[3 + 2] cycloaddition of nonstabilized azomethine ylides and 2-benzothiazolamines to access imidazolidine derivatives

A simple and practical method for the construction of 1,3,5-trisubstituted imidazolidine derivatives via [3 + 2] cycloaddition reaction has been developed. This reaction could smoothly proceed between nonstabilized azomethine ylides generated in situ and 2-benzothiazolamines to deliver a wide scope of differently substituted imidazolidines in high yields (up to 98%). The structure of one example was confirmed by X-ray single-crystal structure analysis.

An effective method for the synthesis of functionalized imidazolidine derivatives via a [3 + 2] cycloaddition reaction from nonstabilized azomethine ylides generated in situ from 2-benzothiazolamines in high yields (up to 98%) has been developed.

Heterocyclic compounds are important structural motifs that are frequently discovered in natural products and biologically active molecules, with wide applications and potency in the field of medicinal chemistry.¹ Among them, the 2-aminobenzothiazole scaffolds, which contain a core of isothiourea motifs as a privileged scaffold, are ubiquitous in natural products, drugs and bioactive compounds.² Some examples of biologically active molecules and pharmaceuticals containing benzothiazoles are shown in Fig. 1. These compounds display a variety of important biological activities, such as anti-HIV, anticancer, antineoplastic and anticonvulsant activity, and so on.³Open in a separate windowFig. 1Selected examples of biologically active compounds containing a 2-aminobenzothiazole scaffolds.Due to their momentous and potent biological activities and structural diversifications, more organic and medicinal chemists have been significantly attracted to developing effective and advanced methodologies for the construction of benzazole scaffolds.⁴ The 2-benzothiazolamines could serve as alternative C4 synthons with various reaction partners in [4 + 2] cycloadditions for the straightforward and convenient access to 2-aminobenzothiazole scaffolds, and this type of reaction has been well established (Scheme 1a).⁵ By contrast, the 2-benzothiazolamines which acted as C2 synthons in cycloaddition reactions have been very limited.⁶ Therefore, the development of efficient cycloaddition between the 2-benzothiazolamines as C2 synthons and suitable reaction partners to provide diverse functionalized heteroarenes molecules is always in great demand.Open in a separate windowScheme 1Previous reports and our protocol.On the other hand, the 1,3-dipole cycloaddition is recognized one of the most efficient and powerful methods for building five membered heterocyclic rings from simple starting materials.⁷ In particular, the nonstabilized azomethine ylides generated in situ from N-benzyl-substituted compounds were a highly reactive intermediate with unsaturated compounds, such as activated alkenes,⁸ aromatic ketones,⁹ aromatic aldehydes,¹⁰ phthalic anhydrides,¹¹ imines,¹² cyano compounds¹³ or stable dipoles,¹⁴ to build various N-containing heterocycles via [3 + 2] or [3 + 3] cycloaddition reactions (Scheme 1b). Despite the progress were well developed via 1,3-dipolar cycloadditions employing nonstabilized azomethine ylides as the substrates, challenges still remain. Herein, we would like to present an effective process to furnish functionalized 1,3,5-trisubstituted imidazolidine derivatives via [3 + 2] cycloaddition strategy from 2-benzothiazolamines with nonstabilized azomethine ylides generated in situ (Scheme 1c). In contrast, the desired product was not obtained via [4 + 3] cycloaddition reaction.Initially, we used 2-benzothiazolimine 1a and N-(methoxymethyl)-N-(trimethylsilyl-methyl)-benzyl amine 2a which could in situ form azomethine ylide in the presence of acid as model substrates to optimize the reaction conditions. The results were shown in

Dearomative [3 + 2] cycloaddition reaction of nitrobenzothiophenes with nonstabilized azomethine ylides

A highly diastereoselective dearomative [3 + 2] 1,3-dipolar cycloaddition reaction of nitrobenzothiophenes with an in situ-generated nonstabilized azomethine ylides has been developed. The transformation provides a series of functionalized fused tricyclic benzo[4,5]thieno[2,3-c]pyrroles in good yields (up to 92%) under mild reaction conditions. In addition, a gram-scale experiment and the synthetic transformation of the cycloadduct further highlighted the synthetic utility. The relative configurations of the typical products were clearly confirmed by X-ray crystallography.

A simple and efficient method for the synthesis of benzo[4,5]thieno[2,3-c]pyrroles via dearomative [3 + 2] 1,3-dipolar cycloaddition reaction of nitrobenzothiophenes with an in situ-generated nonstabilized azomethine ylides have been developed.

