Catalytic Aminium Radical-Cation Salt (Magic Blue)-Initiated SN2-Type Nucleophilic Ring-Opening Transformations of Aziridines.

A simple and atom economic protocol for the construction of C-X/C-C bonds via catalytic aminium radical-cation salt (Magic Blue)-initiated SN2-type nucleophilic ring-opening transformations of racemic and nonracemic aziridines with different hetero and carbon nucleophiles to afford various amino ethers, thioethers, and amines in up to 99% yield, and with perfect enantiospecificity for some substrates but reduced ee with others (for nonracemic aziridines), is developed. This aminium radical-cation salt-initiated, SN2-type nucleophilic ring-opening strategy, along with various cyclization protocols, is employed to synthesize various biologically significant compounds.

Ring-Opening Cyclization (ROC) of Aziridines with Propargyl Alcohols: Synthesis of 3,4-Dihydro-2H-1,4-oxazines.

Activated aziridines react with propargyl alcohols in the presence of Zn(OTf)2 as the Lewis acid catalyst following an SN2-type ring-opening mechanism to furnish the corresponding amino ether derivatives. Those amino ethers further undergo intramolecular hydroamination via 6-exo-dig cyclization in the presence of Zn(OTf)2 as the catalyst and tetrabutylammonium triflate salt as an additive under one-pot two-step reaction conditions. However, for nonracemic examples, ring-opening and cyclization steps were conducted under two-pot conditions. The reaction works well without any additional solvents. The final 3,4-dihydro-2H-1,4-oxazine products were obtained with 13 to 84% yield and 78 to 98% enantiomeric excess (for nonracemic examples).

Stereoselective Routes to Hexahydropyrroloindoles and Tetrahydropyrroloquinolines from Activated Aziridines and Electron Deficient 3H-Indoles.

An unprecedented and novel synthetic route to hexahydropyrrolo[2,3-b]indoles bearing cis-contiguous stereocenters with excellent stereoselectivities (ee of >99%, dr of ≤99:1) has been disclosed that proceeds through the ring opening of activated aziridines with electron deficient 4-substituted indoles followed by a novel cyclization in a domino fashion, thereby obviating the use of 3-substituted indoles as the prerequisite nucleophile. Another efficient synthetic route to tetrahydropyrrolo[4,3,2-de]quinolines in excellent yields (≤93%) and excellent enantioselectivity (ee of >99%) has been established via ring opening of activated aziridines with 4-bromo-1-methyl-1H-indole at relatively higher temperatures followed by Cu(I)-catalyzed intramolecular C-N cyclization in the same pot. The stability and the formation of products at different temperatures are explained by computational studies.

Stereoselective Synthesis of Hexahydroimidazo[1,2-a]quinolines via SN2-Type Ring-Opening Hydroarylation-Hydroamination Cascade Cyclization of Activated Aziridines with N-Propargylanilines.

A novel synthetic approach for the construction of 1,2,3,3a,4,5-hexahydroimidazo[1,2-a]quinolines in good yields (up to 75%) with excellent stereoselectivity (dr up to 94:6, ee up to >99%) under one-pot domino ring-opening cyclization (DROC) conditions has been developed. The DROC protocol proceeds through a Lewis acid catalyzed SN2-type ring-opening of activated aziridines with N-propargylanilines followed by intramolecular cyclization comprising concomitant hydroarylation and hydroamination steps in a domino fashion.

A synthetic route to 1,4-disubstituted tetrahydro-ß-carbolines and tetrahydropyranoindoles via ring-opening/Pictet-Spengler reaction of aziridines and epoxides with indoles/aldehydes.

A simple and efficient synthetic route to various 1,4-disubstituted tetrahydro-ß-carbolines and tetrahydropyrano[3,4-b]indoles in high yields and stereoselectivity via LiClO4-catalyzed SN2-type ring opening of aziridines and epoxides with indoles followed by p-toluenesulfonic acid (PTSA) catalyzed Pictet-Spengler reaction is described.

