Rh(iii)-catalyzed spiroannulation of 3-arylquinoxalin-2(1H)-ones with alkynes: practical access to spiroquinoxalinones

The Rh(iii)-catalyzed synthesis of spiroquinoxalinone derivatives from 3-arylquinoxalin-2(1H)-ones and alkynes via a C–H functionalization/[3 + 2] annulation sequence has been developed. This method, featuring low catalyst loading, was amenable to Gram scale synthesis and tolerated a variety of functional groups and substitution patterns on the aryl rings, providing the target products in good to excellent yields.

The use of imines as a H acceptor for Rh(iii)-catalyzed spirocyclization of 3-arylquinoxalinones and alkynes via a C–H functionalization/[3 + 2] annulation sequence has been achieved.     

Cycloaddition of Huisgen 1,4-dipoles: synthesis and rapid epimerization of functionalized spiropyrido[2,1-b][1,3]oxazine-pyrroles and related products

1,4-Dipolar cycloaddition has emerged as a powerful tool for the synthesis of various cyclic compounds. In the present work, 1H-pyrrole-2,3-diones are proposed as new dipolarophiles for 1,4-dipolar cycloaddition. Their [4 + 2] cycloaddition with dipoles generated from dimethyl acetylenedicarboxylate and pyridine was found to proceed regioselectively affording spiro[pyrido[2,1-b][1,3]oxazine-2,3′-pyrroles] as diastereomeric mixtures which exist in rapid equilibrium in solution. It was established that this phenomenon of rapid epimerization is a characteristic of other similar spiropyrido[2,1-b][1,3]oxazines and even related spiroquinolizines, which was demonstrated by the investigation of related products of previously reported, and reproduced in this work, 1,4-dipolar cycloaddition reactions.

Rapid epimerization of cycloadducts from Huisgen 1,4-dipoles has been investigated through the synthesis of new spiropyrido[2,1-b][1,3]oxazine-pyrroles and repetition of syntheses from the literature.     

Copper-catalyzed chemoselective synthesis of 4-trifluoromethyl pyrazoles

A series of 4-trifluoromethyl pyrazoles have been prepared via the copper-catalyzed cycloaddition of 2-bromo-3,3,3-trifluoropropene with a variety of N-arylsydnone derivatives under mild conditions. This new protocol under optimized reaction conditions [Cu(OTf)₂/phen, DBU, CH₃CN, 35 °C] afforded 4-trifluoromethyl pyrazoles in moderate to excellent yields with excellent regioselectivity.

A copper-catalyzed chemoselective synthesis of 4-trifluoromethyl pyrazoles via cycloaddition of 2-bromo-3,3,3-trifluoropropene with N-arylsydnones has been developed.     

Transition metal catalyzed [6 + 2] cycloadditions

The [6 + 2] cycloaddition reactions are one of the important synthetic transformations to construct eight membered carbo-/heterocyclic systems. The present review is an attempt to update readers on transition metal catalyzed [6 + 2] cycloaddition reactions of various 6π-contributing substrates such as cycloheptatrienes (CHT), cyclooctatetrenes (COTT), allenals, vinylcyclobutanones, fulvene etc. employing rhodium, cobalt, titanium, copper, platinum, ruthenium, rhenium and diphenylprolinolsilyl ethers etc. as catalysts. The transition metal catalyzed [6 + 2] cycloaddition reactions with a variety of functionalized substrates provide straightforward access to eight membered cyclic and/or 5/8, 6/8 etc. condensed carbo-/heterocyclic molecules in moderate to good yields.

The [6 + 2] cycloaddition reactions are one of the important synthetic transformations to construct eight membered carbo-/heterocyclic systems.     

