Synthesis of New Fused and Spiro 1,5‐Benzodiazepines

[1,3‐Dihydro‐4‐phenyl(1,5)benzodiazepin‐2‐ylidene]malononitrile 1_a was treated with formaline and some different primary amines to give the corresponding pyrimido(1,5)benzodiazepines 2_a–d . Treatment of compound 1_a with halo reagents yielded the corresponding pyrrolobenzodiazepines 3_a,b . The reaction of compound 1_a with active methylenes, bidentates, S,S‐ and N,S‐acetals afforded the corresponding spiro(1,5)‐benzodiazepines 4_a‐c–8_a,b , respectively.     

Synthesis of Some Heterocyclic Compounds from 1H‐Indole‐2,3‐Dione: A Direct One‐Pot Synthesis of Spiro Indolone Derivatives

Some spiro indolone derivatives 5_a,b and 6 were synthesized through one‐pot synthesis via the ternary condensation of 1H‐indole‐2,3‐dione 1 , 3‐methyl‐1‐phenyl‐2‐pyrazolin‐5‐one 2 and active methylenes, namely malononitrile, ethyl cyanoacetate 4_a,b and pyrazolone 2 , respectively. The same derivatives can be obtained via other methods, through reactions of 3‐[3‐methyl‐5‐oxo‐1‐phenyl‐1,5‐dihydro‐pyrazol‐(4Z)‐ylidene]‐1,3‐dihydro‐indol‐2‐one 3 with the corresponding active methylenes. Reaction of 3 with amines and with ethyl vinyl ether was studied.     

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.     

A Facile One‐Pot Synthesis of Functionalized 1,5‐Dihydro‐2H‐[1]benzopyrano[2,3‐b]pyridin‐5‐ones

The highly reactive 1 : 1 intermediate generated in the reaction between dialkyl acetylenedicarboxylate (=but‐2‐ynedioic acid dialkyl ester) 4 and triphenylphosphine was trapped by 2‐amino‐4‐oxo‐4H‐1‐benzopyran‐3‐carboxaldehydes 5 to yield highly functionalized dialkyl‐1,5‐dihydro‐5‐oxo‐1‐phenyl‐2H‐[1]benzopyrano[2,3‐b]pyridine‐2,3‐dicarboxylates in high yield.     

Synthesis of Novel Pyrazino[2,1‐a]isoindolediones via Intramolecular Hydroamination of 2,3‐Dihydro‐3‐oxo‐2‐(prop‐2‐yn‐1‐yl)‐1H‐isoindole‐1‐carboxamides

Novel derivatives of pyrazino[2,1‐a]isoindolediones were synthesized through 6‐exo‐dig intramolecular hydroamination of 2,3‐dihydro‐3‐oxo‐2‐(prop‐2‐yn‐1‐yl)‐1H‐isoindole‐1‐carboxamides followed by 1,3‐H shift, in the presence of sodium hydride in DMF at 80°. All products were obtained in good yields (60 – 80%) within short reaction time (40 – 60 min).     

New Approaches to the Synthesis of 4‐(2‐Aminophenyl)‐1,3‐dihydro‐2H‐imidazol‐2‐ones and 3‐Ureidoindoles and a Study of Their Interconversion

3‐Alkyl/aryl‐3‐ureido‐1H,3H‐quinoline‐2,4‐diones ( 2 ) and 3a‐alkyl/aryl‐9b‐hydroxy‐3,3a,5,9b‐tetrahydro‐1H‐imidazo[4,5‐c]quinoline‐2,4‐diones ( 3 ) react in boiling concentrated HCl to give 5‐alkyl/aryl‐4‐(2‐aminophenyl)‐1,3‐dihydro‐2H‐imidazol‐2‐ones ( 6 ). The same compounds were prepared by the same procedure from 2‐alkyl/aryl‐3‐ureido‐1H‐indoles ( 4 ), which were obtained from the reaction of 3‐alkyl/aryl‐3‐aminoquinoline‐2,4(1H,3H)‐diones ( 1 ) with 1,3‐diphenylurea or by the transformation of 3a‐alkyl/aryl‐9b‐hydroxy‐3,3a,5,9b‐tetrahydro‐1H‐imidazo[4,5‐c]quinoline‐2,4‐diones ( 3 ) and 5‐alkyl/aryl‐4‐(2‐aminophenyl)‐1,3‐dihydro‐2H‐imidazol‐2‐ones ( 6 ) in boiling AcOH. The latter were converted into 1,3‐bis[2‐(2‐oxo‐2,3‐dihydro‐1H‐imidazol‐4‐yl)phenyl]ureas ( 5 ) by treatment with triphosgene. All compounds were characterized by ¹H‐ and ¹³C‐NMR and IR spectroscopy, as well as atmospheric pressure chemical‐ionisation mass spectra.     