Stereoselective Syntheses of Highly Functionalized Imidazolidines and Oxazolidines via Ring-Opening Cyclization of Activated Aziridines and Epoxides with Amines and Aldehydes.

A mild one-pot stereospecific synthetic route to highly functionalized imidazolidines and oxazolidines via SN2-type ring-opening of the corresponding activated aziridines and epoxides with amines followed by p-toluenesulfonic acid (PTSA)-catalyzed intramolecular cyclization with aldehydes has been developed. The methodology tolerates a variety of functional groups and furnishes the desired products in high yields (up to 92%) with excellent stereoselectivities (de, ee > 99%). Interestingly, imidazolidines were formed as the cis-isomers, whereas oxazolidines were produced as trans-isomers exclusively.

Stereospecific Synthesis of Highly Substituted Piperazines via an One-Pot Three Component Ring-Opening Cyclization from N-Activated Aziridines, Anilines, and Propargyl Carbonates.

A simple and efficient one-pot three-component synthetic route to highly substituted and functionalizable piperazines in high yields with excellent stereoselectivity (de, ee >99%) is reported. The SN2-type ring-opening of N-activated aziridines by anilines followed by Pd-catalyzed annulation with propargyl carbonates gives rise to the final piperazine products.

Stereoselective Construction of Pyrazinoindoles and Oxazinoindoles via Ring-Opening/Pictet-Spengler Reaction of Aziridines and Epoxides with 3-Methylindoles and Carbonyls.

A highly efficient and stereoselective route to access 1,3-disubstituted 1,2,3,4-tetrahydropyrazino[1,2- a]indoles and 3,4-dihydro-1H-[1,4]oxazino[4,3- a]indoles with excellent stereoselectivity (de, ee >99%) via base mediated ring opening of aziridines/epoxides with 3-methylindoles followed by BF3·OEt2 catalyzed Pictet-Spengler reaction is accomplished. Interestingly, PTSA promoted cyclization led to the formation of oxidized 3,4-dihydropyrazino[1,2- a]indoles in excellent yields via an unprecedented Pictet-Spengler-detosylation cascade.

Synthesis of Nonracemic 1,4-Benzoxazines via Ring Opening/Cyclization of Activated Aziridines with 2-Halophenols: Formal Synthesis of Levofloxacin.

Novel 3,4-dihydro-1,4-benzoxazine derivatives have been synthesized by an efficient and simple method in excellent enantio- and diastereospecificity (ee > 99%, de > 99%). The reaction proceeds via Lewis acid-catalyzed SN2-type ring opening of activated aziridines with 2-halophenols followed by Cu(I)-catalyzed intramolecular C-N cyclization in a stepwise fashion under one-pot conditions to furnish the 3,4-dihydro-1,4-benzoxazine derivatives in excellent yields (up to 95%). The strategy offers a short and efficient synthesis to ( S)-3-methyl-1,4-benzoxazine ( S)-3v, a late stage intermediate in the synthesis of levofloxacin.

Stereoselective synthesis of 3-spiropiperidino indolenines via SN2-type ring opening of activated aziridines with 1H-indoles/Pd-catalyzed spirocyclization with propargyl carbonates.

3-Spiropiperidino indolenines have been synthesized via novel Lewis acid-catalyzed SN2-type ring opening of activated aziridines with 1H-indoles followed by Pd-catalyzed dearomative spirocyclization with propargyl carbonates in up to 88% yields. The step and pot-economic transformation comprises sequential C-C, C-N, and C-C bond forming steps generating two stereogenic centers including an all-carbon quaternary stereocenter to furnish the products in diastereomerically pure (dr >99 : 1) forms with excellent enantiomeric excess (ee up to >99%). The synthetic versatility of the strategy has been illustrated by converting the synthesized products into spirocyclic indolenine 2-piperidinones, dihydropiperidines, and 5-alkynylated piperidines.

