Studies with Heterocyclic β‐Enaminoniriles: A Simple Route for the Synthesis of Polyfunctionally Substituted Thiophene,Imidazo[1,2:1′,6′]pyrimido[5,4‐b]thiophene and Thieno[3,2‐d]pyrimidine Derivatives

Reaction of 3,5‐diaminothiophene‐2‐carbonitrile derivatives 3a‐c with ethoxycarbonylmethyl isothiocyanate and/or N‐[bis(methylthio)methylene]glycine ethyl ester led to formation of 7‐substituted‐8‐amino‐5‐thioxo‐6H‐imidazo[1,2:1′,6′]pyrimido[5,4‐b]thiophene‐2(3H)‐one derivatives 6a‐c and 7‐substituted‐8‐amino‐5‐(methylthio)imidazo[1,2:1′,6′]pyrimido[5,4‐b]thiophene‐2(3H)‐one 7a‐c , respectively. Also, the synthetic potential of the β‐enaminonitrile moiety in 3a‐c has been explored; it proved to be a promising candiate for the synthesis of 1,6‐disubstituted‐2,4‐diamino‐7,8‐dihydro‐8‐oxopyrrolo[1,2‐a]thieno[2,3‐e]pyrimidine derivatives 10a‐f and pyrido[2′,3′:6,5]pyrimido[3,4‐a]benzimidazole derivatives 12a,b .     

Synthesis of Indeno[1,2‐d]pyrimidin‐5‐Ones and Their Fluorescence in Solid State

New fluorescent compounds, 2‐substituted indeno[1,2‐d]pyrimidin‐5‐ones ( 3a , 3b , 3c , 3d ) were synthesized in good yield by the reaction of 2‐[bis(methylsulfanyl)methylene]indan‐1,3‐dione ( 1 ) with the respective amidine derivatives [guanidine carbonate ( 2a ), acetamidine hydrochloride ( 2b ), S‐methylisothiourea sulfate ( 2c ), and S‐benzylisothiourea sulfate ( 2d )]. 4‐Substituted amino‐2‐aminoindeno[1,2‐d]pyrimidin‐5‐ones ( 7b , 7c , 7d ) were synthesized by a one‐pot reaction of 1 , 2a and the respective amine compounds ( 4b , 4c , 4d ) in pyridine. These fused pyrimidine derivatives showed fluorescence in the solid state.     

Catalytic Enantioselective Synthesis of a 3‐Aryl‐3‐benzyloxindole (=3‐Aryl‐3‐benzyl‐1,3‐dihydro‐2H‐indol‐2‐one) Exhibiting Antitumor Activity

A palladium‐catalyzed intramolecular α‐arylation of an amide in the presence of a bulky chiral N‐heterocyclic carbene ligand is the key step in the first catalytic synthesis of (3R)‐6‐chloro‐3‐(3‐chlorobenzyl)‐1,3‐dihydro‐3‐(3‐methoxyphenyl)‐2H‐indol‐2‐one ((R)‐ 5 ). This oxindole, in racemic form, had been shown previously to be an anticancer agent. (R)‐ 5 was obtained with an overall yield of 45% and with 96% enantioselectivity.     

Reaction of cyclic imidates with α,β‐unsaturated esters: Synthesis of new pyrrolo[2,1‐b]‐1,3‐oxazine and pyrido[2,1‐b]‐1,3‐oxazine derivatives

The cycloaddition reaction of cyclic imidates, 2‐benzyl‐5,6‐dihydro‐4H‐1,3‐oxazines 1a , 1b , 1c , 1d , 1e , 1f , with dimethyl acetylenedicarboxylate 2 , trimethyl ethylenetricarboxylate 4 , or dimethyl 2‐(methoxymethylene)malonate 6 afforded new fused heterocyclic compounds, such as methyl (6‐oxo‐3,4‐dihydro‐2H‐pyrrolo[2,1‐b]‐1,3‐oxazin‐7‐ylidene)acetates 3a , 3b , 3c , 3d , 3e , 3f (71–79%), dimethyl 2‐(6‐oxo‐3,4,6,7‐tetrahydro‐2H‐pyrrolo[2,1‐b]‐1,3‐oxazin‐7‐yl)malonates 5b , 5c , 5d , 5e , 5f (43–71%), or methyl 6‐oxo‐3,4‐dihydro‐2H,6H‐pyrido[2,1‐b]‐1,3‐oxazine‐7‐carboxylates 7a , 7b , 7c , 7d , 7e , 7f (32–59%), respectively. In these reactions, 1a , 1b , 1c , 1d , 1e , 1f (cyclic imidates, iminoethers) functioned as their N,C‐tautomers (enaminoethers) 2 to α,β‐unsaturated esters 2 , 4, and 6 to give annulation products 3 , 5 , and 7 following to the elimination of methanol, respectively. J. Heterocyclic Chem., (2011).     

