Synthesis of dispiro[oxindole‐pyrrolidine]‐thiazolo[3,2‐a][1,3,5]triazines by 1,3‐dipolar cycloaddition

The 1,3‐dipolar cycloaddition of an azomethine ylide generated by a decarboxylative route from sarcosine and isatin to 7‐arylmethylidene‐3‐aryl‐3,4‐dihydro‐2H‐thiazolo[3,2‐a][1,3,5]triazin‐6(7H)‐ones afforded novel dispiro[oxindole‐pyrrolidine]‐thiazolo[3,2‐a][1,3,5]triazines in moderate yields. The structures of the products were determined and characterized thoroughly by NMR, MS, IR, and elemental analysis. The results of experiment indicated that this 1,3‐dipolar cycloaddition proceeded with high stereoselectivity and regioselectivity. J. Heterocyclic Chem., (2011).     

Synthesis of Dispiro[indole‐3,2′‐pyrrolidine‐3′,2″‐pyrrolizine]‐1″,2(1H)‐diones via Azomethine Ylide 1,3‐Dipolar Cycloaddition

The 1,3‐dipolar cycloaddition of azomethine ylide generated in situ from isatin and sarcosine to 2‐arylmethylidene‐2,3‐dihydro‐1H‐pyrrolizin‐1‐ones afforded novel 1′‐methyl‐4′‐(aryl)‐1″H‐dispiro[indole‐3,2′‐pyrrolidine‐3′,2″‐pyrrolizine]‐1″,2(1H)‐diones in good yields. The structures of all the products were characterized thoroughly by NMR, infrared spectroscopy, mass spectrum, and elemental analysis.     

One‐Pot Synthesis of Dispiro[oxindole‐3,3′‐pyrrolidines] by Three‐Component [3+2] Cycloadditions of in situ‐Generated Azomethine Ylides with 3‐Benzylidene‐2,3‐dihydro‐1H‐indol‐2‐ones

An efficient one‐pot, three‐component synthesis of novel dispiro[oxindole‐3,3′‐pyrrolidines] by 1,3‐dipolar cycloaddition of azomethine ylides, in situ generated by reaction of 1,2‐diones with sarcosine and subsequent decarboxylation, with a series of (E)‐3‐benzylidene‐2,3‐dihydro‐1H‐indol‐2‐ones is reported. Molecular complexity is generated in only one synthetic step. All reactions proceed with excellent regioselectivity and in good‐to‐excellent yields. The workup is easy, the reaction times are short, and no catalyst is required.     

Synthesis of Novel Spiro Thiazolo[3,2-a][1,3,5]triazines via 1,3-Dipolar Cycloaddition of Azomethine Ylide

The 1,3‐dipolar cycloaddition of an azomethine ylide generated by a decarboxylative route from sarcosine and acenaphthenequinone to 7‐arylmethylidene‐3‐aryl‐3,4‐dihydro‐2H‐thiazolo[3,2‐a][1,3,5]triazin‐6(7H)‐ones afforded novel dispiro[acenaphthylene‐1,2′‐pyrrolidine]‐3′,7′ ′‐[1,3]thiazolo[3,2‐a][1,3,5]triazines in moderate yields. The structures of the products were determined and characterized thoroughly by NMR, MS, IR, elemental analysis and X‐ray crystallographic analysis. The results of experiment indicated that this 1,3‐dipolar cycloaddition proceeded with high stereoselectivity and regioselectivity.     

A greener approach for the synthesis of 1-N-methyl-(spiro[2.3′]oxindolespiro[3.2″]/spiro[2.3′]indan-1,3-dionespiro[2.2″])cyclopentanone-4-aryl pyrrolidines

N,N-Dimethylammonium N′,N′-dimethyl carbamate (DIMCARB), a reusable reaction medium, has been used in the synthesis of a number of monoarylidene cyclopentanones. These compounds are used as dipolarophiles in the 1,3-dipolar cycloaddition reaction of an azomethine ylide, generated in situ by the decarboxylation method for the synthesis of spiropyrrolidines by the application of microwave methodology.     