Stereospecific Synthesis of 1,4,5,6-Tetrahydropyrimidines via Domino Ring-Opening Cyclization of Activated Aziridines with α-Acidic Isocyanides.

An expeditious synthetic route to access structurally diverse 1,4,5,6-tetrahydropyrimidines via domino ring-opening cyclization of activated aziridines with α-acidic isocyanides has been established. The transformation proceeds via Lewis acid mediated SN2-type ring opening of activated aziridines with α-carbanion of the isocyanides followed by a concomitant 6- endo- dig cyclization in a domino fashion to furnish the 1,4,5,6-tetrahydropyrimidine derivatives in excellent yields (up to 84%) and also in diastereo- and enantiomerically pure form (dr >99:1, ee >99%).

Temperature-modulated diastereoselective transformations of 2-vinylindoles to tetrahydrocarbazoles and tetrahydrocycloheptadiindoles.

Direct and expedient access to densely substituted tetrahydrocarbazoles and tetrahydrocycloheptadiindoles bearing multiple contiguous stereocentres has been achieved via a two-fold divergent diastereoselective (dr up to >99 : 1) transformation of 2-vinylindoles. The high-yielding conversions (yield up to 87%) that are amenable for a wide range of substituted 2-vinylindoles proceed through Lewis acid-catalyzed [4 + 2] and [4 + 3] cyclization-aromatization cascade reactions, respectively, involving a heretofore-unprecedented reversal of the polarity (umpolung) of 2-vinylindoles. The two synthetic routes are effortlessly transposable into each other by merely modulating the temperature to furnish the corresponding products in a selective and exclusive fashion. In addition, another novel synthetic route to tetrahydroindolocarbazoles has been developed that advances via a formal [4 + 2] cyclization of 4-vinylindoles involving sequential C3 Michael addition-dearomatization-aromatization cascade reactions.

Stereospecific Syntheses of Enaminonitriles and ß-Enaminoesters via Domino Ring-Opening Cyclization (DROC) of Activated Cyclopropanes with Pronucleophilic Malononitriles.

Two novel synthetic protocols for the syntheses of highly functionalized five-membered carbocyclic enaminonitriles and ß-enaminoesters have been developed via domino ring-opening cyclization (DROC) and DROC/decarboxylative tautomerization of activated cyclopropanes with malononitrile pronucleophiles, respectively. Both of the efficient strategies (yield up to 93%) have been generalized with various donor-acceptor and acceptor cyclopropanes as well as with malononitrile derivatives. The stereospecific variants of the two SN2-type DROC strategies have also been developed by employing enantiopure donor-acceptor (DA) cyclopropanes to synthesize the corresponding nonracemic products with excellent stereoselectivities (dr up to >99:1, ee up to >99%).

Memory of Chirality Concept in Asymmetric Intermolecular Michael Addition of α-Amino Ester Enolates to Enones and Nitroalkenes.

A highly stereoselective asymmetric intermolecular conjugate addition of α-amino ester derivatives to cyclic enones via the memory of chirality (MOC) concept in high yields with excellent diastereo- and enantioselectivity (dr >99:1, up to 99% ee) is reported. The applicability and the generality of the strategy was demonstrated by its further exploration to acyclic α,ß-unsaturated ketone and aromatic nitroalkenes, resulting in the formation of δ-keto-α-amino ester derivative and γ-nitro-α-amino ester derivatives, respectively, with excellent ee and dr.

Synthetic route to chiral indolines via Cu(OAc)2-catalyzed ring-opening/C(sp2)-H activation of activated aziridines.

A simple strategy for the synthesis of highly functionalized indolines via Lewis acid catalyzed ring-opening of activated aziridines with various nucleophiles followed by Cu(OAc)2-mediated intramolecular C-H amination in one-pot has been developed with excellent enantio- and diastereospecificity (ee 99%; de >99%). The reaction proceeds via Cu(OAc)2-catalyzed SN2-type ring-opening of 2-phenyl-N-(2-pyridinesulfonyl)aziridine with alcohols and arene, followed by copper-mediated pyridine-2-sulfonamide directed intramolecular C(sp2)-H activation/cyclization in a stepwise fashion to furnish the indoline derivatives in excellent yields (up to 91%).

