Facile assembly of 1,5-diazocan-2-ones via cyclization of tethered sulfonamides to cyclopropenes

The sulfonamide moiety was evaluated as an activating and stabilizing functional group in the metal-templated strain release-driven intramolecular nucleophilic addition of amines to cyclopropenes to generate 1,5-diazocan-2-ones.

The sulfonamide moiety was evaluated as an activating and stabilizing functional group in the metal templated strain release-driven intramolecular nucleophilic addition of amines to cyclopropenes to generate 1,5-diazocan-2-ones.     

Unexpected cyclization of ortho-nitrochalcones into 2-alkylideneindolin-3-ones

An original, facile, and highly efficient method for the preparation of 2-(3-oxoindolin-2-ylidene)acetonitriles from ortho-nitrochalcones is described. The featured transformation is a triggered Michael addition of the cyanide anion to the chalcone followed by a cascade cyclization mechanistically related to the Baeyer–Drewson reaction.

Highly efficient cascade involving Michael addition and Baeyer–Drewson reaction is triggered by cyanide anion and transforms ortho-nitrochalcones into 2-(3-oxoindolin-2-ylidene)acetonitriles.     

Straightforward synthesis of quinazolin-4(3H)-ones via visible light-induced condensation cyclization

A green, simple and efficient method is developed for the synthesis of quinazolin-4(3H)-ones via visible light-induced condensation cyclization of 2-aminobenzamides and aldehydes under visible light irradiation. The reaction proceeds using fluorescein as a photocatalyst in the presence of TBHP without the need for a metal catalyst. In addition, this reaction tolerates a broad scope of substrates and could afford a variety of desirable products in good to excellent yields. Thus, the present synthetic method provides a straightforward strategy for the synthesis of quinazolin-4(3H)-ones.

Visible light was used as a readily available and renewable clean energy source for the green and metal catalyst free synthesis of quinazolin-4(3H)-ones. High and excellent yields of the desired products were obtained with good functional group tolerance.

In recent years, synthesis of nitrogen-containing heterocycles has drawn considerable attention due to their widespread occurrence in natural and synthetic organic molecules.¹ Among them, quinazolin-4(3H)-ones are common core structures found in a large number of natural products and synthetic drugs showing a broad range of biological and therapeutic activities (Fig. 1). For example, Pegamine, isolated from Peganum harmala, exhibits cytotoxic activity.² Afloqualone is a centrally acting muscle relaxant useful in the management of various conditions, including cerebral palsy, cervical spondylosis, and multiple sclerosis.³ Bouchardatine could significantly reduce lipid accumulation, and mainly inhibited early differentiation of adipocytes through proliferation inhibition and cell cycle arrest in a dose-dependent manner.⁴ Idelalisib have been shown to exhibit a broad spectrum of antimicrobial, antitumor, antifungal and cytotoxic activities.⁵ Ispinesib is one of the most potent kinesin spindle protein (KSP) inhibitors and is currently in clinical trials for cancer treatment.⁶ Sclerotigenin, isolated from organic extracts of the sclerotia of penicillium sclerotigenum, is responsible for most of the antiinsectan activity against crop pests.⁷ Besides, a number of quinazolin-4(3H)-ones have been synthesized to provide synthetic drugs and to design more effective medicines.^8,9Open in a separate windowFig. 1Representing natural and synthetic molecules containing quinazolin-4(3H)-one moieties.Owing to their pharmacological importance, considerable attention has been devoted to the development of simple and efficient methods for their construction (Scheme 1). Typically, quinazolin-4(3H)-ones are synthesized by acid or base-catalyzed condensation of amides with alcohols/aldehydes.^10,11 In some cases, an excess of hazardous oxidants, for instance KMnO₄, I₂, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), are employed in the reaction, which are significant limitations in this method.^12–14 Over the past decades, various metal-based catalysts such as copper-catalyzed cyclization of 2-halobenzoic acids with amidines, palladium-catalyzed benzylic C–H amidation with benzyl alcohols and vanadium-catalyzed redox condensation of benzamides with alcohols or aldehydes have been reported for the synthesis of quinazolin-4(3H)-ones.^15–17 Although these approaches result in an excellent formation of the product, most of them are suffering from its own limitations such as corrosive or non-benign acid/base catalyst, hazardous oxidants, precious metal-based catalysts, complexity in work-up and relatively harsher reaction conditions. Therefore, development of a green, simple and efficient synthetic approach for the preparation of quinazolin-4(3H)-ones from inexpensive and easily available starting materials under relatively mild conditions is desirable.Open in a separate windowScheme 1Our work for synthesis of quinazolin-4(3H)-ones.Visible light-induced reaction, which is widely recognized as an attractive “green synthesis pathway” in organic synthesis, has become a fast-developing research area in the past decades.^18–21 In spite of simple operation and mild reaction conditions, the common transition metals (e.g., iridium and ruthenium) employed as photocatalysts are usually expensive, toxic and not easily available. Nevertheless, organic dyes, which have shown similar photocatalytic activity in some reactions, could be more attractive candidates than the common transition metals, because they are usually relatively cheap, less toxic and accessible.²² In particular, fluorescein has been very recently studied as photocatalyst due to its cheap and commercially available characteristics.²³In this study, we focus our attention on developing a straightforward method to prepare quinazolin-4(3H)-ones with 2-aminobenzamides and aldehydes using fluorescein as photocatalyst via visible light-induced condensation cyclization, in which the synthesis of quinazolin-4(3H)-ones would proceed in good to excellent yields under mild conditions without the need for metal catalyst (Scheme 1). This method lays a solid foundation for the synthesis of quinazolin-4(3H)-ones. Moreover, this visible light-induced strategy has great potential in the synthesis of other types of useful organic molecules.At the initial stage of investigation, 2-aminobenzamide (1a) and benzaldehyde (2a) were chosen as the model substrates under blue LED irradiation, and a series of reaction conditions including photocatalysts, oxidants, solvents and reaction time were optimized. Initially, the reaction was performed in the presence of 10 mol% fluorescein as photocatalyst and the desired product, 2-phenylquinazolin-4(3H)-one (3aa), was obtained in 89% yield (

