Synthesis of p‐tert‐Butyl‐calix[6] ‐biscrown‐3 via Intramolecular Ring‐closure of 1,4‐Bis (2‐(2‐chloroethoxy) ethoxy) ‐p‐tert‐butyl‐calix[6]arene

With a variation in reaction conditions, 1, 4‐bis (2‐(2‐chloroethoxy)ethoxy)‐calix[6]arene (3) and l,3,5‐tris(2‐(2‐chloroethoxy) ethoxy)‐calix [6] arene (4) or 4 and 4‐chloroethoxyethoxy‐calix[6]crown‐3 (5) were selectively synthesized from p‐tert‐butyl‐calix [6] arene and 2‐(2‐chloroethoxy)ethyltosylate. l,3–4,6‐p‐tert‐butylcalix[6]‐bis‐crown‐3 (6) with (u,u,u,d,d,d) conformation and 1,3–4,5‐p‐tert‐butylcalix[6]‐biscrown‐3 (7) with self‐anchored (u,u, u, u, u, d) conformation were synthesized through an intramolecularly ring‐closing condensation of 1, 4‐bis (2‐(2‐chloroethoxy)ethoxy)‐p‐tert‐butyl‐calix[6]arene (3) in 25% and 15% yield, respectively. Using 5 instead of 3, only 7 was obtained in 65% high yield. 6 and 7 show different complexation properties toward alkali metal and ammonium ions.     

Synthesis and Characterization of Enantiomerically Pure cis‐ and trans‐3‐Fluoro‐2,4‐dioxa‐9‐aza‐3‐phosphadecalin 3‐Oxides as Acetylcholine Mimetics and Inhibitors of Acetylcholinesterase

The title compounds, the P(3)‐axially and P(3)‐equatorially substituted cis‐ and trans‐configured 9‐benzyl‐3‐fluoro‐2,4‐dioxa‐9‐aza‐3‐phosphadecalin 3‐oxides (=9‐benzyl‐3‐fluoro‐2,4‐dioxa‐9‐aza‐3‐phosphabicyclo[4.4.0]decane 3‐oxides=7‐benzyl‐2‐fluorohexahydro‐4H‐1,3,2‐dioxaphosphorino[4,5‐c]pyridine 2‐oxides) were prepared (ee >99%) and fully characterized (Schemes 2 and 4). The absolute configurations were deduced from that of their precursors, the enantiomerically pure ethyl 1‐benzyl‐3‐hydroxypiperidine‐4‐carboxylates and 1‐benzyl‐3‐hydroxypiperidine‐4‐methanols which were unambiguously assigned. Being configuratively fixed and conformationally constrained phosphorus analogues of acetylcholine, the title compounds represent acetylcholine mimetics and are suitable probes for the investigation of molecular interactions with acetylcholinesterase. As determined by kinetic methods, all of the compounds are moderate irreversible inhibitors of the enzyme.     

Synthesis and Characterization of Enantiomerically Pure cis‐ and trans‐3‐Fluoro‐2,4‐dioxa‐7‐aza‐3‐phosphadecalin 3‐Oxides as Acetylcholine Mimetics and Inhibitors of Acetylcholinesterase

The title compounds, the P(3)‐axially and P(3)‐equatorially substituted cis‐ and trans‐configured 7‐benzyl‐3‐fluoro‐2,4‐dioxa‐7‐aza‐3‐phosphadecalin 3‐oxides (=7‐benzyl‐3‐fluoro‐2,4‐dioxa‐7‐aza‐3‐phosphabicyclo[4.4.0]decane 3‐oxides=5‐benzyl‐2‐fluorohexahydro‐4H‐1,3,2‐dioxaphosphorino[5,4‐b]pyridine 2‐oxides) were prepared (ee>99%) and fully characterized (Schemes 2 and 4). The absolute configurations were established from that of their precursors, the enantiomerically pure cis‐ and trans‐1‐benzyl‐3‐hydroxypiperidine‐2‐methanols which were unambiguously assigned. Being configuratively fixed and conformationally constrained phosphorus analogues of acetylcholine, they mimic rotamers of acetylcholine and are suitable probes for the investigation of molecular interactions with acetylcholinesterase. As determined by kinetic methods, the compounds are irreversible inhibitors of the enzyme displaying significant stereoselectivity.     