Regioselective 1,3‐Dipolar Cycloadditions of (1Z)‐1‐(Arylmethylidene)‐5,5‐dimethyl‐3‐oxopyrazolidin‐1‐ium‐2‐ide Azomethine Imines to Acetylenic Dipolarophiles

The 5,5‐dimethylpyrazolidin‐3‐one ( 4 ), prepared from ethyl 3‐methylbut‐2‐enoate ( 3 ) and hydrazine hydrate, was treated with various substituted benzaldehydes 5a – i to give the corresponding (1Z)‐1‐(arylmethylidene)‐5,5‐dimethyl‐3‐oxopyrazolidin‐1‐ium‐2‐ide azomethine imines 6a – i . The 1,3‐dipolar cycloaddition reactions of azomethine imines 6a – h with dimethyl acetylenedicarboxylate (=dimethyl but‐2‐ynedioate; 7 ) afforded the corresponding dimethyl pyrazolo[1,2‐a]pyrazoledicarboxylates 8a – h , while by cycloaddition of 6 with methyl propiolate (=methyl prop‐2‐ynoate; 9 ), regioisomeric methyl pyrazolo[1,2‐a]pyrazolemonocarboxylates 10 and 11 were obtained. The regioselectivity of cycloadditions of azomethine imines 6a – i with methyl propiolate ( 9 ) was influenced by the substituents on the aryl residue. Thus, azomethine imines 6a – e derived from benzaldehydes 5a – e with a single substituent or without a substituent at the ortho‐positions in the aryl residue, led to mixtures of regioisomers 10a – e and 11a – e . Azomethine imines 6f – i derived from 2,6‐disubstituted benzaldehydes 5f – i gave single regioisomers 10f – i .     

Synthesis and Antibacterial Activity of New 2,5‐Diaryl‐3‐styryl‐4H,2,3,3a,5,6,6a‐hexahydropyrrolo[3,4‐d]isoxazole‐4,6‐diones

The synthesis of some biologically interesting pyrrolo‐isoxazolidine derivatives has been accomplished by the 1,3‐dipolar cycloaddition reaction of substituted open chain conjugated azomethine N‐oxides 1 with substituted N‐aryl maleimides 2 leading to the formation of new stereoisomeric 2,5‐diaryl‐3‐styryl‐4H,2,3,3a,5,6,6a‐hexahydropyrrolo[3,4‐d]isoxazole‐4,6‐dione derivatives 3 in excellent yields. These stereoisomers have been characterized as cis‐ 3A and trans‐ 3B on the basis of their ¹H‐NMR spectral measurements. The synthesized compounds have been screened for their antibacterial activities and have been found to be active against the bacteria Escherichia coli and Pseudomonas aeruginosa up to a significant extent.     

1,3‐Dipolar cycloaddition of unstabilized N‐methyl azomethine ylide to nitrobenzene annelated with azoles

The 1,3‐dipolar cycloaddition of unstabilized N‐methyl azomethine ylide to mononitro benzazoles was studied. Depending on the nature of substituents and annelated azoles, the reaction affords previously unknown isoindole fused heterocyclic systems. The reactivity of the cycloadducts was examined. J. Heterocyclic Chem., (2011).     

Synthesis of spiro thiazolo[3,2‐a]pyrimidine compounds by one‐pot sequential 1,3‐dipolar cycloadditions

A new class of spiro thiazolo[3,2‐a]pyrimidine compounds were synthesized by the one‐pot sequential 1,3‐dipolar cycloaddition of azomethine ylide (generated from isatin and sarcosine)–nitrile oxide to 2‐arylmethylidene‐6,7‐dihydro‐5H‐thiazolo[3,2‐a]pyrimidin‐3‐ones in moderate yields. The structures of all the products were characterized thoroughly by NMR, MS, IR, elemental analysis, and NMR together with X‐ray crystallographic analysis. J. Heterocyclic Chem., (2011).     