The synthesis of imidazo[1,5-a]quinolines via a decarboxylative cyclization under metal-free conditions

An iodine-mediated decarboxylative cyclization was developed from α-amino acids and 2-methyl quinolines under metal-free conditions, affording a variety of imidazo[1,5-a]quinolines with moderate to good yields.

An iodine-mediated decarboxylative cyclization was developed from α-amino acids and 2-methyl quinolines under metal-free conditions, affording a variety of imidazo[1,5-a]quinolines with moderate to good yields.     

Radioimmunoassay of 5-hydroxy-3-indole acetic acid

A direct radioimmunoassay of the methyl ester of urinary and serum 5-hydroxy-3-indole acetic acid is described. The antiserum, raised in a rabbit against a conjugate of bovine serum albumin with 5-hydroxytryptamine hemisuccinamide, contained two antigenic fractions, one binding N-acyl 5-hydroxytryptamine, and the other binding methyl ester of 5-hydroxy-3-indole acetic acid, and N-acyl 5-hydroxytryptamine. The N-acyl 5-hydroxytryptamine binding fraction was removed by affinity chromatography on a N-acyl 5-hydroxytryptamine agarose gel in the presence of excess methyl ester of 5-hydroxy-3-indole acetic acid. The antibody methyl ester of 5-hydroxy-3-indole acetic acid complexes were dissociated and this affinity-purified antiserum was used in all experiments. Polyethylene glycol in combination with goat anti-rabbit IgG was used to separate bound and unbound 125I-labeled Bolton-Hunter reagent- 5-hydroxytryptamine conjugate. Sample preparation (esterification of 5-hydroxy-3-indole acetic acid to its methyl ester) was performed with trimethylsilyldiazomethane in dioxane. In the analysis of urine, the reagents used in the methylation served as diluents, contributing to the final dilution of 1:1100. In the analysis of serum, a deproteination step (ethanol precipitation) prior to methylation was necessary to obtain reproducible results. The methylated 5-hydroxy-3-indole acetic acid was then extracted with ethyl acetate and the extract redissolved in assay buffer. The minimal detectable concentration of methyl ester of 5-hydroxy-3-indole acetic acid was 1.1 mumol/l (0.21 mg/l 5-hydroxy-3-indole acetic acid) urine or 100 fmol/tube.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metal- and base-free tandem sulfonylation/cyclization of 1,5-dienes with aryldiazonium salts via the insertion of sulfur dioxide

A metal- and base-free 5-endo-trig sulfonylative cyclization between 1,5-dienes, aryldiazonium salts and SO₂ (from SOgen) is presented. This method could successfully produce sulfonylated pyrrolin-2-ones in one pot with excellent regioselectivity and good-to-excellent yields. This strategy features mild reaction conditions and broad substrate scope. Moreover, a scale-up reaction and three synthetic applications demonstrate the practicality of this method. Lastly, control experiments indicate that the 5-endo-trig sulfonylative cyclization may proceed in a radical pathway.

A new metal- and base-free method for synthesizing sulfonylated pyrrolin-2-ones from 1,5-dienes, aryldiazonium salts and SO₂ is presented. This transformation features mild reaction conditions and broad substrate scope.     

