An unprecedented Tf2NH-catalyzed formal [3 + 2] cycloaddition of ynamides with dioxazoles was developed to construct various polysubstituted 4-aminooxazoles. This approach features a metal-free catalytic bimolecular assembly of oxazole motifs, a low-cost catalyst, exceptionally mild reaction conditions, a very short reaction time, a broad substrate scope, and high efficiency. This metal-free protocol may find applications in pharmaceutical-oriented synthesis.

A silver-catalyzed intermolecular tandem cyclization of nitrones with 2-azetine was developed for the synthesis of 2,3-disubstituted quinolines under mild conditions with good yields. This approach features a C–N bond cleavage of 2-azetine and an N–O bond cleavage of nitrones via a radical pathway. The results of this study provide a new reaction pattern for nitrones and may find applications in the synthesis of other heterocycles.

Oxadiazolones are first employed as the three-atom coupling partners in the Tf2NH-catalyzed cycloaddition with ynamides. This formal [3 + 2] cycloaddition allows a rapid synthesis of aminoimidazoles with a broad substrate scope. The approach also features a metal-free catalytic cycloaddition process, which may find applications in the synthesis of bioactive molecules. Besides, the resulting N-methyl products can further be readily converted to free N–H aminoimidazoles.

2-Trifluoromethyl-5-(arylsulfonyl)methyl pyrroles and 2-trifluoromethyl-4-(arylsulfonyl)methyl pyrroles were selectively synthesized from trifluoromethyl-substituted 3-aza-1,5-enynes via a cyclization/sulfonyl group migration cascade catalyzed by AgOOCCF3 and CsOPiv, respectively. Alkylvinyl-substituted pyrroles were generated from seven-atom skeleton 3-aza-1,5-enynes via aryl sulfinic acid elimination in the presence of Cs2CO3. Two ion-pair intermediates were proposed and a key intermediate, aza-diene–yne, was successfully isolated in the mechanistic studies.

A strategy for achieving diastereodivergent azidations of enynes has been developed, employing azide transfer from the M–N3 complex to alkyl radicals. Following this concept, the diastereoselectivity has been switched by modulating the transition metals and the ligands. The Mn(III)-mediated radical cyclization/azidation cascade of 1,7-enynes afforded trans-fused pyrrolo[3,4-c]quinolinones, whereas the Cu(II)/bipyridine system gave cis-products.

A ruthenium-catalyzed intermolecular [3 + 2] cycloaddition of 2H-azirines and activated alkynes is reported, which provides polysubstituted pyrroles in moderate to good yields. This approach features a C–N bond cleavage of 2H-azirines by a ruthenium catalyst. The results of this study would provide a complementary method to synthesize polysubstituted pyrroles from the known 2H-azirine approaches and advance 2H-azirine chemistry.

Rh(III)-catalyzed C–H activation assisted by an oxidizing directing group has evolved to a mild and redox-economic strategy for the construction of heterocycles. Despite the success, these coupling systems are currently limited to cleavage of an oxidizing N–O or N–N bond. Cleavage of an oxidizing C–N bond, which allows for complementary carbocycle synthesis, is unprecedented. In this article, α-ammonium acetophenones with an oxidizing C–N bond have been designed as substrates for Rh(III)-catalyzed C–H activation under redox-neutral conditions. The coupling with α-diazo esters afforded benzocyclopentanones, and the coupling with unactivated alkenes such as styrenes and aliphatic olefins gave ortho-olefinated acetophenoes. In both systems the reactions proceeded with a broad scope, high efficiency, and functional group tolerance. Moreover, efficient one-pot coupling of diazo esters has been realized starting from α-bromoacetophenones and triethylamine. The reaction mechanism for the coupling with diazo esters has been studied by a combination of experimental and theoretical methods. In particular, three distinct mechanistic pathways have been scrutinized by DFT studies, which revealed that the C–H activation occurs via a C-bound enolate-assisted concerted metalation–deprotonation mechanism and is rate-limiting. In subsequent C–C formation steps, the lowest energy pathway involves two rhodium carbene species as key intermediates.

