Diastereoselective synthesis of dispirooxindoles via [3+2] cycloaddition of azomethine ylides to 3-phenacylideneoxindoles and evaluation of their cytotoxicity

The three-component reaction of 1,2,3,4-tetrahydroisoquinoline, isatins and 3-phenacylideneoxindoles in refluxing ethanol afforded dispiro[indoline-3,1′-pyrrolo[2,1-a]isoquinoline-3′,3′-indolines] (4a–4x) in good yields via 1,3-dipolar cycloaddition of in situ generated azomethine ylide with the exocyclic double bond of 3-phenacylideneoxindoles. ¹H NMR spectra and single crystal structures indicated the reaction has high regioselectivity and diastereoselectivity. Furthermore, their biological activities have been preliminarily demonstrated by in vitro evaluation against mouse breast cancer cells 4T1 and human liver cancer cells HepG2 by MTT assay. The results demonstrated that some of the compounds showed cytotoxicities to cell lines of 4T1 and HepG2, and indicated that novel spirooxindoles may become potential lead compounds for further biological screenings of their medicinal applications.

The three-component reaction of 1,2,3,4-tetrahydroisoquinoline, isatins and 3-phenacylideneoxindoles in refluxing ethanol afforded dispiro[indoline-3,1′-pyrrolo[2,1-a]isoquinoline-3′,3′-indolines] (4a–4x) in good yields via 1,3-dipolar cycloaddition.     

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

Synthesis of quinolines via sequential addition and I2-mediated desulfurative cyclization

An efficient one-pot approach for the synthesis of quinolines from o-aminothiophenol and 1,3-ynone under mild conditions is disclosed. With the aid of ESI-MS analysis and parallel experiments, a three-step mechanism is proposed—a two-step Michael addition–cyclization condensation step leading to intermediate 1,5-benzothiazepine catalyzed by zirconocene amino acid complex Cp₂Zr(η¹-C₉H₁₀NO₂)₂, followed by I₂-mediated desulfurative step.

An efficient one-pot approach is proposed for the synthesis of quinolines through Lewis acid-catalyzed cyclization and iodine-mediated desulfurization reactions.     

[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 EntryAdditiveSolventTimeYield of 3a^b (%)1AcOHCHCl₃12482TfOHCHCl₃12513TFACHCl₃3904HClCHCl₃12205TFACH₂Cl₂1986TFADCE3827TFAEtOAc6758TFAToluene12709TFAMeOH123110TFACH₃CN37111TFADioxane125912TFAEt₂O124613TFATHF1262Open in a separate window^aReaction conditions: 2-benzothiazolimine 1a (0.1 mmol, 1.0 equiv.), N-(methoxymethyl)-N-(trimethylsilyl-methyl)-benzyl-amine 2a (0.12 mmol, 1.2 equiv.), addition (0.01 mmol, 0.1 equiv.) and solvent (1.0 mL) in a test tube at room temperature.^bYield of the isolated product.After establishing the optimal reaction conditions, the scope and limitations of this [3 + 2] cycloaddition reaction for formation of 1,3,5-trisubstituted imidazolidines were examined. The results were shown in †)¹⁵ was unequivocally confirmed by X-ray crystallographic analysis (see ESI^†). On the other hand, when the R² groups were heteroaromatic substituted group, such as 2-furanyl, 3-thienyl, 1-naphthyl and 2-naphthyl, the cycloaddition reaction were well tolerated and could also proceed smoothly without obvious interference to produce corresponding pyrazoles 3k–3n in 92–96% yields. Meanwhile, substituted substrates at the C4 or C6-position of the 2-aminobenzothiazole, such as Me and Cl were also reacting smoothly to afford the corresponding products in 95%, 96% yields (3o–3p), respectively. Notably, the 2-benzoxazolimine as substrate also reacted smoothly with azomethine ylides 2a to deliver the corresponding product 3q in high yield (94%). Especially, when using (R)-nonstabilized azomethine ylide as the chiral substrate in the cycloaddition reaction, the reaction could proceed smoothly under the standard conditions to afford the corresponding chiral product 3r in 95% yield as single diastereomer only. The chiral center was determined by NOESY analysis (see ESI^†). Nevertheless, as for the R² group, when it was changed from an aryl group to an alkyl group, the reaction did not take place (3s). The possible reason may be due to the low activity of alkyl substituted substrate.Substrate scopes for the formation of 1,3,5-trisubstituted imidazolidine derivatives 3^a

Synthesis,anti-mycobacterial and cytotoxic evaluation of substituted isoindoline-1,3-dione-4-aminoquinolines coupled via alkyl/amide linkers

A series of secondary amine-substituted isoindoline-1,3-dione-4-aminoquinolines were prepared via microwave heating and assayed for their anti-mycobacterial activities. The compound with a butyl chain as a spacer between the two pharmacophores and piperidine as the secondary amine component on the isoindoline ring was the most potent and non-cytotoxic among the synthesized compounds, exhibiting a minimum inhibitory concentration (MIC₉₉) of 6.25 μg mL⁻¹ against Mycobacterium tuberculosis.

