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.     

Reactivity of 2‐substituted imidazo[1,2‐b]pyridazines: Preparation of 3‐nitro,nitroso and chloro derivatives

The synthesis of 2‐substitutedimidazo[1,2‐b]pyridazines and their reactivity towards electrophilic substitutions are reported. The nitration was shown to be very dependent on the nature of the 2 substituent. Nitrosation using sodium nitrite in acetic acid media as a general method failed in all cases whereas chlorination was observed in warm hydrochloric acid. In order to ascertain the structure of some chloro derivatives, chlorination using N‐chlorosuccinimide was also reported. Depending of the nature of the substituent, the reaction occurred at the C‐3 imidazolic position and/or at the substituent on position 2. The 3‐nitroso‐2‐phenyl derivative was finally obtained using an alternative synthetic pathway by direct condensation of 3‐amino‐6‐chloropyridazine to ω‐chloro‐ω‐nitrosoacetophenone. The structural determinations were ascertained using high field ^lH and ¹³C‐NMR.     

Synthesis of Novel Pyrano[2,3‐b]pyridines from α,α′‐Bis(substituted‐benzylidene)cycloalkanones

In this paper, we describe a two‐step synthesis of a series of tacrine analogues. In the first step, α,α'‐bis(substituted‐benzylidene)cycloalkanones are reacted with malononitrile to afford 2‐amino‐3‐cyano‐4H‐pyrans. The second step involves the conversion of pyrans to pyrano[2,3‐b]pyridines with the use of AlCl₃ as catalyst.     

A Convenient One‐Pot Synthesis of Thieno[2′,3′:4,5]Pyrimido[1,2‐b]‐[1,2,4,5]Tetrazines

A novel series of thieno[2′,3′:4,5]pyrimido[1,2‐b][1,2,4,5]tetrazin‐6‐one derivatives 14 were prepared from the reaction of 3‐amino‐2‐thioxo‐1,2,3,5,6,7‐hexahydro‐4H‐cyclopenta[4,5]thieno[2,3‐d]pyrimidin‐4‐one 3 or its methylthio 4 with hydrazonoyl chlorides 9 . The mechanism of the studied reactions has been discussed and further evidence for the assigned structure of the products is based on alternative synthesis. A single crystal X‐ray analysis of compound 14e has been carried out.     

The Synthesis of Some New 7‐Methyl‐3‐substituted‐1,2,4‐triazolo[3,4‐b]benzothiazoles

New 7‐Methyl‐3‐substituted‐1,2,4‐triazolo[3,4‐b]benzothiazoles were synthesized from p‐methylaniline to 5 with various aromatic carbonic acids. The yielded product 6a‐j was investigated with Elemental analyses, NMR, MS and IR techniques.     

Synthesis and Molecular Recognition of Water‐Soluble S6‐Corona[3]arene[3]pyridazines

We report the efficient and scalable synthesis and molecular‐recognition properties of novel and water‐soluble S₆‐corona[3]arene[3]pyridazines. The synthesis comprises a one‐pot nucleophilic aromatic substitution reaction between diesters of 2,5‐dimercaptoterephthalate and 3,6‐dichlorotetrazine followed by the inverse electron‐demand Diels–Alder reaction of the tetrazine moieties with an enamine and exhaustive saponification of esters. The resulting S₆‐corona[3]arene[3]pyridazines, which adopt a 1,3,5‐alternate conformation in the crystalline state, are able to selectively form stable 1:1 complexes with dicationic guest species in water with association constants ranging from (1.10±0.06)×10³ M ^?1 to (1.18±0.06)×10⁵ M ^?1. The easy availability, large cavity size, strong and selective binding power render the water‐soluble S₆‐corona[3]arene[3]pyridazines useful macrocyclic hosts in various disciplines of supramolecular chemistry.     

Synthesis of new racemic and optically active N‐phosphonoalkyl bicyclic β‐amino acids via the kabachnik–fields reaction as potential biologically active compounds

Novel racemic and optically active constrained N‐phosphonoalkyl bicyclic β‐amino acids have been synthesized via the Kabachnik–Fields reaction of the (RS) or (R)‐1‐aminobicyclo[2.2.2]octane‐2‐carboxylic acids with paraformaldehyde and benzaldehyde, and the dimethyl‐H‐phosphonate. The structure of obtained compounds was characterized by NMR (¹H, ¹³C, and ³¹P), LC/MS, and X‐ray diffraction analyses. © 2012 Wiley Periodicals, Inc. Heteroatom Chem 23:123–130, 2012; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.20759     

Synthesis and Cytotoxicity Studies of Cyclohepta[b]indoles,Benzo[6,7]Cyclohepta[1,2‐b]Indoles,Indeno[1,2‐b]Indoles,and Benzo[a]Carbazoles

Synthesis and biological evaluation of various tricyclic and tetracyclic indoles are described. A number of these compounds possess in vitro activity against human nasopharyngeal carcinoma (HONE‐1) and gastric adenocarcinoma (NUGC‐3) cell lines.     