An Efficient One‐Pot Four‐Component Synthesis of Functionalized Imidazo[1,2‐a]pyridines

An efficient one‐pot four‐component protocol for the synthesis of imidazo[1,2‐a]pyridines was developed by condensing ethane‐1,2‐diamine ( 2 ), 1,1‐bis(methylthio)‐2‐nitroethene ( 1 ), aldehydes 3 , and activated methylene compounds in EtOH under reflux conditions (Tables 1–3). The features of this procedure are operational simplicity, good yields of products, in situ preparation of heterocyclic ketene aminals (HKA), and catalyst‐free conditions.     

Synthesis of 4‐amino‐3‐cyano‐2‐ methylsulfanyl‐1H‐[1,5]benzodiazepine,benzo[1,3]azole,and pyrazolobenzo[1,3]azole derivatives via a new utility of bis(methylsulfanyl)methylene derivatives

Novel polysubstituted 1,5‐benzodiazepine 5 , 2,2‐bis(methylthio)benzoxazoles 8a–d , 2,2‐bis‐ (acetyl)benzoxazole 8e , 2‐(3‐methyl‐1‐phenylpyrazolo‐ 4‐yl)benzoazole derivatives 16a–c , as well as the previously reported 2‐di[cyano(acetyl)‐methylene]benzothiazoles 7a,b have been obtained via a new utility of ketene dithioacetals 1a,b and 12 with aniline derivatives 2 . Rationales for the reactions pathways are presented. © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:407–412, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20031     

Synthesis of New Azocompounds and Fused Pyrazolo[5,1‐c][1,2,4]triazines Using Heterocyclic Components

Diazotization of 3‐methyl‐4‐phenyl‐1H‐pyrazol‐5‐amine 1 in hydrochloric acid has been reported to afford the corresponding diazonium salt 2 . The latter underwent azocoupling with a variety of active methylene compounds (barbituric 3a and thiobarbituric 3b acid, 2‐hetarylpyrimidine‐4,6‐dione 6a , 6b , 4‐hydroxy‐6‐methylpyridin‐2(1H)‐one 10a , 4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one 10b , 4‐hydroxy‐1‐p‐tolyl‐1H‐pyrazole‐3‐carboxylic acid ethyl ester 14 , 1,3‐thiazolidine‐2,4‐dione 16a , 2‐thioxo‐1,3‐thiazolidin‐4‐one 16b ) to yield new pyrazolylazo derivatives. Fused pyrazolo[5,1‐c][1,2,4]triazines 5 , 9a , 9b , 12 , 13 were obtained by heterocyclization reactions. Copyright © 2013 HeteroCorporation     

An Efficient One‐pot Synthesis of Novel Spiro Cyclic 2‐Oxindole Derivatives of Pyrimido[4,5‐b]Quinoline,Pyrido[2,3‐d:6,5‐d′]Dipyrimidine and Indeno[2′,1′:5,6]Pyrido [2,3‐d]Pyrimidine in Water

A novel and facile one‐pot synthesis of spiro cyclic 2‐oxindole derivatives of pyrimido[4,5‐b]quinoline‐4,6‐dione, pyrido[2,3‐d:6,5‐d′]dipyrimidine‐2,4,6‐trione, and indeno[2′,1′:5,6]pyrido [2,3‐d]pyrimidine employing 6‐aminothiouracil (or 6‐aminouracil), isatin, and cyclic 1,3‐diketone (e.g. 1,3‐indanedione, dimedone, or barbituric acid) has been developed.     