One‐pot four component condensation for the synthesis of novel dispirooxindole pyrrolidine linked 1,2,3‐triazoles via stereo‐ and regioselective [3 + 2] cycloaddition reaction in PEG‐400

A one‐pot four component condensation of isatin, sarcosine, 2‐[2‐oxo‐1‐(prop‐2‐ynyl)indolin‐3‐ylidene]malononitrile and aryl azides has been reported for the synthesis of novel dispirooxindole pyrrolidine linked 1,2,3‐triazole conjugates using Cu(I) as a catalyst in PEG‐400 by stereoselective [3 + 2] azide‐alkyne cycloaddition followed by [3 + 2] azomethine ylide and alkene cycloaddition. Structures have been confirmed by spectral and X‐ray studies. Crystal packing of 5a has also been reported. Rapid reaction, easy work‐up and high yields are the salient features of the present protocol.     

An Easy Access to the Synthesis of Sugar‐Based N‐Methyl‐Pyrrolidine via [3 + 2] Cycloaddition Methodology

Sugar‐based N‐methyl‐pyrrolidine derivatives have been synthesized by the cycloaddition reaction of the ylide generated from sarcosine and paraformaldehyde with the sugar‐derived dipolarophile. All the newly synthesized products were characterized by NMR (¹H, ¹³C), mass spectroscopy and elemental analysis.     

A highly regioselective synthesis of 1‐n‐methyl‐spiro‐[2,3′“]‐oxindole‐spiro‐[3,2”]indane‐1“, 3”‐dione‐4‐arylpyrrolidines through 1,3‐dipolar cycloaddition protocol

2‐Arylidene‐1,3‐indanediones undergo a regioselective 1,3‐dipolar cycloaddition reaction with the azomethine ylide derived from isatin and sarcosine by decarboxylative route affording a series of 1‐N‐methyl — spiro[2.3′“]oxindole‐spiro[3.2”]indane‐1“,3”‐diones‐4‐aryl pyrrolidines. The structures were established by spectroscopic techniques as well as single crystal X‐ray analysis. Density functional theory at B3L YP/6‐31G^* and the semi empirical AM₁ calculations were employed to rationalize the observed results. The experimental regioselectivity of 1,3‐dipolar cycloadditions could be corroborated nicely with the computed Fukui frontier orbital energies and reaction energies.     

Diastereoselective Synthesis of Novel Pyrrolidine or Pyrrolizine‐Fused Benzo‐δ‐sultams via 1,3‐Dipolar Cycloadditions

The synthesis of novel pyrrolidine or pyrrolizine‐fused benzosultams is described. A number of (E)‐N‐(2‐formylphenyl)‐N‐alkyl‐2‐phenylethenesulfonamides derivatives were synthesized and subjected to intramolecular [3 + 2] cycloaddition with azomethine ylides derived in situ from the reaction with sarcosine, phenylglycine, and L‐proline.     

Nickel‐Catalyzed Synthesis of N‐Aryl‐1,2‐dihydropyridines by [2+2+2] Cycloaddition of Imines with Alkynes through T‐Shaped 14‐Electron Aza‐Nickelacycle Key Intermediates

Despite there being a straightforward approach for the synthesis of 1,2‐dihydropyridines, the transition‐metal‐catalyzed [2+2+2] cycloaddition reaction of imines with alkynes has been achieved only with imines containing an N‐sulfonyl or ‐pyridyl group. Considering the importance of 1,2‐dihydropyridines as useful intermediates in the preparation of a wide range of valuable organic molecules, it would be very worthwhile to provide novel strategies to expand the scope of imines. Herein we report a successful expansion of the scope of imines in nickel‐catalyzed [2+2+2] cycloaddition reactions with alkynes. In the presence of a nickel(0)/PCy₃ catalyst, a reaction with N‐benzylidene‐P,P‐diphenylphosphinic amide was developed. Moreover, an application of N‐aryl imines to the reaction was also achieved by adopting N‐heterocyclic carbene ligands. The isolation of an (η²‐N‐aryl imine)nickel(0) complex containing a 14‐electron nickel(0) center and a T‐shaped 14‐electron five‐membered aza‐nickelacycle is shown. These would be considered as key intermediates of the reaction. The structure of these complexes was unambiguously determined by NMR spectroscopy and X‐ray analyses.     

