Ti-superoxide catalyzed oxidative amidation of aldehydes with saccharin as nitrogen source: synthesis of primary amides

A new heterogeneous catalytic system (Ti-superoxide/saccharin/TBHP) has been developed that efficiently catalyzes oxidative amidation of aldehydes to produce various primary amides. The protocol employs saccharin as amine source and was found to tolerate a wide range of substrates with different functional groups. Moderate to excellent yields, catalyst reusability and operational simplicity are the main highlights. A possible mechanism and the role of the catalyst in oxidative amidation have also been discussed.

Heterogeneous catalytic system using Ti-superoxide and saccharin with TBHP has been developed which catalyzes oxidative amidation of aldehyde to produce primary amides. It tolerates a wide range of substrates with different functional groups.     

Direct synthesis of amides and imines by dehydrogenative homo or cross-coupling of amines and alcohols catalyzed by Cu-MOF

Oxidative dehydrogenative homo-coupling of amines to imines and cross-coupling of amines with alcohols to amides was achieved with high to moderate yields at room temperature in THF using Cu-MOF as an efficient and recyclable heterogeneous catalyst under mild conditions. Different primary benzyl amines and alcohols could be utilized for the synthesis of a wide variety of amides and imines. The Cu-MOF catalyst could be recycled and reused four times without loss of catalytic activity.

Oxidative dehydrogenative homo or cross-coupling of amines with alcohols to imines and amides was achieved with high to moderate yields at room temperature using Cu-MOF as an efficient and recyclable heterogeneous catalyst.     

Facile synthesis of α-alkoxyl amides via scandium-catalyzed oxidative reaction between ynamides and alcohols

A novel and efficient scandium-catalyzed oxidative reaction between ynamides and alcohols for the facile synthesis of various α-alkoxyl amides is reported in this paper. The reaction avoids the need for the use of α-diazo carbonyls which are unstable and may cause some safety concerns. Instead, by using alkynes as the starting materials, this protocol features readily available substrates, compatibility with a broad range of functional groups, simple procedure, mild reaction conditions, and high chemoselectivity.

A novel scandium-catalyzed oxidative reaction between ynamides and alcohols has been developed, allowing the concise and efficient synthesis of various substituted α-alkoxyl amides.     

Programing a cyanide-free transformation of aldehydes to nitriles and one-pot synthesis of amides through tandem chemo-enzymatic cascades

Nitriles are broadly applied to synthesize pharmaceuticals, agrochemicals, and materials because of their versatile transformation. Although various methods have been developed for introducing a nitrile group into organic molecules, most of them entail the use of highly toxic chemicals, transition metals, or harsh conditions. In this work, we reported a greener chemo-enzymatic cascade to synthesize alky and aryl nitriles from readily accessible aldehydes, that were further transformed into corresponding amides via an artificial enzyme cascade. A biphasic reaction system was designed to bridge chemical synthesis and enzymatic catalysis through simple phase separation. The biphasic system mainly perfectly avoided the inactivation of hydroxylamine on aldoxime dehydratase from Pseudomonas putida (OxdF1) and nitrile hydratase from Aurantimonas manganoxydans ATCC BAA-1229 (NHase1229). For the synthesis of various nitriles, moderate isolation yields of approximately 60% were obtained by the chemo-enzymatic cascade. Interestingly, two seemingly conflicting reactions of dehydration and hydration were sequentially proceeded to synthesize amides by the synergistic catalysis of OxdF1 and NHase1229 in E. coli cells. An isolation yield of approximately 62% was achieved for benzamide at the one-liter scale. In addition, the shuttle transport of substrates and products between two phases is convenient for the product separation and n-hexane recycling. Thus, the chemo-enzymatic cascade shows a potential application in the cyanide-free and large-scale synthesis of nitriles and amides.

A chemo-enzymatic cascade was developed for the cyanide-free synthesis of nitriles from aldehydes and further one-pot transformation into amides.     