Synthesis and Reactions of the Novel 6‐ethyl‐4‐hydroxy‐2,5‐dioxo‐5,6‐dihydro‐2H‐pyrano[3,2‐c]quinoline‐3‐carboxaldehyde

The novel 6‐ethyl‐4‐hydroxy‐2,5‐dioxo‐5,6‐dihydro‐2H‐pyrano[3,2‐c]quinoline‐3‐carboxaldehyde ( 2 ) was efficiently synthesized from Vilsmeier–Haack formylation of 3‐(1‐ethy1‐4‐hydroxy‐2‐oxo‐(1H)‐quinolin‐3‐yl)‐3‐oxopropanoic acid ( 1 ). The aldehyde 2 was allowed to react with some nitrogen nucleophiles producing a variety of hydrazones 3 – 7 . Reaction of aldehyde 2 with hydrazine hydrate and hydroxylamine hydrochloride afforded pyrazole and isoxazole annulated pyrano[3,2‐c]quinoline‐2,5(6H)‐dione, respectively. The reactivity of aldehyde 2 was examined toward some active methylene nitrile, namely, malononitrile, ethyl cyanoacetate, and cyanoacetamide leading to 2‐iminopyrano[2′,3′:4,5]pyrano[3,2‐c]quinolines 10 – 12 , respectively. Also, some novel pyrazolo[4″,3″:5′,6′]pyrano[2′,3′:4,5]pyrano[3,2‐c]quinolines ( 13 , 14 ) and thiazolo[5″,4″:5′,6′]pyrano[2′,3′:4,5]pyrano[3,2‐c]quinolines ( 15 , 16 ) were synthesized. Structures of the new synthesized products were deduced on the basis of their analytical and spectral data.     

Construction of Novel Tetrahydro‐β‐carboline‐1‐thione Spirooxindoles by Brønsted Acid Mediated Formal [3+3] Cyclization of 3‐Indolylmethanols with 3‐Isothiocyanato Oxindoles

p‐Toluenesulfonic acid mediated formal [3+3] cyclization of 3‐indolylmethanols with 3‐isothiocyanato oxindoles was realized. This transformation allowed for the synthesis of a series of novel tetrahydro‐β‐carboline‐1‐thione spirooxindoles in moderate to excellent yields (up to 99%) with generally good diastereoselectivities (up to >20:1). The structure of one product was determined by an X‐ray crystal structural analysis.     

C1‐Symmetric Bicyclo[2.2.2]octa‐2,5‐diene (bod*) Ligands in Rhodium‐Catalyzed Asymmetric 1,4‐Addition of Arylboronic Acids to Enones and 1,2‐Addition to N‐[(4‐Nitrophenyl)sulfonyl]imines

A set of ten C₁‐symmetric chiral bicyclo[2.2.2]octa‐2,5‐dienes (bod*) 2 (Fig. 1) were tested as ligands in Rh‐catalyzed arylation reactions. The 1,4‐addition of arylboronic acids to cyclohex‐2‐en‐1‐one, cyclopent‐2‐en‐1‐one, and tert‐butyl cinnamate proceeded smoothly with excellent enantioselectivities (up to 99% ee; Tables 1–3). The challenging 1,2‐addition of triphenylboroxine to N‐[(4‐nitrophenyl)sulfonyl]imines yielded the product in high yield and in good enantioselectivity (up to 92% ee; Table 4). Generally, the use of C₁‐symmetric chiral bod* ligands bearing bulky substituents resulted in lower enantioselectivities, whereas several electron‐poor and electron‐rich bod* ligands gave higher enantioselectivities than the benchmark ligands reported in literature.     