A series of secondary amine-substituted isoindoline-1,3-dione-4-aminoquinolines were prepared via microwave heating and assayed for their anti-mycobacterial activities.     

A [3 + 2] cycloaddition/C-arylation of isatin N,N′-cyclic azomethine imine 1,3-dipole with arynes

A [3 + 2] annulation/C-arylation of isatin N,N′-cyclic azomethine imine 1,3-dipole 1 with in situ generated arynes has been established for the synthesis of 3,3-disubstituted oxindole scaffolds. These highly functionalized scaffolds were assembled in moderate yields (up to 85% yield). The novel spirooxindole scaffolds displayed moderate antitumor activities, which represented promising lead compounds for antitumor drug discovery.

A [3 + 2] annulation/C-arylation reaction of 1,3-dipole 1 with arynes has been established for the synthesis of oxindole scaffolds.

The construction of new heterocyclic architectures is of great importance because such privileged scaffolds that widely occur in natural products and drugs increase the returns of drug-discovery studies.¹ Among these scaffolds, the 3,3-disubstituted oxindoles are associated with interesting biological properties (Fig. 1). For instance, nelivaptan could be used as an orally active non-peptide vasopressin receptor antagonist.² NITD609 has been identified for potential treatment of malaria based on in vivo activity, having single dose efficacy in a rodent malaria model.³ Moreover, other bioactive 3,3-disubstituted oxindoles have also attracted considerable attention due to their high activities, such as poliovirus inhibitor,⁴ MDM2 inhibitor SAR405838 (ref. 5) and anti-bacterial agents.⁶ Given the biological significance of functionalized 3,3-disubstituted oxindoles, synthesis of this class of compounds with high structural diversity from readily available starting materials by using simple manipulations is highly desirable.Open in a separate windowFig. 1Representative biologically active compounds containing the 3,3-disubstituted oxindole skeleton.Recently, 1,3-dipolar cycloadditions (1,3-DCs) are among the most powerful approaches for the construction of carbon–carbon bonds and heterocycles.⁷ And the Wang''s group reported an abnormal [3 + 2] cycloaddition of a new isatin N,N′-cyclic azomethine imine 1,3-dipoles with maleimides, an unusual Michael reaction between these 1,3-dipoles with β-nitrostyrenes and an abnormal [3 + 2] cycloaddition between these 1,3-dipoles and 3-methyleneoxindole, which are very scarce examples of 1,3-dipolar cycloaddition reaction (Scheme 1a).⁸ After that, we disclosed an DMAP-catalyzed direct alkylation at the a-position of the cyclic amine of these isatin N,N′-cyclic azomethine imine 1,3-dipoles with Morita–Baylis–Hillman carbonates and developed an efficient way to synthesize seven-membered heterocyclic spirooxindoles via a [3 + 4] cycloaddition reaction of these 1,3-dipoles with N-(ortho-chloromethyl)aryl amides (Scheme 1a).⁹ Furthermore, the Moghaddam''s group reported an unexpected abnormal [3 + 3] tandem Michael addition/N-cyclization of these 1,3-dipoles and 2-arylidenemalononitrile under DABCO catalysis (Scheme 1a).¹⁰ During the course of the studies on these isatin N,N′-cyclic azomethine imine 1,3-dipoles, the related studies envisioned that these 1,3–dipoles have been utilized as valuable building blocks in cycloaddition reactions with alkenes. Given our ongoing interest in 1,3-dipolar cycloaddition and spirooxindole alkaloids, we envisioned the reaction of the isatin N,N′-cyclic azomethine imine 1,3-dipoles and arynes would be one approach to obtaining new pyrazole-spirooxindole derivatives via [3 + 2] cycloadditions (Scheme 1b).Open in a separate windowScheme 1(a) Previous reports of isatin N,N′-cyclic azomethine imine 1,3-dipoles. (b) Design of the new [3 + 2] cycloaddition.Our investigations started with the screening of the reaction between the isatin N,N′-cyclic azomethine imine 1,3-dipole 1a and the unsubstituted aryne precursor 2a in the presence of CsF in CH₃CN at room temperature for 2 h. To our delight, the desired product 3a was obtained in 20% yield (entry 1, EntryF-source (equiv.)Additive (equiv.)SolventTemp (°C)Time (h)Yield of 3a^b (%)1CsF (2.0)—MeCNrt2202TBAF (2.0)—MeCNrt2Trace3KF (2.0)—MeCNrt2154CsF (2.0)18-C-6 (2.0)MeCNrt2555CsF (2.0)18-C-6 (2.0)MeCN501536CsF (2.5)18-C-6 (2.0)MeCNrt2647CsF (3.0)18-C-6 (2.0)MeCNrt2518CsF (4.0)18-C-6 (2.5)MeCNrt2539CsF (2.5)18-C-6 (3.0)MeCNrt26710CsF (2.5)18-C-6 (3.0)DMFrt24511CsF (2.5)18-C-6 (3.0)CH₂Cl₂rt233 12 CsF (2.5) 18-C-6 (3.0) THF rt 2 72 13CsF (2.5)18-C-6 (3.5)THFrt26914CsF (2.5)18-C-6 (3.0)1,4-Dioxanert2Trace15CsF (2.5)18-C-6 (3.0)EArt45516CsF (2.5)18-C-6 (3.0)DCErt42717CsF (2.5)18-C-6 (3.0)MeOHrt40Open in a separate window^aUnless noted otherwise, reaction of 1a (0.2 mmol), 2a (0.25 mmol), fluoride source (0.5 mmol) and 18-C-6 (0.6 mmol) was performed in 3.0 mL of solvent under Ar.