Colorimetric assay of urinary 5-hydroxy-3-indoleacetic acid

We describe a method for 5-hydroxy-3-indoleacetic acid in urine based on its reaction with nitrosonaphthol in the presence of mercaptoethanolamine, an odorless compound. Mercaptoethanolamine shifts the color maximum from 540 nm to 640 nm, intensifies the color and discharges the color of interfering substances. The method is rapid and free from interferences.     

Synthesis of C2-tetrasubstituted indolin-3-ones via Cu-catalyzed oxidative dimerization of 2-aryl indoles and cross-addition with indoles

An efficient protocol for the synthesis of 2,2-disubstituted indolin-3-ones under mild conditions has been developed. This reaction involves the copper-catalyzed in situ oxidative de-aromatization of 2-arylindoles to indol-3-one, followed by self-dimerization as well as cross-addition with indoles under mild conditions. The result generates a wide variety of C2-tetrasubstituted indolin-3-ones with good to high yields (62–82%).

A general protocol for the synthesis of 2,2-disubstituted indolin-3-ones has been developed through self-dimerization of 2-aryl indoles and cross-addition with indoles under mild Cu-catalyzed oxidative conditions with good to high yields.     

Gas chromatography of 5-hydroxy-3-methylindole in human urine

Electron capture gas chromatography was used to estimate the urinary 5-hydroxy-3-methylindole in epileptic patients and normal controls. The urine was filtered, concentrated in vacuo, extracted into benzene-ethanol and passed through a silica gel column. The dried eluate was dissolved in acetonitrile, tri-fluoroacetylated and estimated by gas chromatography as di-trifluoroacetylated 5-hydroxy-3-methylindole. This structure was confirmed by gas chromatography-mass spectrometry. 5-Hydroxy-3-methylindole was excreted at high concentrations in some epileptics and at low concentrations in normal control subjects.     

Fluorescence polarization immunoassay of urinary 5-hydroxy-3-indoleacetic acid

Fluorescence polarization immunoassay of 5-hydroxy-3-indoleacetic acid in urine is described and compared with liquid chromatography (electrochemical detection) and colorimetry. Reports of in-house performance data and results of clinical trials are included to emphasize the usefulness of the assay for routine work.     

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.     

Copper coordination compounds with (5Z,5Z′)-2,2′-(alkane-α,ω-diyldiselenyl)-bis-5-(2-pyridylmethylene)-3,5-dihydro-4H-imidazol-4-ones. Comparison with sulfur analogue

A series of new organic ligands (5Z,5Z′)-2,2′-(alkane-α,ω-diyldiselenyl)-bis-5-(2-pyridylmethylene)-3,5-dihydro-4H-imidazol-4-ones (L) consisting of two 5-(2-pyridylmethylene)-3,5-dihydro-4H-imidazol-4-one units linked with polymethylene chains of various lengths (n = 2–10, where n is the number of CH₂ units) have been synthesized. The reactions of these ligands with CuCl₂·2H₂O and CuClO₄·6H₂O gave Cu²⁺ or Cu¹⁺ containing mono- and binuclear complexes with Cu₂LCl_x (x = 2–4) or CuL(ClO₄)_y (y = 1, 2) composition. It was shown that the agents reducing Cu²⁺ to Cu¹⁺ in the course of complex formation can be both a ligand and an organic solvent in which the reaction is carried out. This fundamentally distinguishes the selenium-containing ligands L from their previously described sulfur analogs, which by themselves are not capable of reducing Cu²⁺ during complexation under the same conditions. A higher cytotoxicity and reasonable selectivity to cancer cell lines for synthesized complexes of selenium-containing ligands was shown; unlike sulfur analogs, ligands L themselves demonstrate a high cytotoxicity, comparable in some cases to the toxicity of copper-containing complexes.

Mono- and binuclear Cu(+1/+2) complexes of bis-5-(2-pyridyimethylene)-2-selenohydantoins were obtained by the reactions of corresponding ligands with copper(+2) chloride or perchlorate in BuOH/DCM mixtures.     

Synthesis of poly-functionalized benzofurans via one-pot domino oxidation/[3+2] cyclization reactions of a hydroquinone ester and ynamides

Densely substituted amino-functionalized benzofurans were concisely accessed via the first one-pot domino oxidation/[3+2] cyclization of a hydroquinone ester and easily accessible ynamides under mild conditions in a short time. The complex benzofurans were able to be efficiently synthesized all from simple and inexpensive starting materials in two steps.

Efficient method for the construction of poly-functionalized benzofurans has been developed via one-pot domino oxidation/[3+2] cyclization reactions.