Consecutive Reaction of Bis [2,2,2－trifluoroethyl] phosphite. One－pot Synthesis of Substituted 3－Cyano－β, γ－unsaturated Nitriles with Exclusive or Predominant E－Selectivity

The consecutive reaction of bis [ 2, 2, 2-trifluoroethyl] phosphite and its application to the one-pot synthesis of 3-cyano-β, γ-unsaturated nitriles with exdusive or predominant E-selectivity (E: Z = 100-85: 0-15) and excellent yields (94%-99%) are described.     

Functional Ionic Liquids Promoted Double Michael Reaction of Benzofuran‐3‐one or 1‐Indone and Symmetric Dienones: Construction of Spiro[benzofuran‐2,1’‐cyclohexane]‐3‐one or Spiro[cyclohexane‐1,2’‐indene]‐1’,4(3’H)‐dione Derivatives

The double Michael reactions between benzofuran‐3‐one or 1‐indone and symmetric dienones in the presence of catalytic ionic liquids were successfully developed and spiro[benzofuran‐2,1’‐cyclohexane]‐3‐one or spiro[cyclohexane‐1,2’‐indene]‐1’,4(3’H )‐dione derivatives containing a spiro quaternary stereogenic center, which widely exist in biologically active products and building blocks in organic synthesis, were obtained in excellent yields (up to 99%). This catalytic system was also extended to the double Michael reaction of less reactive 1‐indone and the desired products were also obtained in 31%‐62% yields. The catalytic system was highly active and efficient for a broad of substrates under mild conditions.     

Synthesis of 4‐(1‐phenyl‐1H‐pyrazol‐3‐yl)‐[1,2,4]triazolo[4,3‐a]quinoxalines and their 4‐halogenopyrazolyl analogs

Synthesis of {3‐[1‐(ethoxycarbonyl)‐[1,2,4]triazolo[4,3‐a]quinoxalin‐4‐yl]‐1‐phenyl‐1H‐pyrazol‐5‐yl}methyl ethyl oxalate ( 2 ), ethyl 4‐[5‐(acetoxymethyl)‐1‐phenyl‐1H‐pyrazol‐3‐yl]‐[1,2,4]triazolo[4,3‐a]quioxaline‐1‐carboxylate ( 4 ), [4‐halo‐1‐phenyl‐3‐(1‐phenyl‐[1,2,4]triazolo[4,3‐a]quioxalin‐4‐yl)‐1H‐pyrazol‐5‐yl]methyl acetate ( 11 ), {4‐halo‐3‐[1‐methyl‐[1,2,4]triazolo[4,3‐a]quinoxalin‐4‐yl]‐1‐phenyl‐1H‐pyraz‐ol‐5‐yl}methyl acetate ( 13 ), and [3‐([1,2,4]triazolo‐[4,3‐a]quinoxalin‐4‐yl)‐4‐halo‐1‐phenyl‐1H‐pyrazol‐5‐yl] methyl formate ( 15 ) was accomplished. The structural investigation of the new compounds is based on chemical and spectroscopic evidences. J. Heterocyclic Chem., (2011)     

A Novel,One‐Pot Four‐Component Route to 2′‐Thioxo‐2′,3′‐dihydrospiro[indole‐3,6′‐[1,3]thiazin]‐2‐one Derivatives

An efficient route to 2′,3′‐dihydro‐2′‐thioxospiro[indole‐3,6′‐[1,3]thiazin]‐2(1H)‐one derivatives is described. It involves the reaction of isatine, 1‐phenyl‐2‐(1,1,1‐triphenyl‐λ⁵‐phosphanylidene)ethan‐1‐one, and different amines in the presence of CS₂ in dry MeOH at reflux (Scheme 1). The alkyl carbamodithioate, which results from the addition of the amine to CS₂, is added to the α,β‐unsaturated ketone, resulting from the reaction between 1‐phenyl‐2‐(1,1,1‐triphenyl‐λ⁵‐phosphanylidene)ethan‐1‐one and isatine, to produce the 3′‐alkyl‐2′,3′‐dihydro‐4′‐phenyl‐2′‐thioxospiro[indole‐3,6′‐[1,3]thiazin]‐2(1H)‐one derivatives in excellent yields (Scheme 2). Their structures were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS) and by elemental analyses.     