^bIsolated yield based on 1a.With the favorable reaction conditions established, the substrate scope and limitations of this catalyst-free self [3 + 2] cycloaddition of isatin N,N′-cyclic azomethine imine 1,3-dipole 1 with aryne precursors 2 were explored (Scheme 2). To our delight, most isatin N,N′-cyclic azomethine imines 1 and aryne precursors 2 were well tolerated. First, we evaluated the different 1,3-dipoles 1 with diverse substituents. It seems that the electronic nature of the substituents had intriguingly impact on the reaction. In general, substrates with electron-donating groups at the 5-position of 1 resulting in the formation of the cycloaddition products in good yields (3f: 78%; 3g: 85%). In addition, a few 1,3-dipoles 1 with diverse N-substituted groups, including that with a free NH group, showed inert reactivity and failed to deliver the expected product. Only N-methyl could smoothly afford the desired products with good results (3b: 57%). Interestingly, reactions carried out using the 1,3-dipoles 1 with electron-withdrawing groups resulted in the formation of the 3,3-disubstituted oxindole products in moderate yields (products 3h–3k), probably because the latter substituent would lower the nucleophilicity of the 1,3-dipoles 1. Next, the tolerance of substituents on the aryne moiety was also studied.Open in a separate windowScheme 2The reaction scope.^{a,b a}Typical conditions: reaction of 1 (0.2 mmol), 2 (0.25 mmol), CsF (0.5 mmol) and 18-C-6 (0.6 mmol) was performed in 3.0 mL of THF at room temperature under Ar. ^bIsolated yield based on 1.The cycloaddition products 3l–3o are formed in moderate to good yields when this reaction was performed using unsymmetrical 3-substituted or 4-substituted arynes generated from the precursors. The unsymmetrical 4-methyl aryne afforded an inseparable mixture of regioisomers 3m and 3m′ in 59% yield and a 1.47 : 1 regioisomer ratio. Similarly, inseparable regioisomeric products were formed when the reaction was carried out using unsymmetrical 4-methoxy, 3-methyl and 3-methoxy arynes. Moreover, the unsymmetrical naphthalyne was well tolerated to furnish the separable regioisomeric products 3p and 3p′ in 78%.In order to address the viability and potential synthetic application of this reaction, a gram-scale scale-up and several applications were carried out (Scheme 3). Under identified conditions, product 3a was obtained without a significant loss of efficiency (69%) with a 4 mmol scale (Scheme 3a). To further illustrate synthetic applications of this method, we conducted a Suzuki coupling of product 3j with N-Boc-1,2,5,6- tetrahydropyridine-4-boronic acid pinacol ester, and then deprotection of the Boc group, which afforded product 4 in 52% yield (Scheme 3b).Open in a separate windowScheme 3Follow-up Chemistry.On the basis of our results and the previous studies,^7d,8–10 two plausible mechanisms was proposed as illustrated in Scheme 4. One approach, the in situ generated aryne (formed by the fluoride induced 1,2-elimination from 2) reacts with the isatin N,N′-cyclic azomethine imines 1 to generate the final product 3 through a thermal [3 + 2] annulation. The other, the more stable intermediate I was formed by the tautomerism of 1 in the presence of a base. Then intermediate I underwent C-arylation reaction with the in situ generated aryne with a double bond shift to generate the final product 3h, 3i and 3j (Scheme 4).Open in a separate windowScheme 4Plausible reaction mechanism.Drawing inspiration from these 3,3-disubstituted oxindoles, a number of new drugs and lead compounds have been developed, especially in the field of anti-tumor.¹¹ Therefore, the target compounds were assayed for in vitro antitumor activity against hepatocellular carcinoma (Hep3B) using the standard MTT method (CompoundsIC₅₀ (nM)Hep3B3aN.D.^a3bN.D.3fN.D.3gN.D.3h>10 0003i>10 0003j4986.03k>10 0003lN.D.3m/3m′N.D.3n/3n′N.D.3o/3o′N.D.3p/3p′N.D.4601.7Infigratinib224.2Open in a separate window^aNot determined.In summary, we have established an efficient method for the [3 + 2] annulation/C-arylation of isatin N,N′-cyclic azomethine imine 1,3-dipole 1 with in situ generated arynes, which constructed biologically important 3,3-disubstituted oxindoles in average good yields (up to 85% yield). The present methodology is both concise and mild, practical and one-pot method. The in vitro antitumor activity assay indicated that these scaffolds displayed moderate antitumor activities. Further chemical modification and biological exploration of these compounds are underway in our laboratory.     