Benzofuran derivatives are valuable structural motifs that are often found in natural products and biologically active compounds.¹ Various methods have been developed for the synthesis of those heterocyclic scaffolds,^2,3 among which the intramolecular annulation of preformed ortho-alkynylated phenols catalyzed by transition metals is the most general way.^2e–o Recently, Li and coworkers reported a novel iron-catalyzed tandem oxidative coupling and annulation process to access benzofurans from simple phenols and β-keto esters (Scheme 1a),^3a and the group of Dominguez disclosed a one-pot approach to benzofurans from 2-hydroxybenzophenones and N,N-dimethylacetamide promoted by copper under oxidative conditions (Scheme 1b).^3b Both of the two methods provided direct access to benzofuran derivatives from simple easy accessible starting materials under oxidative conditions, but all the reactions were performed at high temperature and with relatively high catalyst loading. Fast reactions under mild conditions are undoubtedly more desirable. In this context, we report the direct synthesis of densely substituted benzofurans from simple and inexpensive starting materials via the first one-pot domino oxidation/[3+2] cyclization of a hydroquinone derivative and ynamides under mild conditions (Scheme 1c).Open in a separate windowScheme 1Direct accesses to benzofuran derivatives under oxidative conditions.Over the past decades, ynamides, as powerful synthons, have been involved in the transition-metal catalyzed cyclization reactions for the construction of diverse building blocks of functionalized molecules including important pharmacophores.⁴ Although various cyclic systems have been achieved via the reactions of ynamides,^4a–q to the best of our knowledge, construction of amino-functionalized benzofurans from ynamides have not been reported. Therefore, we initiated our design to access benzofuran derivatives via the [3+2] cyclizations of ynamides with quinones. Quinones can be easily oxidized from hydroquinones, which provides the possibility for coupling the oxidation and cyclization into a one-pot domino process.^5,6b Before coupling the two steps together, we first chose to optimize the cyclization step.First, we started the investigation with ynamide 1a and quinone 2a. Lewis acids have been reported as good activators of quinones.^6,7a However, by the use of Lewis acid Sc(OTf)₃ as the catalyst, there was no desired benzofuran product formation at all while the ynamide hydrolysis byproduct 4a formed exclusively (7 Quinone ester 2b was easily synthesized via oxidation of commercially available methyl 2,5-dihydroxybenzoate (5). Gratifyingly, the reaction of 1a with quinone ester 2b catalyzed by Sc(OTf)₃ afforded the desired [3+2] cyclization product 3a in 89% yield within 5 min with only trace amount of hydrolysis product detected ( EntryCatalyst (10 mol%)SolventRTimeYield^b (3a) [%]Yield^b (4a) [%]1Sc(OTf)₃CH₂Cl₂H5 min—912^cSc(OTf)₃CH₂Cl₂H2 h—333Sc(OTf)₃CH₂Cl₂CO₂Me5 min89Trace4Cu(OTf)₂CH₂Cl₂CO₂Me5 min61185Yb(OTf)₃CH₂Cl₂CO₂Me5 min8346AlCl₃CH₂Cl₂CO₂Me30 min33Trace7Sc(OTf)₃THFCO₂Me5 min8058Sc(OTf)₃PhMeCO₂Me5 min86Trace9^dSc(OTf)₃CH₂Cl₂CO₂Me5 min90Trace10^eSc(OTf)₃CH₂Cl₂CO₂Me5 min88^f911^d,gSc(OTf)₃CH₂Cl₂CO₂Me5 min91Trace12^d,hSc(OTf)₃CH₂Cl₂CO₂Me5 min88Trace13^d,h,iSc(OTf)₃CH₂Cl₂CO₂Me5 min91TraceOpen in a separate window^aUnless otherwise noted, reactions were carried out using ynamide 1a (0.10 mmol), 2 (0.15 mmol) with catalyst (0.01 mmol) in solvent 2.0 mL at room temperature (25 °C) in air.^bIsolated yields relative to 1a.^c100 mg 4 Å molecular sieves were added and under Ar atmosphere.^d2b (0.12 mmol) was used.^e1a (0.12 mmol), 2b (0.10 mmol) was used.^fYield relative to 2b.^gCatalyst (0.005 mmol) was used.^hCatalyst (0.002 mmol) was used.