Rapid Access for the Synthesis of 1‐N‐Methyl‐spiro[2.3′]oxindole‐spiro[3.7″] (3″‐Aryl)‐5″‐methyl‐3″,3a″,4″,5″,6″,7″‐hexahydro‐2H‐pyrazolo[4,3‐c]pyridine‐4‐aryl‐pyrrolidines Through Sequential 1,3‐Dipolar Cycloaddition and Annulation

The 1,3‐dipolar cycloaddition of an azomethine ylide, generated from isatin and sarcosine by a decarboxylative route with various p‐substituted 3,5 bis(aryl methylidene)N‐methyl‐4‐piperidinones in refluxing methanol, proceeded regioselectively to give novel dispiroheterocycles. The product on subsequent annulation with hydrazine hydrate afforded 1‐N‐methyl‐spiro[2.3′]oxindole‐spiro[3.7″](3″‐aryl)‐5″‐methyl‐3″,3a″,4″,5″,6″,7″‐hexahydro‐2H‐pyrazolo[4,3‐c]pyridine‐4‐aryl‐pyrrolidines in good yield.     

An Efficient Four‐component Reaction for the Synthesis of Spiroheterocyclic Compounds

A series of 6‐amino‐8‐aryl‐3,4‐dihydro‐1H‐spiro[naphthalene‐2,2'‐[1,3] dioxolane]‐5,7‐dicarbonitrile and 8‐arylidene‐4‐aryl‐7,8‐dihydro‐5H‐spiro[quinazoline‐6,2'‐[1,3] dioxolan]‐2‐amine derivatives have been synthesized from the reactions of 1,4‐dioxaspiro[4.5] decan‐8‐one, aromatic aldehydes, and malononitrile (or guanidine carbonate) under different conditions with high yields. In this research, it was found the DBU–THF was efficient reaction condition for obtaining 6‐amino‐8‐aryl‐3,4‐dihydro‐1H‐spiro[naphthalene‐2,2'‐[1,3]dioxolane]‐5,7‐dicarbonitrile derivatives, while 95% EtOH and NaOH was the preferred condition for the synthesis of 8‐rylidene‐4‐aryl‐7,8‐dihydro‐5H‐spiro[quinazoline‐6,2'‐[1,3]dioxolan]‐2‐amine derivatives. To the best of our knowledge, these Spiroheterocycles were first reported in our research. The other advantages of this process were short‐reaction time, wide scope substrates, and simple set‐up.     

Synthesis of spiro[benzopyrazolonaphthyridine-indoline]-diones and spiro[chromenopyrazolopyridine-indoline]-diones by one-pot, three-component methods in water

The synthesis of spiro[benzo[h]pyrazolo[3,4-b][1,6]naphthyridine-7,3′-indoline]-2′,6(5H)-diones and spiro[chromeno[4,3-b]pyrazolo[4,3-e]pyridine-7,3′-indoline]-2′,6(6aH,10H)-diones via a one-pot, three-component reaction of 4-hydroxycoumarin or 4-hydroxy-1-methylquinolin-2(1H)-one, isatins and 1H-pyrazol-5-amines in water is reported.     

Reaction of thioketones with propiolic acids

The reaction of adamantane-2-thione with propiolic acid afforded a novel type of cycloadduct, spiro[adamantane-2,2'-6'H-[1,3]-oxathiin]-6'-one (3a), in quantitative yield. The reaction of thiobenzophenone with propiolic acid gave 2,2-diphenyl-6'H-[1,3]-oxathiin]-6'-one and 4-phenyl-3-thia-3,4-dihydronaphthoic acid in 34% and 35% yields, respectively. The reaction might proceed through a concerted process, as confirmed by kinetics. The reaction of adamantane-2-thione with 2-butynoic acid or phenylpropiolic acid gave the corresponding adducts regioselectively. Interestingly, only one isomer was obtained by the reaction of thiofenchone with propiolic acid, suggesting that the reaction proceeded diastereospecifically. Oxidation of adducts by dimethyldioxirane or m-chloroperoxybenzoic acid gave the corresponding sulfoxides and sulfones. The sulfoxides were thermally decomposed to give disulfide or another type of 1,3-oxathiin-6-one.     