The dearomative cycloaddition reactions are a powerful synthetic strategy to obtain valuable structural motifs which exist in numerous biologically active natural products, pharmaceutical agents, and also in synthetic and materials building blocks.¹ Among them, indole substrates gained more and more research interest to develop effective methods for the construction of indole-based skeletons and their functionalization via dearomative transformation.² Because the unique properties of indole ring systems are ubiquitous in biologically active alkaloids,³ the range of methodologies that have been explored to access dearomatized indole heterocycles is extremely extensive. In contrast to the dearomative reactions of indole substrates, the analogous benzothiophenes derivatives have been less explored.⁴ In addition, the benzo[b]thiophene derivatives that have found widespread application are frequently found in many bioactive compounds, pharmaceuticals, and as synthetic building blocks.⁵ Therefore, the development of efficient synthetic method to realize the dearomatization of benzo[b]thiophenes for the construction of diverse functionalized heteroarenes molecules continues to be an important and highly desirable in the organic synthetic community.On the other hand, 1,3-dipolar cycloaddition of azomethine ylides with electron deficient dipolarophiles that have a wide range of applications in organic synthesis, is a useful and facile synthetic process for five or six membered heterocyclic rings in one step.⁶ Especially, nonstabilized azomethine ylides generated in situ are highly active intermediates,⁷ with electron-deficient benzoheterocycles, including 2-nitroindoles or 3-nitroindoles (Scheme 1a)⁸ and benzo[b]thiophene 1,1-dioxides (Scheme 1b)⁹ as robust electrophiles to construct various polycyclic heterocyclic skeletons via the dearomative [3 + 2] 1,3-dipolar cycloaddition reaction in the simple way. However, 3- and 2-nitrobenzothiophenes have been uncovered as electrophiles for the dearomative 1,3-dipolar cycloaddition reactions with nonstabilized azomethine ylides to provide S-containing polyheterocyclic compounds. Enormous efforts have been devoted to the development of ever more efficient synthetic methods for the construction and direct functionalization of these heteroaromatic compounds. Herein, we describe a dearomative [3 + 2] cycloaddition reaction of 3-nitrobenzothiophenes with nonstabilized azomethine ylides without metal catalysts under mild reaction conditions, providing a convenient and efficient access to functionalized fused tricyclic benzo[4,5]thieno[2,3-c]pyrroles derivatives bearing two contiguous stereocenters. Additionally, we also successfully extended this new protocol to 2-nitrobenzothiophene and 2-nitrobenzofuran for the corresponding dearomatization products.Open in a separate windowScheme 1Dearomative cycloaddition reaction of electron-deficient heteroarenes with nonstabilized azomethine ylides.Initially, we chosed 3-nitrobenzothiophene 1a and N-(methoxymethyl)-N-(trimethylsilyl-methyl)-benzyl-amine 2a which generated in situ nonstabilized azomethine ylide in the presence of trifluoroacetic acid (TFA) as model substrates to optimize the reaction conditions. As the results are shown in EntrySolventTimeYield of 3a^b (%)1CH₂Cl₂12902CH₂Cl₂24903CHCl₃24814DCE24805EtOAc24<56CH₃CN24<57Toluene24<58THF24229Et₂O242010Dioxane247311^cCH₂Cl₂127212^dCH₂Cl₂129013^eCH₂Cl₂246214CH₂Cl₂664Open in a separate window^aUnless noted otherwise, reactions were performed with 3-nitrobenzothiophene 1a (0.1 mmol) and 2a (0.12 mmol), TFA (0.1 mmol, 1 equiv.) in solvent (1.0 mL) at rt.^bYield of the isolated product and dr >20 : 1 by ¹H NMR analysis.^cThe reaction was performed at 40 °C.^d1.2 equiv. TFA were used.^e0.5 equiv. TFA were used.With the optimized conditions in hand, we set out to investigate the scope and limitation of 3-nitrobenzothiophenes 1 with nonstabilized azomethine ylides via dearomative [3 + 2] cycloaddition reaction to provide fused tricyclic benzo[4,5]thieno[2,3-c]pyrroles. The representative results are summarized in †).¹² For its structural details, see the ESI.^†10 The other products were assigned by analogy. However, when the 2c substrate reacts with 3-nitrobenzothiophene 1a and 3-cyanobenzothiophene 1q reacts with N-(methoxymethyl)-N-(trimethylsilyl-methyl)-benzyl-amine 2a under the standard conditions (entries 16 and 17). These reactions didn''t work. These reactions revealed that the compounds 2c and 1q had significantly lower reactivity. Subsequently, when we tried the reaction of 3-2-methyl-3-nitrobenzothiophene 1r with N-(methoxymethyl)-N-(trimethylsilyl-methyl)-benzyl-amine 2a under the standard conditions (entry 18). Unfortunately, it was observed that the reaction did not take place. The possible reason may be due to the increased steric hindrance at the C2-position of the 2-methyl-3-nitrobenzothiophene, inhibiting the cycloaddition reaction.Substrate scope and limitations of the [3 + 2] cycloaddition^a

Synthesis of spirocyclic Δ4-isoxazolines via [3 + 2] cycloaddition of indanone-derived ketonitrones with alkynes

A [3 + 2] cycloaddition of indanone-derived nitrones and alkynes under mild conditions is developed, allowing facile synthesis of spirocyclicindenyl isoxazolines with structural diversity. The sequential protocol of generated in situ ketonitrone from unsaturated ketones and N-alkylhydroxylamines is also achieved successfully, affording the desired products in considerable yield with moderate to good diastereoselectivity. Moreover, the spirocyclic product can be conveniently transformed into indenyl-based allylic alcohol and enamide.

A [3 + 2] cycloaddition of indanone-derived nitrones with alkynes under mild conditions has been developed. It is a highly efficient and straightforward method for the synthesis of diverse spirocyclicindenyl isoxazolines.     

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.     

Pd-catalyzed [3 + 2] cycloaddition of vinylcyclopropanes with 1-azadienes: synthesis of 4-cyclopentylbenzo[e][1,2,3]oxathiazine 2,2-dioxides

The palladium-catalyzed [3 + 2] cycloaddition of vinylcyclopropanes and 1-azadienes has been developed under mild reaction conditions, giving the multisubstituted cyclopentane derivatives in good to excellent yields with moderate to good diastereoselectivities. The relative configuration of both diastereomers of the products have been determined through X-ray crystallographic diffraction.

Pd-catalyzed [3 + 2] cycloaddition of vinylcyclopropanes with 1-azadienes gave highly functionalized cyclopentane derivatives in high yields.