ⁱHydroquinone ester 5 (0.12 mmol), Ag₂O (0.24 mmol), and MgSO₄ (0.24 mmol) were mixed in CH₂Cl₂ (2.0 mL) and the mixture was stirred for 2 h, and then 1a (0.10 mmol) and Sc(OTf)₃ (0.002 mmol) were added.With the best cyclization reaction conditions in hand, next we tried to combine the oxidation step with the [3+2] cyclization into a one-pot domino process.^5a Hydroquinone ester 5 was first mixed with oxidant Ag₂O and MgSO₄ in CH₂Cl₂ and the mixture was stirred for 2 h. Then 1a and Sc(OTf)₃ were directly added to the above mixture.^8,9 To our delight, the one-pot domino oxidation/[3+2] cyclization occurred efficiently, affording 3a in 91% yield (Scheme 2).Open in a separate windowScheme 2Substrate scope of the one-pot domino oxidation/[3+2] cyclization reaction. Reaction conditions: hydroquinone ester 5 (0.12 mmol), Ag₂O (0.24 mmol), and MgSO₄ (0.24 mmol) were mixed in CH₂Cl₂ (2.0 mL) and the mixture was stirred for 2 h, and then 1 (0.10 mmol) and Sc(OTf)₃ (0.002 mmol) were added.In general, the reactions of 5 with a series of ynamides in the one-pot system afforded poly-substituted benzofurans 3 in good to excellent yields (85–96%). Ynamides with both aromatic and alkyl groups at the terminal position could be tolerated, furnishing 3-aromatic or 3-alkyl substituted benzofurans with high yields (Scheme 2). The reactions of alkyl-terminated ynamides gave slightly higher yields than that of aromatic-terminated ones (3a, 3bvs.3c; 3evs.3f; 3gvs.3h). For ynamides with sulfonyl system, the triisopropylsilyl-terminated ynamide was successfully applied in the one-pot reaction, and the desired product 3d was obtained in 85% yield. The reactions of ynamides with propiolactam system also worked well to give 3e (85%) and 3f (91%). Ynamides derived from indole ester reacted well with 5 in this one-pot system, giving rise to the interesting 1-benzofuranyl indole derivatives (3g, 3h) in perfect yields, 90% and 96% respectively.It is worth to mention that ynamides (1) used here were all easily prepared in one step via copper-catalyzed oxidative cross coupling of corresponding simple amides and terminal alkynes according to literature procedures,^4q,10 which indicates that the complex poly-functionalized benzofurans (3) were able to be efficiently synthesized all from simple and inexpensive staring materials in only two steps (Scheme 3). A large scale reaction was performed to synthesize 1-benzofuranyl indole 3h. Starting from simple commercial available 1-heptyne, methyl indole-3-carboxylate, and methyl 2,5-dihydroxybenzoate (5), 1.64 g of 3h was obtained in two steps with high efficiency (Scheme 3b).Open in a separate windowScheme 3(a) Concise access to complex benzofurans from simple and inexpensive starting materials. (b) A large scale reaction for the synthesis of 3h.The postulated mechanisms resulting in the formation of densely substituted benzofurans 3 are proposed as shown in Scheme 4. Hydroquinone 5 is first oxidized by Ag₂O to give quinone ester 2b, which is subsequently activated by Sc(OTf)₃. According to Johnson et al.,^4q ynamides may also be functioned by the scandium Lewis acid to increase the nucleophilicity. A undergoes nucleophilic attack by the ynamide to give keteniminium ion B. Then, 1,2-proton shift followed by the intramolecular cyclization of B furnishes intermediate C. Finally, after tautomerization and release of Sc(OTf)₃, desired product 3 is formed.Open in a separate windowScheme 4Proposed mechanism for the one-pot domino oxidation/[3+2] cyclization.In summary, we have developed a fast and step-economical one-pot domino oxidation/[3+2] cyclization reactions of a hydroquinone ester and ynamides. A series of densely functionalized benzofurans were concisely achieved in good to excellent yields from simple and inexpensive starting materials under mild conditions. A gram scale reaction proved that the one-pot reaction was able to be scaled up easily. Further studies on the expansion of the reaction scope and on the construction of other heterocycles based on the domino strategy used in this study are ongoing and will be reported in due course.     