Rh(III)-catalyzed, chelation-assisted C–H activation and selenylation of arenes has been achieved. Arenes bearing oxime, azo, pyridyl, and N-oxide chelating groups are viable substrates, and electrophilic selenyl chlorides and diselenides are used as selenylating reagents. The catalytic system is highly efficient under mild conditions over a broad range of substrates with excellent functional group tolerance.

A base-catalyzed selective cycloisomerization of 3-aza-1,5-enynes is developed. This transformation provides a facile access to highly functionalized 2-azabicyclo[3.2.0]hept-2-enes and sulfonyl vinyl-substituted pyrroles. The chemoselectivity was controlled by the substituent pattern of the substrates.

An unprecedented formal [3+2] annulation of propargylamides with TMSN3 to deliver functionalized tetrazoles is developed. Oxygen-atom transfer (OAT) from the amide group to the CC bond was realized via a NIS-triggered-cyclization/ring-opening cascade pathway. The OAT process enables the amide to serve as a two-atom unit in the reactions. Notably, in situ umpolung of azide occurred when terminal propargylamides were employed in this reaction, providing an array of diiodomethylated dihydroimidazoles.

Methyleneaziridines reacted with diynes to generate fused anilines. This reaction involved a C2–C3 bond cleavage of methyleneaziridine. This work provides a new reaction pattern of methyleneaziridine.

The DABCO-catalyzed reaction of propargyl alcohols with dialkyl acetylene dicarboxylates and N-bromo-/N-iodosuccinimides under mild conditions has been developed. The reactions give 3-bromo-/3-iodo-2H-pyrans in up to 98% yield.

Cyclization reactions of propargylic amides, due to their rapid assembly of structural complexity and good functional group compatibility, have gained considerable attention in recent years. These transformations have been successfully achieved with transition metals, halogen sources, Bronsted acids, and strong bases. Generally, the cyclizations proceed through a 5-exo-dig or 6-endo-dig fashion to furnish heterocycles.Figure optionsDownload full-size imageDownload as PowerPoint slide

An unprecedented NIS-mediated ring-closure/opening cascade reaction of allylamides is developed. The substrates with various functionalities were well tolerated and the scope can be extended to allylic carboxylates. Notably, the resulting iodinated chain products are versatile building blocks for the synthesis of oxazolines and epoxides. Furthermore, propargylamides can also undergo this reaction smoothly, providing the corresponding diiodoketones in good yields. The protocol offers a value route to explore new reaction patterns of other functionalized alkenes or alkynes.

A highly efficient Cu-catalyzed ring expansion reaction of 2H-azirines with terminal alkynes has been developed. This transformation provides a powerful method for the synthesis of 3-alkynyl polysubstituted pyrroles under mild conditions in good yields. The direct transformation process, specific selectivity, and good tolerance to a variety of substituents make it an alternative approach to the reported protocols.

An efficient gold(I)-catalyzed alkenylation of β-alkyne-substituted pyrroles is reported. The intramolecular reaction gives straightforward access to different types of seven-membered-ring-fused pyrroles with endo-selectivity, and the intermolecular reaction with alkynes provides functionalized pyrrole derivatives.

A convenient method to access 5H-benzo[b]carbazol-6-yl ketones via a sequential Cu-catalyzed Friedel–Crafts alkylation reaction of indoles with 2-(2-(alkynyl)benzylidene)malonates and iodine-promoted electrophilic cyclization followed by nucleophilic substitution and aromatization was developed. The products of the functional 5H-benzo[b]carbazol-6-yl ketones were obtained with up to 98% yield.

NIS-mediated iodocyclization of N-sulfonyl propargylamides for the synthesis of various oxazolidines and iodoalkylidenedihydrooxazoles via a 5-exo-dig process is developed. The resulting iodoalkylidenedihydrooxazoles can be further transformed into the corresponding oxazoles in the presence of dioxygen.