The cyclopentane framework is ubiquitous in nature and it is also an important structural moiety in many pharmaceuticals, agrochemicals, and materials.¹ The development of simple, fast and efficient synthetic methods for highly substituted cyclopentanes has attracted much attention. Among various methods for synthesis of cyclopentane structure, the cycloaddition reaction is a very attractive one.²Under palladium catalysis conditions, vinylcyclopropane derivatives underwent a ring-opening reaction to generate the zwitterionic allylpalladium intermediate, which reacted with carbon–carbon, carbon–oxygen, carbon–nitrogen double bonds and diazo compounds to provide a variety of five-membered cyclic compounds.³ In the past decades, this type of annulation reactions has emerged as a powerful tool for the synthesis of carbocyclic and heterocyclic compounds.² Diverse substrates including isocyanates,⁴ aldehydes,⁵ isatins,⁶ 3-diazooxindoles,⁷ electron-deficient alkenes such as para-quinone methides,⁸ α,β-unsaturated aldehydes,⁹ β,γ-unsaturated α-keto esters,¹⁰ nitroolefins,¹¹ azlactone- and Meldrum''s acid alkylidenes,¹² and α-nucleobase substituted acrylates,¹³ have been exploited in palladium-catalyzed [3 + 2] cycloadditions of vinyl cyclopropane, delivering biologically interesting functionalized heterocyclic compounds and cyclopentane derivatives. In 2015, Liu and He reported a palladium-catalyzed [3 + 2] cycloaddition of vinyl cyclopropane and α,β-unsaturated imines generated in situ from aryl sulfonyl indoles, providing the optically enriched spirocyclopentane-1,3′-indolenines with high diastereoselectivity.¹⁴ This is the only example where α,β-unsaturated imines were employed in Pd-catalyzed [3 + 2] cycloaddition reaction of vinyl cyclopropane.As a type of α,β-unsaturated imines, cyclic 1-azadienes such as (E)-4-styrylbenzo[e][1,2,3]oxathiazine 2,2-dioxides 2 are easily accessible and stable (Scheme 1). In particular, they contain the sulfonate-moiety, which is an interesting biologically important motif, and has a great potential in the synthesis of bioactive molecules.¹⁵ The cyclic 1-azadienes have been used in a series of annulation reactions such as [2 + n],^16–18 [3 + n],¹⁹ and [4 + n]²⁰ annulation reactions. Based on the electron-deficient nature of the carbon–carbon double bond in these cyclic 1-azadienes, in 2016, Chen and Ouyang developed cinchona-derived tertiary amine-catalyzed asymmetric [3 + 2] annulation of isatin-derived Morita–Baylis–Hillman (MBH) carbonates with cyclic 1-azadienes to form spirooxindole.¹⁷ In the same year, our group demonstrated a phosphine-catalyzed [3 + 2] annulation of MBH carbonates with cyclic 1-azadienes.¹⁸ Considering that the 1-azadiene 2 is an electron-deficient alkene with good reactivity, its reaction with a zwitterionic π-allyl Pd complex formed via ring-opening of vinylcyclopropane may be feasible. However, this type of cyclic 1-azadienes have never been used in Pd-catalyzed annulation reactions involving vinylcyclopropanes. As our continuing interest on cycloaddition reactions,²¹ herein we disclose a [3 + 2] cycloaddition of palladium-catalyzed vinyl cyclopropane with cyclic 1-azadienes to afford the multisubstituted cyclopentane derivatives (Scheme 1).Open in a separate windowScheme 1[3 + 2] Cycloaddition of 1,3-zwitterions with cyclic 1-azadienes.We carried out an initial screening with 2-vinylcyclopropane-1,1-dicarbonitrile 1a and (E)-4-styrylbenzo[e][1,2,3]oxathiazine 2,2-dioxide 2a in CH₂Cl₂ (DCM) at room temperature in the presence of Pd₂(dba)₃·CHCl₃ (2.5 mol%) (22 Under the optimized reaction conditions, we attempted to develop asymmetric variant of this reaction. Unfortunately, the two enantiomers of the product could not be resolved at present stage.²³Optimization of the reaction conditions^a

Construction of cyclopentane-fused coumarins via DBU-catalyzed [3+2] cycloaddition of 3-homoacyl coumarins with cyclic 1-azadienes

The metal-free DBU catalyzed [3+2] cycloaddition of 3-homoacyl coumarins with cyclic 1-azadienes proceeded smoothly to furnish the corresponding highly functionalized cyclopentane-fused coumarins with excellent diastereoselectivity and complete chemoselectivity and in good yields under mild conditions.

A metal-free DBU catalyzed [3+2] cycloaddition of 3-homoacyl coumarins with cyclic 1-azadienes has been developed for the synthesis of cyclopentane-fused coumarins with excellent diastereoselectivity and complete chemoselectivity.

Coumarins¹ and cyclopentane scaffolds² are widely distributed in natural products and display a wide range of biological and pharmacological activities. When combining coumarin skeletons with cyclopentane moieties, the cyclopentane-fused coumarins show interesting biological activities. For example, aflatoxins, which occur naturally, exhibit acute toxicity, teratogenicity, mutagenicity and carcinogenicity (Fig. 1).³ Herbertenolide, which belongs to the family of sesquiterpenoids, was first isolated from the leafy liverwort Herberta adunca, the extract of which showed significant inhibition against the growth of certain plant pathogenic fungi (Fig. 1).⁴ Not surprisingly, the strategies for synthesis of cyclopentane-fused coumarins have attracted much attention.⁵Open in a separate windowFig. 1Bioactive molecule bearing cyclopentane-fused coumarin.Recently, the group of Lin developed a 1,3-dipolar precursor 3-homoacyl coumarin, which is an efficient synthon for the construction of cyclopentane-fused coumarins under the catalysis of bases (Scheme 1a and b).⁶ However, the partners reacted with 3-homoacyl coumarins were focus on α,β-unsaturated carbonyl compounds and conjugated dienes. The other dipolarophiles, such as aza-dienes, might also be potential candidates for the [3+n] cycloadditions with 3-homoacyl coumarins but never been developed.Open in a separate windowScheme 1The reaction of 3-homoacyl coumarins with dipolarophiles catalyzed by Brønsted base.The cyclic 1-azadienes are extensive used dipolarophiles and have been widely involved in a series of cyclization reactions as two-,⁷ three-⁸ or four⁹ member synthons. While the organocatalytic [3+2] cycloaddition of cyclic 1-azadiene as two synthons has rarely been investigated.^7b,c In 2016, Chen''s^7b and Guo''s^7c group respectively developed a asymmetric [3+2] annulation reaction of Morita–Baylis–Hillman carbonates with cyclic 1-azadienes catalyzed by Lewis base. Encouraged by these works above and as our continuing efforts on cycloadditions,¹⁰ herein we expected to achieve the first [3+2] cycloaddition reaction of 3-homoacyl coumarins with cyclic 1-azadienes catalyzed by Brønsted base for synthesis of various functionalized cyclopentane-fused coumarins derivatives efficiently (Scheme 1d). However, Huang''s group reported a enantioselective 1,4-addition reaction of benzofuran azadiene with 3-homoacyl coumarin, instead of cycloaddition (Scheme 1c).¹¹ To achieve our assumption in high chemoselectivity would be a challenging work.In an initial experiment, cyclic 1-azadiene 1a and 6-bromo-3-(2-oxo-2-phenylethyl)-2H-chromen-2-one 2a were employed as the model substrates to carry out the reaction in CH₂Cl₂ at room temperature in the presence of DABCO. To our delight, the desired [3+2] cycloadduct 3aa was obtained in 56% yield ( EntryBaseSolventTime (h)Yield^b (%)dr^c1DABCOCH₂Cl₂2456>20 : 12DMAPCH₂Cl₂2460>20 : 13DBUCH₂Cl₂1278>20 : 14Et₃NCH₂Cl₂2467>20 : 15DBUTHF1286>20 : 16DBUToluene1231>20 : 17DBUDCE1276>20 : 18DBUCH₃CN1273>20 : 1Open in a separate window^aReactions were carried out with 1a (0.1 mmol), 2a (0.12 mmol), and base (20 mol%) in 2 mL of solvent at rt.^bIsolated yields.^cDetermined by ¹H NMR.Under optimal reaction conditions, the substrate scope of the cyclic 1-azadienes 1 was investigated and the results were summarized in EntryR¹ in 13Yield^b (%)dr^c12-FC₆H₄ (1b)3ba85>20 : 123-FC₆H₄ (1c)3ca90>20 : 134-FC₆H₄ (1d)3da85>20 : 143-ClC₆H₄ (1e)3ea86>20 : 154-ClC₆H₄ (1f)3fa80>20 : 163-BrC₆H₄ (1g)3ga79>20 : 174-BrC₆H₄ (1h)3ha80>20 : 184-CNC₆H₄ (1i)3ia75>20 : 192-MeC₆H₄ (1j)3ja79>20 : 1103-MeC₆H₄ (1k)3ka76>20 : 1114-MeC₆H₄ (1l)3la73>20 : 1122-OMeC₆H₄ (1m)3ma67>20 : 1133-OMeC₆H₄ (1n)3na75>20 : 1144-OMeC₆H₄ (1o)3oa77>20 : 1152-Naphthyl (1p)3pa72>20 : 1162-Thienyl (1q)3qa74>20 : 1Open in a separate window^aReactions were carried out with 1 (0.1 mmol), 2a (0.12 mmol), and DBU (20 mol%) in 2 mL of THF at rt for 12–48 h.^bIsolated yields.^cDetermined by ¹H NMR.Subsequently, we performed the application of cyclic 1-azadiene 1a in DBU-catalyzed [3+2] cycloaddition with a variety of 3-homoacyl coumarins 2 under the optimal conditions (12Substrate scope of 3-homoacyl coumarins 2^a

