Reactivity of allenoates toward aziridines: [3+2] and formal [3+2] cycloadditions

The reactivity of buta-2,3-dienoates toward aziridines is reported. Allenoates react as 2π-component in the [3+2] cycloaddition with the azomethine ylide generated from cis-1-benzyl-2-benzoyl-3-phenylaziridine affording 4-methylenepyrrolidines in a site-, regio-, and stereoselective fashion. Under conventional thermolysis, cis- and trans-2-benzoyl-1-cyclohexyl-3-phenylaziridines showed a different reactivity. These aziridines participate in formal [3+2] cycloadditions with allenes via C-N bond cleavage of the three-membered ring leading to functionalized pyrroles.     

A highly diastereoselective synthesis of 3-carbethoxy-2,5-disubstituted-3-pyrrolines by phosphine catalysis

Tributylphosphine was used as catalyst to facilitate a [3+2] cycloaddition between γ-substituted allenoates and N-sulfonylimines. The resulting adducts, 3-carbethoxy-2,5-disubstituted-3-pyrrolines, were formed in excellent yields with high diastereoselectivity. The reaction went to completion in several hours at room temperature, and the starting materials were easily prepared with one step from commercially available compounds via known procedures.     

Phosphine‐mediated Highly Enantioselective Spirocyclization with Ketimines as Substrates

Phosphine‐catalyzed enantioselective annulation reactions involving ketimines are a daunting synthetic challenge owing to the intrinsic low reactivity of ketimine substrates. A highly enantioselective [3+2] cycloaddition reaction that makes use of isatin‐derived ketimines as reaction partners was developed. Notably, both simple and γ‐substituted allenoates could be utilized, and various 3,2′‐pyrrolidinyl spirooxindoles with a tetrasubstituted stereocenter were obtained in excellent yields and with nearly perfect enantioselectivity (>98 % ee in all cases).     

Rhodium(I)‐Catalyzed Intermolecular Aza‐[4+3] Cycloaddition of Vinyl Aziridines and Dienes: Atom‐Economical Synthesis of Enantiomerically Enriched Functionalized Azepines

A new synthetic application of vinyl aziridines as N‐containing three‐atom components in a rhodium‐catalyzed [4+3] cycloaddition reaction is described. The reaction proceeds well with various silyl dienol ethers and vinyl aziridines, and enables the efficient synthesis of highly functionalized azepines in an enantioselective manner with net inversion of absolute configuration. The salient features of the transformation include the use of readily available substrates, high selectivity, and mild reaction conditions, as well as the versatile functionalization of the products.     

Phosphine-mediated diverse reactivity of γ-substituted allenoates with aldehydes: syntheses of highly functionalized chromans and (E,E)-1,3-dienes

As an extension of our previous studies, the phosphine-mediated diverse reactivity of γ-substituted allenoates with aldehydes has been further investigated. Under the catalysis of tris(p-chlorophenyl)phosphine (20 mol %), ethyl 2,3-pentadienoate, namely ethyl γ-methyl allenoate, readily undergoes a formal [4+2] annulation with dual-functional salicylaldehydes, giving highly functionalized chromans in 47-97% yields. This transformation represents a novel reactivity pattern of electron-deficient allenes with aldehydes. Conversely, when the γ substituent in the allenoate changes from methyl to benzyl or the employed phosphine from weakly nucleophilic triarylphosphine to strongly trialkylphosphine, the phosphine-mediated reactivity of γ-substituted allenoates with aldehydes will be steered to a stoichiometric olefination reaction, leading to the highly stereoselective formation of (E,E)-1,3-dienes. Thus, under the mediation of equivalent PPh₃, ethyl γ-benzyl allenoate readily condenses with salicylaldehydes, affording (E,E)-1,3-dienes in 34-84% yields; with strongly nucleophilic 1,3,5-triaza-7-phosphaadamantane (PTA) used instead of PPh₃, ethyl γ-methyl allenoate also gives the corresponding olefination products in 32-73% yields with reactive aromatic aldehydes. On the basis of our previous studies and current work, these chemical transformations of γ-substituted allenoates with aldehydes, as well as their diverse reactivity, have been mechanistically rationalized.     

Phosphine-catalyzed [4+2] Annulations of α-Aminonitriles with Allenoates: Synthesis of Functionalized Tetrahydropyridines

Phosphine-catalyzed [4+2] annulations of 2-(acetoxymethyl)buta-2,3-dienoates with α-aminonitriles have been developed, in which α-aminonitriles serve as C, N-bisnucleophilic reaction partners and 2-(acetoxymethyl)buta- 2,3-dienoates as "C4 synthons" respectively. A number of α-aminonitriles could be successfully applied to giving multifunctional desired products using PPh₃ as catalyst. This method provides a facile entry to access polysubstituted tetrahydropyridines bearing quaternary carbon centers. The possible reaction mechanism was also proposed.     