Efficient synthesis of spirooxindolyl oxazol-2(5H)-ones via palladium(ii)-catalyzed addition of arylboronic acids to nitriles

A versatile synthesis of spirooxindolyl oxazol-2(5H)-ones via palladium(ii)-catalyzed addition of arylboronic acids to nitriles is described. A wide range of spirooxindolyl oxazol-2(5H)-ones and other spirocyclic frameworks incorporating the oxazol-2(5H)-one unit can be readily prepared in good to high yields under the optimal conditions.

A versatile synthesis of spirooxindolyl oxazol-2(5H)-ones and derivatives via palladium(ii)-catalyzed addition of arylboronic acids to nitriles is described.

Rapid and efficient construction of pharmaceutical and biologically relevant compounds plays a very important role in modern organic synthesis, and constitutes the original impetus for the development of various novel synthetic approaches. The efficient construction of spirocyclic frameworks has been a topic of great relevance in organic synthesis due to their inherent three-dimensional architectures and the pronounced biological activities.¹ In particular, the spirocyclic oxindoles have emerged as attractive synthetic targets because of their prevalence in numerous natural and unnatural products.² Notably, the enhanced biological activities have been observed by the incorporation of a spiro five-membered azaheterocyclic ring at the C3 position of the oxindole core (Fig. 1).³ Thereby, a variety of synthetic methods have been developed to access analogous compounds possessing such privileged structure moieties.⁴Open in a separate windowFig. 1Examples of spiro oxindoles containing natural products and biological relevant compounds.As one of the important N–O heterocyclic compounds, oxazolidinones and their derivatives have been widely used not only as synthetic building blocks,⁵ but also as pharmaceuticals⁶ and agrochemicals,⁷ owing to a diverse range of biological activities.⁸ Although great contributions have been made to access these valuable scaffolds,⁹ the construction of structurally diverse spirooxindolyl oxazol-2(5H)-ones, characterized by a spiro ring fusion at the C3 position of the oxindole core with oxazol-2(5H)-one motif, has received less attention from synthetic community,¹⁰ despite the fact that these spirocyclic heterocycles could be promising candidates possessing biological responses. In 2017, He and co-workers reported a formal [3 + 2] cycloaddition reaction of in situ generated azaoxyallyl cation with cyclic ketones for the synthesis of spiro-4-oxazolidinones.^11a In 2018, Alla and co-workers described a copper-catalyzed one-pot multicomponent protocol for the synthesis of spiro(indoline-3,5′-oxazolidine)-2,2′-diones starting from ketones, arylacetylenes and isocyanates.^11bRecently, the transition-metal-catalyzed addition of organoboron reagents to nitriles has received remarkable progress,¹² since the elegant works on the addition of arylpalladium species to the cyano group reported by Larock and Lu et al.,¹³ in which nitriles served as C building blocks and provided aryl ketones. In virtue of palladium-catalyzed tandem addition of organoboron reagents to nitriles/cyclization protocol, this approach enabled the combination of organoboron reagents and nitriles to construct a diversity of nitrogen-containing heterocycles such as 2-aminobenzophenones, benzofurans, and indoles, in which nitrile serves as C–N synthon instead and is incorporated into heterocyclic frameworks in an atom-economical fashion.¹⁴ However, the development of transition-metal-catalyzed tandem sequence involving the addition of organoboron reagents to nitriles to construct structural novel three-dimensional architectures such as spirocyclic systems is still undeveloped.We have recently developed both intramolecular and intermolecular cyclization approaches to prepare indole and thiophene fused polycyclic derivatives via Pd-catalyzed direct C–H bond addition to nitriles.¹⁵ Given the promising biological activities of spirooxindoles-containing molecules in medicinal chemistry and our ongoing interest in the development of efficient catalytic processes to prepare diverse aza-heterocyclic frameworks, herein, we report an efficient synthetic approach to prepare spirooxindolyl oxazol-2(5H)-ones via palladium(ii)-catalyzed addition of arylboronic acids to nitriles.As functionalized nitriles, cyanohydrins which are readily prepared from ketones and aldehydes have demonstrated considerable synthetic potential as useful building blocks.¹⁶ We chose the Pd(ii)-catalyzed reaction of 3-cyano-1-methyl-2-oxoindolin-3-yl ethyl carbonate 1a, which is readily prepared from isatin and ethyl cyanoformate, and phenylboronic acid 2a as a model reaction for the optimization of the reaction conditions (ii) catalyst proven to be essential to this transformation since no reaction happened without them (†). In addition, the reaction also was evaluated with Ni(ii) catalyst system. However, Ni(ii)-catalyzed reaction gave the inferior to that of Pd(ii) catalytic system (†).Effects of reaction parameters^a

Quantitative determination of 3-ethyl-5-hydroxy-4,5-dimethyl-Δ3-pyrrolin-2-one in urine using gas-liquid chromatography

A method is presented for the quantitation in urine of 3-ethyl-5-hydroxy-4,5-dimethyl-Δ³-pyrrolin-2-one, a substance associated with hepatic porphyria and psychiatric disorders. The method involves gas-liquid chromatography following solvent extraction using one of two other heterocyclic compounds as internal standards. Quantitation of this substance in the urine of a group of normal subjects is also reported.     

Preparation of spiro[indole-3,5′-isoxazoles] via Grignard conjugate addition/spirocyclization sequence

A highly efficient one-pot procedure combining conjugate addition of Grignard reagents to (2-nitroalkenyl)indoles and sub-sequent Brønsted acid-assisted spirocyclization allowed for preparation of 4′H-spiro[indole-3,5′-isoxazoles] in a diastereomerically selective fashion. Utilization of alkyl Grignard reagents provided an easy access to 4′-alkylsubstituted derivatives hardly available by other means.