The Pseudo‐Michael Reaction of 2‐Hydrazinylidene‐1‐Arylimidazolidines with Diethyl Ethoxymethylenemalonate

The pseudo‐Michael reaction of 2‐hydrazinylidene‐1‐arylimidazolidines with diethyl ethoxymethylenemalonate (DEEM) was investigated. The reaction yields the chain adduct, namely diethyl{[2‐(1‐arylimidazolidin‐2‐ylidene)hydrazinyl]methylidene}propanedioates. This is contrary to the pseudo‐Michael reaction of DEEM with 1‐aryl‐4,5‐dihydro‐1H‐imidazol‐2‐amines that does not allow isolation of chain derivatives and leads to cyclic imidazo[1,2‐a]pyrimidine derivatives while even at thermodynamic control. At first cyclization of diethyl{[2‐(1‐arylimidazolidin‐2‐ylidene)hydrazinyl]methylidene}propanedioates leads to ethyl 1‐aryl‐5(1H,8H)oxo‐2,3‐dihydro‐imidazo[2,1‐c][1,2,4]triazepine‐6‐carboxylates. 1,5‐Sigmatropic shift, following the cyclization, caused isomerization of 5(1H,8H)oxo‐2,3‐dihydro‐imidazo[2,1‐c][1,2,4]triazepine‐6‐carboxylates to ethyl 1‐aryl‐5(1H)hydroxy‐2,3‐dihydroimidazo[2,1‐c][1,2,4]triazepine‐6‐carboxylates. Presence of both isomers in the reaction product was detected in the NMR spectra. The structure of all the compounds was confirmed with spectroscopic studies (¹H NMR and MS). The structure of diethyl{[2‐(1‐phenylimidazolidin‐2‐ylidene)hydrazinyl]methylidene}propanedioate was also confirmed by X‐ray crystallography. In the addition reaction, thermodynamics and HOMO–LUMO orbitals of the reactants were studied by using quantum chemical calculations.     

Synthesis of 1‐Acyl‐3,4‐dihydroquinazoline‐2(1H)‐thiones by Cyclization of N‐[2‐(Isothiocyanatomethyl)phenyl] Amides Generated in situ from N‐[2‐(Azidomethyl)phenyl] Amides

An efficient method for the preparation of 1‐acyl‐3,4‐dihydroquinazoline‐2(1H)‐thiones 5 has been developed. The reaction of N‐[2‐(azidomethyl)phenyl] amides 3 , easily prepared by a three‐step sequence starting with (2‐aminophenyl)methanols, with Ph₃P, followed by CS₂, allowed generation of N‐[2‐(isothiocyanatomethyl)phenyl]‐amide intermediates 4 , which underwent cyclization on treatment with NaH to furnish the corresponding desired products in generally good yields.     

Total Synthesis of the Biologically Active,Naturally Occurring 3,4‐Dibromo‐5‐[2‐bromo‐3,4‐dihydroxy‐6‐(methoxymethyl)benzyl]benzene‐1,2‐diol and Regioselective O‐Demethylation of Aryl Methyl Ethers

3,4‐Dibromo‐5‐[2‐bromo‐3,4‐dihydroxy‐6‐(methoxymethyl)benzyl]benzene‐1,2‐diol ( 2 ), a natural product, has been synthesized for the first time starting from (3‐bromo‐4,5‐dimethoxyphenyl)methanol ( 5 ) in five steps and with an overall yield of 34%. The reaction of some methoxymethyl‐substituted aryl methyl ethers with BBr₃, followed by the addition of MeOH, afforded the corresponding methoxymethyl‐substituted arylphenols in high yields.     

