Green Synthesis of 1‐(1,2,4‐Triazol‐4‐yl)spiro[azetidine‐2,3′‐(3H)indole]‐2′,4′(1′H)‐diones as Potential Insecticidal Agents

One pot green synthesis of 1‐(1,2,4‐triazol‐4‐yl)spiro[azetidine‐2,3′‐(3H)‐indole]‐2′,4′(1′H)‐diones was carried out by the reaction of indole‐2,3‐diones,4‐amino‐4H‐1,2,4‐triazole and acetyl chloride/chloroacetyl chloride in ionic liquid [bmim]PF₆ with/without using a catalyst. It was also prepared by conventional method via Schiff's bases, 3‐[4H‐1,2,4‐triazol‐4‐yl]imino‐indol‐2‐one. Further, the corresponding phenoxy derivatives were obtained by the reaction of chloro group attached to azetidine ring with phenols. The synthesized compounds were characterized by analytical and spectral (IR, ¹H NMR, ¹³C NMR, and FAB mass) data. Evaluation for insecticidal activity against Periplaneta americana exhibited promising results.     

Thermal cyclization of 3‐azido‐2‐phenyl‐indan‐l‐one to 5h‐indeno[1,2‐b]indol‐10‐one

3‐Azido‐2‐phenylindan‐1‐one ( 4 ), which was obtained from 3‐chloro‐2‐phenylindan‐1‐one ( 3 ), cyclizes on thermolysis to 5H‐indeno[1,2‐b]indol‐10‐one ( 5 ). Reaction of 3‐azido‐2‐phenylindan‐1‐one ( 4 ) with triphenylphosphane gives 2‐phenyl‐3‐(triphenylphosphoranylideneamino)‐indan‐1‐one ( 6 ), which can be hydrolyzed to 3‐amino‐2‐phenylindan‐1‐one ( 7 ). Attempts to perform a similar cyclization sequence with 3‐chloro‐2‐pyridylindan‐1‐ones failed.     

A Facile Synthesis of Novel (Z)‐ethyl‐3‐(5‐substituted‐1‐alkyl/aryl‐1H‐indol‐3‐yl)‐2‐(1H‐tetrazol‐5‐yl)acrylate

A novel route was developed for synthesis of high potential 1H‐tetrazoles by using conventional method. Tetrazole scaffold is a promising pharmacophore fragment, frequently used in the development of various novel drugs. Here, the novel (Z)‐3‐(N‐alkyl‐indol‐3‐yl)‐2‐(1H‐tetrazole‐5‐yl)acrylates 5 ( a – i ) have been synthesized from (Z)‐ethyl‐3‐(1H‐indol‐3‐yl)2‐(1H‐tetrazol‐5‐yl)acrylates 4 ( a – c ) by using various alkylating agents such as Dimethyl Sulphate (DMS), Diethyl Sulphate (DES), and benzyl chloride; 4 ( a – c ) were synthesized from sodium azide in the presence of copper sulfate in dimethylformamide; 3 ( a – c ) have been prepared by Knoevenagel condensation of indole‐3‐carbaldehyde 1 ( a – c ) and ethylcyanoacetate 2 in the presence of L‐Proline as a catalyst at room temperature in ethanol for an hour. This is an efficient and clean click chemistry method that has various advantages such as easy workup, higher yields, shorter reaction times, and more economical.     

Synthesis of New Derivatives of 4‐(4,7,7‐Trimethyl‐7,8‐dihydro‐6H‐benzo[b]pyrimido[5,4‐e][1,4]thiazin‐2‐yl)morpholine

Cyclocondensation of 5‐amino‐6‐methyl‐2‐morpholinopyrimidine‐4‐thiol ( 1 ) and 2‐bromo‐5,5‐dimethylcyclohexane‐1,3‐dione ( 2 ) under mild reaction condition afforded 4,7,7‐trimethyl‐2‐morpholino‐7,8‐dihydro‐5H‐benzo[b ]pyrimido[5,4‐e ][1,4]thiazin‐9(6H )‐one ( 3 ). The ¹H and ¹³C NMR data of compound ( 3 ) are demonstrated that this compound exists primarily in the enamino ketone form. Reaction of compound ( 3 ) with phosphorous oxychloride gave 4‐(9‐chloro‐4,7,7‐trimethyl‐7,8‐dihydro‐6H‐benzo[b ]pyrimido[5,4‐e ][1,4]thiazin‐2‐yl)morpholine ( 4 ). Nucleophilic substitution of chlorine atom of compound ( 4 ) with typical secondary amines in DMF and K₂CO₃ furnished the new substituted derivatives of 4‐(4,7,7‐trimethyl‐7,8‐dihydro‐6H‐benzo[b ]pyrimido[5,4‐e ][1,4]thiazin‐2‐yl)morpholine ( 5a , 5b , 5c , 5d , 5e , 5f , 5g , 5h ). All the synthesized products were characterized and confirmed by their spectroscopic and microanalytical data.     