One‐Pot Stereoselective Synthesis of 2‐Acylaziridines and 2‐Acylpyrrolidines from N‐(Propargylic)hydroxylamines

The stereoselective direct transformation of N‐(propargylic)hydroxylamines into cis‐2‐acylaziridines was achieved by the combined use of AgBF₄ and CuCl. Copper salts were found to promote the transformation of the intermediary 4‐isoxazolines into 2‐acylaziridines and both 3‐aryl‐ and 3‐alkyl‐substituted 2‐acylaziridines could be prepared by using this method. Furthermore, subsequent 1,3‐dipolar cycloaddition of azomethine ylides that were generated in situ from the intermediary 2‐acylaziridines with maleimides was achieved in a stereoselective one‐pot procedure to afford the corresponding 2‐acylpyrrolidines, which consisted of an octahydropyrrolo[3,4‐c]pyrrole skeleton.     

Thermal [2+3]‐Cycloadditions of trans‐1‐Methyl‐2,3‐diphenylaziridine with CS and CC Dipolarophiles: An Unexpected Course with Dimethyl Dicyanofumarate

The thermal reaction of trans‐1‐methyl‐2,3‐diphenylaziridine (trans‐ 1a ) with aromatic and cycloaliphatic thioketones 2 in boiling toluene yielded the corresponding cis‐2,4‐diphenyl‐1,3‐thiazolidines cis‐ 4 via conrotatory ring opening of trans‐ 1a and a concerted [2+3]‐cycloaddition of the intermediate (E,E)‐configured azomethine ylide 3a (Scheme 1). The analogous reaction of cis‐ 1a with dimethyl acetylenedicarboxylate ( 5 ) gave dimethyl trans‐2,5‐dihydro‐1‐methyl‐2,5‐diphenylpyrrole‐3,4‐dicarboxylate (trans‐ 6 ) in accord with orbital‐symmetry‐controlled reactions (Scheme 2). On the other hand, the reactions of cis‐ 1a and trans‐ 1a with dimethyl dicyanofumarate ( 7a ), as well as that of cis‐ 1a and dimethyl dicyanomaleate ( 7b ), led to mixtures of the same two stereoisomeric dimethyl 3,4‐dicyano‐1‐methyl‐2,5‐diphenylpyrrolidine‐3,4‐dicarboxylates 8a and 8b (Scheme 3). This result has to be explained via a stepwise reaction mechanism, in which the intermediate zwitterions 11a and 11b equilibrate (Scheme 6). In contrast, cis‐1,2,3‐triphenylaziridine (cis‐ 1b ) and 7a gave only one stereoisomeric pyrrolidine‐3,4‐dicarboxylate 10 , with the configuration expected on the basis of orbital‐symmetry control, i.e., via concerted reaction steps (Scheme 10). The configuration of 8a and 10 , as well as that of a derivative of 8b , were established by X‐ray crystallography.     

Catalytic Asymmetric Formal [3+3] Cycloaddition of an Azomethine Ylide with 3‐Indolylmethanol: Enantioselective Construction of a Six‐Membered Piperidine Framework

A catalytic asymmetric formal [3+3] cycloaddition of 3‐indolylmethanol and an in situ‐generated azomethine ylide has been established to construct a chiral six‐membered piperidine framework with two stereogenic centers. This approach not only represents the first enantioselective cycloaddition of isatin‐derived 3‐indolylmethanol, but also has realized an unusual enantioselective formal [3+3] cycloaddition of azomethine ylide rather than its common [3+2] cycloadditions. Besides, this protocol combines the merits of a multicomponent reaction and organocatalysis, which efficiently assembles a variety of isatin‐derived 3‐indolylmethanols, aldehydes, and amino esters into structurally diverse spiro[indoline‐3,4′‐pyridoindoles] with one all‐carbon quaternary stereogenic center in high yields and excellent enantioselectivities (up to 93 % yield, >99 % enantiomeric excess (ee)). Although the diastereoselectivity of the reaction is generally moderate, most of the diastereomers can be separated by using column chromatography followed by preparative TLC.     