Synthesis of spiro[4.4]thiadiazole derivatives via double 1,3-dipolar cycloaddition of hydrazonyl chlorides with carbon disulfide

An operationally simple and convenient synthesis method toward a series of diverse spiro[4.4]thiadiazole derivatives via double [3 + 2] 1,3-dipolar cycloaddition of nitrilimines generated in situ from hydrazonyl chlorides with carbon disulfide has been achieved under mild reaction conditions.

A simple and convenient synthesis method for spiro[4.4]thiadiazole derivatives via double [3 + 2] 1,3-dipolar cycloaddition of nitrilimines generated in situ from hydrazonyl chlorides with carbon disulfide has been achieved.

The spirocyclic compounds having cyclic structures connected through just one carbon atom have attracted much interest from synthetic chemists and medicinal chemists because of their ubiquitous presence in the core of a plethora of natural products and non-natural products, many of which display a broad range of pharmacological and biological activities.¹ Moreover, spiro-compounds are unique because of their rigidity and distinctly three-dimensional structure and have proved to be very interesting for medicinal chemistry or as ligand and catalyst motifs in asymmetric synthesis.² Due to the importance of the spirocyclic architectures, the methods for synthesis of the spirocyclic moiety are too many to enumerate. Some common strategies to afford spirocyclic scaffolds include radical cyclizations,³ Diels–Alder reactions,⁴ cycloaddition,⁵ and ring expansion,⁶ among others. Many of the known methods for synthesizing spiro structures are through constructing a new ring of which the substrates include a carbo- or heterocycle structure.⁷ To the best of our knowledge, a few approaches have offered efficient ways on the formation of two rings through a double 1,3-dipolar cycloaddition in one pot for constructing spirocyclic scaffold.⁸ Therefore, the design and development of innovative and efficient methodologies via double 1,3-dipolar cycloaddition under mild reaction conditions for synthesizing bioactive content spirocyclic scaffolds from readily available precursors is in great demand in both organic and medicinal chemistry.On the other hand, the 1,3-dipolar cycloaddition reaction (1,3-DCs) has been one of the most prominent reactions to build five- or six-membered heterocycle in one step in the field of organic synthesis.⁹ In particular, nitrilimines generated in situ from the corresponding hydrazonyl chloride in the presence of a base are highly active intermediates in organic synthesis and have been widely used as useful synthons for preparing bioactive nitrogen heterocyclic derivatives and spirocyclic compounds through the [3 + 2],¹⁰ [3 + 3]¹¹ and [3 + 4]¹² cycloaddition reactions. In addition, the Lu group reported 1,3-dipolar cycloaddition of nitrilimines with carbon dioxide (CO₂), providing elegant access to 1,3,4-oxadiazole-2(3H)-ones derivatives.¹³ Meanwhile, carbon disulfide (CS₂) that it is an analogue of CO₂, has been used for the synthesis of various sulfur-containing heterocyclic compounds for agricultural, medicinal, and pharmaceutical applications.¹⁴ Based on the above literatures and in continuation of our interest in synthesis of heterocycles, we disclose a novel protocol for the synthesis of spiro[4.4]thiadiazole derivatives double 1,3-dipolar cycloaddition of nitrilimines generated in situ from hydrazonyl chlorides with carbon disulfide under mild conditions.In our initial investigation, we chose the hydrazonyl chloride as the nitrilimine precursor with CS₂ as the model reaction to optimize the reaction conditions. The results of these experiments are summarized in EntryBaseSolventYield of 3a^b (%)1NoneCH₂Cl₂02TEACH₂Cl₂603DABCOCH₂Cl₂564^bDBUCH₂Cl₂Trace5Na₂CO₃CH₂Cl₂626K₂CO₃CH₂Cl₂707Cs₂CO₃CH₂Cl₂928NaOHCH₂Cl₂909KOHCH₂Cl₂8810Cs₂CO₃CHCl₃8011Cs₂CO₃DCE8512Cs₂CO₃EtOAc7013Cs₂CO₃Toluene6114Cs₂CO₃THFTrace15Cs₂CO₃Et₂OTrace16Cs₂CO₃Dioxane5617Cs₂CO₃MeCN6218^cCs₂CO₃CH₂Cl₂8019^dCs₂CO₃CH₂Cl₂92Open in a separate window^aUnless noted otherwise, reactions were performed with hydrazonyl chloride 1a (0.2 mmol), carbon disulfide (0.3 mmol, 1.5 equiv.), base (0.2 mmol, 1 equiv.) in solvent (1.0 mL) at rt for 12 h.^bIsolated yield by chromatography on silica gel.^cReaction was performed with carbon disulfide (0.2 mmol, 1 equiv.) for 24 h.^dCarbon disulfide (1.0 mmol, 5 equiv.).Substrate scope of the double 1,3-dipolar cycloaddition^a

DFT exploration of [3 + 2] cycloaddition reaction of 1H-phosphorinium-3-olate and 1-methylphosphorinium-3-olate with methyl methacrylate