Synthesis of Analogues of Indole Alkaloids from Sea Sponges – Aplysinopsins by the Reaction of Amines with (4Z)‐4‐[(1H‐indol‐3‐yl)‐methylene]‐1,3‐oxazol‐5(4H)‐ones

A new two‐step approach toward the synthesis of aplysinopsin analogues 5‐(1‐R‐1H‐indol‐3‐ylmethylene)‐2‐aryl‐3,5‐dihydroimidazol‐4‐ones consisting in obtaining and reaction of 4‐(1‐R‐1H‐indol‐3‐ylmethilene)‐2‐Ar‐4H‐oxazol‐5‐ones with amines was developed. The configuration of starting compounds and final products was determined by ¹³С and ¹H‐nmr spectroscopy.     

N‐(X‐Chlorophenyl)‐4‐hydroxy‐2‐methyl‐2H‐1,2‐benzothiazine‐3‐carboxamide 1,1‐dioxide (with X = 2 and 4)

The structures of N‐(2‐chlorophenyl)‐4‐hydroxy‐2‐methyl‐2H‐1,2‐benzothiazine‐3‐carboxamide 1,1‐dioxide and N‐(4‐chlorophenyl)‐4‐hydroxy‐2‐methyl‐2H‐1,2‐benzothiazine‐3‐carboxamide 1,1‐dioxide, both C₁₆H₁₃ClN₂O₄S, are stabilized by extensive intramolecular hydrogen bonds. The 4‐chloro derivative forms dimeric pairs of molecules lying about inversion centres as a result of intermolecular N—H...O hydrogen bonds, forming 14‐membered rings representing an R₂²(14) motif; the 2‐chloro derivative is devoid of any such intermolecular hydrogen bonds. The heterocyclic thiazine rings in both structures adopt half‐chair conformations.     

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.     

Green approach for the synthesis of 3‐methyl‐1‐phenyl‐4‐((2‐phenyl‐1H‐indol 3‐yl)methylene)‐1H‐pyrazole‐5(4H)‐ones and their DNA Cleavage,antioxidant, and antimicrobial activities

3‐Methyl‐1‐phenyl‐4‐((2‐phenyl‐1H‐indol‐3‐yl)methylene)‐1H‐pyrazol‐5(4H)‐ones (5a‐i) was prepared by the condensation reaction of different 3‐formyl‐2‐phenylindole derivatives (2a‐i) and 3‐methyl‐1‐phenyl‐2‐pyrazoline‐5‐one in quantitative yield by applying various green synthetic methods as grinding, microwave irradiation using different catalysts under solvent‐free mild reaction conditions with high product yields. The structures of the synthesized compounds were characterized on the basis of elemental analysis, infrared, ¹HNMR, ¹³C NMR, and mass spectral data. The synthesized compounds were screened for free radical scavenging, antimicrobial, and DNA cleavage activities. Most of the tested compounds belonging to the 3‐methyl‐1‐phenyl‐4‐((2‐phenyl‐1H‐indol‐3‐yl)methylene)‐1H‐pyrazol‐5(4H)‐ones series exhibited promising activities.     

Two isomeric 2‐[4‐chloro‐2‐fluoro‐5‐(prop‐2‐ynyloxy)phenyl]hexahydro­isoindole‐1,3‐dione compounds