Regio- and stereoselective synthesis of spiropyrrolidine-oxindole and bis-spiropyrrolizidine-oxindole grafted macrocycles through [3 + 2] cycloaddition of azomethine ylides

A convenient and efficient method for the regioselective macrocyclization of triazole bridged spiropyrrolidine-oxindole, and bis-spiropyrrolizidine-oxindole derivatives was accomplished through intra and self-intermolecular [3 + 2] cycloaddition of azomethine ylides. The chalcone isatin precursors 9a–i required for the click reaction were obtained from the reaction of N-alkylazidoisatin 4 and propargyloxy chalcone 8a–i which in turn were obtained by the aldol condensation of propargyloxy salicylaldehyde 6 and substituted methyl ketones 7a–i. The regio- and stereochemical outcome of the cycloadducts were assigned based on 2D NMR and confirmed by single crystal XRD analysis. High efficiency, mild reaction conditions, high regio- and stereoselectivity, atom economy and operational simplicity are the exemplary advantages of the employed macrocyclization procedure.

Spiropyrrolidine-oxindole grafted and bis-spiropyrrolizidine-oxindole grafted macrocyles with triazole as a spacer unit have been achieved via regioselective and stereoselective intra and self-intermolecular [3 + 2] cycloaddition of azomethine ylides (click reaction).     

Pd-catalyzed [3 + 2] cycloaddition of cyclic ketimines and trimethylenemethanes toward N-fused pyrrolidines bearing a quaternary carbon

A Pd-catalyzed [3 + 2] cycloaddition of N-sulfonyl cyclic ketimines and trimethylenemethanes (TMM) was developed that afforded N-fused pyrrolidines bearing a quaternary carbon. Under mild reaction conditions, structurally diverse N-sulfonyl cyclic imines, including sulfamate-fused aldimines, aryl- or styryl-substituted sulfamate-derived ketimines, and N-sulfonyl cyclic ketimines, were tolerated as reactants, affording N-fused pyrrolidines with high efficiency.

A facile route to access N-fused pyrrolidines bearing a quaternary carbon from N-sulfonyl ketimines and commercially available trimethylenemethanes has been developed.     

DABCO-promoted highly diastereo- and regioselective construction of C-3 functionalized spirooxindoles via [3 + 2] cycloaddition of 2-aryl/heteroarylidene-1H-indene-1,3(2H)-diones with N-2,2,2-trifluoroethylisatin ketimines at ambient conditions

The application of 2-aryl/heteroarylidene-1H-indene-1,3(2H)-dione as an activated olefin source in the DABCO-catalyzed [3 + 2] cycloaddition with N-2,2,2-trifluoroethylisatin ketimines has been disclosed. This highly efficient 1,3-dipolar cycloaddition reaction offered a variety of trifluoro methyl group bearing spiro-pyrrolidine linked oxindoles with four consecutive stereocentres in good to excellent yield and excellent diastereoselectivity. The synthetic practicality of the protocol was established by demonstrating the enantioselective construction of spiro-pyrrolidine-oxindoles with two vicinal spiro-quaternary chiral centres in good yield excellent enantioselectivity (>90% ee) by using ultralow loading of quinine as the catalyst at room temperature.

A highly chemo- and regioselective construction of spiropyrrolidine oxindole is devised via DABCO catalysed [3 + 2] cycloaddition reaction.     

Efficient and stereoselective one-pot synthesis of benzo[b]oxazolo[3,4-d][1,4]oxazin-1-ones

An efficient and mild one-pot convergent synthesis protocol has been developed for benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one derivatives through the Mitsunobu reaction and sequential cyclization. Various tricyclic fused benzoxazinyl-oxazolidinones (20 examples) were obtained in good to excellent yields and high enantioselectivities with facile operation. Furthermore, four stereoisomers were afforded respectively in high ee values (>97.8%) via using different chiral 2,3-epoxy-4-trityloxybutanol. This methodology has been applied to the synthesis of key intermediates of drug candidates.

An efficient and mild one-pot convergent synthesis protocol has been developed for benzo[b]oxazolo[3,4-d][1,4]oxazin-1-one derivatives through the Mitsunobu reaction and sequential cyclization.     