Synthesis of 2-Aryl and 2-Hetaryl Derivatives of 2'-Aminospiro[(1,3-dioxane)-5,5'-thiazolin]-4'-one and Spiro[(1,3-dioxane)-5,5'-thiazolidine]2',4'-dione

2-(Het)aryl derivatives of 2'-aminospiro[(1,3-dioxane)-5,5'-thiazolin]-4'-one or spiro[(1,3-dioxane)-5,5'-thiazolidine]-2',4'-dione are formed by the acid catalyzed interaction of 2-amino-5,5-bis(hydroxymethyl)-4-thiazolinone or its oxo analog 5,5-bis(hydroxymethyl)thiazolidine-2,4-dione with (hetero)aromatic aldehydes.     

DOTTADs--readily made novel metal ligands with multivariant functionality--trans-DOTTADs and semi-DOTTADs

Two new ligand systems related to the previously described DOTTADs have been generated in a simple one step reaction. The first, trans-DOTTADs, were formed by Vilsmeier formylation (followed by cyclisation and N-demethylation) of 2,6-dimethyl-3,5-pyrazine-dicarboxylic acid, to give the novel bis-pyridinopyrazine dialdehyde ligands. The corresponding pyrazine diester, reacted similarly to an intermediate iminium ion stage, which gave trans-DOTTAD imines on work-up with amines. The treatment of Hantzsch ester with two equivalents of benzaldehyde gave 7-phenyl-2-(2-phenylethenyl)-7,8-dihydropyrano[4,3-b]pyridin-5-one-3-carboxylic acid. This product underwent similar cyclisation with Vilsmeier reagents to give, for example, 6-methyl-2-(2-phenylethenyl)-8-(phenylhydroxymethyl)-6H-[1,6]naphthyridin-5-one-3-carboxylic acid, an example of a semi-DOTTAD.     

Synthesis of derivatives of 4-alkylthiouracil,cytosine, pyrido[2,3-d]pyrimidine,and pyrimido[4,5-d]pyrimidine from the N,S- and N,N-acetals of diacetylketene and isocyanates

The action of alkyl and aryl isocyanates on the N,S-acetals of diacetylketene leads to the formation of 4-alkylthio-5-acetyl-1-alkyl(aryl)-6-methyl-1H-pyrimidin-2-ones (derivatives of 4-alkylthiouracils). The reaction of the synthesized thiouracils with amines or the reaction of the N,N-acetals of diacetylketene (N,N-ADK) with an equi-molar amount of aryl isocyanates leads to the formation of substituted 4-amino-5-acetyl-1H-pyrimidin-2-ones (derivatives of cytosine). From the latter and isocyanates or directly from N,N-ADK and an excess of the isocyanate, derivatives of 4-methylene-1H,3H, 4H-pyrimido[4,5-d]pyrimidine-2,7-dione were obtained. The exception was the condensation of 3-[N-(4,6-dimethyl-2-pyrimidinyl)diaminomethylene]pentane-2,4-dione with aryl isocyanates, which led to 3H,8H-pyrido[2,3-d]pyrimidine-2,5-diones.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 11, pp. 2593–2599, November, 1991.     

Synthesis of Spiro[benzo[h]chromene-4,3′-indoles] and Spiro[benzo[f]chromene-1,3′-indoles]

Russian Journal of Organic Chemistry - New spiro heterocycles, spiro[benzo[h]chromene-4,3′-indoles] and spiro[benzo[f]chromene-1,3′-indoles], have been synthesized in 50–60% yield...     

Thiazolo[4,3-c][1,4]benzodiazepines. I. Synthesis of amidine derivatives

Reactivity of 1,2,3,10,11,11a-hexahydro-5H-thiazolo[4,3-c][1,4]benzodiazepin-5-one-11-thione and 1,2,3,10,11,11a-hexahydro-5H-thiazolo[4,3-c][1,4]benzodiazepine-5,11-dithione was evaluated against various amines. The synthetic pathways involved in these reactions which led to new thiazolo[4,3-c]-[1,4]benzodiazepine amidines are described.     