The molecular structures of 2‐[4‐chloro‐2‐fluoro‐5‐(prop‐2‐ynyloxy)phenyl]‐1,3,4,5,6,7‐hexahydro­isoindole‐1,3‐dione, C₁₇H₁₃ClFNO₃, (I), and the isomeric compound 2‐[4‐chloro‐2‐fluoro‐5‐(prop‐2‐ynyloxy)phenyl]‐cis‐1,3,3a,4,7,7a‐hexahydro­isoindole‐1,3‐dione, (II), are, as anticipated, significantly different in their conformations and in the distances between the farthest two atoms. The six‐membered ring of the 1,3,4,5,6,7‐hexahydro­isoindole‐1,3‐dione moiety in (I) adopts a half‐chair conformation. The dihedral angle between the five‐membered dione ring of (I) and the benzene ring is 50.96 (7)°. The six‐membered ring of the cis‐1,3,3a,4,7,7a‐hexahydro­isoindole‐1,3‐dione moiety in (II) adopts a boat conformation. The dihedral angle in (II) between the five‐membered dione ring and the benzene ring is 61.03 (13)°. In the crystal structures, the molecules are linked by C—H⋯O hydrogen bonds and weak π–π interactions. Compound (I) is a much more potent herbicide than (II). The Cl⋯H distances between the farthest two atoms in (I) and (II) are 11.37 and 9.97 Å, respectively.     

Synthesiss of novel 3‐(2‐thienyl)‐1,2‐diazepino[3,4‐b]quinoxalines with algicidal activity

The reaction of the quinoxaline N‐oxide 1 with thiophene‐2‐carbaldehyde gave 6‐chloro‐2‐[1‐methyl‐2‐(2‐thienylmethylene)hydrazino]quinoxaline 4‐oxide 5 , whose reaction with 2‐chloroacrylonitrile afforded 8‐chloro‐2,3‐dihydro‐4‐hydroxy‐1‐methyl‐3‐(2‐thienyl)‐1H‐1,2‐diazepino[3,4‐b]quinoxaline‐5‐carbonitrile 6 . The reaction of compound 6 with various alcohols in the presence of a base effected alcoholysis to provide the 5‐alkoxy‐8‐chloro‐2,3,4,6‐tetrahydro‐1‐methyl‐4‐oxo‐3‐(2‐thienyl)‐1H‐1,2‐diazepino[3,4‐b]‐quinoxalines 7a‐d . The reaction of compounds 7a and 7b with diethyl azodicarboxylate effected dehydrogenation to give the 5‐alkoxy‐8‐chloro‐4,6‐dihydro‐1‐methyl‐4‐oxo‐3‐(2‐thienyl)‐1H‐1,2‐diazepino[3,4‐b]‐quinoxalines 8a and 8b , respectively. Compounds 8a and 8b were found to show good algicidal activities against Selenastrum capricornutum and Nitzchia closterium.     

Synthesis of New Heterocyclic Compounds Using 2‐(3,3‐dimethyl‐1H‐pyrroloisoquinolin‐2(3H)‐ylidene)malonaldehydes

Isoquinolin‐5‐ylhydrazinium chloride 13 and 5‐bromoisoquinolin‐8‐ylhydrazinium chloride 14 were converted via Fischer syntheses with 3‐methylbutan‐2‐one into indolenines, 2,3,3‐trimethyl‐3H‐pyrrolo[2,3‐f]isoquinoline 15 and 5‐bromo‐2,3,3‐trimethyl‐3H‐pyrrolo[3,2‐h]isoquinoline 16 , respectively. Exposure of the indolenines to the Vilsmeier reagent produced diformyl compounds 17 and 18 , which reacted with arylhydrazines to give the corresponding pyrazoles 19a , 19b , 19c , 19d , 19e , 19f , 19g , 19h , 19i and 20a , 20b , 20c , 20d , 20e , 20f , 20g . Reaction of 17 with thiourea gave a pyrimidine‐2(1H)‐thione 23 or with hydroxylamine hydrochloride, an isoxazole 24 .     

Pd‐Catalyzed Cyclocarbonylation of 2‐(2‐Bromoaryl)indoles with CO as a C1 Source: Selective Access to 6 H‐Isoindolo[2,1‐a]indol‐6‐ones and Indeno[1,2‐b]indol‐10(5 H)‐ones

A highly efficient and regioselective synthetic route to 6 H‐isoindolo[2,1‐a]indol‐6‐ones and indeno[1,2‐b]indol‐10(5 H)‐ones through the Pd‐catalyzed cyclocarbonylation of 2‐(2‐bromoaryl)indoles under atmospheric CO pressure has been achieved. Notably, the regioselectivity of the reaction was exclusively dependent on the structural characteristics of the indole substrates. With N‐unsubstituted indoles as the starting materials, the reaction afforded 6H‐isoindolo[2,1‐a]indol‐6‐ones in good‐to‐excellent yields. On the other hand, with N‐substituted indoles as the substrates, the reaction gave indeno[1,2‐b]indol‐10(5 H)‐ones in a highly regioselective manner.     