Synthesis of highly substituted tetrahydroquinolines using ethyl cyanoacetate via aza-Michael–Michael addition

A three-component cascade reaction involving 2-alkenyl aniline, aldehydes, and ethyl cyanoacetate in the presence of DBU to synthesize highly substituted 1,2,3,4-tetrahydroquinolines is reported. The reaction proceeded through the Knoevenagel condensation of ethyl cyanoacetate with aldehydes followed by the aza-Michael–Michael addition with 2-alkenyl anilines to prepare the tetrahydroquinoline scaffolds.

A three-component cascade reaction involving 2-alkenyl aniline, aldehydes, and ethyl cyanoacetate in the presence of DBU to synthesize highly substituted 1,2,3,4-tetrahydroquinolines is reported.     

Synthesis of substituted 3,4-dihydroquinazolinones via a metal free Leuckart–Wallach type reaction

The 3,4-dihydroquinazolinone (DHQ) moiety is a highly valued scaffold in medicinal chemistry due to the vast number of biologically-active compounds based on this core structure. Current synthetic methods to access these compounds are limited in terms of diversity and flexibility and often require the use of toxic reagents or expensive transition-metal catalysts. Herein, we describe the discovery and development of a novel cascade cyclization/Leuckart–Wallach type strategy to prepare substituted DHQs in a modular and efficient process using readily-available starting materials. Notably, the reaction requires only the addition of formic acid or acetic acid/formic acid and produces H₂O, CO₂ and methanol as the sole reaction byproducts. Overall, the reaction provides an attractive entry point into this important class of compounds and could even be extended to isotopic labelling via the site-selective incorporation of a deuterium atom.

A novel cascade cyclization/Leuckart–Wallach type strategy to prepare biologically important 3,4-dihydroquinazolinones is presented.     

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).     

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

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.     

Preparation of substituted triphenylenes via nickel-mediated Yamamoto coupling

Substituted triphenylenes show promise as organic semiconductors because of their ability to form columnar liquid crystalline phases featuring extended π-stacked arrays. While there are several methods for preparing triphenylenes, including oxidative cyclization reactions such as the Scholl reaction, as well as transition metal-catalyzed aryne cyclotrimerization, these methods are not effective for electron deficient triphenylenes. Here we demonstrate that the nickel-mediated Yamamoto coupling of o-dibromoarenes is a concise and efficient way to prepare substituted triphenylenes, including electron-deficient systems that are otherwise challenging to prepare. We also demonstrate the application of this approach to prepare electron deficient discotic mesogens composed of triphenylenes bearing imide and thioimide groups.

Nickel-mediated Yamamoto coupling provides a concise and efficient synthesis of triphenylene derivatives, including electron-deficient discotic mesogens.     

Synthesis of 1,4,5,6-tetrahydropyridazines and pyridazines via transition-metal-free (4 + 2) cycloaddition of alkoxyallenes with 1,2-diaza-1,3-dienes

We developed an economical and practical protocol for the synthesis of 1,4,5,6-tetrahydropyridazines. A diverse range of alkoxyallenes and 1,2-diaza-1,3-dienes undergo (4 + 2) cycloaddition to generate the desired products in excellent yields. The high efficiency, wide substrate scope and good functional group tolerance of this process, coupled with operational simplicity, render the method synthetically attractive. The utility of the cycloaddition is also demonstrated by the preparation of various pyridazines from 1,4,5,6-tetrahydropyridazines.