A Molecular Electron Density Theory (MEDT) study of the regio- and stereoselectivity of the [3 + 2] cycloaddition (32CA) reaction of 1H-phosphorinium-3-olate and 1-methylphosphorinium-3-olate with methyl methacrylate was carried out using the B3LYP/6-31G(d) method. In order to test the method dependence for the most favorable reaction path leading to the 1H-substituted 6-exo cycloadduct (CA) various functionals using higher basis sets were taken into consideration in the gas phase. An analysis of the energetic parameters indicates that the reaction path leading to 6-exo CA are kinetically as well as thermodynamically favored in the gas phase, THF and ethanol. The calculated energetic parameters of the 32CA reaction of these phosphorus derivatives were compared with those of methyl acrylate and their nitrogen analogues. Investigation of the global electron density transfer at the TSs indicates that these 32CA reactions have non-polar character, while electron localisation function topological analysis of the C–C bond formation along the most favorable reaction path indicates that these 32CA reactions take place through a non-concerted two-stage one-step mechanism, via highly asynchronous TSs.

These phosphorus cycloadducts are kinetically and thermodynamically more favorable than their nitrogen analogues, providing incentives to experimentalists in the quest to synthesise phosphorus containing heterocycles.     

Retraction: Metal-free [2+2+1] cycloaddition polymerization of alkynes,nitriles, and oxygen atoms to functional polyoxazoles

Retraction of ‘Metal-free [2+2+1] cycloaddition polymerization of alkynes, nitriles, and oxygen atoms to functional polyoxazoles’ by Lichao Dong et al., RSC Adv., 2020, 10, 24368–24373, DOI: 10.1039/D0RA04249H.

We, the named authors, hereby wholly retract this RSC Advances article as there is insufficient data to support the structure of the final polymer product, and therefore, the conclusions are not fully supported. In Fig. 1 the peaks of the ¹H-NMR spectrum are stacked together and therefore the spectrum cannot be used as proof of the polymer structure. In Fig. 2, the ¹³C-NMR spectrum, the peaks on the benzene ring cannot correspond to before and after polymerization. Therefore, further research and characterization work is needed to determine the structure of the resulting polymer.The corresponding authors regret this oversight and apologise for any inconvenience to readers. Signed: Lichao Dong, Tian Lan, Yin Liang, Shifeng Guo and Hao ZhangDate: 18 April 2021 Retraction endorsed by Laura Fisher, Executive Editor, RSC Advances     

Retracted Article: Metal-free [2+2+1] cycloaddition polymerization of alkynes,nitriles, and oxygen atoms to functional polyoxazoles

The metal-free [2+2+1] cycloaddition polymerization of alkynes, nitriles, and O-atoms for the regioselective assembly of highly substituted oxazole compounds has been achieved by the use of iodosobenzene (PhIO) with trifluoromethanesulfonic acid (TfOH). The present reaction could be applied to a facile synthesis of polyoxazoles. In this work, the cycloaddition polymerization of 4-cyano-4′-ethynylbiphenyl and PhIO was developed and modified polyoxazole was prepared. All experimental conditions such as polymerization solvent, temperature, catalyst and time were systematically studied. The structure of the obtained polyoxazole was characterized by GPC and NMR, and its thermal properties were studied by TGA. In addition, the good thermal stability of polyoxazoles with unreacted terminal alkynes and cyano groups makes them potentially useful for modifying resins.

The metal-free [2+2+1] cycloaddition polymerization of alkynes, nitriles, and O-atoms for the regioselective assembly of highly substituted oxazole compounds has been achieved by the use of iodosobenzene (PhIO) with trifluoromethanesulfonic acid (TfOH).     

Selective formation of dihydrofuran fused [60] fullerene derivatives by TEMPO mediated [3 + 2] cycloaddition of medium chain β-keto esters to C60

In this study, β-keto esters as readily available bio-based building blocks were used to decorate the C₆₀ sphere. Generally, cyclopropanated fullerene derivatives are obtained by the standard Bingel–Hirsch procedure. Herein, omitting the iodine from the reaction mixture and adding TEMPO afforded dihydrofuran fused C₆₀ fullerene derivatives. The mechanism of the reaction shifted from nucleophilic aliphatic substitution to oxidative [3 + 2] cycloaddition via fullerenyl cations as an intermediate. This mechanism is proposed based on a series of control experiments with radical scavengers. Therefore, dihydrofuran-fused C₆₀ derivatives were selectively obtained in good yields and their structures were established based on UV-Vis, IR, NMR spectroscopy and mass spectrometry. The electrochemical properties of the synthesized compounds were investigated by cyclic voltammetry. DFT calculations were performed in order to investigate the difference in stability, electronic properties and π-electron delocalization between methano and furano fullerenes.

In this study, β-keto esters as readily available bio-based building blocks were used to decorate the C₆₀ sphere.     

Acid-promoted iron-catalysed dehydrogenative [4 + 2] cycloaddition for the synthesis of quinolines under air

An acid-promoted iron-catalysed dehydrogenative [4 + 2] cycloaddition reaction was developed for the synthesis of quinolines using air as a terminal oxidant. Acetic acid was the best cocatalyst for the cycloaddition of N-alkyl anilines with alkenes or alkynes under air. Various quinoline derivatives were obtained in satisfactory-to-excellent yields, and no other byproducts besides water were produced in the reaction. The zebrafish model has become an important vertebrate model for evaluating drug effects. We tested the activity of 3n in zebrafish. The test results showed that 1 μg mL⁻¹3n treatments resulted in morphological malformation, and 0.01–0.1 μg mL⁻¹3n treatments led to potent angiogenic defects in zebrafish embryos. The results of this study will be of great significance for promoting drug research in cardiovascular and cerebrovascular diseases.

An acid-promoted iron-catalysed dehydrogenative [4 + 2] cycloaddition reaction was developed for the synthesis of quinolines using air as a terminal oxidant. Various quinoline derivatives were obtained, and no other byproducts besides water.