One-pot procedure combining conjugate addition of Grignard reagents to (2-nitroalkenyl)indoles and subsequent acid-assisted spirocyclization allowed for diastereoselective preparation of 4′H-spiro[indole-3,5′-isoxazoles].     

Rapid and halide compatible synthesis of 2-N-substituted indazolone derivatives via photochemical cyclization in aqueous media

Indazolone derivatives exhibit a wide range of biological and pharmaceutical properties. We report a rapid and efficient approach to provide structurally diverse 2-N-substituted indazolones via photochemical cyclization in aqueous media at room temperature. This straightforward protocol is halide compatible for the synthesis of halogenated indazolones bearing a broad scope of substrates, which suggests a new avenue of great importance to medicinal chemistry.

A straightforward protocol for the rapid construction of privileged indazolone architectures suggests a new avenue of great importance to medicinal chemistry.

The indazolone ring system constitutes the core structural element found in a large family of nitrogen heterocycles as exemplified by those shown in Scheme 1.¹ Indazolone derivatives have been receiving much attention due to their promising pharmacological activities. Given the unique bioactive core skeleton, indazolone derivatives exhibit a wide range of biological and pharmaceutical properties such as antiviral and antibacterial activities (1–4),² new prototypes for antichagasic drugs (5),³ antihyperglycemic properties (6),⁴ TRPV1 receptor antagonists for analgesics (7),⁵ anti-flammatory agents (8),⁶ angiotensin II receptor antagonists (9),⁷ highly potent CDKs inhibitors for anticancer (10)⁸ and so on.⁹ The privileged indazolone structures have high potential as core components for the development of related compounds leading to medicinal agents.Open in a separate windowScheme 1Biologically active molecules containing indazolone skeletons.Due to their versatility in pharmaceutical applications, many synthetic approaches have been developed for the construction of indazolone skeletons (Scheme 2), including CuO-mediated coupling of 2-haloarylcarboxylic acids with methylhydrazine,¹⁰ cyclization of N-aryl-o-nitrobenzamides through Ti(vi) reagent or Zn(ii) reagent,¹¹ Cu(i)-mediated intramolecular C–N bond formation or a base-mediated intramolecular SNAr reaction of 2-halobenzohydrazides,¹² Cu(i)-catalyzed oxidative C–N cross-coupling and dehydrogenative N–N formation sequence,¹³ Rh-catalyzed C–H activation/C–N bond formation and Cu-catalyzed N–N bond formation between azides and arylimidates,¹⁴ Friedel–Crafts cyclization of N-isocyanates using Masked N-isocyanate precursors,¹⁵ PIFA-mediated intramolecular oxidative N–N bond formation by trapping of N-acylnitrenium intermediates,¹⁶ and recently reported reaction of o-nitrobenzyl alcohol with primary amines in basic conditions.¹⁷ These approaches are complementary providing avenue to access various substitution patterns,¹⁸ however most methods rely on the requirements for transition-metal catalysts. In fact, the procedures for synthesis indazolone skeletons from Friedel–Crafts cyclization of N-isocyanates and Davis–Beirut derived reaction still suffer from harsh reaction conditions such as high reaction temperature (i.e. more than 150 °C or 20 equiv. of KOH at 100 °C for 24 h).^15,17b Very recently, one photochemical route was reported for preparation of indazolone skeletons from o-nitrobenzyl alcohols and primary amines,¹⁹ however, this approach still need long reaction time (24 hours) and halogen substituted substrate could not be compatible in the reaction conditions.^19b Thus, the efficient and general methods tolerating a wide scope of readily available starting materials for synthesis of indazolones without a transition-metal catalyst involved are still in great demand.Open in a separate windowScheme 2Representative approaches for the preparation of indazolone skeletons. o-Nitrobenzyl alcohol derivatives have shown many applications in material science and chemical biology area as a photolabile protecting group (Scheme 3a).²⁰ Upon UV light-activation, o-nitrobenzyl alcohol derivatives generate corresponding aryl-nitroso compounds via photoisomerization.