Combined experimental and computational study of Al2O3 catalyzed transamidation of secondary amides with amines

Amides are the most extensively used substances in both synthetic organic and bioorganic chemistry. Unfortunately, the traditional synthesis of amides suffers from some important drawbacks, including low atom efficiency, high catalyst loading, separation of products from the reaction mixture and production of byproducts. Al₂O₃ is an amphoteric catalyst that activates the carbonyl carbon of the secondary amide group and helps the C–N cleavage of the reactant amide group by attacking the N–H hydrogen. By using the concepts of amphoteric properties of Al₂O₃, amides were synthesized from secondary amides and amines in the presence of triethylamine solvent. Several aliphatic and aromatic amines were used for the transamidation of N-methylbenzamide in the presence of the Al₂O₃ catalyst. Moreover, using the Gaussian09 software at the DFT level, HUMO, LUMO and the intrinsic reaction coordinates (IRCs) have also been calculated to find out the transition state of the reaction and energy. In this study, five successful compounds were synthesized by the transamidation of secondary amides with amines using a reusable Al₂O₃ catalyst. The catalyst was reused several times with no significant loss in its catalytic activity. The products were purified by recrystallization and column chromatography techniques. This catalytic method is effective for the simultaneous activation of the carbonyl group and N–H bond by using the Al₂O₃ catalyst.

Amides are the most extensively used substances in both synthetic organic and bioorganic chemistry.     

One-pot method for the synthesis of 1-aryl-2-aminoalkanol derivatives from the corresponding amides or nitriles

We have identified a novel one-pot method for the synthesis of β-amino alcohols, which is based on C–H bond hydroxylation at the benzylic α-carbon atom with a subsequent nitrile or amide functional group reduction. This cascade process uses molecular oxygen as an oxidant and sodium bis(2-methoxyethoxy)aluminum hydride as a reductant. The substrate scope was examined on 30 entries and, although the respective products were provided in moderate yields only, the above simple protocol may serve as a direct and powerful entry to the sterically congested 1,2-amino alcohols that are difficult to prepare by other routes. The plausible mechanistic rationale for the observed results is given and the reaction was applied to a synthesis of a potentially bioactive target.

A one-pot method for β-amino alcohol synthesis based on α-hydroxylation and subsequent amide or nitrile functional group reduction has been identified and examined.     

One-pot synthesis of cup-like ZSM-5 zeolite and its excellent oxidative desulfurization performance

A one-step method to synthesize small size cup-like hollow ZSM-5 single crystals is reported in this paper. Characterization methods show that the product has a typical ZSM-5 structure and most crystals are uniform, mono dispersed crystal shells with distinct hollow structure. The average size of a single crystal is about 350 nm. Every cup-like hollow ZSM-5 crystal can act as a microreactor in the reaction, and the ZSM-5 based catalyst POM-MOF-ZSM-5 (polyoxometalates (POM), metal–organic frameworks (MOF)) shows excellent oxidative desulfurization performance of DBT (dibenzothiophene).

One-pot synthesis of small size cup-like hollow ZSM-5 single crystals and their oxidative desulfurization performance.     

One-pot multicomponent green LED photoinduced synthesis of chromeno[4,3-b]chromenes catalyzed by a new nanophotocatalyst histaminium tetrachlorozincate

Histaminium tetrachlorozincate nanoparticles are prepared, characterized and applied as an effective and recoverable photocatalyst in the one-pot, green and multi-component synthesis of various chromenes by the reaction of dimedone and/or 1,3-cyclohexanedione, arylaldehyde and 4-hydroxycoumarin in high yields under solventless conditions at ambient temperature. This new catalyst is characterized by FT-IR, XRD, EDX, NMR, SEM and TEM techniques. The incorporation of histaminium ions into the framework of ZnCl₄²⁻ significantly affected the photocatalytic activity of tetrachlorozincate such that good reusability and recyclability are attained. Moreover, reactive species such as ˙O₂⁻ and hydroxyl radicals have proved to be active species in the presented photocatalytic reaction. In addition, the hot filtration test confirms enough stability of the photocatalyst and no significant leaching and destruction of the framework in the course of the reaction. The major advantages of the presented methodology include easy work-up, cost effectiveness, nontoxic nature, broad substrate scope, 100% atom economy, ease of separation, and environment friendly reaction conditions. Finally, the catalyst could be reused many times without significant loss of activity.