Synthesis and NMR‐Spectroscopic Investigations with 4‐Chloroacyl‐1‐phenylpyrazolin‐5‐ones

The synthesis of various 4‐acylpyrazolones bearing in the acyl moiety either a terminal chloro‐substituent or a terminal ortho‐chlorophenyl group was achieved by reaction of 3‐methyl‐1‐phenyl‐2‐pyrazolin‐5‐one (tautomer to 3‐methyl‐1‐phenyl‐1H‐pyrazol‐5‐ol) with the corresponding acid chloride using calcium hydroxide / 1,4‐dioxane. In one case (reaction with chlorobutanoyl chloride) a spontaneous cyclization occurred leading to the corresponding oxepino[2,3‐c]pyrazole. Detailed NMR spectroscopic investigations with all prepared compounds were performed.     

Synthesis,spectral, and antimicrobial studies of 1‐butyl‐3‐substituted‐4‐(2‐aryl‐1H‐indol‐3‐yl)‐2‐azetidinones

Ketene generated from acetyl chloride or chloroacetyl chloride adds on indolyl Schiff's base double bond to afford 1‐butyl‐3‐substituted‐4‐(2‐aryl‐1H‐indol‐3‐yl)‐2‐azetidinones in THF. The reaction proceeds stereospecifically via concerted trans [2+2] cycloaddition. The synthesized compounds have been characterized by elemental analyses and spectral data (IR, PMR, and mass). All synthesized compounds have been evaluated for antibacterial and antifungal activities, and 4g to 4l have shown promising results. © 2004 Wiley Periodicals, Inc. Heteroatom Chem 15:494–501, 2004; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20052     

Synthesis of Certain New Thiazole and 1,3,4‐Thiadiazole Derivatives via the Utility of 3‐Acetylindole

2‐(2‐(1‐(1H‐Indol‐3‐yl)ethylidene)‐hydrazinyl)‐4‐substituted 5‐(aryldiazenyl)thiazoles and 5‐((1‐(1H‐indol‐3‐yl)ethylidene)hydrazono)‐2‐substituted‐4‐phenyl‐4,5‐dihydro‐1,3,4‐thiadiazoles were synthesized via reaction of hydrazonoyl halides and 2‐(1‐(1H‐indol‐3‐yl)ethylidene)hydrazine‐1‐carbothioamide and alkyl 2‐(1‐(1H‐indol‐3‐yl)ethylidene)hydrazine‐1‐carbodithioate in ethanolic triethylamine. Structures of the newly synthesis were elucidated on the basis of elemental analysis, spectral data, and alternative synthetic route whenever possible.     

Synthesis and Biological Activities of 7‐Arylazo‐7H‐pyrazolo[5,1‐c][1,2,4] Triazol‐6(5H)‐Ones and 7‐Arylhydrazono‐7H‐[1,2,4]triazolo[3,4‐b] [1,3,4]thiadiazines

Two series of 7‐arylazo‐7H‐3‐(2‐methyl‐1H‐indol‐3‐yl)pyrazolo[5,1‐c][1,2,4]triazol‐6(5H)‐ones 4 and 7‐arylhydrazono‐7H‐3‐(2‐methyl‐1H‐indol‐3‐yl)‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazines 7 were prepared via reactions of 4‐amino‐3‐mercapto‐5‐(2‐methyl‐1H‐indol‐3‐yl)‐1,2,4‐triazole 1 with ethyl arylhydrazono‐chloroacetate 2 and N‐aryl‐2‐oxoalkanehydrazonoyl halides 5 , respectively. A possible mechanism is proposed to account for the formation of the products. The biological activity of some of these products was also evaluated.     

‘Click Synthesis’ of 1H‐1,2,3‐Triazolyl‐Based Oxiconazole (=(1Z)‐1‐(2,4‐Dichlorophenyl)‐2‐(1H‐imidazol‐1‐yl)ethanone O‐[(2,4‐Dichlorophenyl)methyl]oxime) Analogs

The ‘click synthesis’ of some oxiconazole analogs 5a – 5v having 1H‐1,2,3‐triazolyl residues by Huisgen cycloaddition was achieved in four steps (Scheme 1). Oximation of phenacyl chloride ( 1 ) followed by azidation of 2‐chloro‐1‐phenylethanone oxime ( 2 ) provided azido ketoxime 3 . The CuI‐catalyzed Huisgen cycloaddition of 3 with terminal alkynes gave the 4‐substituted (at the triazole) 2‐(1H‐1,2,3‐triazol‐1‐yl)‐1‐phenylethanone oximes 4a – 4i . The O‐alkylation of 4a – 4i with various alkyl halides resulted in the formation of the target molecules 5a – 5v in good yields.     