Isatins 3-C annulation vs ring-opening: Two different pathways for synthesis of spiro compounds via multicomponent reactions

An efficient synthesis of spiro compounds via two different pathways from the reactions of isatins, 3-phenylisoxazol-5(4H)-one (3-ethylisoxazol-5(4H)-one), and pyrazol-5-amine (6-aminopyrimidine-2,4(1H,3H)-dione) were reported. The catalyst Amberlyst-15 could be easy recycled and reused for many time without any appreciable loss in catalytic activity. The new type spiro compounds were gained through the ring-opening of isatins process. The structures of spiro[indoline-3,4′-isoxazolo[5,4-b]pyrazolo[4,3-e]pyridin]-2-one, spiro[isoxazolo[5,4-b]quino line-4,5′-pyrrolo[2,3-d]pyrimidine]-2′,4′,6′(1′H,3′H,7′H)-trione, and spiro[indoline-3,4′-pyrazolo[3,4-b]pyridine]-2,6′(5′H)-dione were successfully confirmed by ¹H NMR, ¹³C NMR, HRMS, and X-ray crystal diffraction analysis.     

Synthesis of new heterocyclic systems—substituted spiro[chromene-4,3′-indoles] and spiro[indole-3,4′-quinolines]

Methods have been developed for the synthesis of new heterocyclic systems, spiro[chromene-4,3′- indoles] and spiro[indole-3,4′-quinolines] by the base-catalyzed domino reaction of isatins with 5,5-dimethylcyclohexane- 1,3-dione (or 5,5-dimethyl-3-anilinocyclohex-2-en-1-one) and ethyl cyanoacetate.     

Synthesis and Antimalarial‐Activity Evaluation of Tetraoxane?Triazine Hybrids and Spiro[piperidine‐4,3′‐tetraoxanes]

A series of tetraoxane? triazine hybrids and spiro[piperidine‐4,3′‐tetraoxanes] have been synthesized, and all the compounds were screened for in vitro antimalarial activity against chloroquine‐sensitive (D6) and chloroquine‐resistant (W2) strains of Plasmodium falciparum. Most of the spiro[piperidine‐4,3′‐tetraoxanes] exhibited moderate to good antimalarial activities, and two compounds have shown good antimalarial activity with IC₅₀ values in the range of 0.30 to 0.70 μM against both the strains with high selectivity index and no cytotoxicity towards mammalian kidney cell line.     

A spirocyclic oxindole analogue:Synthesis and antitumor activities

A new synthesis of spirocyclic oxindole analogue spiro[piperidine-4,3’-pyrrolo[2,3-b]pyridin]-2’（1’H）-one 1 is described.The key steps involve dialkylation of arylacetonitrile and cyclization of the azaoxindole ring by an intramolecular Buchwald-Hartwig amidation of carboxylic ami Je and aryl chloride.A small library was obtained by reductive amination of 1 with various aldehydes and was screened against human lung cancer cell A549,human liver cancer cell BEL7402,and human colon cancer cell HCT-8.The results show that most of the 1（?）rary compounds 2 have some inhibitory activities.2-（Trifluoromethoxy） benzylic substituted spirocyclic azaoxindole 2e was identified as a nanomolar inhibitor against human lung cancer cell A-549(IC₅₀=50 nmol/L).     

Reaction of 2-Oxoindolin-3-Ylidene Derivatives with Heterocyclic Enamines. A Convenient One-Pot Synthesis of Pyrimido [5,4:5',6']Pyrido[2,3-b]-Indole-2,4-Dione and Spiro Indolin-2-One-3,5'-Pyrido [2,3-d] Pyrimidines

The reaction of 6-aminouracils 2a, b with 2-oxoindolin-3-ylideneacetophenones 1a-h afforded Pyrimido[5,4:5', 6'] pyrido-[2, 3-b] indole- 2,4-diones 3 a-k via a regiospecific Michael addition, followed by cyclization. Alternatively, the reaction of 2a with 2-oxoindolin-3-ylidenemalononitriles 6a, b gave rise to regiospecific formation of spiro indolin-2-one-3, 5'-pyrido[2,3-d]pyrimidines 7a,b.     