Regio‐ and stereoselective synthesis of 1‐benzopyrano[2,3‐b]pyrrolo[2,3‐d]pyridines: A microwave‐accelerated intramolecular [3+2] cycloaddition reaction of azomethine ylide

Regio‐ and stereoselective syntheses of tetracyclic compounds having chromone, pyrrolidine, and piperidine rings have been accomplished by an intramolecular [3+2] cycloaddition reaction involving azomethine ylide. The reactions were carried out thermally as well as by irradiation with microwave. The latter process accelerates the reaction. The selectivities were investigated by density functional theory computation. J. Heterocyclic Chem., (2011).     

Synthesis of Novel Spiro Pyrano[2,3‐d]thiazolo[3,2‐a]pyrimidine via 1,3‐Dipolar Cycloaddition of Azomethine Ylide

The reaction involving 4‐phenyl‐octahydro‐pyrano[2,3‐d]pyrimidine‐2‐thione, ethyl chloroacetate and the appropriate aromatic aldehyde yielded 2‐arylmethylidene‐5‐phenyl‐5a,7,8,9a‐tetrahydro‐5H,6H‐pyrano[2,3‐d][1,3]thiazolo[3,2‐a]pyrimidin‐3(2H)‐ones. The 1,3‐dipolar cycloaddition of 2‐arylmethylidene‐5‐phenyl‐5a,7,8,9a‐tetrahydro‐5H,6H‐pyrano[2,3‐d][1,3]thiazolo[3,2‐a]pyrimidin‐3(2H)‐ones with azomethine ylide generated by a decarboxylative route from sarcosine and acenaphthenequinone afforded 4′‐aryl‐1′‐methyl‐5″‐phenyl‐5a″,7″,8″,9a″‐tetrahydro‐2H,5″H,6″H‐dispiro[acenaphthylene‐1,2′‐pyrrolidine‐3′,2″‐pyrano[2,3‐d][1,3]thiazolo[3,2‐a]pyrimidine]‐2,3″‐diones in moderate yields. The structures of the products were determined and characterized thoroughly by NMR, MS, IR, elemental analysis, and X‐ray crystallographic analysis.     

Reactions of Diazomethanes with 5‐Benzylidene‐3‐phenylrhodanine – A Computational Study

It has been shown previously that the reaction of diazomethane with 5‐benzylidene‐3‐phenylrhodanine ( 1 ) in THF at ?20° occurs at the exocyclic C?C bond via cyclopropanation to give 3a and methylation to yield 4 , respectively, whereas the corresponding reaction with phenyldiazomethane in toluene at 0° leads to the cyclopropane derivative 3b exclusively. Surprisingly, under similar conditions, no reaction was observed between 1 and diphenyldiazomethane, but the 2‐diphenylmethylidene derivative 5 was formed in boiling toluene. In the present study, these results have been rationalized by calculations at the DFT B3LYP/6‐31G(d) level using PCM solvent model. In the case of diazomethane, the formation of 3a occurs via initial Michael addition, whereas 4 is formed via [3+2] cycloaddition followed by N₂ elimination and H‐migration. The preferred pathway of the reaction of 1 with phenyldiazomethane is a [3+2] cycloaddition, subsequent N₂ elimination and ring closure of an intermediate zwitterion to give 3b . Finally, the calculations show that the energetically most favorable reaction of 1 with diphenyldiazomethane is the initial formation of diphenylcarbene, which adds to the S‐atom to give a thiocarbonyl ylide, followed by 1,3‐dipolar electrocyclization and S‐elimination.