A Facile Synthesis of Oxoindenothiazine and Dioxospiro(indene‐2,4′‐thiazine) Derivatives from (Substituted ethylidene)hydrazinecarbothioamides

(E)‐2‐[2‐(1‐Substituted ethylidene)hydrazinyl]‐5‐oxo‐9b‐hydroxy‐5,9b‐dihydroindeno[1,2‐d][1,3]‐thiazine‐4‐carbonitriles and (E)‐5‐oxo‐[(E)‐(1‐substituted ethylidene)hydrazinyl]‐2,5‐dihydroindeno[1,2‐d][1,3]thiazine‐4‐carbonitriles have been obtained from the reaction of 2‐(substituted ethylidene)hydrazinecarbothioamides with 2‐(1,3‐dioxo‐2,3‐dihydro‐1H‐inden‐2‐ylidene)propanedinitrile ( 1 ) in ethyl acetate solution. However, (Z)‐6′‐amino‐1,3‐dioxo‐3′‐substituted‐2′‐[(E)‐(1‐phenylethylidene)hydrazono]‐1,2′,3,3′‐tetrahydrospiro(indene‐2,4′‐[1,3]thiazine)‐5′‐carbonitriles were observed during the reaction of N‐substituted‐2‐(1‐phenylethylidene)hydrazinecarbothioamides with ( 1 ). The structure assignment of products has been confirmed on the basis of ¹H‐, ¹³C‐NMR, and mass spectrometry, as well as theoretical calculations.     

A facile synthesis of 3‐Substituted 5‐Oxo‐1,2,4‐thiadiazoles from amidoximes

The reaction of amidoximes 1 with 1,1′‐thiocarbonyldiimidazole (TCDI) followed by treatment with silica gel or boron trifluoride diethyl etherate (BF₃·OEt₂) provided 3‐substituted 4,5‐dihydro‐5‐oxo‐1,2,4‐thiadiazoles 2 in moderate yields. The Lewis acids are considered to promote the rearrangement of the thioxocarbamate intermediates 5 to the thiol carbarn ate intermediates 7 , which cyclize to afford 4,5‐dihydro‐5‐oxo‐1,2,4‐thiadiazoles 2 .     

Synthesis,structure and biological activity of new 6,6‐dimethyl‐2‐oxo‐4‐{2‐[5‐organylsilyl(germyl)]furan(thiophen)‐2‐yl}vinyl‐5,6‐dihydro‐2H‐pyran‐3‐carbonitriles

New 6,6‐dimethyl‐2‐oxo‐4‐{2‐[5‐alkylsilyl(germyl)]furan(thiophen)‐2‐yl}vinyl‐5,6‐dihydro‐2H‐pyran‐3‐carbonitriles (IC₅₀: 1–6 µg ml^?1) have been prepared by the condensation of corresponding silicon‐ and germanium‐containing furyl(thienyl)‐2‐carbaldehydes with 3‐cyano‐4,6,6‐trimethyl‐5,6‐dihydropyran‐2‐one using piperidine acetate as a catalyst. The obtained carbonitriles were identified using NMR (¹H, ¹³C and ²⁹Si) spectroscopy and GC‐MS. The structure of 6,6‐dimethyl‐2‐oxo‐4‐[2‐(5‐trimethylsilyl)thiophen‐2‐yl]‐5,6‐dihydro‐2H‐pyran‐3‐carbonitrile was studied using X‐ray diffractometry. The influences of the heterocycle and the structure of the organoelement substituent on cytotoxicity and on matrix metalloproteinase inhibition have been studied. Copyright © 2015 John Wiley & Sons, Ltd.     