Synthesis of 5‐chloro‐2‐methyl‐3‐(5‐methylthiazol‐2‐yl)‐4(3H)‐quinazolinone and related compounds with potential biological activity

Eight new 2‐methyl‐4(3H)‐quinazolinones (8a‐8d, 9c, 9d, 10c, 10d) with one or two chlorine atoms in the benzene ring and a 5‐methyl‐1,3‐thiazol‐2‐yl, 4‐methyl‐1,3‐thiazol‐2‐yl, and 5‐ethyl‐1,3,4‐thiadiazol‐2‐yl substituent in position 3 of the heterocyclic ring were synthesized and characterized. The two step procedure (Scheme 1) utilizes chlorosubstituted anthranilic acids (3a‐3d) and acetic anhydride as the starting materials, with the respective chlorosubstituted 2‐methyl‐4H‐3,1‐benzoxazin‐4‐ones (4a‐4d) as the intermediates. The quinazoline derivatives were characterized by their melting points, elemental analyses and the mass, ultraviolet, infrared, and ¹H and ¹³C nmr spectra. The new compounds are expected to be biologically active.     

3‐Methylthio‐pyrano[4,3‐c]pyrazol‐4(2H)‐ones from 3‐(bis‐methylthio)methylene‐2H‐pyran‐2,4‐diones and hydrazines

A useful synthesis of 3‐methylthio‐6‐methyl‐pyrano[4,3‐c]pyrazol‐4(2H)‐ones via 3‐(bis‐methylthio)methylene‐5,6‐dihydro‐6‐alkyl(aryl)‐2H‐pyran‐2,4‐dione with hydrazine as well as methyl and phenyl hydrazines is described and the mechanism of the formation is discussed. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:342–344, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10158     

Synthesis of Novel Pyrimido[4,5‐b]quinolin‐4‐ones with Potential Antitumor Activity

The 5,6,7,8,9,10‐hexahydro‐2‐methylthiopyrimido[4,5‐b]quinolines 4a , 4b , 4c , 4d , 5a , 5b , 5c , 5d and their oxidized forms 6a , 6b , 6c , 6d , 7a , 7b , 7c , 7d were obtained from the reaction of 6‐amino‐2‐(methylthio)pyrimidin‐4(3H)‐one 2 or 6‐amino‐3‐methyl‐2‐(methylthio)pyrimidin‐4(3H)‐one 3 and α,β‐unsaturated ketones 1a , 1b , 1c , 1d using BF₃.OEt₂ as catalyst and p‐chloranil as oxidizing agent. Some of the new compounds were evaluated in the US National Cancer Institute (NCI), where compound 5a presented remarkable activity against 46 cancer cell lines, with the most important GI₅₀ values ranging from 0.72 to 18.4 μM from in vitro assays.     

Synthesis of 2,4‐disubstituted 6‐phenyl‐7H‐pyrrolo[3,2‐d]‐pyrimidin‐7‐one 5‐oxides

A relatively short and efficient method for the utilization of 4,6‐dichloro‐2‐methylthio‐5‐nitropyrimidine ( 1 ) in the synthesis of the poly substituted pyrrolo[3,2‐d]pyrimidin‐7‐one 5‐oxides ( 6a ‐g) is reported. Some new 4‐substituted 6‐chloro‐2‐methylthio‐5‐nitropyrimidines ( 2a‐e ) were prepared by reaction of 4,6‐dichloro‐2‐methylthio‐5‐nitropyrimidine ( 1 ) with amines. 4‐Substituted 2‐methylthio‐5‐nitro‐6‐phenylethynylpyrimidines ( 3a‐e ), obtained from 4‐substituted 6‐chloro‐2‐methylthio‐5‐nitropyrimidines ( 2a‐e ) via palladium‐catalyzed Sonagashira coupling reaction with 1‐phenylacetylene, underwent smooth cyclization reaction in boiling 2‐propanol in the presence of catalytic amount of pyridine to give 4‐substituted 2‐methylthio‐6‐phenyl‐7H‐pyrrolo[3,2‐d]pyrimidin‐7‐one 5‐oxides ( 4a‐e ). The methylthio group of the latter compounds can be easily and selectively oxidized by m‐chloroperbenzoic acid and replaced with different amines.     