Diastereoselective synthesis of functionalized tetrahydro-γ-carbolines via a [3 + 3] cycloaddition of 2,2′-diester aziridines with β-(indol-2-yl)-α,β-unsaturated ketones

A Sc(OTf)₃-catalyzed [3 + 3] cycloaddition of 2,2′-diester aziridines with β-(indol-2-yl)-α,β-unsaturated ketones was developed, affording polysubstituted tetrahydro-γ-carbolines in single diastereoisomers in good to excellent yields.     

Silver Catalyzed Decarbonylative [3 + 2] Cycloaddition of Cyclobutenediones and Formamides

As an important moiety in natural products, N,O-acetal has attracted wide attention in the past few years. An efficient method to construct N,O-acetal has been developed. Using silver catalyst, cyclobutenediones were smoothly converted to the corresponding γ-aminobutenolides in the presence of formamides, in which cyclobutenediones likely proceed with a key decarbonylative [3 + 2] cycloaddition process. In this way, a series of products with varied substituents were isolated in moderate yield and fully characterized.     

Oxidation of Enones for Regioselective [3+2] Cycloaddition through γ-Enone Radical Intermediates

Herein, an oxidization reaction of enones with a Cu^II complex that leads to a new type of regioselective [3+2] cycloaddition is reported. Highly functionalized cyclopentenes and spirocyclic compounds are obtained in moderate-to-good yields. This cycloaddition reaction occurred through the formation of γ-enone radicals, providing a rarely explored reactivity pattern for enones.     

Synthesis of novel N-aryl-N-(1H-tetrazol-5-yl)benzenesulfonamides in water

N-Aryl-N-(1H-tetrazol-5-yl)benzenesulfonamides were synthesized via an eco-friendly protocol using ZnBr₂-catalyzed [2 + 3] cycloaddition reaction of N-cyano-N-arylbenzenesulfonamides and sodium azide under reflux conditions in water. The products were obtained in excellent yields via an easy work-up procedure.     

Rhodium-catalyzed synthesis of 2,3 – Disubstituted N-methoxy pyrroles and furans via [3+2] cycloaddition between metal carbenoids and activated olefins

For the first time, we report the synthesis of 2-substituted N-alkoxy pyrrole 3-carboxylate and furan 3-carboxylate via Rh-catalyzed [3+2] cycloaddition between α-diazo oxime ether or α-diazo carbonyl compounds with vinyl equivalents in a one-pot process. We have demonstrated ethyl vinyl ether as well as vinyl acetate as vinyl equivalents and both were found to give excellent yields. We have also demonstrated the synthesis of N-alkoxy dihydropyrrole derivatives by carrying out the reaction at low temperature.     

Synthesis of substituted imidazolines via [3+2]-cycloaddition of aziridines with nitriles

An efficient synthesis of 2,4-disubstituted 1H-imidazolines from aziridines and nitriles in the presence of BF₃-Et₂O or triethyloxonium tetrafluoroborate has been described. The reaction proceeds via a [3+2]-cycloaddition reaction. Most of the nitriles successfully underwent cycloaddition reactions with aziridines even at room temperature in a very short time.     

A density functional theory study of the stereoselectivity of Cu(OTf)2-catalyzed [3+2] cycloaddition of trifluoromethylated N-acylhydrazones and isoprene: A concerted asynchronous mechanism

Here we employ density functional theory calculations to systematically investigate the underlying mechanism of Cu(OTf)₂-catalyzed [3+2] cycloaddition reactions in the synthesis of CF₃-substituted pyrazolidines. About eight possible initial configurations of the [3+2] reaction is considered, and all relevant reactants, transition states, and products are optimized. Based on these structures, internal reaction coordinate paths, and wavefunction analysis results, we conclude that the Cu(OTf)₂-catalyzed [3+2] cycloaddition follows a concerted asynchronous mechanism. The C N bond forms immediately after the formation of the C C bond. Among the eight reaction paths, the energy barrier for the [3+2] reaction that leads to the CF₃-substituted syn-pyrazolidine is the lowest, ∼5.4 kcal/mol, which might result in the diastereoselectivity that is observed in the experiment. This work not only gives the detailed mechanism of the Cu(OTf)₂-catalyzed [3+2] cycloaddition but can also be helpful for the future designation of Cu(OTf)₂-based cycloaddition processes.     