The DABCO-catalyzed reaction of propargyl alcohols with methyl 2-perfluoroalkynoate to give trifluoromethylated furans in up to 98% yield under mild conditions has been developed. The established allene–enol and control experiments indicate that the reaction should proceed through a Michael addition and Claisen rearrangement/cyclization process.

A Ni-catalyzed [3 + 2] cycloaddition via C–C bond cleavage of methyleneaziridines under mild conditions was developed. This reaction gave substituted pyrroles with excellent regioselectivity and a pendant alkyne unit, which is advantageous for further derivatization.

Rhodium(III)-catalyzed C–H activation–amidation of arenes bearing chelating groups has been achieved using N-arenesulfonated imides as efficient amidating reagents without using any base additive. Pyridine, oxime, and pyrimidine proved to be viable directing groups.

A facile synthetic route to access polyfluoroalkyl functionalized cyclobutenes bearing an exo cyclic double bond from 3-aza-1,5-enynes is reported. The reaction proceeds via a thermal aza-Claisen rearrangement to give an allene-imine intermediate; subsequent cyclization affords the cyclobutene core. The kinetics of the transformation of starting material and the intermediate was studied by 1H NMR spectroscopy, where a consecutive reaction was revealed.

Tetrasubstituted pyrroles can be obtained via the reaction of terminal alkynes and imines using nBuLi as the base in one step with high chemoselectivity (method 1). Alternatively, the intermediate propargylamines can also react with imines to afford tetrasubstituted pyrroles when using LiHMDS as the base (method 2), which provides a complementary method to construct the pyrroles with different substituents.

An efficient rhodium/olefin–sulfoxide catalyzed asymmetric conjugate addition of organoboronic acids to various unsaturated esters has been developed, where 2-methoxy-1-naphthyl sulfinyl functionalized olefin ligands have been shown to be highly effective, and are especially applicable to unsaturated methyl esters with up to 99% yield and 91% ee.

The Michael addition and three-component cyclization reaction of amines, alkynes and dialkyl acetylene dicarboxylates to form pyridones has been developed. Aliphatic amines and aromatic amines could selectively be converted into N-alkyl-disubstituted 2-pyridones and N-aryl-trisubstituted 2-pyridones with good yields in the presence of wet ethanol, which means a suitable amount of water is required for this reaction. The Michael addition and cyclization reaction process was confirmed through deuterium-labeling experiments, intermediates isolation and control experiments.

Silver(I)-catalyzed [3,3] rearrangement of N-sulfonyl propargylamides affords functionalized oxazoles with highly regioselective migration of the sulfonyl group by the introduction of acyloxy groups. The allenylamides, generated from the corresponding propargylamides, can also undergo the silver-catalyzed cyclization to give various 5-vinyloxazoles.

Cp*Rh(III)-catalyzed intermolecular C–C couplings between activated α-diazocarbonyl compounds and arenes bearing a range of azacyclic directing groups have been achieved. This catalytic alkylation reaction operates under mild conditions with good functional group tolerance.

The reaction of N-sulfonyl propargylamides in the presence of a base catalyst selectively affords 5-sulfonylmethyl oxazoles via 1,4-sulfonyl migration. Allenes have been established as the key intermediates. Experimental evidence has been provided to support a two-step mechanism in the cyclization.

An iron-catalyzed [2 + 2 + 2] cycloaddition reaction of diynes and cyanamides at room temperature is reported. Highly substituted 2-aminopyridines were obtained in good to excellent yields with high regioselectivity. Insights toward the reaction process were investigated through in situ IR spectra and control experiments. In this iron-catalyzed cycloaddition reaction, the active iron species was generated only in the presence of both alkynes and nitriles. The lower reaction temperature, broad substrates scope, and inversed regioselectivity make it a complementary method to the previously developed iron catalytic system.