(His.)ZnCl₄ nanocatalyst is realized for the preparation of chromenes with a green LED. ˙O₂⁻, OH˙ and h⁺ are reactive species for this reaction. Complementary tests assured good stability and reusability of the nanophotocatalyst.     

DIPEA-induced activation of OH− for the synthesis of amides via photocatalysis

The development of green protocols for photocatalysis where water acts as a nucleophile, induced by a weak organic base, is difficult to achieve in organic chemistry. Herein, an efficient light-mediated strategy for the synthesis of amides in which a weak organic base acts as a reductant to induce the formation of OH– from water under metal-free conditions is reported. A mechanistic study reveals that the generation of an N,N-diisopropylethylamine (DIPEA) radical via single electron transfer (SET), with the assistance of photocatalyst, that increases the nucleophilicity of the water molecules with respect to the cyanides is essential. Moreover, the removal rate of nitrile in wastewater can be as high as 83%, indicating that this strategy has excellent potential for nitrile degradation.

Under weak organic base condition DIPEA as a reductant to increase the nucleophilicity of H₂O an excellent potential system for nitrile degradation.

The synthesis of amides is a subject of continuous interest and great importance because of their important applications in detergents, agrochemicals, polymers and pharmaceuticals.¹ Traditional methods for their synthesis require the transformation of an acid into the corresponding acyl chloride, facilitated by the use of the Schotten–Baumann reaction.² Although these methods produce amides in good yields, stoichiometric amounts of an activating reagent are required, making these poorly atom economic processes. Various strategies for carboxamide synthesis, such as oxidative alcohol–amine and aldehyde–amine coupling reactions, amine dehydrogenation or oxidation reactions, and C–N coupling reactions, have been developed in recent years.³ Despite this, one of the most straightforward and atom-economical ways to synthesize amides remains the hydration of organonitriles.⁴ Conventional strategies mostly use strong inorganic bases to generate strongly nucleophilic hydroxide ions, require tough conditions, and are sensitive, especially when using bioactive molecules,⁵ to the substrate. Moreover, water molecules are usually used as nucleophiles in the hydration of nitriles. Thus, compared to the use of strong basic conditions, the direct nucleophilic addition of water to the cyano group is kinetically slow due to the high energy of the carbon–nitrogen triple bond.⁶ To circumvent these problems, transition metal (TM) catalytic procedures, where the metal center of the catalyst acts as a Lewis acid to activate the nitrile and the ligand acts as a Lewis base-activated nucleophile, have been developed in recent years.⁷ But these protocols are associated with certain debilitating disadvantages that include the presence of toxic transition metal cations within the molecular structure of the reagents and difficulties in preventing over-hydrolysis to the corresponding carboxylic acids.Recently, there have been some reports that reductants have been used to change the morphology of water to increase its nucleophilicity.⁸ Organoamine bases, such as N,N-diisopropylethylamine (DIPEA), have acted in the role of both base and nitrogen radical intermediate and are considered to be reductants.⁹ However, DIPEA does not lose electrons easily and therefore has a low reductive activity, which means the nitrogen center has to cross a higher energetic barrier. Recently, it was shown that DIPEA could reductively quench many excited photocatalysts by single electron transfer (SET) to generate nitrogen-centered radicals.¹⁰ For example, Xu and coworkers¹¹ proposed a new approach using DIPEA to construct difluoroalkylated diarylmethane compounds via visible light photocatalytic radical–radical cross-coupling reactions, in which DIPEA can carry out electron transfer due to the induction of the photocatalyst. It indicates that photooxidation–reduction and organic amine reduction are, when exposed to sufficient light intensity, co-catalytic processes and can generate nitrogen-centered radicals so that the downstream reaction process can continue.¹² Herein, an efficient light-mediated strategy for the synthesis of amides in which a weak organic base acts as a reductant to induce the formation of OH– from water under metal-free conditions is reported.Initially, the reaction of the benzonitrile (1a) was selected for the screening of the reaction conditions (Fig. 1, ​,22 and ​and33.Optimization of the reaction conditions^a