Interaction of 3‐(2‐Aminophenyl)‐6‐R1‐1,2,4‐triazin‐5‐ones with Acylating Reagents: An Efficient Method for Preparation of 6‐Substituted 3‐R1‐2H‐[1,2,4]triazino[2,3‐c]quinazolin‐2‐ones

The series of 6‐substituted 3‐R¹‐2H‐[1,2,4]triazino[2,3‐c]quinazolin‐2‐one was prepared via condensation of 3‐(2‐aminophenyl)‐6‐R¹‐1,2,4‐triazin‐5‐ones with acylating reagents. Particularities of ¹H NMR spectra have been also discussed based on the comparison of experimental and theoretical results for 3‐methyl‐6‐phenyl‐2H‐[1,2,4]triazino[2,3‐c]quinazolin‐2‐one and its 4,3‐isomer.     

Reaction of 2,3‐Dichloro‐1,4‐Naphthoquinone with 1‐Phenylbiguanide and 2‐Guanidinebenzimidazole

When 2,3‐dichloro‐1,4‐naphthoquinone (DCHNQ) ( 1 ) is allowed to react with 1‐phenylbiguanide (PBG) ( 2 ), 4‐chloro‐2,5‐dihydro‐2,5‐dioxonaphtho[1,2‐d]imidazole‐3‐carboxylic acid phenyl amide ( 4 ), 6‐chloro‐8‐phenylamino‐9H‐7,9,11‐triaza‐cyclohepta[a]naphthalene‐5,10‐dione ( 5 ) and 4‐dimethyl‐amino‐5,10‐dioxo‐2‐phenylimino‐5,10‐dihydro‐2H‐benzo[g]quinazoline‐1‐carboxylic acid amide ( 6 ) were obtained. While on reacting 1 with 2‐guanidinebenzimidazole (GBI) ( 3 ) the products are 3‐(1H‐benzoimidazol‐2‐yl)‐4‐chloro‐3H‐naphtho[1,2‐d]imidazole‐2,5‐dione ( 7 ) and 3‐[3‐(1H‐benzoimidazol‐2‐yl)‐ureido]‐1,4‐dioxo‐1,4‐dihydronaphthalene‐2‐carboxylic acid dimethylamide ( 8 ).     

Synthesis and Evaluation of Bioactivity of Thiazolo[3,2‐b]‐[1,2,4]‐triazoles and Isomeric Thiazolo[2,3‐c]‐[1,2,4]‐triazoles

Synthesis of 2‐(o‐nitrophenyl)‐6‐arylthiazolo[3,2‐b]‐[1,2,4]‐triazoles 4 and its isomer 3‐(o‐nitrophenyl)‐5‐arylthiazolo[2,3‐c]‐[1,2,4]‐triazoles 6 has been achieved starting from the appropriate 1‐(o‐nitrobenzoyl)‐3‐thiosemicarbazide 1 . Compound 1 on condensation with α‐haloketones gives 2‐(o‐nitrobenzoyl)hydrazino‐4‐arylthiazole hydrobromide 5 , which, on cyclization with POCl₃, affords thiazolo[3,2‐b]‐[1,2,4]‐triazoles 6 and not the isomeric thiazolo[3,2‐b]‐[1,2,4]‐triazoles 4 . This has been established by an unequivocal synthesis of 4 through polyphosphoric acid cyclization of 5‐aroylmethylmercapto‐3‐o‐nitrophenyl‐[1,2,4]‐triazole 3 . Compound 3 was synthesized by condensation of α‐haloketones with 5‐mercapto‐3‐(o‐nitrophenyl)‐[1,2,4]‐triazole 2 , obtained cyclization of 2‐(o‐nitrobenzoyl)hydrazinecarbothioamide 1 with NaOH. The antibacterial and antifungal activities of some of the compounds have also been evaluated.     