A simple synthesis of 4‐chloro‐5‐hydroxy‐1H‐benzo[g]indoles

The reaction of methyl 2‐(3‐chloro‐1,4‐dioxo‐1,4‐dihydronaphthalen‐2‐yl)propenoate ( 2a ) with primary amines gave 4‐chloro‐5‐hydroxy‐3‐methoxycarbonyl‐1H‐benzo[g]indoles 5a‐f as major compounds and 3‐methoxycarbonyl‐4,9‐dioxo‐2,3,4,9‐tetrahydro‐1H‐benzo[f]indoles 6a‐d as minor ones. Whereas the reaction of 3‐(3‐chloro‐1,4‐dioxo‐1,4‐dihydronaphthalen‐2‐yl)‐3‐buten‐2‐one ( 2b ) with primary amines afforded the corresponding 1H‐benzo[g]indoles 5g‐i as major products and 3‐acetyl‐4,9‐dihydro‐4,9‐dioxo‐1H‐benzo[f]indoles 7g, h as minor products.     

Seven 3‐methylidene‐1H‐indol‐2(3H)‐ones related to the multiple‐receptor tyrosine kinase inhibitor sunitinib

The solid‐state structures of a series of seven substituted 3‐methylidene‐1H‐indol‐2(3H)‐one derivatives have been determined by single‐crystal X‐ray diffraction and are compared in detail. Six of the structures {(3Z)‐3‐(1H‐pyrrol‐2‐ylmethylidene)‐1H‐indol‐2(3H)‐one, C₁₃H₁₀N₂O, (2a); (3Z)‐3‐(2‐thienylmethylidene)‐1H‐indol‐2(3H)‐one, C₁₃H₉NOS, (2b); (3E)‐3‐(2‐furylmethylidene)‐1H‐indol‐2(3H)‐one monohydrate, C₁₃H₉NO₂·H₂O, (3a); 3‐(1‐methylethylidene)‐1H‐indol‐2(3H)‐one, C₁₁H₁₁NO, (4a); 3‐cyclohexylidene‐1H‐indol‐2(3H)‐one, C₁₄H₁₅NO, (4c); and spiro[1,3‐dioxane‐2,3′‐indolin]‐2′‐one, C₁₁H₁₁NO₃, (5)} display, as expected, intermolecular hydrogen bonding (N—H...O=C) between the 1H‐indol‐2(3H)‐one units. However, methyl 3‐(1‐methylethylidene)‐2‐oxo‐2,3‐dihydro‐1H‐indole‐1‐carboxylate, C₁₃H₁₃NO₃, (4b), a carbamate analogue of (4a) lacking an N—H bond, displays no intermolecular hydrogen bonding. The structure of (4a) contains three molecules in the asymmetric unit, while (4b) and (4c) both contain two independent molecules.     

First synthesis of 2‐(2,4,4‐trimethyl‐3,4‐dihydro‐2H‐benzo[h]chromen‐2‐yl)‐1‐naphthol and 3‐(2,4,4‐trimethyl‐3,4‐dihydro‐2H‐benzo[g]chromen‐2‐yl)‐2‐naphthol from 1‐ and 2‐naphthol derivatives

Two new structurally isomeric, 2‐(2,4,4‐trimethyl‐3,4‐dihydro‐2H‐benzo[h]chromen‐2‐yl)‐1‐naphthol ( 1 ) and 3‐(2,4,4‐trimethyl‐3,4‐dihydro‐2H‐benzo[g]chromen‐2‐yl)‐2‐naphthol ( 3 ) have been synthesized from 2‐acetyl‐1‐naphthol and ethyl‐3‐hydroxy‐2‐naphthoate, respectively, involving Grignard reaction, dehydration of the corresponding tertiary alcohols, and hetero Diels–Alder dimerization. The two benzochromenes ( 1 and 3 ) have been fully characterized by IR, NMR, and HRESIMS data. Their structures are further supported by crystallography of their corresponding acetates ( 2 and 4 ). J. Heterocyclic Chem., (2011).