We developed an economical and practical protocol for the synthesis of 1,4,5,6-tetrahydropyridazines and pyridazines via cyclization of alkoxyallenes and 1,2-diaza-1,3-dienes.

For several years, we have been developing the methodologies of cumulative dienes¹ for the synthesis of heterocyclic compounds.² In the past few decades, allenes have attracted significant attention in organic synthesis.³ By virtue of their reactive and cumulative double bonds, allenes are widely used as valuable C3-feedstocks.⁴ Functional groups at the double bonds of allene moieties strongly influence the reactivities, and thus allow site- and regioselective transformations. For example allenoates, bearing electron-withdrawing substituents (carboxylic ester groups) at the allene moieties, lead to preferred reactions with nucleophiles attacked on the central carbon, and have been thoroughly studied.⁵ Nevertheless, investigations of alkoxyallenes are still limited.⁶ As special enol ethers, alkoxyallenes were frequently employed as strong nucleophiles via deprotonations and metalations.⁷ Moreover, the electronic bias imposed by the alkoxyl groups makes them unique dienophiles; the electron-deficient or electron-rich double bonds could engage in cycloadditions.Recently, Goeke⁸ and Luo⁹et al. developed (4 + 2) annulation of alkoxyallenes with cyclopentadienes and β,γ-unsaturated α-keto esters, respectively (Scheme 1). These established methods employed expensive heavy metals (Au, In), which maybe resulting in the contamination of medicinal products. Accordingly, there is a clear demand for the development of transition-metal-free protocols with high efficiency, operational simplicity, atom economy and general applicability.Open in a separate windowScheme 1Transition-metal-catalyzed (4 + 2) cycloadditions of alkoxyallenes.In 2015, Favi et al. developed (4 + 2) cycloaddition of alkoxyallene with α-halohydrazones (precursors of 1,2-diaza-1,3-dienes), but in which only methoxyallene could be employed as the dienophile (Scheme 2a).¹⁰ The approach allows access to 1,4,5,6-tetrahydropyridazines, which are versatile building blocks and prevalent in a large number of pharmacologically active molecules.¹¹ However, the cyclization suffered from moderate conversion and narrow substrates scope, required long reaction time (up to 7 days) and high stoichiometric ratio of reactants (methoxyallene/Na₂CO₃/α-halohydrazone = 7 : 5 : 1).Open in a separate windowScheme 2(4 + 2) cycloadditions of alkoxyallenes with 1,2-diaza-1,3-dienes.Currently, there is an increased drive to find new ways to maximize synthetic efficiency and minimize waste in chemical and pharmaceutical industries.¹² As part of our group''s continuous interest in cumulene chemistry and transition-metal-free synthesis,¹³ the (4 + 2) annulation of alkoxyallene with 1,2-diaza-1,3-dienes was thus systematically reinvestigated, and in this context, we demonstrate that the cyclization can proceed with a broad range of substrates, producing a wide variety of 1,4,5,6-tetrahydropyridazines in high efficiency. Besides, it was found that these adducts could further convert into pyridazines (Scheme 2b).The investigations began with assaying the (4 + 2) cycloaddition between benzyloxyallene 1a and α-halohydrazone 2a, as shown in EntryR2XBaseSolventTemp. (°C)Time (h)Yield^b (%)1Bz2a4.0Na₂CO₃MeOHRT72NR2Bz2a4.0Na₂CO₃DCMRT72873Bz2a4.0Na₂CO₃CHCl₃RT72894Bz2a4.0Na₂CO₃TolueneRT72905Bz2a4.0TEATolueneRT72<56Bz2a4.0DIPEATolueneRT72<57Bz2a4.0K₂CO₃TolueneRT72728Bz2a4.0KOAcTolueneRT72809Bz2a4.0K₂HPO₄TolueneRT729410Bz2a4.0K₂HPO₄Toluene40169211Bz2a4.0K₂HPO₄Toluene50164512Cbz2b4.0K₂HPO₄Toluene40169413Ac2c4.0K₂HPO₄Toluene40166814Boc2d4.0K₂HPO₄Toluene40169015Cbz2b2.0K₂HPO₄Toluene40169416Cbz2b1.0K₂HPO₄Toluene401689Open in a separate window^aReaction conditions: 1a (X equiv.), 2 (0.2 mmol), base (2.0 equiv., 0.4 mmol), solvent (2 mL).^bYield was that of the isolated product. NR: no reaction.After extensive experimentation to reduce the amount of α-halohydrazone 2b, we identified the following optimal protocol: reaction of 1a and 2b with a stoichiometric ratio of 2.0 : 1.0 in the presence of K₂HPO₄ (2.0 equiv.) in toluene at 40 °C for 16 h (benzyloxyallene/K₂HPO₄/α-halohydrazone = 2 : 2 : 1). It is also worth mentioning that all the reactions were conducted open to air with no need for exclusion of air or moisture.The structure of 3aa (CCDC 1904934) was unambiguously assigned by single crystal X-ray diffraction analysis (Fig. 1). The structure of 3 were assigned by analog.¹⁴Open in a separate windowFig. 1Determining the structure of 3aa.Having identified the optimized reaction conditions, the substrate scope of the cyclization was studied, and a variety of 1,4,5,6-tetrahydropyridazines 3 were synthesized in decent yields ( Open in a separate window^aReactions were performed with 1a (0.4 mmol), 2 (0.2 mmol), K₂HPO₄ (0.4 mmol) in toluene (2.0 mL) at 40 °C for 16 h.^bYield was that of the isolated product. See ESI for details.We next explored the possibility that the alkoxyallenes can bear other substituents, such as methyl (1b), cyclohexyl (1c), phenyl (1d) and cinnamyl (1e) groups. In fact, these alkoxyallenes proved to be compatible with the reaction conditions and led to smooth cyclization with α-halohydrazone 2b in good to excellent yields (15 Unfortunately, despite vigorous efforts, a qualified single crystal of 3fb for X-ray crystallographic analysis could not be obtained to determine the relative configuration. Systematic experimentation of the annulation of 3-substituted alkoxyallenes is ongoing.Substrate scope with respect to allene 1^a,b