Syntheses of Tetrahydrobenzoazepinoindoles and Dihydrobenzodiazepinoindoles via Ring-Opening Cyclization of Activated Aziridines with 2-(2-Bromophenyl)-1H-indoles.

Two efficient, modular, step- and pot-economic strategies to access various 5,6,7,12-tetrahydrobenzo[2,3]azepino[4,5-b]indoles and 6,7-dihydro-5H-benzo[5,6][1,4]diazepino[1,7-a]indoles are disclosed that advance via SN2-type regioselective ring opening of enantiopure aziridines with 2-(2-bromophenyl)-1H-indoles at their C3 and indolyl N centers, respectively, followed by Cu-mediated C-N cyclization which furnishes the products in excellent yields with outstanding enantiomeric excesses (up to >99%).

Domino ring-opening cyclization (DROC) of activated aziridines and epoxides with nitrones via dual-catalysis "on water".

An efficient and green "on water" regio- and stereoselective synthetic route to chiral 1,2,4-oxadiazinanes and 1,4,2-dioxazinanes with excellent yields (up to 99%) and de/ee (>99%) has been developed for the first time via the domino ring-opening cyclization (DROC) of N-activated aziridines and epoxides with nitrones using LiClO4/Bu4NBF4 a dual catalyst system. The developed green strategy features a broader substrate scope and mild reaction conditions, and successfully overcomes the competitive oxidative ring opening of aziridines. Further synthetic significances of this green protocol are the formation of the products (i) as single diastereomers starting from a mixture of cis/trans disubstituted aziridines via dynamic kinetic epimerization (DKE) and (ii) via a multicomponent approach starting from N-methyl hydroxylamine hydrochloride, benzaldehyde and aziridine.

A Synthetic Route to Chiral 1,4-Disubstituted Tetrahydro-ß-Carbolines via Domino Ring-Opening Cyclization of Activated Aziridines with 2-Vinylindoles.

A simple and efficient strategy for the synthesis of various 1,4-disubstituted tetrahydro-ß-carbolines with excellent stereoselectivity (de, ee up to >99%) via domino ring opening cyclization (DROC) of activated aziridines with 2-vinylindoles is described. The reaction proceeds through LiClO4-catalyzed Friedel-Crafts-type alkylation of 2-vinylindoles with activated aziridines followed by an intramolecular aza-Michael reaction in a domino fashion.

A Stereoselective Route to Tetrahydrobenzoxazepines and Tetrahydrobenzodiazepines via Ring-Opening and Aza-Michael Addition of Activated Aziridines with 2-Hydroxyphenyl and 2-Aminophenyl Acrylates.

A simple and efficient synthetic route to 2,3,4,5-tetrahydrobenzoxazepines and -benzodiazepines bearing easily functionalizable appendages has been developed by ring-opening of activated aziridines with 2-hydroxyphenyl acrylates and 2-aminophenyl acrylate, respectively, and subsequent intramolecular C-N bond formation through palladium-catalyzed aza-Michael reaction. The straightforward synthetic approach delivers the desired molecular scaffolds in high yields (up to 82%) with excellent stereoselectivity (ee up to 94%).

Domino Ring-Opening Cyclization of Activated Aziridines with Indoles: Synthesis of Chiral Hexahydropyrroloindoles.

A highly enantioselective synthetic route to hexahydropyrrolo[2,3-b]indoles via Lewis acid-catalyzed SN2-type ring opening of activated aziridines with indoles having substitutions at 3- and other positions followed by cyclization in a domino fashion has been developed. Hexahydropyrrolo[2,3-b]indoles have been detosylated in the same pot to afford the corresponding products with free NH group in excellent yields (up to 95%) and enantioselectivity (up to >99%).