Gold-catalyzed synthesis of oxazoles from alkynyl triazenes and dioxazoles

A gold-catalyzed regioselective [3 + 2] cycloaddition of alkynyl triazenes with 1,2,4-dioxazoles was developed. The triazene group in the products could be replaced to obtain iodo-oxazoles, providing potential transformations to diverse oxazole structures. This protocol features readily available starting materials, mild reaction conditions and scalability. A plausible mechanism involving a nitrene transfer process was proposed.

A gold-catalyzed regioselective [3 + 2] cycloaddition of alkynyl triazenes with 1,2,4-dioxazoles was developed.     

Asymmetric [4 + 2] cycloaddition synthesis of 4H-chromene derivatives facilitated by group-assisted-purification (GAP) chemistry

In this work, we present a strategy for the preparation of functionalized 4H-chromene derivatives via a Cs₂CO₃-catalyzed [4 + 2] cycloaddition of enantiopure chiral salicyl N-phosphonyl imines with allenoates. Fifteen examples were achieved in excellent yields and diastereoselectivity. The products were purified simply by washing the crude mixture with hexanes following the Group-Assisted Purification (GAP) chemistry/technology to bypass traditional separation methods. The absolute configuration was unambiguously determined by X-ray structure analysis.

A new asymmetric method for the synthesis of highly functionalized 4H-chromenes was developed via Group-Assisted Purification (GAP) chemistry and shown in good to high yield and excellent diastereoselectivity.     

Regioselective ring expansion followed by H-shift of 3-ylidene oxindoles: a convenient synthesis of N-substituted/un-substituted pyrrolo[2,3-c] quinolines and marinoquinolines

Herein, we report a simple and metal-free protocol for the synthesis of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolines. The present method under mild reaction conditions with wide functional group compatibility gives several unexplored N-substituted/unsubstituted 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolines and marinoquinolines in good to excellent yields. Mechanistic insights for the synthesis of N-substituted pyrroloquinolines reveal the ring expansion of 3-ylideneoxindoles and H-shift as the key steps.

Herein, we report a simple and metal-free protocol for the synthesis of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinolines.     

Iodine-catalyzed synthesis of benzoxazoles using catechols,ammonium acetate,and alkenes/alkynes/ketones via C–C and C–O bond cleavage

An efficient metal-free synthesis strategy of benzoxazoles was developed via coupling catechols, ammonium acetate, and alkenes/alkynes/ketones. The developed methodology represents an operationally simple, one-pot and large-scale procedure for the preparation of benzoxazole derivatives using molecular iodine as the catalyst.

A metal-free one-pot multi-component method for the efficient synthesis of 2-aryl benzoxazoles via coupling of catechols, ammonium acetate and alkenes/alkynes/ketones using an I₂–DMSO catalyst system is illustrated.     

Cu/TEMPO catalyzed dehydrogenative 1,3-dipolar cycloaddition in the synthesis of spirooxindoles as potential antidiabetic agents

A series of spiro-[indoline-3,3′-pyrrolizin/pyrrolidin]-2-ones, 4, 5 and 6 were synthesized in a sequential manner from Cu–TEMPO catalyzed dehydrogenation of alkylated ketones, 1 followed by 1,3-dipolar cycloaddition of azomethine ylides via decarboxylative condensation of isatin, 2 and l-proline/sarcosine, 3 in high regioselectivities and yields. The detailed mechanistic studies were performed to identify the reaction intermediates, which revealed that the reaction proceeds via dehydrogenative cycloaddition. Additionally, the regio and stereochemistry of the synthesized derivatives were affirmed by 2D NMR spectroscopic studies. The synthesized derivatives were explored further with molecular docking, in vitro antioxidant, and anti-diabetic activities.