TiO2 Nanoparticles Immobilized on Carbon Nanotubes: An Efficient Heterogeneous Catalyst in Cyclocondensation Reaction of Isatins with Malononitrile and 4-Hydroxycoumarin or 3,4-Methylenedioxyphenol under Mild Reaction Conditions

TiO₂ nanoparticles supported on carbon nanotubes (TiO₂-CNTs) as an efficient heterogeneous catalyst was used for the synthesis of spiro[3,4′]1,3-dihydro-2H-indol-2-one-2′-amino-5′-oxo-4'H,5'H-pyrano[3′,2′-c]chromen-3′-yl cyanides and spiro[3,8′]1,3-dihydro-2H-indol-2-one-6′-amino-8'H-[1′,3′]dioxolo[4′,5′-g]chromen-7′-yl cyanides via the cyclocondensation reaction of isatins with malononitrile and 4-hydroxycoumarin or 3,4-methylenedioxyphenol in aqueous media at room temperature. This reaction offers several sustainable and economic benefits such as high yields of products, convenient operation, and use of non-toxic catalyst in water media.     

Selective Synthesis Dispiro[indoline‐3,2′‐pyrrolidine‐3′,3″‐quinoline] Derivatives and Spiro[imidazole‐4,3′‐quinoline] Derivatives via 1,3‐Dipolar Cycloaddition Reaction

A new class of spiro compounds as dispiro[indoline‐3,2′‐pyrrolidine‐3′,3″‐quinoline] and spiro[imidazole‐4,3′‐quinoline] have been developed from quinolone derivative adopting modern synthetic methodologies.     

Catalytic asymmetric synthesis of spirooxindoles by a mannich-type reaction of isothiocyanato oxindoles

Easy access: a strontium/Schiff base complex as catalyst for the title reaction provided straightforward access to enantiomerically enriched spiro[imidazolidine-4,3'-oxindole] compounds, as well as a spiro[imidazoline-4,3'-oxindole] through a two-step conversion from the Mannich adduct.     

Heterocyclizations via POCl3-Based Multicomponent Reactions: A New Approach to One-Pot Synthesis of a New Spirosystem, 7-Methyl-5-[4-(aryl/heteryl)thiazol-2-yl]-5,6-diazaspiro[2,4]hept-6-en-4-ones

A novel multicomponent reaction involving phenacylbromide, thiosemicarbazide, and α-acetyl-γ-butyrolactone in the presence of POCl₃, forming 7-methyl-5-[4-(aryl/heteryl)thiazole-2-yl]-5,8-diaza spiro[2,4]hept-6-en-4-ones in good yields, is described.     

Syntheses of spiro[indazole-3,3′-indolin]-2′-ones and spiro[indazole-3,3′-indolin]-2′-imines via 1,3-dipolar cycloadditions of arynes and studies on their isomerization reactions

A 1,3-dipolar cycloaddition reaction of arynes with 3-diazoindolin-2-ones under mild conditions in excellent yields has been developed, which allows facile access to a library of labile spiro[indazole-3,3′-indolin]-2′-ones. Spiro[indazole-3,3′-indolin]-2′-imines could be obtained as well following the same protocol. The isomerization reaction of spiro[indazole-3,3′-indolin]-2′-ones under thermal or acidic conditions has been efficiently achieved to afford a wide range of indazolo-[2,3-c]quinazolin-6(5H)-ones and the one-pot synthesis of indazolo-[2,3-c]quinazolin-6(5H)-ones from arynes and 3-diazoindolin-2-ones is also described. Whereas, spiro[indazole-3,3′-indolin]-2′-imines could not undergo the same rearrangement.     

Regioselective Addition of 5-Amino-l,2,4-Triazoles and Its Analogues with Arylsulfonyl Isocyanates

5-Amino-3-benzyl (aryl)thio-1,2,4-triazoles and its analogues (pyrazole) 1 are important intermediates for the syntheses of a lot of biological active compounds^[1,2]. In our previous paper^[3], we reported the regioselective addition of 1 with aryl isocyanates and the experimental results showed that the orientation of the addition of 5-amino-3-benzyl (aryl)thio-1,2,4-triazoles and its analogues with the aryl isocyanates can be directed by controlling the reaction temperature.The 1-position adduct 2 was obtained regiospecifically below 120℃, whereas the 5-position adduct 3 was obtained selectively when the reaction temperature was raised to 170℃ (Scheme 1).