Synthesis of 4‐((2‐hydroxynaphthalen‐1‐yl)(aryl)methyl)‐5‐methyl‐2‐phenyl‐1H‐pyrazol‐3(2H)‐ones using nano‐Zn‐[2‐boromophenyl‐salicylaldimine‐methylpyranopyrazole]Cl2 nanoparticles

Nano‐Zn‐[2‐boromophenyl‐salicylaldimine‐methylpyranopyrazole]Cl₂ (nano‐[Zn‐2BSMP]Cl₂) as a nanoparticle Schiff base complex and a catalyst was introduced for the solvent‐free synthesis of 4‐((2‐hydroxynaphthalen‐1‐yl)(aryl)methyl)‐5‐methyl‐2‐phenyl‐1H‐pyrazol‐3(2H)‐ones by the multicomponent condensation reaction of various aromatic aldehydes, β‐naphthol, ethyl acetoacetate, and phenyl hydrazine at room temperature.     

One‐Pot Synthesis of 2‐Substituted 4‐Aryl‐4,5‐dihydro‐3,1‐benzoxazepines from 2‐(2‐Aminophenyl)‐1‐arylethanols via Dehydration of the Corresponding Amides

An efficient method for the preparation of 2‐substituted 4‐aryl‐4,5‐dihydro‐3,1‐benzoxazepine derivatives under mild conditions has been developed. The reaction of 2‐(2‐aminophenyl)ethanols 1 with acid chlorides in the presence of excess Et₃N in THF at room temperature gave the corresponding N‐acylated intermediates 2 , which were dehydrated by treatment with POCl₃ to give 2‐substituted 4‐aryl‐4,5‐dihydro‐3,1‐benzoxazepines 3 in a one‐pot reaction.     

Synthesis of 2‐Substituted 3‐Alkylidene‐2,3‐dihydro‐1H‐isoindol‐1‐imines through Cyclization of [1‐(2‐Cyanophenyl)alkylidene]aminide Intermediates Generated from the Reaction of 2‐(1‐Azidoalkyl)benzonitriles with NaH

A convenient sequence for the preparation of 3‐alkylidene‐2,3‐dihydro‐1H‐isoindol‐1‐imine derivatives 6 has been developed. Thus, 2‐(1‐azidoalkyl)benzonitriles 2 , readily accessible from 2‐alkylbenzonitriles, are allowed to react with NaH in DMF at 0° to room temperature to generate [1‐(2‐cyanophenyl)alkylidene]aminide intermediates 3 , of which cyclization and the subsequent rearrangement, followed by alkylation with alkyl halides, affords 2‐substituted 1‐alkylidene‐2,3‐dihydro‐1H‐isoindol‐2‐imines 6 in generally moderate yields.     

A Novel and Efficient Synthesis of 3‐[(4,5‐Dihydro‐1H‐pyrrol‐3‐yl)carbonyl]‐2H‐chromen‐2‐ones (=3‐[(4,5‐Dihydro‐1H‐pyrrol‐3‐yl)carbonyl]‐2H‐1‐benzopyran‐2‐ones)

An efficient one‐pot synthesis of 3‐[(4,5‐dihydro‐1H‐pyrrol‐3‐yl)carbonyl]‐2H‐chromen‐2‐one (=3‐[(4,5‐dihydro‐1H‐pyrrol‐3yl)carbonyl]‐2H‐1‐benzopyran‐2‐one) derivatives 4 by a four‐component reaction of a salicylaldehyde 1 , 4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one, a benzylamine 2 , and a diaroylacetylene (=1,4‐diarylbut‐2‐yne‐1,4‐dione) 3 in EtOH is reported. This new protocol has the advantages of high yields (Table), and convenient operation. The structures of these coumarin (=2H‐1‐benzopyran‐2‐one) derivatives, which are important compounds in organic chemistry, were confirmed spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS) and by elemental analyses. A plausible mechanism for this reaction is proposed (Scheme 2).     

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 .     