Synthesis of new derivatives of 3‐aryl‐1,5‐dimethyl‐1H‐[1,2,4]triazolo[4′,3′:1,2]pyrimido[4,5‐e][1,3,4]oxadiazines as potential antiproliferative agents

Starting from pyrimido[4,5‐e][1,3,4]oxadiazines ( 3a , 3b , 3c ) , a synthetic pathway to [1,2,4]triazolo[4′,3′:1,2]pyrimido[4,5‐e][1,3,4]oxadiazines ( 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i ) is described. The reaction of pyrimido[4,5‐e][1,3,4]oxadiazines ( 3a , 3b , 3c ) with hydrazine hydrate afforded the corresponding hydrazino derivatives ( 4a , 4b , 4c ) . Further treatment of these compounds with different orthoesters in acetic acid gave the corresponding [1,2,4]triazolo[4′,3′:1,2]pyrimido[4,5‐e][1,3,4]oxadiazines ( 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h , 5i ) . Compound ( 3a ) and ( 5b ) , as examples, were tested on different cancer cell lines including HeLa, MCF‐7, and HepG2. Malignant cells were cultured in DMEM medium and incubated with different concentrations of the titled compounds. Cell viability was quantitated by MTT assay. J. Heterocyclic Chem., (2010).     

Synthesis of novel 1,4‐dihydropyrido[3′,2′:5,6]thiopyrano[4,3‐c]‐pyrazoles and 5H‐pyrido[3′,2′:5,6]thiopyrano[4,3‐d]pyrimidines as potential antiproliferative agents

The synthesis of new planar derivatives characterized by the presence of a pyridothiopyranopyrazole or pyridothiopyranopyrimidine nucleus, carrying a substituted aryl group, is reported. The novel 1,4‐dihydropyrido[3′,2′:5,6]thiopyrano[4,3‐c]pyrazole derivatives were obtained by condensation of 2,3‐dihydro‐3‐hydroxymethylenethiopyrano[2,3‐b]pyridin‐4(4H)‐ones with appropriate hydrazines. The preparation of 2‐substituted pyrido[3′,2′:5,6]thiopyrano[4,3‐d]pyrimidines was accomplished from the intermediate 2,3‐dihy‐dro‐3‐dimethylaminomethylenethiopyrano[2,3‐b]pyridin‐4(4H)‐ones by reaction with the appropriate binucleophile amidines. The antiproliferative activity of some new products was tested by an in vitro assay on human tumour cell lines (HL‐60 and HeLa), but none of them showed any significant effects in the tests performed. Accordingly, linear flow dichroism measurements indicated their inability to form a molecular complex with DNA.     

Convenient and Efficient Synthesis of 11‐Amino‐2,8‐substituted‐2,3,8,9‐tetrahydrobenzo[4,5]thieno[2,3‐b]quinolinone Derivatives

The Gewald reactions of 5‐substituted‐1,3‐cyclohexanedione, malononitrile, and powdered sulfur were carried out to give the corresponding products 2‐amino‐5‐substituted‐7‐oxo‐4,5,6,7‐tetrahydrobenzo[b]thiophene‐3‐carbonitrile derivatives 1 . The intermediate enamines 2 were prepared by reaction of compounds 1 and 5‐substituted‐1,3‐cyclohexanedione with hydrochloric acid as catalyst. The title compounds 11‐amino‐2,8‐substituted‐2,3,8,9‐tetrahydrobenzo[4,5]thieno[2,3‐b]quinolinone 3 were synthesized by cyclization of compounds 2 in the presence of K₂CO₃ and Cu₂Cl₂. The structures of all compounds were characterized by elemental analysis, IR, MS, and ¹H‐NMR spectra.     

Cyclocondensation of 3-amino-2-iminonaphtho[1,2-d]-thiazole with α-ketocarboxylic acid derivatives: Synthesis of 2-substituted 3-Oxo-3H-naphtho[1′,2′:4,5]thiazolo-[3,2-b][1,2,4]triazines as potential anti-HIV agents

The cyclocondensation of 3-amino-2-iminonaphtho[1,2-d]thiazole ( 1 ) with a series of α-keto mono- and dicarboxylic acid derivatives 5a-i under different conditions was investigated. When the experiments were performed by refluxing in glacial acetic acid, the corresponding cyclized products, 2-substituted 3-oxo-3H-naphtho[1′,2′:4,5]thiazolo[3,2-b][1,2,4]triazines 4 were obtained in fair to good yields. On the other hand, when the reaction was conducted in boiling ethanol, it gave only the open chain condensates 6 , or in rare cases, together with minor amount of 4 . Since the intermediates 6 exist as mixture of both E- and Z-isomers, cyclization through heating was found insufficient. In any event representative compounds 4b,g,i have been evaluated for anti-HIV activity, but none of them were active.     