Nickel catalyzed intramolecular oxidative coupling: synthesis of 3-aryl benzofurans

Recent research has been focused on the transition metal-catalyzed reactions. Herein we have developed nickel-catalyzed synthesis of 3-aryl benzofurans from ortho-alkenyl phenols via intramolecular dehydrogenative coupling. Notably, simple O₂ gas served as an oxidant, without using any sacrificial hydrogen acceptor. The strategy enabled the synthesis of 3-aryl benzofurans in good to excellent yields.

We have developed nickel-catalyzed synthesis of 3-aryl benzofurans from ortho-alkenyl phenols via intramolecular dehydrogenative coupling. O₂ gas served as an oxidant and 3-aryl benzofurans were synthesized in good to very good yields.     

One-pot multicomponent synthesis of thieno[2,3-b]indoles catalyzed by a magnetic nanoparticle-supported [Urea]4[ZnCl2] deep eutectic solvent

In this study, we have developed the synthesis of thieno[2,3-b]indole dyes via a multicomponent reaction of cheap and available reagents such as sulfur, acetophenones, and indoles using a magnetic nanoparticle-supported [Urea]₄[ZnCl₂] deep eutectic solvent as a green catalyst. The synthesis of a series of diversely functionalized thieno[2,3-b]indole has been successfully performed in a one-pot reaction. Among a total of 25 compounds synthesized, there are 21 new compounds with full characterization such as FT-IR, ¹H and ¹³C NMR, HRMS (ESI). Due to the deep eutectic solvent coated surface of the magnetic nanoparticles, the catalyst could be recovered by an external magnet and reused in five consecutive runs without a considerable decrease in catalytic activity.

We have developed the synthesis of thieno[2,3-b]indole dyes via a multicomponent reaction of cheap and available reagents using a magnetic nanoparticle-supported [Urea]₄[ZnCl₂] deep eutectic solvent as a green catalyst.     

One-pot synthesis of 3,4-dihydropyrimidin-2(1H)-ones catalyzed by SO3H@imineZCMNPs as a novel,efficient and reusable acidic nanocatalyst under solvent-free conditions

The synthesis of 3,4-dihydropyrimidin-2(1H)-one derivatives was accomplished efficiently via a three-component reaction between ethyl acetoacetate, various types of aldehydes, and urea in the presence of 10 mg SO₃H@imineZCMNPs as a novel, environment friendly, and reusable heterogeneous magnetic nanocatalyst under solvent-free conditions at 90 °C. The desired products were obtained with high quantitative yields. The catalyst was separated by simple isolation from the reaction mixture using a permanent magnet and reused several times without any significant loss of catalytic activity. The synthesized catalyst was fully characterized through various techniques including thermogravimetric analysis, Fourier transform infrared spectroscopy, scanning electron microscopy, transmission electron microscopy, X-ray diffraction, and the Hammett acidity test. This methodology tolerates most substrates and has the salient features of green reaction conditions, lower catalyst loading, high quantitative yields, low cost, the absence of solvents, and easy isolation and reusability of the catalyst.

The synthesis of 3,4-dihydropyrimidin-2(1H)-one derivatives was accomplished via a three-component reaction in the presence of SO₃H@imineZCMNPs as a novel, environment friendly, and reusable heterogeneous magnetic nanocatalyst under solvent-free conditions at 90 °C.     