Conjugate Addition of Lithiated (S)‐4‐Isopropyl‐3‐ [(methylthio)methyl]‐5,5‐diphenyloxazolidin‐2‐one to Cinnamoyl Derivatives: Preparation of Enantiomerically Pure 1,4‐Diols

The Li derivative of (S)‐4‐isopropyl‐3‐[(methylthio)methyl]‐5,5‐diphenyloxazolidin‐2‐one (Li‐ 2 ; synthetically equivalent to a chiral formyl anion) adds to enones and enoates in a 1,4‐fashion. Best results are obtained with 1,3‐diarylpropenones (chalcones; Scheme 2), trityl enones, and 2,6‐di(tert‐butyl)‐4‐methoxyphenyl cinnamates (Scheme 3), with yields up to 80% and diastereoselectivities up to and above 99 : 1 of the products ( 5a – f and 8a , b , e ) containing three stereogenic centers! X‐Ray crystal‐structure analysis reveals that the C,C‐bond formation occurs preferentially with relative topicity ul (Re/Si; Fig. 2). The MeS group of the 1,4‐adducts can be replaced by RO groups in Hg²⁺‐assisted substitutions, with subsequent removal and facile recovery of the chiral auxiliary (Schemes 4–6). 4‐Hydroxycarbonyl derivatives (‘homoaldols') and mono‐, di‐, and trisubstituted 1,4‐diols are, thus, accessible in enantiomerically pure forms (cf. 15, 16 , and 18 – 20 ).     

[2 + 3]‐Cycloadditions of Phosphonodithioformate S‐Methanides with CS,NN,and CC Dipolarophiles

The reaction of the methyl (dialkoxyphosphinyl)‐dithioformates (= methyl dialkoxyphosphinecarbodithioate 1‐oxides) 10 with CH₂N₂ at − 65° in THF yielded cycloadducts which eliminated N₂ between − 40 and − 35° to give the corresponding phosphonodithioformate S‐methanides ( =methylenesulfonium (dialkoxyoxidophosphino)(methylthio)methylides) 11 (Scheme 3). These reactive 1,3‐dipoles were intercepted by aromatic thioketones to yield 1,3‐dithiolanes. Whereas the reaction with thiobenzophenone ( 12b ) led to the sterically more congested isomers 15 regioselectively, a mixture of both regioisomers was obtained with 9H‐fluorene‐9‐thione ( 12a ). Trapping of 11 with phosphono‐ and sulfonodithioformates led exclusively to the sterically less hindered 1,3‐dithiolanes 16 and 18 , respectively (Scheme 4). In addition, reactive CC dipolarophiles such as ethenetetracarbonitrile, maleic anhydride, and N‐phenylmaleimide as well as the NN dipolarophile dimethyl diazenedicarboxylate were shown to be efficient interceptors of 11 (Scheme 5).     

Biologically active 1‐arylpiperazines. Synthesis of N‐[3‐(4‐aryl‐1‐piperazinyl)propyl] derivatives of benzoxazinone and benzoxazolinone

The synthesis of new N‐[3‐(4‐aryl‐1‐piperazinyl)propyl] derivatives of 1H‐2,4‐benzoxazin‐3(4H)‐one ( 1a‐b ), 2H‐1,4‐benzoxazin‐3(4H)‐one ( 2a‐b, 3a‐b and 4b ), and benzoxazolin‐2‐one ( 5a‐b ), as biologically active agents, is described.     

Synthesis of Certain 3-Aminopyrazolo[5,4-b]pyridine and 3,4-Substituted Pyrido[2′,3′：3,4]pyrazolo[5,1-c][1,2,4]triazine Derivatives

2-Thioxo-1,2-dihydropyridine derivatives 2a, 2b were reacted with methyl iodide to give 2-methylthiopyridines 3a, 3b, which were reacted with hydrazine hydrate to produce 3-aminopyrazolo[5,4-b]pyridines 4a, 4b. Compounds 4a, 4b were diazotized to afford the corresponding diazonium salts 5a, 5b, which were reacted with some active methylene compounds 6a-6h to give the corresponding pyrido[2′,3′ ： 3,4]pyrazole[5,1-c][1,2,4]triazines 7-14.     