4‐(2‐Hydroxyphenyl)‐2‐phenyl‐2,3‐dihydro‐1H‐1,5‐benzodiazepine and the 2‐(2,3‐dimethoxyphenyl)‐, 2‐(3,4‐dimethoxyphenyl)‐ and 2‐(2,5‐dimethoxyphenyl)‐substituted derivatives

The 1,5‐benzodiazepine ring system exhibits a puckered boat‐like conformation for all four title compounds [4‐(2‐hydroxyphenyl)‐2‐phenyl‐2,3‐dihydro‐1H‐1,5‐benzodiazepine, C₂₁H₁₈N₂O, (I), 2‐(2,3‐dimethoxyphenyl)‐4‐(2‐hydroxyphenyl)‐2,3‐dihydro‐1H‐1,5‐benzodiazepine, C₂₃H₂₂N₂O₃, (II), 2‐(3,4‐dimethoxyphenyl)‐4‐(2‐hydroxyphenyl)‐2,3‐dihydro‐1H‐1,5‐benzodiazepine, C₂₃H₂₂N₂O₃, (III), and 2‐(2,5‐dimethoxyphenyl)‐4‐(2‐hydroxyphenyl)‐2,3‐dihydro‐1H‐1,5‐benzodiazepine, C₂₃H₂₂N₂O₃, (IV)]. The stereochemical correlation of the two C₆ aromatic groups with respect to the benzodiazepine ring system is pseudo‐equatorial–equatorial for compounds (I) (the phenyl group), (II) (the 2,3‐dimethoxyphenyl group) and (III) (the 3,4‐dimethoxyphenyl group), while for (IV) (the 2,5‐dimethoxyphenyl group) the system is pseudo‐axial–equatorial. An intramolecular hydrogen bond between the hydroxyl OH group and a benzodiazepine N atom is present for all four compounds and defines a six‐membered ring, whose geometry is constant across the series. Although the molecular structures are similar, the supramolecular packing is different; compounds (I) and (IV) form chains, while (II) forms dimeric units and (III) displays a layered structure. The packing seems to depend on at least two factors: (i) the nature of the atoms defining the hydrogen bond and (ii) the number of intermolecular interactions of the types O—H...O, N—H...O, N—H...π(arene) or C—H...π(arene).     

One‐Pot Diastereoselective Synthesis of Densely Functionalized 2H‐Indeno[2,1‐b]furans. Single‐Crystal X‐Ray Structure of Dimethyl 8,8a‐Dihydro‐8‐oxo‐8a‐(2,2,2‐trichloroethoxy)‐2H‐indeno[2,1‐b]furan‐2,3‐di­carboxylate

Highly reactive 1 : 1 intermediates were produced in the reaction of Ph₃P and dialkyl acetylenedicarboxylates (=dialkyl but‐2‐ynedioates). Protonation of these intermediates by alcohols (2,2,2‐trichloroethanol, propargyl alcohol (=prop‐2‐yn‐1‐ol), MeOH, benzyl alcohol, and allyl alcohol (=prop‐2‐en‐1‐ol) led to vinyltriphenylphosphonium salts 4 , which underwent a Michael addition reaction with the conjugate base to produce the corresponding stabilized phosphonium ylides 5 (Scheme). Wittig reaction of the stabilized phosphonium ylides with ninhydrin ( 6 ) led to the corresponding densely functionalized 2H‐indeno[2,1‐b]furans 10 in fairly good yields (Table 1). The structures of the final products were confirmed by IR, ¹H‐ and ¹³C‐NMR spectroscopy, and mass spectrometry. The configuration of dimethyl 8,8a‐dihydro‐8‐oxo‐8a‐(2,2,2‐trichloroethoxy)‐2H‐indeno[2,1‐b]furan‐2,3‐dicarboxylate ( 10a ) was established by a single‐crystal X‐ray structure determination, establishing that the one‐pot multicomponent condensation reaction was completely diastereoselective.     

Synthesis of 2,N,N‐Trisubstituted 1H‐Indole‐1‐carbothioamides from 2‐(Acylmethyl)phenyl Isocyanides

A convenient procedure for the synthesis of 2,N,N‐trisubstituted 1H‐indole‐1‐carbothioamides from 2‐(acylmethyl)phenyl isocyanides has been developed. Thus, these isocyanides are converted into (Z)‐ [1‐alkyl (or phenyl)‐2‐(2‐isothiocyanatophenyl)ethenyl] 1,1‐dimethylethyl carbonates via an easy two‐step sequence. Treatment with secondary amines gave thiourea intermediates which afforded with CF₃COOH (TFA) the desired products in fair‐to‐good yields.