The construction of quinoline motifs has received intensive attention owing to their potential application in photovoltaic devices¹ and pharmaceuticals,² such as anticancer, antiviral, antifungal, antiplatelet aggregation, antimalarial, antibacterial, antileishmanial and anti-inflammatory medicine.³ Because of their importance, many methods have been reported for the synthesis of quinolines.⁴ Among them, the most attractive strategy for the synthesis of these compounds is the dehydrogenative [4 + 2] cycloaddition through transition-metal catalysis and Lewis/Bronsted acid catalysis. In its most general and classical form, dehydrogenative [4 + 2] cycloaddition catalysed by transition metals such as Fe,⁵ Cu,⁶ Pd,⁷ and others,⁸ has been used as a potent tool for the synthesis of quinolone derivatives (Scheme 1a). However, these methods require the presence of excess peroxides, chloranil, potassium persulfate or other oxidants to promote the cycloaddition reaction and to obtain good product yields. Furthermore, in these processes, the formation of stoichiometric amounts of acid or tetrachlorohydroquinone waste as byproducts is a substantial problem that has limited their use. To overcome these drawbacks, several methods that utilise oxygen as a terminal oxidant have been reported.⁹ However, in many cases, the industrial use of these methods is problematic owing to operational difficulty. Therefore, the development of more efficient and economical synthetic methods is still necessary. Undoubtedly, the use of air as a terminal oxidant is the best choice. In addition, in the field of transition-metal catalysis, iron is one of the most commonly used base metals and has been widely applied in various coupling reactions.¹⁰ Therefore, it is desirable to develop an iron-catalysed dehydrogenative cycloaddition for the synthesis of quinoline under air.Open in a separate windowScheme 1Different strategies for [4 + 2] cycloaddition of N-alkyl anilines and alkenes or alkynes by transition-metal catalysis.Herein, we report the first acid-promoted iron-catalysed dehydrogenative [4 + 2] cycloaddition of N-alkyl anilines with alkenes or alkynes using air as a terminal oxidant (Scheme 1b). Iron-catalysed cycloaddition reaction for the synthesis of quinolines under air has always been a challenge because of metal deactivation after the end of the catalytic cycle. We commenced our studies by treating N-benzylaniline (1a) and styrene (2a) with 5 mol% iron as a catalyst. Initially, we tried to use a variety of iron catalysts to catalyse the cycloaddition of N-alkyl anilines and olefins under air ( EntryCatalyst (5 mol%)Acid (0.3 mmol)Solvent T (°C)Yield^a (%)1Fe(OTf)₂NoToluene120Trace2FeCl₂NoToluene120Trace3FeCl₃NoToluene120284Fe₂O₃NoToluene120Trace5Fe₂(SO₄)₃NoToluene120Trace6Fe(OTf)₃NoToluene120337Fe(OTf)₃NoEthanol12008Fe(OTf)₃NoMysitylene120269Fe(OTf)₃NoDioxane120010Fe(OTf)₃NoNitrobenzene1202811Fe(OTf)₃NoAcetonitrile1202312Fe(OTf)₃NoToluene1504213Fe(OTf)₃NoToluene1404914Fe(OTf)₃NoToluene1001615Fe(OTf)₃NoToluene80816Fe(OTf)₃NoToluene60Trace17Fe(OTf)₃NoToluene40018Fe(OTf)₃H₂SO₄Toluene140019Fe(OTf)₃TfOHToluene140020Fe(OTf)₃TFAToluene1406521Fe(OTf)₃PTSAToluene1406122^bFe(OTf)₃BNPAToluene1405723Fe(OTf)₃HCOOHToluene1404224Fe(OTf)₃BzOHToluene14050 25 Fe(OTf) ₃ AcOH Toluene 140 82 26Fe(OTf)₃PhB(OH)₂Toluene1403527Fe(OTf)₃B(OH)₃Toluene1401528Fe(OTf)₃PhenolToluene1405429^cFe(OTf)₃AMSAToluene1405130NoAcOHToluene140TraceOpen in a separate window^aIsolated yields.^bBNPA = 1,1′-binaphthyl-2,2′-diylhydrogen-phosphate.^cAMSA = aminomethanesulfonic acid.The optimal solvent for the reaction was toluene (Scheme 2), could be formed in the reaction from the interaction of the imine intermediate and FeL₃, which could not catalyse the conversion of imines to quinoline. Critically, the FeL₂ species was difficult to oxidize to FeL₃ under air conditions. Inspired by Birk''s work,¹¹ we envisaged that the addition of an acid may promote the oxidation of Fe(ii) to Fe(iii) under air. Based on this assumption, we proposed that FeL₃ can undergo ligand exchange with HL′ to generate the active catalytic species L₂FeL′. A subsequent oxidation reaction provided LFeL′, which was easier oxidize to L₂FeL′ than FeL₂ under air, enabling the next catalytic cycle.Open in a separate windowScheme 2Proposed strategy.Based on this hypothesis, we investigated some strong acids and moderate acids. Trifluoroacetic acid (TFA) was a cocatalyst that promoted the Fe-catalysed [4 + 2] cycloaddition of N-alkyl anilines and alkenes to deliver 2,4-diphenylquinoline in 65% yield (Scheme 3, entries 21–22). For further improvement of the reaction, other acid such as formic acid (HCOOH), benzoic acid (BzOH), acetic acid (AcOH), phenylboronic acid, boric acid, phenol and carbamic acid were tested (Open in a separate windowScheme 3Reaction conditions: substrate 1 (0.2 mmol), aryl olefin (0.4 mmol), Fe(OTf)₃ (10 μmol), AcOH (0.3 mmol), toluene (1.0 mL), at 140 °C under air for 24 h, and isolated yields of the products.With the optimized reaction conditions in hand, a series of aryl ethylenes were investigated for extending the substrate scope (Scheme 3). This acid-promoted iron-catalysed dehydrogenative [4 + 2] cycloaddition reaction displayed good functional group tolerance. Aryl ethylenes with electron-neutral or electron-donating groups on the aryl rings, such as alkyl, phenyl and naphthyl, all gave the corresponding 2,4-diarylquinoline with high selectivity in good yields. Aryls containing an electron-withdrawing group such as fluoro, chloro, bromo and ester were also tolerated and afforded the corresponding 2,4-diarylquinolines 3e–3n in moderate to good yields. Moreover, the reaction of N-benzylaniline 1b containing a substituent (MeO) at the para-position of the aniline ring also produced the corresponding quinoline products 3o in 79% yield. These results indicated that different groups, such as methyl, phenyl, fluoro, chloro, bromo and methoxyl on benzene rings, were tolerated under the optimized reaction conditions. Notably, the retention of the F, Cl and Br atoms in the structures of the products should make the products considerably useful in organic transformations. Unfortunately, the current method could not be applied to olefins containing N heteroatoms, which was likely because of the strong coordination of N atoms with iron.Next, the scope of arylacetylenes was also investigated, and the results are summarized in Scheme 4. Arylacetylenes could be used instead of arylethylenes for the synthesis of 2,4-diarylquinoline under the optimized reaction conditions. Similar good results were obtained, as shown in Scheme 4. Quinoline derivatives 3a–3g, 3i, 3k–3m and 3o were obtained in satisfactory to good yields (63–96%).Open in a separate windowScheme 4Reaction conditions: substrate 1 (0.2 mmol), aryl alkyne (0.4 mmol), Fe(OTf)₃ (10 μmol), AcOH (0.3 mmol), toluene (1.0 mL), at 140 °C under air for 24 h, and isolated yields of the products.To test the synthetic utility of the current method, a gram scale dehydrogenative [4 + 2] cycloaddition reaction of N-benzyl-4-methoxyaniline with methyl-2-vinylbenzoate was conducted under the optimal conditions, providing the target 3n in 45% yield. To demonstrate the potential of our approach, we conducted molecular docking studies of human phenylethanolamine N-methyltransferase (hPNMT) and the quinoline derivatives. The studies were performed to help visualize possible interactions between hPNMT and the quinoline derivatives. The results showed that methyl-2-(6-methoxy-2-phenylquinolin-4-yl)benzoate 3n may have π–π interactions with ARG 90, and π–cation interactions with TYR 27 in hPNMT. Based on this docking result, 3n is highly likely to be a potent inhibitor of hPNMT. The results of the docked poses of hPNMT and 3n are shown in the ESI.^† The zebrafish model has become an important vertebrate model for evaluating drug effects. ¹² To demonstrate the drug effect of 3n on the vascular system in the trunk of zebrafish embryos, we tested the activity of 3n in zebrafish. The test results showed treatment of zebrafish embryos with 1 μg mL⁻¹3n resulted in morphological malformation, and treatment with 0.01–0.1 μg mL⁻¹3n led to potent angiogenic defects (Scheme 5b). The results of this study will be of great significance for promoting drug research in cardiovascular and cerebrovascular diseases.Open in a separate windowScheme 5Gram-scale synthesis and the drug effect of 3n treatment on vascular in the trunk of Tg(kdrl:EGFP) zebrafish embryos at 48 hpf. (A–D) control group and 1, 0.1, 0.01 μg mL⁻¹3n treated groups. Scale bar, 75 μm.To gain a better understanding of the role of the acid, air and iron in the current cycloaddition reaction, additional experiments were conducted. First, control experiments showed that the absence of any of the three components, air, AcOH and Fe(OTf)₃, significantly reduced the reaction yield, implying that each of the components was essential to this reaction. To clarify that the reaction was undergoing the production of an imine intermediate, we employed N-benzylideneaniline as a substrate to test if 2,4-diphenylquinoline could be obtained (Scheme 6). To our great surprise, 3a was obtained in 99% yield. The results showed that a cycloaddition reaction occurred after N-benzylaniline was oxidized to an imine. Based on these results, we proposed the following catalytic cycle: FeL₃ first underwent ligand exchange with AcOH to generate an active catalytic species L₂FeOAc, leading to subsequent oxidative dehydrogenation to provide the imine intermediate and intermediate LFeOAc while releasing HL. The imine intermediate can then undergo a [4 + 2] cycloaddition with an alkyne or alkene, forming the desired 2,4-diarylquinoline or dihydroquinoline. A subsequent dehydrogenation reaction of dihydroquinoline provided the target product. The intermediate LFeOAc underwent an oxidation reaction in the presence of air to regenerate the catalytic species L₂FeOAc.Open in a separate windowScheme 6Mechanistic experiments.     