Syntheses of New Unsymmetrical 2,5‐Disubstituted‐1,3,4‐oxadiazoles and 1,2,4‐Triazolo[3,4‐b]‐1,3,4‐thiadiazoles Bearing Thieno[2,3‐c]pyrazolo Moiety

New series of (thieno[2,3‐c]pyrazolo‐5‐yl)‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazoles 10a , 10b , 10c and (thieno[2,3‐c]pyrazol‐5‐yl)‐1,3,4‐oxadiazol‐3(2H)‐yl)ethanones 6a , 6b , 6c has been synthesized from thieno[2,3‐c]pyrazole‐5‐carbohydrazide 3 by multistep reaction sequence. (5‐Aryl‐1,3,4‐oxadiazol‐2‐yl)‐1H‐thieno[2,3‐c]pyrazoles 4a , 4b , 4c were also synthesized from thieno[2,3‐c]pyrazole‐5‐carbohydrazide 3 by cyclization with various aromatic carboxylic acids. The hydrazide 3 was obtained by reaction of thieno[2,3‐c]pyrazole‐5‐carboxylate 2 with hydrazine hydrate in good yield, and compound 2 was obtained by the reaction of 5‐chloro‐3‐methyl‐1‐phenyl‐1H‐pyrazole‐4‐carbaldehyde 1 and 2‐ethyl thioglycolate in presence of sodium alcoholate in good yield.     

Syntheses of Some 3—[1′（1′H）—Substituent—pyrazol—5′—yl] benzo [5,6] coumarins

3-[1′(1′H)-Substituent-pyrazol-5′-yl]benzo[5,6]coumarins and 3-(1′,2′-oxazol-5′-yl)benzo[5,6]coumarin were prepared via condensation of 3-(2′-formyl-1′-chlorovinyl)benzo[5,6] coumarin with hydrazine derivatives or hydroxylamine.Reaction of 3-[1′(1′H)-pyrazol-5′-yl]benzo[5,6]coumarin with alkyl halides,olefinic compunds or acid chlorides are described.     

Heterocyclization reaction of 2‐(2‐methylaziridin‐1‐yl)‐3‐ureidopyridines under appel's conditions

The reaction of 2‐(2‐methylaziridin‐1‐yl)‐3‐ureidopyridines 12 with triphenylphosphine, carbon tetra‐chloride, and triethylamine (Appel's conditions) led to the corresponding carbodiimides 13 , which underwent intramolecular cycloaddition reaction with aziridine under the reaction conditions to give the pyridine‐fused heterocycles, 2,3‐dihydro‐1H‐imidazo[2′,3′:2,3]imidazo[4,5‐b]pyridines 16 and 12,13‐dihydro‐5H‐1,3 ‐benzodiazepino [2′,3′:2,3] imidazo[4,5‐b]pyridines 17 .     

Reactions of 2‐amino‐3‐cyano‐4,5,6,7‐tetrahydrobenzo[b]thiophene and 2‐amino‐3‐cyano‐4,7‐diphenyl‐5‐methyl‐4H‐pyrano[2,3‐c] pyrazole with phenylisocyanate,carbon disulfide,and thiourea

2‐Amino‐3‐cyano‐4,5,6,7‐tetrahydrobenzo[b]thiophene 1a or 2‐amino‐3‐cyano‐4,7‐di‐ phenyl‐5‐methyl‐4H‐pyrano[2,3‐c]pyrazole 2a reacted with phenylisocyanate in dry pyridine to give 2‐(3‐phenylureido)‐3‐cyanobenzo[b]thiophene 1b or 2‐disubstituted amino‐3‐cyanopyranopyrazole 2b derivative. However, when 1a and 2a were refluxed with carbon disulfide in 10% ethanolic sodium hydroxide solution, they afforded the thieno[2,3‐d]pyrimidin‐2,4‐dithione derivative 5 in the former case, 2,4‐dicyano‐1,3‐bis(dithio carboxamino)cyclobuta‐1,3‐ diene 6 and pyrazolopyranopyrido[2,3‐d]pyrimidin‐ 2,4‐dithione derivative 7 in the latter one. Treatment of 2a with thiourea in refluxing ethanol in the presence of potassium carbonate gave 2,2′‐dithiobispyrimidine derivative 9 (major) in addition to pyranopyrazole derivative 10 and 2,2′‐dithiobis ethoxypyrimidine derivative 11 in minor amounts. The structures of all products were evidenced by microanalytical and spectral data. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:6–11, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20070     