Synthesis of the diketopyrrolopyrrole/terpyridine substituted carbazole derivative based polythiophenes for photovoltaic cells

A series of conjugated polythiophenes (PTs) having low band gap energies (PDPP, PDPCz21, PDPCz11), with 2-ethylhexyl-functionalized 2,5-thienyl diketopyrrolopyrrole (TDPP) as the electron acceptor and terpyridine-substituted carbazole (TPCz) as the electron donor, have been synthesized and studied for their applicability in polymer-based photovoltaic cells (PVCs). The thermal stability and solvent solubility of PTs increased upon increasing the content of the TPCz derivative. PVCs were fabricated having the following architecture: indium tin oxide/poly(3,4-ethylenedioxythiophene):polystyrenesulfonate/PT:6,6-phenyl-C₇₁-butyric acid methyl ester (PC₇₁BM)/Ca/Ag. The compatibility between the PT and PC₇₁BM improved upon increasing the TPCz content. The photovoltaic properties of the PDPCz21-based PVCs were superior to those of their PDPP- and PDPCz11-based counterparts.

A series of conjugated polythiophenes (PTs) having low band gap energies (PDPP, PDPCz21, PDPCz11) have been synthesized and studied for their applicability in polymer-based photovoltaic cells (PVCs).     

Multicomponent synthesis of substituted pyridines via a catalytic intermolecular aza-Wittig/Diels–Alder sequence

A three-component synthesis of polysubstituted pyridines has been developed, based upon the synthesis of 2-azadienes by a redox-neutral catalytic intermolecular aza-Wittig reaction and their subsequent Diels–Alder reactions. The two-pot process has been demonstrated using a range of aryl and heteroaromatic aldehydes, substituted α,β-unsaturated acids and push–pull enamines, to give rapid access to diverse tri- and tetrasubstituted pyridines.

A three-component synthesis of polysubstituted pyridines, based upon the Diels–Alder reactions of 2-azadienes formed by a novel redox-neutral catalytic intermolecular aza-Wittig reaction.     

Synthesis of 3,6-diaryl-1H-pyrazolo[3,4-b]pyridines via one-pot sequential Suzuki–Miyaura coupling

A practical synthesis of diarylpyrazolo[3,4-b]pyridine derivatives by a combination of chemoselective Suzuki–Miyaura cross-coupling reactions was developed. The sequential arylation strategy can be performed in a one-pot manner without much loss of efficiency when compared to the corresponding stepwise synthesis. These conditions are applicable to the coupling of a wide variety of aryl and heteroaryl-boronic acids with pyrazolo[3,4-b]pyridines with high selectivity of the C3 over the C6 position, thus enabling the rapid construction of a diverse array of medicinally important diarylpyrazolo[3,4-b]pyridines.