Practical one-pot amidation of N-Alloc-, N-Boc-, and N-Cbz protected amines under mild conditions

A facile one-pot synthesis of amides from N-Alloc-, N-Boc-, and N-Cbz-protected amines has been described. The reactions involve the use of isocyanate intermediates, which are generated in situ in the presence of 2-chloropyridine and trifluoromethanesulfonyl anhydride, to react with Grignard reagents to produce the corresponding amides. Using this reaction protocol, a variety of N-Alloc-, N-Boc-, and N-Cbz-protected aliphatic amines and aryl amines were efficiently converted to amides with high yields. This method is highly effective for the synthesis of amides and offers a promising approach for facile amidation.

One-pot efficient transformation of N-Alloc-, N-Boc-, and N-Cbz protected amines to amides was achieved by using 2-chloropyridine and trifluoromethanesulfonyl anhydride as well as Grignard reagent and MgCl₂.     

Transfer hydrogenation of aldehydes catalyzed by silyl hydrido iron complexes bearing a [PSiP] pincer ligand

The synthesis and characterization of a series of silyl hydrido iron complexes bearing a pincer-type [PSiP] ligand (2-R₂PC₆H₄)₂SiH₂ (R = Ph (1) and ⁱPr (5)) or (2-Ph₂PC₆H₄)₂SiMeH (2) were reported. Preligand 1 reacted with Fe(PMe₃)₄ to afford complex ((2-Ph₂PC₆H₄)SiH)Fe(H)(PMe₃)₂ (3) in toluene, which was structurally characterized by X-ray diffraction. ((2-ⁱPr₂PC₆H₄)SiH)Fe(H)(PMe₃) (6) could be obtained from the reaction of preligand 5 with Fe(PMe₃)₄ in toluene. Furthermore, complex ((2-ⁱPr₂PC₆H₄)Si(OMe))Fe(H)(PMe₃) (7) was isolated by the reaction of complex 6 with 2 equiv. MeOH in THF. The molecular structure of complex 7 was also determined by single-crystal X-ray analysis. Complexes 3, 4, 6 and 7 showed good to excellent catalytic activity for transfer hydrogenation of aldehydes under mild conditions, using 2-propanol as both solvent and hydrogen donor. α,β-Unsaturated aldehydes could be selectively reduced to corresponding α,β-unsaturated alcohols. The catalytic activity of penta-coordinate complex 6 or 7 is stronger than that of hexa-coordinate complex 3 or 4.

The synthesis and characterization of a series of silyl hydrido iron complexes bearing a [PSiP] pincer ligand were reported. These complexes showed good to excellent catalytic activity for transfer hydrogenation of aldehydes under mild conditions.     

Biomimetic synthesis of galantamine via laccase/TEMPO mediated oxidative coupling

Laccase-mediated intramolecular oxidative radical coupling of N-formyl-2-bromo-O-methylnorbelladine afforded a novel and isolable spirocyclohexadienonic intermediate of galantamine. High yield and conversion of substrate were obtained in the presence of the redox mediator 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO). This laccase procedure, with an overall yield of 34%, represents a scalable and environmentally friendly alternative to previously reported syntheses of galantamine based on the use of potassium ferricyanide as an unspecific radical coupling reagent.

Laccase-mediated intramolecular oxidative radical coupling of N-formyl-2-bromo-O-methylnorbelladine afforded a novel and isolable spirocyclohexadienonic intermediate of galantamine.     

Metal- and oxidant-free electrochemically promoted oxidative coupling of amines

The selective oxidation of amines into imines is a priority research topic in organic synthesis and has attracted much attention over the past few decades. However, the oxidation of amines generally suffers from the drawback of transition-metal, even noble-metal catalysts. Thus, the strategy of metal- and oxidant-free selective synthesis of imines is highly desirable yet largely unmet. This paper unravels a metal-free and external oxidant-free electrochemical strategy for the oxidative coupling methodology of amines. This general transformation is compatible with various functional amines and led to functionalized imines in moderate to satisfactory yields.

This paper presents a metal-free and external oxidant-free electrochemical method for the oxidative coupling methodology of amines in moderate to satisfactory yields.     