Metal-free cyclization and N-iodosuccinimide-induced electrophilic iodocyclization of readily available 3-aza-1,5-enynes have been developed. The reactions selectively give 1,2-dihydropyridines and 3-iodo-1,2-dihydropyridines involving an aza-Claisen rearrangement and a 6π-electrocyclization step. Furthermore, the reaction could be carried out in 10 g scale for the synthesis of 1,2-dihydropyridines.

A highly efficient Cu-catalyzed asymmetric Friedel–Crafts alkylation reaction of indoles with arylidene malonates using simple, stable, and easily prepared bis-sulfonamide diamine ligands was developed. The desired products were obtained in up to 99% yield with 96% ee.

Palladium-catalyzed desulfitative and denitrogenative arylation of azoles with arylsulfonyl hydrazides has been achieved. A broad scope of azoles and arylsulfonyl hydrazides has been used to produce arylated azoles in high yields.

Direct oxidation coupling of tertiary amines and dialkyl- or diphenyl-substituted phosphonates was developed. The reaction was mediated by DDQ under room temperature. Various phosphonates and N-aryl tetrahydroisoquinolines were tolerated in this reaction, and α-aminophosphonates were obtained with up to 99% yield.

The rapid generation of molecular in a relatively easy manner has made the cycloaddition reaction a powerful tool in the synthesis of different membered ring compounds. Clearly, iron catalysts are becoming a much more interesting and viable choice for this purpose. In this review, a number of promising results in the iron catalyzed cycloaddition reactions in the last decades were summarized. Special attention has been paid to the asymmetric cycloaddition reactions.

An efficient rhodium/olefin–sulfoxide catalyzed asymmetric conjugate addition of organoboronic acids to a variety of nitroalkenes has been developed, where 2-methoxy-1-naphthyl sulfinyl functionalized olefin ligands have shown to be highly effective and are applicable to a broad scope of aryl, alkyl, and heteroaryl nitroalkenes.

Chiral bis(sulfonamide)-diamine served as new type of ligand for a Cu(OTf)2-catalyzed asymmetric Friedel–Crafts alkylation reaction of indoles with nitroalkenes. The desired products were obtained with up to 99% yield and 97% ee.

A series of bis(sulfonamide)−diamine (BSDA) ligands were synthesized from commercially available chiral α-amino alcohols and diamines. The chiral BSDA ligand 3a, coordinated with Cu(I), catalyzes the enantioselective Henry reaction with excellent enantioselectivity (up to 99%). Moreover, with the assistance of pyridine, a CuBr−3a system promotes the diastereoselective Henry reaction with various aldehyde substrates and gives the corresponding syn-selective adduct with up to a 99% yield and 32.3:1 syn/anti selectivity. The enantiomeric excess of the syn adduct was 97%.

A class of readily available and easily tunable benzene backbone-based olefin–sulfoxide ligands was developed for the rhodium-catalyzed asymmetric conjugate addition reaction of arylboronic acids to enones with up to 97% yield and 97% ee.

Chiral ligands 1–2 with l-prolinol backbone have been applied to the enantioselective phenylacetylene addition to aldehydes, providing chiral propargylic alcohols in high yields and moderate enantioselectivities. Only the ligand 1 in combination with Ti(OiPr)4 afforded the products with opposite absolute configuration in significant enantiomeric excesses and high yields. The ratio of Ti(OiPr)4 to the ligand had great influence on the enantiomeric excess of the product.The readily synthesized chiral ligand 1 in combination with Ti(OiPr)4 provided the products with opposite absolute configuration in significant enantiomeric excesses and high yields. The ratio of Ti(OiPr)4 to the ligand had great influence on the enantiomeric excess of the product.