An efficient method to produce diarylpyrazolo[3,4-b]pyridines derivatives via combination of chemoselective Suzuki–Miyaura cross-coupling reactions has been developed.     

Continuous-flow synthesis of 3,5-disubstituted pyrazoles via sequential alkyne homocoupling and Cope-type hydroamination

A flow chemistry-based approach is presented for the synthesis of 3,5-disubstituted pyrazoles via sequential copper-mediated alkyne homocoupling and Cope-type hydroamination of the intermediary 1,3-diynes in the presence of hydrazine as nucleophilic reaction partner. The proposed multistep methodology offers an easy and direct access to valuable pyrazoles from cheap and readily available starting materials and without the need for the isolation of any intermediates.

A telescoped continuous-flow method is presented for the synthesis of 3,5-disubstituted pyrazoles via copper-mediated alkyne homocoupling and Cope-type hydroamination of the intermediary 1,3-dialkynes.     

One-pot synthesis of new alkyl 1-naphthoates bearing quinoline,pyranone and cyclohexenone moieties via metal-free sequential addition/oxidation reactions

A mild and one-pot synthetic pathway was successfully developed for the synthesis of new naphthoate-based scaffolds containing quinoline, pyranone and cyclohexenone moieties via a multistep reaction between acenaphthoquinone and various 1,3-diketones in the presence of different primary aliphatic and benzylic alcohols. This reaction proceeds via a sequential addition/oxidation mechanistic process including a metal-free addition step of acenaphthoquinone and 1,3-diketones followed by the H₅IO₆-mediated C–C oxidative cleavage of the corresponding vicinal diols at room temperature. The alcohols play a dual role, as the reaction solvent as well as the nucleophile, to conduct the reaction process toward naphthoate formation. All alkyl naphthoate derivatives prepared in this work are new compounds and were definitively characterized using ¹H-NMR, ¹³C-NMR and HRMS analysis, while X-ray crystallography was carried out for one of the products. The synthesis of a naphthalene-based nucleus attached to heterocyclic moieties is noteworthy to follow in the near future for diverse applications in biology, medicine, metal complex design, and semiconductor and optical materials.

Various new alkyl 1-naphthoates bearing quinoline, pyranone and cyclohexenone moieties were successfully synthesized by a one-pot sequential addition/oxidation process.     

Synthesis of physically crosslinked PAM/CNT flakes nanocomposite hydrogel films via a destructive approach

Carbon nanotube (CNT)-based hydrogels have recently found a wide variety of applications due to the unique physical and chemical properties of CNTs. CNTs can be used as a nanofiller and/or crosslinker to produce nanocomposite hydrogels with good mechanical and structural properties. In this research, a novel method was reported for producing polyacrylamide (PAM)/oxidized-multiwalled carbon nanotube (O-MWCNT) flakes nanocomposite hydrogel films without using any organic cross-linker or surfactant. Through a mechanism dependent on the reactive oxygen species (ROS), some O-MWCNTs were broken down in situ into small flakes in the aqueous solutions containing acrylamide (AM) and sodium persulfate (NaPS) at the temperature range of 85–90 °C. Simultaneously, in situ polymerization of the AM monomers occurred using free radicals, which resulted in the formation of PAM chains. The flakes acted as crosslinkers by forming hydrogen bonds with PAM chains and formed a hydrogel network after 48 h at room temperature. The hydrogels were characterized by different techniques (FT-IR, Raman, FE-SEM, TEM, TGA, tensile test). The porous structure of the hydrogel films as well as micro-network structures with unique morphologies were observed by SEM. The O-MWCNT flakes and some undegraded O-MWCNTs in the hydrogel network were also observed by TEM. The results showed that PC₂I₂H hydrogel film, as an evolved hydrogel, has excellent swelling performance in aqueous solutions at different pH and temperatures. In addition, this hydrogel showed a tensile strength of 103 MPa in the dry state and an elongation of 703% in the swollen state.

Novel PAM/CNT flakes nanocomposite hydrogel films were synthesized by in situ degradation of the oxidized-MWCNTs into flakes using persulfate activation. The flakes crosslinked the PAM chains via hydrogen bonding to form a hydrogel network.     

Solvent-free synthesis of 3,5-isoxazoles via 1,3-dipolar cycloaddition of terminal alkynes and hydroxyimidoyl chlorides over Cu/Al2O3 surface under ball-milling conditions

Scalable, solvent-free synthesis of 3,5-isoxazoles under ball-milling conditions has been developed. The proposed methodology allows the synthesis of 3,5-isoxazoles in moderate to excellent yields from terminal alkynes and hydroxyimidoyl chlorides, using a recyclable Cu/Al₂O₃ nanocomposite catalyst. Furthermore, the proposed conditions are reproducible to a 1.0-gram scale without further milling time variations.