Synthesis of novel series of 3,5-disubstituted imidazo[1,2-d] [1,2,4]thiadiazoles involving SNAr and Suzuki–Miyaura cross-coupling reactions

The first access to 3,5-disubstituted imidazo[1,2-d][1,2,4]thiadiazole derivatives is reported. The series were generated from 2-mercaptoimidazole, which afforded the key intermediate bearing two functional positions. The S_NAr reactivity toward tosyl release at the C-3 position was investigated and a regioselective electrophilic iodination in C-5 position was performed to allow a novel C–C bond using Suzuki–Miyaura reaction. Palladium-catalyzed cross-coupling conditions were optimized. A representative library of various boronic acids was employed to establish the scope and limitations of the method. To complete this methodological study, the influence of the nature of the C-3 imidazo[1,2-d][1,2,4]thiadiazole substitutions on the arylation in C-5 was investigated.

A convenient design of 3,5-disubstituted imidazo[1,2-d][1,2,4]thiadiazoles is reported from 2-mercaptoimidazole, which afforded a versatile platform that was then used to access a variety of original heterocycles.     

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.     

Base-iodine-promoted metal-catalyst-free reactions of [60]fullerene with β-keto esters for the selective formation of [60]fullerene derivatives

In this study, methanofullerenes and 2′,3′-dihydrofuran C₆₀ derivatives were selectively synthesized in high yields via the reactions of C₆₀ with β-keto esters under mild conditions by controlling the addition sequence and molar ratio of iodine and base. The structures of the products were determined by spectroscopic characterization. Moreover, a possible reaction mechanism for the selective formation of fullerene derivatives was proposed.

In this study, methanofullerenes and 2′,3′-dihydrofuran C₆₀ derivatives were selectively synthesized in high yields via the reactions of C₆₀ with β-keto esters under mild conditions by controlling the addition sequence and molar ratio of iodine and base.     

Synthesis of tetrahydrochromenes and dihydronaphthofurans via a cascade process of [3 + 3] and [3 + 2] annulation reactions: mechanistic insight for 6-endo-trig and 5-exo-trig cyclisation

Substituted tetrahydrochromenes and dihydronaphthofurans are easily accessible by the treatment of β-tetralone with trans-β-nitro styrene derived Morita–Baylis–Hillman (MBH) acetates through a formal [3 + 3]/[3 + 2] annulation. The reaction proceeds through a cascade Michael/oxa-Michael pathway with moderate to good yields. A DFT study was carried out to account for the formation of the corresponding six and five-membered heterocycles via 6-endo-trig and 5-exo-trig cyclization.

A [3 + 3] and [3 + 2] annulation strategy using nitrostyrene derived MBH primary and secondary nitro allylic acetate for the construction of tetrahydrochromenes and dihydronaphthofurans at room temperature.