An Efficient and Facile Synthesis of Functionalized Indole‐3‐yl Pyrazole Derivatives Starting from 3‐Cyanoacetylindole

The versatile hitherto reported 3‐(1H‐indol‐3‐yl)‐1H‐pyrazol‐5‐amine ( 4 ) was synthesized by the reaction of 3‐cyanoacetylindole ( 3 ) with hydrazine hydrate in refluxing ethanol and used as a key intermediate for the synthesis of novel pyrazolo[1,5‐a ]pyrimidines via its reactions with appropriate 1,3‐biselectrophilic reagents or through three‐component condensations with triethyl orthoformate and compounds possessing an activated methylene group. Besides, the applicability and synthetic potency of ( 4 ) to attain polyfunctionally substituted imidazo[1,2‐b ]pyrazole, pyrazolo[1,5‐a ][1,3]diazepine and pyrazolo[1,5‐c ][1,3,5]thiadiazine derivatives of an expected pharmaceutical interest have been investigated. The mechanistic aspects for the formation of the newly synthesized compounds are discussed.     

Synthetic studies with 3‐Oxo‐N‐[4‐(3‐oxo‐ 3‐phenylpropionylamino)‐phenyl]‐3‐phenylpropionamide

3‐Oxo‐N‐[4‐(3‐oxo‐3‐phenylpropionylamino)‐phenyl]‐3‐phenylpropionamide 1 and its derivative 2‐benzoyl‐N‐[4‐(2‐benzoyl‐3‐(dimethylamino‐acryloylamino)‐phenyl]‐3‐dimethylaminoacrylamide 12 are used for the synthesis of the hitherto not known bis‐heterocyclic amine and bis‐heterocyclic carboxamide derivatives. Plausible mechanisms are discussed for the formation of the new compounds. J. Heterocyclic Chem., (2012).     

Synthesis and Reactivity of 3‐oxoprop‐1‐en‐1‐olate Derivative as a Building Block for the Synthesis of Azole and Azine Derivatives

Several new heterocyclic compounds such as 7‐substituted pyrazolo[1,5‐a ]pyrimidine ( 5a–e ) derivatives have been synthesized by the reactions of the versatile unreported sodium 3‐(4‐methyl‐2‐(4‐methylphenylsulfonamido)thiazol‐5‐yl)‐3‐oxoprop‐1‐en‐1‐olate (2) with amino heterocyclic ( 3a–e ) derivatives. Reaction of (2) with hydrazonyl halide ( 7a–d ) and hydroximoyl chloride ( 11a,b ) derivatives followed by reaction with hydrazine hydrate afforded pyrazolo[3,4‐d ]pyridazine and isoxazolo[3,4‐d ]pyridazine derivatives, respectively incorporating a thiazole moiety have been described. All newly synthesized compounds were elucidated by considering the data of both elemental and spectral analysis.     

A convenient synthesis of novel 7‐phosphonylbenzyl‐2‐substituted pyrazolo[4,3‐e]‐1,2,4‐triazolo[1,5‐c]‐pyrimidine derivatives

A series of pyrazolo[4,3‐e]‐1,2,4‐triazolo‐[1,5‐c]pyrimidine derivatives, bearing phosphonylbenzyl chain in position 7, were conveniently synthesized in an attempt to obtain potent and selective antagonists for the A_2A adenosine receptor or potent pesticide lead compounds. Diethyl[(5‐amino‐4‐cyano‐3‐methylsulfanyl‐pyrazol‐1‐yl)‐benzyl]phospho‐nate ( 3 ), which was prepared by the cyclization of diethyl 1‐hydrazinobenzylphosphonate ( 1 ) with 2‐[bis(methylthio)methylene]malononitrile ( 2 ), reacted with triethyl orthoformate to afford diethyl[(4‐cyano‐5‐ethoxymethyleneamino‐3‐methylsulfanyl‐pyrazol‐1‐yl)‐benzyl]phosphonate ( 4 ), which reacted with various acyl hydrazines in refluxing 2‐methoxyethanol to give the target compounds 5a–h in good yields. Their structures were confirmed by IR, ¹H NMR, ¹³C NMR, MS, and elemental analysis. The crystal structure of 5e was determined by single crystal X‐ray diffraction © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:634–638, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20478