²¹ Based on the distinguishing feature of highly reactive of these photogenerated intermediates, we assumed that the reaction conditions would be crucial for the photoisomerization,^20,22 thus the reactive intermediates should spontaneously and rapidly form indazolone structures via cyclization in the presence of primary amines in suitable reaction conditions (Scheme 3b). Herein, we report a rapid and efficient approach to provide structural diversity 2-N-substituted indazolones via photochemical cyclization in aqueous media at room temperature. This photochemical cyclization reaction is halide compatible for synthesis of halogen substituted indazolones, bearing a broad scope of substrates. This straightforward protocol for rapid construction of halogenated indazolone architectures suggests a new avenue of great importance to medicinal chemistry.Open in a separate windowScheme 3Synthesis of indazolone derivatives via photochemical cyclization.The initial investigation to develop a method for synthesis of indazolone derivatives via photochemical cyclization started with 4-(hydroxymethyl)-3-nitro-N-propylbenzamide 11 and heptan-1-amine 12 upon UV light-activation in methanol, smoothly leading to the formation of indazolone 13 in 52% yield ( EntrySolvent11 : 12Time (h)Yield^f (%)1MeOH2.5 : 13522THF2.5 : 13583 n-BuOH2.5 : 13574CH₃CN2.5 : 13615CH₃CN : H₂O = 3 : 12.5 : 13676CH₃CN : PBS = 3 : 12.5 : 1361 7 n-BuOH : H ₂ O = 3:1 2.5 : 1 3 82 8 n-BuOH : PBS = 3 : 12.5 : 13569MeOH : H₂O = 3 : 12.5 : 133810i-PrOH : H₂O = 3 : 12.5 : 136311 tBuOH : H₂O = 3 : 12.5 : 135512THF : H₂O = 3 : 12.5 : 134913DMF : H₂O = 3 : 12.5 : 134514Dioxane : H₂O = 3 : 12.5 : 136715^b n-BuOH : H₂O = 3 : 12.5 : 13<1016^c n-BuOH : H₂O = 3 : 12.5 : 132217^d n-BuOH : H₂O = 3 : 11.5 : 134518^e n-BuOH : H₂O = 3 : 12.5 : 132819 n-BuOH : H₂O = 3 : 12.5 : 168520PBS2.5 : 131921 n-BuOH : H₂O = 3 : 11 : 2.5346Open in a separate window^aReaction conditions: heptan-1-amine (12, 0.3 mmol), 4-(hydroxymethyl)-3-nitro-N-propylbenzamide (11, 0.75 mmol), solvent 6 mL, exposed to UV lamp with 365 nm, at R.T.^bUV lamp with 254 nm.^cUsing blue light.^dThe ratio of 11/12 = 1.5/1.^eReaction carried out at 50 °C.^fIsolated yield.With the optimal conditions in hand, we investigated the generality for the scope of o-nitrobenzyl alcohols and primary amines ( Open in a separate window^aReaction conditions: primary amines (15, 0.3 mmol), o-nitrobenzyl alcohols derivatives (14, 0.75 mmol), solvent 6 mL, isolated yield.Many drug candidates and drugs are halogenated structures. In drug discovery, insertion of halogen atoms on hit or lead compounds was predominantly performed, with the aim to exploit their steric effects and structure–activity relationship, to form halogen bonds in ligand–target complexes, to optimize the ADME/T property.²³ Given the versatility of halogen atom on bioactive molecules, we next investigated the halogen substituted o-nitrobenzyl alcohols as starting materials for construction of indazolone skeletons (17b as well as aniline failed to give product in the recently reported photochemical approach (see ESI, Fig. S1^†).^19b Of note, in the recently reported photochemical approach, the reaction of chloride substituted o-nitrobenzyl alcohol with alkylamine gave indazolone with low yield, possibly because photocleavage of aryl halide bond is involved in that reaction conditions.^19b These outcomes are significant in view of the challenges in construction of indazolone skeletons, in which additional halogen substitution on substrates is incompatible for indazolones synthesis.^10,19b Importantly, our reaction condition is compatible with halide substrates, suggests a new protocol of importance to photochemical reactions, in which dehalogenation of aryl halide is known to be radical-mediated and exist in some reaction conditions.²⁴Scope of halogen substituted o-nitrobenzyl alcohols for indazolone formation^a

Copper (triazole-5-yl)methanamine complexes onto MCM-41: the synthesis of pyridine-containing pseudopeptides through the 6-endo-dig cyclization of 1,5-enynes

An efficient approach for the synthesis of immobilized copper (triazole-5-yl)methanamine complexes onto MCM-41 (Cu@TZMA@MCM-41), as a novel recyclable nanocatalyst, is described. This nanocatalyst was used for the synthesis of pyridine-containing pseudopeptides through a sequential Ugi/nucleophilic addition/1,5-enyne cyclization reaction and elicited good-to-excellent yields. The nanocatalyst was fully characterized by SEM, EDS, TEM, BET, ICP-OES, TGA, and XRD techniques. Furthermore, the catalyst was recovered by simple filtration and could be used for at least 5 cycles without significant loss of activity.

A sequential Ugi/nucleophilic addition/1,5-enyne cyclization reaction was used for the synthesis of pseudopeptides containing pyridine skeletons in the presence of Cu@TZMA@MCM-41.