A series of spiro-[indoline-3,3′-pyrrolizin/pyrrolidin]-2-ones were synthesized from Cu–TEMPO catalyzed dehydrogenation followed by 1,3-dipolar cycloaddition of azomethine ylides via decarboxylative condensation, resulting in high regioselectivities and yields.     

Cascade synthesis of 2,4-disulfonylpyrroles by the sulfonylation/[2 + 3]-cycloaddition reactions of gem-dibromoalkenes with arylsulfonyl methyl isocyanides

An efficient cascade reaction involving sulfonylation and [2 + 3]-cycloaddition reactions of gem-dibromoalkenes with arylsulfonyl methyl isocyanides was described for the synthesis of 3-aryl-2,4-disulfonyl-1H-pyrroles. The main highlight of this study is the introduction of a new dual-functional reactivity of arylsulfonyl methyl isocyanides as the sulfonyl source as well as a 1,3-dipolar reagent in the same reaction. This system is facilitated by Cs₂CO₃ mediation in DMSO and 100 °C conditions.

An efficient cascade reaction involving sulfonylation and [2 + 3]-cycloaddition reactions of gem-dibromoalkenes with arylsulfonyl methyl isocyanides was described for the synthesis of 3-aryl-2,4-disulfonyl-1H-pyrroles.     

Revisiting the photochemical synthesis of [FeFe]-hydrogenase mimics: reaction optimization,mechanistic study and electrochemical behaviour

The photoreaction of [(μ-S)₂Fe₂(CO)₆] and alkenes or alkynes has been optimized to readily obtain functionalized [FeFe]-hydrogenase mimics. Irradiation under low CO pressure in THF produces the corresponding photo-adducts in good/acceptable (alkenes/alkynes) yields, with retention of the starting olefin stereochemistry. DFT-calculations provide plausible reaction pathways in both, singlet and triplet states. The DFT-calculation based in the singlet state is energetically more favorable. The electrochemical behavior of the synthesized compounds is also presented, including studies in acidic media. The electrochemical properties of the products vary in the presence of a double bond (cycloaddition of [(μ-S)₂Fe₂(CO)₆] to alkynes), respect to a single bond (cycloaddition to alkenes).

The photochemistry of [(μ-S)₂Fe₂(CO)₆] and alkenes or alkynes has been developed to a synthetically useful level. Computational data and electrochemistry of the photoadducts show interesting properties of these compounds.     

DFT and AFIR study on the copper(i)-catalyzed mechanism of 5-enamine-trisubstituted-1,2,3-triazole synthesis via C–N cross-coupling and the origin of ring-opening of 2H-azirines

Understanding the synthesis mechanism of substituted 1,2,3-triazoles is an important and state-of-the-art research area of contemporary copper(i)-catalyzed terminal alkyne and organic azide click reaction (CuAAC), which has invoked increasing close collaborations between experiment and theory including copper catalyzed interrupted click reaction. In this study, the mechanism of Cu(i)-catalyzed 5-enamine-functionalized fully substituted 1,2,3-triazole synthesis was rationalized via density functional theory (DFT) and multicomponent artificial force-induced reaction (MC-AFIR) methods. The reasonable reaction route consists of (a) di-copper catalyzed ring-opening of 2H-azirines, (b) alkyne hydrogen atom transfer, (c) [3 + 2] ring cycloaddition, and (d) C–N bond formation through reductive elimination. The MC-AFIR method was used for the systematic determination of transition states for the C/N–Cu bond formation, C–N bond coupling and crossing points between singlet and triplet states. Our survey on the prereactant complexes suggested that the dicopper-catalyzed 2H-azirine ring-opening and alkyne hydrogen activation are both thermodynamically feasible via a singlet/triplet crossing point. This explains why Et₃N is critical for alkyne hydrogen transfer (HT) before the [3 + 2] cycloaddition reaction, and the C–N cross-coupling product instead of the click product (byproduct). Our DFT results indicate that the transmetalation process is the rate determination step along the triplet state potential energy surface. This study provides important mechanistic insights for the interrupted CuAAC reaction to form 5-enamine-fully-substituted-1,2,3-triazoles. Further insight prediction interprets that solvent and extra strong ligand coordination play a certain role in competitive reactions.