A convenient resolution method for 1,1′-bi-2-naphthol and 4,4′-dibromo-1,1′-spirobiindane-7,7′-diol has been developed with crude (−)-menthyl chloroformate as the resolution reagent in the presence of tetrabutylammonium bromide acting as a phase transfer catalyst in an aqueous NaOH/CH2Cl2 two phase solution. The deprotection of the hydroxy group was carried out via an aqueous KOH/EtOH solution. Both enantiomers of 1,1′-bi-2-naphthol and 4,4′-dibromo-1,1′-spirobiindane-7,7′-diol were obtained in high yields. Both ee’s of (S)-(+) and (R)-(−)-4,4′-dibromo-1,1′-spirobiindane-7,7′-diol were above 99%. Most of the (−)-menthol could be easily recovered in a deprotection procedure and thus be reused for the formation of (−)-menthyl chloroformate without further purification.Graphic(S)-(+)-4,4′-Dibromo-1,1′-spirobiindane-7,7′-diolC17H14Br2O2Ee>99%[α]D18=+93.9 (c 0.5, THF)Source of chirality: resolutionAbsolute configuration: S (assigned by chemical correlation)(1S)-(−)-4,4′-Dibromo-1,1′-spirobiindane-7,7′-diyl bis[(1″R,2″S,5″R)-5-methyl-2-(1-methylethyl)cyclohexyl]carbonateC39H50Br2O6[α]D25=−91.0 (c 1.0, CHCl3)Source of chirality: synthesizedAbsolute configuration: 1S,1″R,2″S,5″R (assigned by chemical correlation)

An unprecedented formal [3+2] annulation of propargylamides with TMSN3 to deliver functionalized tetrazoles is developed. Oxygen-atom transfer (OAT) from the amide group to the CC bond was realized via a NIS-triggered-cyclization/ring-opening cascade pathway. The OAT process enables the amide to serve as a two-atom unit in the reactions. Notably, in situ umpolung of azide occurred when terminal propargylamides were employed in this reaction, providing an array of diiodomethylated dihydroimidazoles.

Oxadiazolones are first employed as the three-atom coupling partners in the Tf2NH-catalyzed cycloaddition with ynamides. This formal [3 + 2] cycloaddition allows a rapid synthesis of aminoimidazoles with a broad substrate scope. The approach also features a metal-free catalytic cycloaddition process, which may find applications in the synthesis of bioactive molecules. Besides, the resulting N-methyl products can further be readily converted to free N–H aminoimidazoles.

Palladium-catalyzed desulfitative and denitrogenative arylation of azoles with arylsulfonyl hydrazides has been achieved. A broad scope of azoles and arylsulfonyl hydrazides has been used to produce arylated azoles in high yields.

2-Trifluoromethyl-5-(arylsulfonyl)methyl pyrroles and 2-trifluoromethyl-4-(arylsulfonyl)methyl pyrroles were selectively synthesized from trifluoromethyl-substituted 3-aza-1,5-enynes via a cyclization/sulfonyl group migration cascade catalyzed by AgOOCCF3 and CsOPiv, respectively. Alkylvinyl-substituted pyrroles were generated from seven-atom skeleton 3-aza-1,5-enynes via aryl sulfinic acid elimination in the presence of Cs2CO3. Two ion-pair intermediates were proposed and a key intermediate, aza-diene–yne, was successfully isolated in the mechanistic studies.

A convenient method to access 5H-benzo[b]carbazol-6-yl ketones via a sequential Cu-catalyzed Friedel–Crafts alkylation reaction of indoles with 2-(2-(alkynyl)benzylidene)malonates and iodine-promoted electrophilic cyclization followed by nucleophilic substitution and aromatization was developed. The products of the functional 5H-benzo[b]carbazol-6-yl ketones were obtained with up to 98% yield.

An efficient rhodium/olefin–sulfoxide catalyzed asymmetric conjugate addition of organoboronic acids to various unsaturated esters has been developed, where 2-methoxy-1-naphthyl sulfinyl functionalized olefin ligands have been shown to be highly effective, and are especially applicable to unsaturated methyl esters with up to 99% yield and 91% ee.

A Ni-catalyzed [3 + 2] cycloaddition via C–C bond cleavage of methyleneaziridines under mild conditions was developed. This reaction gave substituted pyrroles with excellent regioselectivity and a pendant alkyne unit, which is advantageous for further derivatization.