One-pot synthesis of graphene quantum dots and simultaneous nanostructured self-assembly via a novel microwave-assisted method: impact on triazine removal and efficiency monitoring

One-step methods for fabricating green materials endowed with diverse functions is a challenge to be overcome in terms of reducing environmental risk and cost. We report a fast and easy synthesis of multifunctional materials composed of only fluorescent dots with structural flexibility and high sorption capability. The synthesis consists of a one-pot microwave-assisted reaction for the simultaneous formation of graphene quantum dots (GQDs) from organic precursors and their spontaneous self-assembly forming porous architectures. The GQD-assemblies are robust and no signs of degradation were observed with most organic solvents. The ensuing GQDs and their porous solids were fully characterized at the morphological and optical levels. Interestingly, the solid integrates both the advantages of porous materials and the nanoscale, showing a marked sorption capability towards hazardous electron-deficient triazines (112 mg g⁻¹ of sorbent). Moreover, it also exhibits optical-responsive properties based on quantum confinement when it is disassembled acting as a fluorometric sensor in alcoholic solutions. Therefore, these properties enable this novel material to became a convenient bifunctional analytical tool not only for the removal of herbicides in apolar organic solvents but also as a chemosensor to monitor their presence in polar media. This work opens very challenging possibilities of creating porous graphene-based networks for contaminant remediation and monitoring.

Graphene quantum dot (GQDs) assemblies from a one-step microwave reaction as bifunctional materials in remediation of triazines.     

One-pot synthesis of end-functionalised soluble star-shaped polymers by living ring-opening metathesis polymerisation using a molybdenum-alkylidene catalyst

Precise synthesis of soluble star-shaped polymers has been achieved by adopting living ring-opening metathesis polymerisation (ROMP) using a molybdenum-alkylidene catalyst with sequential addition of norbornene and cross-linking agent; the method provides efficient one-pot synthesis of high molecular weight end-functionalised star-shaped polymers (M_n = >1.37 × 10⁵) with more arms (branching) with rather low PDI values (M_w/M_n = 1.17–1.37) under the optimised conditions.

Precise synthesis of star-shaped polymers has been achieved by living ROMP using a molybdenum catalyst with sequential addition of norbornene and cross-linker.     

One-pot synthesis of indoles and quinolinones from ortho-tosylaminophenyl-substituted para-quinone methides

A facile one-pot synthesis has been developed through alkylation/acylation of ortho-tosylaminophenyl-substituted para-quinone methides followed by an intramolecular 1,6-conjugate addition and oxidation sequence. This cascade reaction occurs readily in good yield (up to 95%), providing a divergent synthetic approach to structurally diverse 2,3-disubstituted indoles and 3,4-diaryl-substituted quinolinones.

A facile one-pot synthesis has been developed through alkylation/acylation of ortho-tosylaminophenyl-substituted para-quinone methides followed by an intramolecular 1,6-conjugate addition and oxidation sequence.