Welwitindolinone C synthetic studies. Construction of the welwitindolinone carbon skeleton via a transannular nitrone cycloaddition

Described is the construction of the N-methylwelwitindolinone C core via an efficient strategy that employs a sequential rhodium carbenoid-mediated O-H insertion, Claisen rearrangement and transannular [3+2] nitrone cycloaddition.     

The intramolecular Diels-Alder vinylthiophen (IMDAV) reaction: An easy approach to thieno[2,3-f]isoindole-4-carboxylic acids

The reaction of readily accessible 3-(thien-2-yl)allylamines with maleic anhydride, followed by a domino sequence involving successive acylation/[4+2] cycloaddition steps, leads to the formation of the thieno[2,3-f]isoindole core. The key step, the intramolecular Diels-Alder vinylaren (IMDAV) reaction, proceeds with high level of diastereoselectivity and with formation of a single diastereoisomer of the target product 4,4a,5,6,7,7a-hexahydro-3aH-thieno[2,3-f]isoindole-4-carboxylic acids in excellent yields. If the reaction is carried out at room temperature, it occurs in 2–3 days and the proton migration (H-shift) does not take place at the last stage. In boiling benzene, the reaction is complete after three hours, but in this case a slight impurity of byproducts bearing aromatic thiophene ring – 4a,5,6,7,7a,8-hexahydro-4H-thieno[2,3-f]isoindole-4-carboxylic acids is formed.     

Photoreactions of β-aziridinylacrylonitriles and acrylates with alkenes: the substituent effects on the formation of [3+2] cycloadducts

The photochemical C,C-bond cleavage of trisubstituted aziridines 3-6 and consequent [3+2] cycloaddition with electron-deficient alkenes afforded the novel head-to-head adducts (1,2,3,5-tetrasubstituted pyrrolidines) selectively and efficiently. The aziridines 3 and 5 reacted with molecular oxygen, affording dioxazolidine 26 and cleaved products, respectively. The results may suggest that the C,C-bond of aziridine cleaves biradically. The photoreactions of N-tritylaziridines 7-9 possessing diester, dinitrile, and butadiene groups in the side chain with electron-deficient alkenes yielded 2,3-cis-pyrrolidine derivatives 29, 30, and 33 exclusively. In particular, the dinitrile 8 also reacted with non-electron-deficient alkenes. The formal synthesis of the indolizidine fragment 10 of stellettamides starting from the pyrrolidine (E)-33 was achieved in a convenient manner.     

N‐Heterocyclic Carbene‐Catalyzed [2+2+2] Annulation of Allenoates with Trifluoromethylketones

In contrast with the reported phosphine‐ and DABCO‐catalyzed [3+2] and [2+2] annulation of allenoates with trifluoromethylketone, the [2+2+2] annulation of allenoates and two molecules of trifluoromethylketone was found under the condition of N‐heterocyclic carbene catalysis.     

Highly site, regio-, and stereoselective multicomponent reaction of benzimidazole carbenes, isothiocyanates, and allenoates

The novel three-component reaction of benzimidazole carbenes with isothiocyanates and allenoates proceeded efficiently in a highly site, regio-, and stereoselective manner to produce predominantly spiro[benzimidazoline-2,3′-tetrahydrothiophene] derivatives. The reaction was proposed to occur via a tandem nucleophilic addition of carbenes to isothiocyanates followed by an unusual [3+2] cycloaddition to the less activated carbon-carbon double bond of allenoates.     

The Lewis acid-catalyzed [3+1+1] cycloaddition of azomethine ylides with isocyanides

A Lewis acid-catalyzed [3+1+1] cycloaddition reaction between aliphatic isocyanides and azomethine ylides generated in situ from aziridines, leading to pyrrolidine derivatives, has been developed. This reaction proceeds smoothly under mild conditions and can also be modified by employing aromatic isocyanides to generate four-membered heterocycles, azetidines, through a [3+1] cycloaddition reaction.     

Photoreactions of β-aziridinylacrylonitriles and acrylates with alkenes: formation of head-to-head adducts and application to the preparation of pyrrolizidine alkaloid

The photochemical C,C-bond cleavage of N-benzyl β-aziridinylacrylonitrile 1 and acrylate 2 and the subsequent [3+2] cycloaddition with electron-deficient alkenes afforded head-to-head adducts selectively and efficiently. Irradiation of N-phenyl aziridine 3 with acrylonitrile gave adducts, but photoreaction of N-benzoyl aziridine 4 and thermal reactions of 3 and 4 with alkenes yielded C(γ),N-cleaved products instead of cycloadducts. N-trityl aziridine 5 also reacted with electron-deficient alkenes, affording 2,3-cis-pyrrolidine derivatives exclusively. A formal synthesis of a pyrrolizidine alkaloid, isoretronecanol (27), starting from 5 was achieved in a convenient manner.