A practical and scalable mechanochemical 1,3-dipolar cycloaddition between hydroxyimidoyl chlorides and terminal alkynes catalyzed by Cu/Al₂O₃ allows a quick access to 3,5-isoxazole derivatives.

The addition of oxygen or nitrogen-containing heterocycles in drug candidates has become a common feature of the recently approved drugs by the FDA.^1,2 In particular, isoxazoles are common molecular scaffolds employed in medicinal chemistry due to the non-covalent interactions such as hydrogen bonding (through the N) and π–π stacking (by the unsaturated 5-membered ring).^3–6 Within the isoxazole family, 3,5-isoxazoles (1) are regularly utilized as pharmacophores in medicinal chemistry.^2,5,6 Selected examples including muscimol (GABA_a agonist), isocarboxazib (antidepressant), isoxicam (anti-inflammatory), berzosertib (ATR kinase inhibitor), and sulfamethoxazole (antibiotic) are highlighted in Fig. 1.^7–10Open in a separate windowFig. 1Examples of isoxazoles with pharmacological activity.Various methodologies to synthesize 3,5-isoxazoles have been developed over the years.^7,9,11–13 Specifically, 1,3-dipolar cycloaddition between terminal alkynes (2) and nitrile oxides (4) formed in situ by deprotonation of hydroxyimidoyl chlorides (3) is a standard route to access 3,5-isoxazoles (1) (Fig. 2).^7,9,14 Recent reports have sought to mitigate the environmental impact of this reaction by performing 1,3-dipolar cycloaddition under solvent-free conditions, using green solvents such as water or ionic liquids, under metal-free conditions, or using mild oxidants.^14–28 However, these methodologies have a low atom economy, have a higher hazardous waste production, and are less energy efficient. Therefore, developing a greener methodology that enables rapid and efficient access to these scaffolds is highly desirable.Open in a separate windowFig. 21,3-Dipolar cycloaddition of terminal alkynes and nitrile oxides.Mechanochemistry has been recognized as an environmentally friendly technique as reactions can be performed under solvent-free conditions. Additionally, in some instances, work-up and purification are simplified or absent from procedures, and the process consumes less energy than other solution-based techniques.^29–33 The use of mechanochemical techniques to synthesize isoxazoles is limited. Sherin et al. reported a synthesis of 3,5-isoxazoles (7) by grinding in a mortar and pestle curcumin derivatives (5), hydroxylamine (6), and sub-stoichiometric amounts of acetic acid to form the 3,5-isoxazole (7) in short times and excellent yields (Fig. 3a).³⁴ Likewise, Xu et al. studied the synthesis of trisubstituted isoxazoles (10) via 1,3-dipolar cycloaddition of N-hydroxybenzimidoyl chlorides (8) and N-substituted β-enamino carbonyl (9) compounds by ball-milling (Fig. 3b) in high yields, short reaction times, in the absence of catalyst and liquid additives.³⁵ To our knowledge, mechanochemical synthesis of 3,5-isoxazoles (1) from terminal alkynes (2) and hydroxyimidoyl chloride (3) has not been reported (Fig. 3c). The proposed methodology employs a planetary ball-milling technique that provides a route to access in large scale, short reaction times, and high atom economy the corresponding 3,5-isoxazoles (1). Additionally, it utilizes synthetically accessible or commercially available motifs such as terminal alkynes (2) and hydroxyimidoyl chlorides (3) that are recurrent or easily installed in many substrates. Herein, we report a mechanochemical 1,3-dipolar cycloaddition using the planetary ball-mill to synthesize a wide range 3,5-isoxazoles from a broad library of alkynes and (E,Z)-N-hydroxy-4-nitrobenzimidoyl chloride (3a), ethyl (E,Z)-2-chloro-2-(hydroxyimino)acetate (3b), hydroxycarbonimidic dibromide (3c), or (E,Z)-N-hydroxy-4-methoxybenzimidoyl chloride (3d) in moderate to excellent yields, in short reaction time, and with less waste production than in solution based reactions (Fig. 3c).Open in a separate windowFig. 3Previously reported synthesis of isoxazoles.We began our investigation by performing an optimisation of the 1,3-dipolar cycloaddition reaction between alkyne 2a and hydroxyimidoyl chlorides 3a by milling the selected substrates in a stainless-steel (SS) jar in the planetary ball-mill to obtain 3,5-isoxazole 1a (36,37Optimization of reaction conditions^a