Synthesis of 1‐substituted [1,2,3]triazolo[4,5‐d]pyridazines as precursors for novel tetraazapentalene derivatives

A series of 1‐substituted 4,5‐diformyl‐[1,2,3]triazole derivatives were prepared by 1,3‐dipolar cyclo‐addition of aryl azides with acetylene dicarboxaldehyde mono‐diethylacetal. The triazoles were readily converted into 1‐substituted [1,2,3]triazolo[4,5‐d]pyridazines in good yields. The 1‐(2‐nitrophenyl)‐[1,2,3]triazolo[4,5‐d]pyridazine was found to be a useful intermediate for the generation of the novel 5H‐benzo[1,2,3]triazolo[1′,2′:1,2]triazolo[4,5‐d]pyridazin‐6‐ium inner salt ring system.     

Synthesis of Spiro[cyclohexane-1,2′-[2H]indene] derivatives as inhibitors of steroid 5α-reductase

The spiro[cyclohexane-1,2′-[2H]indene] derivatives 15a , b with molecular dimensions and nucleophilic functional groups similar to known steroid 5α-reductase inhibitors (e.g. 2 ) were synthesized. The spiro[cyclohexane-1,2′-[2H]indene]-1′(3′H),4-dione ( 5 ) was synthesized from 5-methoxyindan-l-one ( = 2,3-dihydro-5-methoxy-1H-inden-1-one). A Grignard reaction and a dehydration step led to the cyclohexene (±)- 7 which, upon a stereoselective hydrogenation catalyzed by Raney-Ni under mild conditions, gave 8a as a pure epimer. Further hydrogenation and hydrogenolysis of 8a over Pd/C at room temperature reduced the keto group to give pure 9a . Finally, the 5′-substituted derivatives 12a , 14a , and 15a were generated by deprotection and Heck-type reaction.     

Synthesis of Ethyl 2‐Arylaminoimidazo[2,1‐b]benzothiazole‐3‐carboxylates

3‐Arylamino‐4‐ethoxycarbonylisoxazol‐5(2H)‐ones, substituted on nitrogen with a benzothiazole group, reacts with triethylamine in ethanol under reflux conditions to provide a convenient synthesis of ethyl 2‐aryl‐aminoimidazo[2,1‐b]benzothiazole‐3‐carboxylates.     

Synthesis of new optically active α,α′,β‐trisubstituted‐β‐lactones as monomers for stereoregular biopolyesters

Various optically active (4R)‐alkyloxycarbonyl‐3,3‐dialkyl‐2‐oxetanones as monomers were synthesized from L‐(S)‐malic acid in six steps to prepare a new family of stereopolyesters for biomedical applications. The synthesis began with an esterification followed of a dialkylation in the aim to introduce hydrophobic groups as methyl or reactive group as allyl. Then, a saponification has permitted to obtain the corresponding diacids that reacted with appropriate alcohols to furnish different monoesters. The last and most important step was activation of hydroxyl group of monoesters with the asymmetric carbon configuration inversion according to the Mitsunobu reaction. Thus, this reaction has provided lactones from monoesters with 100% enantiomeric excess which was confirmed by ¹H NMR and by the synthesis of corresponding isotactic and semicrystalline homopolyesters. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 2586–2597     

Selective Synthesis of 1,2‐Diarylpyrrolo[3,4‐b]pyridine‐5,7‐diones via Cyclization Reaction of β‐Enamino Imides with Cinnamaldehydes

The novel 1,2‐diaryl substituted pyrrolo[3,4‐b]pyridine‐5,7‐diones were selectively synthesized in high yields by the base catalyzed cyclization reaction of 3‐arylamino‐1‐methyl‐1H‐pyrrole‐2,5‐diones with cinnamaldehyde and its derivatives in acetonitrile at room temperature. However, when piperidinium trifluoroacetate was employed as catalyst, the reaction afforded a mixture of 1,2‐diaryl and 1,4‐diaryl substituted pyrrolo[3,4‐b]pyridine‐5,7‐diones in comparable yields.     

β‐Substituted Terthiophene [2]Rotaxanes

Towards polythiophene polyrotaxanes : The β‐substituted terthiophene [2]rotaxanes have been synthesized (see figure). Basic optical and electrochemical properties of the synthesized [2]rotaxanes are also reported.

     

Furan ring opening ‐ indole ring closure: Synthesis of furo[2′,3′:3,4]‐cyclohepta[1,2‐b]indolium chlorides

A new synthetic approach to furo[2′,3′:3,4]cyclohepta[1,2‐b]indolium chlorides is elaborated starting from 2‐acetylaminoaryldifurylmethanes or 2‐aminoaryldifurylmethanes under treatment with methanolic HCl solution. The reaction proceeds in three steps: recyclization, intramolecular cyclization, and disproportionation. In this case the furan ring takes part in building up both pyrrole and seven‐membered rings. The same salts can be obtained directly from 2‐acetylaminobenzaldehydes and 2‐methylfuran under similar conditions without isolation of corresponding 2‐acetylaminoaryldifurylmethanes.