ones afforded novel 1′‐methyl‐4′‐(aryl)‐1″H‐dispiro[indole‐3,2′‐pyrrolidine‐3′,2″‐pyrrolizine]‐1″,2(1H)‐diones in good yields. The structures of all the products were characterized thoroughly by NMR, infrared spectroscopy, mass spectrum, and elemental analysis.     

Thieno[2,3‐d]pyrimidines in the Synthesis of New Fused Heterocyclic Compounds of Prospective Antitumor and Antioxidant Agents (Part II)

Diethyl azodicarboxylate and 3,4,5,6‐tetrachloro‐1,2‐benzoquinone react with cyclopentano‐ and cycloheptano‐fused thienopyrimidines to form the oxidative dimer of the starting material via S—S bond formation. Reaction of two equivalents of 2,2′‐(cyclohexa‐2′,5′‐diene‐1,4‐diylidene)dimalononitrile with thienopyrimidines afforded 3‐(4′,4′‐dicyanomethylene‐cycloalka[a]‐2,5‐dienyl)‐4‐oxo‐6,7,8,9‐tetrahydro‐5H‐cyclo‐hepta[4,5]‐[1,3]thiazolo[3,2‐a]‐thieno[2,3‐d]pyrimidin‐2‐ylidene‐2‐dicarbonitriles. The thioenopyrimidines react with 2‐[1,3‐dioxo‐1H‐inden‐2(3H)‐ylidene]malononitrile to produce 1,3,5′‐trioxo‐1,3,3′,5′‐tetrahydrospiro‐(indene‐2,2′‐thiazolo[2,3‐b]‐cycloalkyl[b]‐thieno[2,3‐d]pyrimidine)‐3′‐carbonitriles. However, the reaction of thienopyrimidines with 2,3‐dicyano‐1,4‐naphthoquinone proceeded to afford the fused cycloalkyl‐thieno form of naphtho[1,3]thiazolo[3,2‐a]thieno[2,3‐d]pyrimidine‐6.7,12‐triones. Reaction of 2‐hydrazino‐5,6,7,8‐tetrahydrobenzo[b]thieno[2,3‐d]pyrimidine‐4(1H)‐one with dimethyl acetylenedicarboxylate and ethyl propiolate, respectively, afforded cyclohexano‐fused (Z)‐dimethyl 2[(E)‐4‐oxo‐3,4‐dihydrothieno[2,3‐d]pyrimidine‐2(1H)‐ylidene)hydrazono]succinate and thieno‐pyrimidinotriazine. Both oxidative dimers of thienopyrimidines showed high inhibition of Hep‐G2 cell growth compared with the growth of untreated control cells. Moreover, the cycloheptano‐fused thiazinothienopyrimidine indicates a promising specific antitumor agent against Hep‐G2 cells because its IC₅₀ is < 20 μM.