The ability to synthesize diverse molecules utilizing nitro allylic MBH acetates in various cascade reactions has received considerable interest.¹ A few molecules synthesized using nitro allylic acetates have shown promising cytotoxic, trypanocidal and AchE inhibition² activity in pharmaceutical and medicinal chemistry. Nitro allylic MBH acetates have been used as main precursors in organocatalysis³ and heterocyclic chemistry,⁴ and as bicyclic skeletons⁵ for the construction of elegant building blocks like tetrahydro-pyranoquinolinones,⁶ sulfonyl furans,⁷ pyranonaphthoquinones,⁸ arenopyrans/arenylsulfanes,⁹ triazoles,^10a tetrasubstituted furans,^10b fused furans,^10c,d tetrasubstituted pyrroles,^11a benzofuranones,^11b and tetrahydropyrano scaffolds/pyranocoumarins.¹² The nitro allylic MBH-acetates can also undergo asymmetric benzylic^13a and allylic alkylation^13b reactions as well as kinetic resolution [KR]^13c,d under normal conditions. These acetates undergo a range of cascade [2 + 3],¹⁴ [3 + 2]¹⁵ and [3 + 3]¹⁶ ring annulation reactions using different substrates. They have been widely utilized in [3 + 2]^17a and [3 + 3]^17b annulation reactions due to their unique nature of 1,2-/1,3-biselectrophilic reactivity to form either five or six membered rings depending on the nature of nucleophiles employed in the reaction^17c,d These adducts are also stable under NHC catalytic conditions to yield cyclopentanes.¹⁸Peng-Fei Xu et al. (Scheme 1, eqn (a)) synthesised tetrahydropyranoindoles through organocatalytic asymmetric C–H functionalization of indoles via [3 + 3] annulation through 6-endo trig cyclization.¹⁹ The Namboothiri group recently developed a metal free regioselective synthesis of α-carbolines via [3 + 3] annulation involving secondary MBH acetate (Scheme 1, eqn (b)).²⁰ Previously, our group carried out a [3 + 3] cyclization reaction of β-naphthol with primary MBH acetate to study the scope of S_N2′ vs. S_N2 reaction.²¹ With our ongoing interest in using nitro styrene derived MBH adducts²² explored the reactivity of primary and secondary MBH acetate with β-tetralone 1 as our model reaction. Initially, the reaction carried out using β-tetralone 1 with primary MBH-acetate 2, predominantly gave a tetrahydrochromene 3via [3 + 3] annulation involving 6-endo trig cyclization through Michael/oxa-Michael cascade process. The possible dihydronaphthofuran product was not observed under the present conditions as primary MBH acetate 2 acts as 1,3-biselectrophile instead of 1,2-biselectrophile (Scheme 1, eqn (c)).Open in a separate windowScheme 1[3 + 3] and [3 + 2] annulation reactions using 1°- and 2°-nitro allylic MBH acetate.On the other hand, the reaction of β-tetralone 1 with secondary MBH acetate 4 gave dihydronaphthofuran instead of the possible tetrahydrochromene product due to the 1,2-biselectrophile nature of secondary MBH acetate (Scheme 1, eqn (d)). The formation of dihydronaphthofuran 5 occurs in an S_N2′ fashion via [3 + 2] annulation involving 5-exo-trig cyclization through Michael followed by intramolecular oxa-Michael reaction with the elimination of HNO₂. Subsequently, we have carried out a DFT calculation to prove the formation of tetrahydrochromene 3 using primary MBH acetate 2 and dihydronaphthofuran 5 in the case of secondary MBH acetate 4.Initially, we carried out the optimization conditions for constructing tetrahydrochromenes 3a using β-tetralone 1 with MBH nitro allylic primary acetate 2a with different bases and solvents. Reaction with organic base, i.e. DABCO using a polar aprotic solvent such as acetonitrile at room temperature gave the desired product in 27% (23 (CCDC-2149875) ( EntryBaseSolventTime (h)Yield (%)dr^b1DABCOCH₃CN52799 : 12DABCOCH₂Cl₂52299 : 13DABCOCHCl₃51999 : 14DMAPTHF54099 : 15TEATHF54599 : 16PPh₃THF54499 : 17K₂CO₃THF46099 : 1 8 Cs ₂ CO ₃ THF 4 77 99 : 19^cCs₂CO₃THF85099 : 110^dCs₂CO₃THF56199 : 111^eCs₂CO₃THF46599 : 112^fCs₂CO₃THF460n.dOpen in a separate window^aUnless otherwise noted, reactions were carried out by and (0.11 mmol) of 1 with (0.11 mmol) of 2a using 0.22 mmol of a base in 1 ml of THF solvent.^bDetermined by ¹H-NMR analysis of crude reaction mixture.^cReaction was carried out using 0.5 equiv. of Cs₂CO₃.^dReaction was carried out using 1.0 equiv. of Cs₂CO₃.^eReaction was carried out using 1.5 equiv. of Cs₂CO₃.^fReaction was carried out using 3.0 equiv. of Cs₂CO₃.Substrate scope for tetrahydrochromenes 3a–f

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.     

A facile,practical and metal-free microwave-assisted protocol for mono- and bis-[1,2,4]triazolo[1,5-a]pyridines synthesis utilizing 1-amino-2-imino-pyridine derivatives as versatile precursors

A facile and effective assembly of several substituted functionalized mono- and bis-[1,2,4]triazolo[1,5-a]pyridines from conveniently attainable 1-amino-2-imino-pyridines has been established. Using microwave irradiation speeds up the reaction efficiently, proceeding with a higher rate and yields than with conventional heating. In the presented protocol, a broad variety of carboxylic acids could be employed effectively to synthesize the respective derivatives via direct metal-free C–N bond construction. Interestingly, other substrates such as aldehydes (or their arylidene malononitriles), phenyl isothiocyanate, glyoxalic acid, and acrylonitriles could also provide the corresponding 1,2,4-triazolo[1,5-a]pyridines successfully. This versatile and convergent approach performs well with both deactivating and activating substrates in an environmentally benign manner compared with other already reported protocols. Other notable merits of the current strategy involve no need for column chromatography, no tedious work-up, and a direct pathway for the fast design of triazolopyridine frameworks. The identity of the newly synthesized compounds was established using several spectroscopic techniques, and X-ray single-crystal tools were employed to authenticate the suggested structures of some representative samples.

A novel and highly efficient, protocol for synthesizing mono- and bis-[1,2,4]triazolo[1,5-a]pyridines has been established utilizing the readily attainable 1-amino-2-imino-pyridines and microwave irradiation as green energy source.