The Cu(i)-catalyzed mechanism of 5-enamined-functionalized fully substituted 1,2,3-triazole synthesis was rationalized by interrupted copper(i)-catalyzed terminal alkynes and organic azides click reaction (CuAAC).     

Nitrileimines as an alternative to azides in base-mediated click [3 + 2] cycloaddition with methylene active nitriles

Nitrileimines were implemented in practical click protocols with oxopropanenitriles for the straightforward 5-amino-1H-pyrazole synthesis via 1,3-dipolar cycloaddition. The reaction proceeds at room temperature in a short time with base catalysis and no chromatographic purification. High purity products were isolated by simple filtration. The selectivity of the reaction was observed.

Nitrileimines were implemented in practical click protocols with oxopropanenitriles for the straightforward 5-amino-1H-pyrazole synthesis via 1,3-dipolar cycloaddition.     

Facile synthesis of 2-substituted benzo[b]furans and indoles by copper-catalyzed intramolecular cyclization of 2-alkynyl phenols and tosylanilines

A catalytic amount of CuCl and Cs₂CO₃ was employed to synthesize a variety of 2-substituted benzo[b]furans and indoles by an intramolecular cyclization of 2-alkynyl phenols and tosylanilines. This protocol features mild conditions, high yields and broad substrate scope, which makes it a practical method for the synthesis of 2-substituted benzo[b]furans and indoles.

A facile and inexpensive copper-catalyzed method was developed for the synthesis of 2-substituted benzo[b]furans and indoles.     

Computational assessments of diastereoselective [4+2] cycloaddition and 1,3-borotopic shift of a dearomatized tertiary boronic ester intermediate: reactivities explained through transition-state distortion energies

Interception of a dearomatized tertiary boronic ester, formed through a kinetically and thermodynamically favorable 1,2-metalate rearrangement/anti-S_N2′ elimination of an activated ortho-lithiated benzyl amine, in a [4+2] cycloaddition or 1,3-borotopic shift has been investigated by density functional theory (DFT). Although superacitvated “naked” Li⁺ was found to greatly promote 1,3-borotopic shift, the diastereoselective [4+2] cycloaddition was favored. It was revealed that the factor that controls the diastereoselectivity was the steric bulk provided by the diene, which is in agreement with experimental diastereoselectivity. A comparison of unreactive dienophiles such as maleic anhydride, diethyl maleate, and others with 4-phenyl-3H-1,2,4-triazole-3,5(4H)-dione (PTAD) was found to be in an excellent agreement with the experiments; where their lack of reactivity is attributed to the high deformation energies of the interacting components to achieve the transition state structure which was pronounced with the high energy of LUMO orbitals.

Interception of dearomatized tertiary boronic ester in a diastereoselective [4+2] cycloaddition or 1,3-borotopic shift in the presence or absence of “naked” Li⁺, understanding reactivities by activation/strain model, were evaluated by DFT calculations.     

Rh(iii)-catalyzed synthesis of tetracyclic isoquinolinium salts via C–H activation and [4+2] annulation of 1-phenyl-3,4-dihydroisoquinolines and alkynes in ethanol

An efficient and convenient method to construct tetracyclic isoquinolinium salts via [Cp*RhCl₂]₂ catalyzed C–H activation and [4 + 2] annulation reactions in ethanol is described. This reaction is very fast and highly efficient in the green solvent ethanol. The reaction works with a broad substrate scope affording the products in good to excellent yields in a short time. Moreover, a ratio of S/C up to 10 000 could be achieved with gram scale synthesis.

An efficient method to construct tetracyclic isoquinolinium salts via C–H activation and [4 + 2] annulation reactions in ethanol is described.