New isochromans. 1. Synthesis and antimicrobial activity of 4‐substituted (±)‐1h‐spiro[benzo[c]pyran‐3(4H), 1′‐cyclohexane]‐1‐ones

The reaction between homophthalic anhydride and cyclohexanone was examined both in the presence of DMAP or BF₃·Et₂O complex as a catalyst. The latter yielded (±)‐1‐oxo‐1H‐spiro[benzo[c]pyran‐3(4H), 1′‐cyclohexane]‐4‐carboxylic acid ( 3 ) in a higher yield (82 %). A series of new (±)‐4‐(N,N‐disubstituted‐1‐carbamoyl)‐1H‐spiro[benzo[c]pyran‐3(4H),1′‐cyclohexane]‐1‐ones ( 5a‐h ) were synthesized from the parent acid 3 by a two‐step reaction. Differentiating microbial screening was performed for most of the synthesized compounds against twelve microorganisms belonging to different taxonomic groups. The spiro acid 3 was active against all bacterial strains with MIC ≥ 20 μg/ml against B. subtillis and P. vulgaris. E. coli was the most sensitive strain to the antibacterial effect of the tested compounds.     

A series of 1‐[2‐aryl‐1‐diazenyl]‐3‐({3‐[2‐aryl‐1‐diazenyl]perhydrobenzo[d]imidazol‐1‐yl}methyl)perhydrobenzo[d]imidazoles. Synthesis and characterization

Reaction of diazonium salts with solutions of 1,2‐diaminocyclohexane mixed with formaldehyde affords the 1‐[2‐aryl‐1‐diazenyl]‐3‐({3‐[2‐aryl‐1‐diazenyl]perhydrobenzo[d]imidazol‐1‐yl}methyl)perhydrobenzo‐[d]imidazoles ( 6 ), a new series of bis‐triazenes with different connectivity than any previous type of bis‐triazene reported. The products have been characterized principally by NMR and IR spectroscopy, elemental analysis and unequivocally by X‐ray crystallography. The methylene protons of the perhydroimidazole rings are diastereotopic giving rise to a doublet of doublets pattern in the ¹H NMR spectra. However, detailed analysis of the NMR spectra shows that there is more than one set of doublet‐of‐doublet signals, suggesting the presence of different rotameric forms of the products. The ¹³C NMR spectral assignments were assisted by COSY and DEPT experiments with selected compounds.     

Photocycloaddition of Cyclohex‐2‐enones to 2‐Methylbut‐1‐en‐3‐yne

Irradiation (350 nm) of 2‐alkynylcyclohex‐2‐enones 1 in benzene in the presence of an excess of 2‐methylbut‐1‐en‐3‐yne ( 2 ) affords in each case a mixture of a cis‐fused 3,4,4a,5,6,8a‐hexahydronaphthalen‐1(2H)‐one 3 and a bicyclo[4.2.0]octan‐2‐one 4 (Scheme 2), the former being formed as main product via 1,6‐cyclization of the common biradical intermediate. The (parent) cyclohex‐2‐enone and other alkylcyclohex‐2‐enones 7 also give naphthalenones 8 , albeit in lower yields, the major products being bicyclo[4.2.0]octan‐2‐ones (Scheme 4). No product derived from such a 1,6‐cyclization is observed in the irradiation of 3‐alkynylcyclohex‐2‐enone 9 in the presence of 2 (Scheme 4). Irradiation of the 2‐cyano‐substituted cyclohexenone 12 under these conditions again affords only traces of naphthalenone 13 , the main product now being the substituted bicyclo[4.2.0]oct‐7‐ene 16 (Scheme 5), resulting from [2+2] cycloaddition of the acetylenic C−C bond of 2 to excited 12 .