Nitrogen-containing heterocycles as privileged structural motifs are widely found in natural products and small molecule pharmaceuticals.¹ In particular, indoles and quinolinones are of great significance in drug discovery because of their diverse biological activities.^2,3 For example, indometacin (I), a synthetic indole acetic acid derivative, is an effective non-steroidal anti-inflammatory drug.^2a Fluvastatin sodium (II) and compound III, two 3-aryl-substituted indole derivatives, have been designed as a HMG-CoA reductase inhibitor^2b and carbonic anhydrase inhibitor,^2c respectively. 4-Phenyl-substituted quinolinone derivatives such as IV, V and VI have been demonstrated to possess excellent antitumor activity (Fig. 1).^3b–d Thus, it is highly desirable to develop more efficient and facile methods to construct these nitrogen-containing heterocycles.Open in a separate windowFig. 1Selected natural products and synthetic compounds containing indole and quinolinone frameworks.Recently, para-quinone methides (p-QMs) have emerged as versatile building blocks due to their intrinsic reactivities.⁴ A large number of transformations based on p-QMs have been achieved since the seminal reports by Fan⁵ and Jørgensen.⁶ For example, annulation reactions based on simple p-QMs and vinyl p-QMs have been reported by Yao, Fan, Zhao, and Waser groups.⁷ In 2016, Enders and co-workers pioneered the design and application of ortho-hydroxyphenyl-substituted p-QMs in [4 + 2] cyclizations.⁸ After that the use of ortho-hydroxyphenyl-substituted p-QMs in [4 + 1], [4 + 2] and [4 + 3] cyclizations reactions was extensively investigated,^9–12 allowing the synthesis of diverse oxygenous heterocyclic motifs (Scheme 1a). Quite recently our group designed in situ generated ortho-tosylaminophenyl-substituted p-QMs and successfully applied this class of substrates in [4 + 2] and [4 + 1] annulation reactions to synthesize tetrahydroquinolines and 2,3-dihydroindoles, respectively (Scheme 1b).¹³Open in a separate windowScheme 1Reported reactions based on p-QMs and our design.Although great progress has been made in the synthesis of oxygen-containing heterocyclic frameworks, the application of p-QMs in the construction of nitrogen-containing heterocyclic frameworks remains underdeveloped. Cyclizations using ortho-tosylaminophenyl-substituted p-QMs as building blocks are still rather limited. Whereas, the privileged status of indoles and quinolinones in organic synthesis and biological applications demands more efficient strategies for their preparation. In 2019, Anand and co-workers reported a one-pot synthesis of oxygen-based heterocycles from 2-hydroxyphenyl-substituted p-QMs, which provided an efficient method for the construction of 2,3-disubstituted benzo[b]furans, 2,3-dihydrobenzofurans and diaryl-substituted coumarin derivatives.¹⁰ Inspired by this work, we wondered whether this strategy could be extended to ortho-tosylaminophenyl-substituted p-QMs, so that we might establish a powerful divergent cascade reaction to synthesize 2,3-dihydroindoles, indoles and quinolinone derivatives.We hypothesized that assembly of 2,3-dihydroindoles could be realized through the union of ortho-tosylaminophenyl-substituted p-QMs and α-halo ketones via N-alkylation followed by intramolecular cyclization. Then, a suitable oxidant can promote the in situ generation of indoles. Although we have reported the synthesis of 2,3-dihydroindoles through a formal [4 + 1] annulation of ortho-tosylaminophenyl-substituted p-QMs with sulfur ylides,^13b the direct one-pot synthesis of 2,3-disubstituted indoles and 3,4-diaryl-substituted quinolinone derivatives from ortho-tosylaminophenyl-substituted p-QMs through N-alkylation/acylation followed by intramolecular 1,6-conjugate addition and oxidation strategy has not been reported yet (Scheme 1c).To verify our hypothesis, we initially tried to identify the optimal conditions for the synthesis of 2,3-dihydroindoles before exploring the one-pot synthesis of indoles. ortho-Tosylaminophenyl-substituted p-QMs 1a and 2-bromoacetophenone 2a were chosen as the model substrates to optimize the reaction conditions ( EntryBase T (°C)SolventYield^b (%)1Et₃N20CH₃CN542DBU20CH₃CN383 ⁱPr₂NH20CH₃CN74Na₂CO₃20CH₃CN45K₂CO₃20CH₃CN56Cs₂CO₃20CH₃CN827Cs₂CO₃20CH₂Cl₂608Cs₂CO₃20CHCl₃579Cs₂CO₃20Acetone8010Cs₂CO₃20Toluene5311Cs₂CO₃20DCE5012^cCs₂CO₃20CH₃CN8013^dCs₂CO₃20CH₃CN7614^eCs₂CO₃20CH₃CN8315Cs₂CO₃35CH₃CN8516Cs₂CO₃50CH₃CN92Open in a separate window^aAll reactions were conducted with 1a (0.11 mmol), 2a (0.10 mmol), base (1.5 equiv.), solvent (1.5 mL), 1.5 h.^bDetermined by ¹H NMR using 1,3,5-trimethoxybenzene as an internal standard; dr > 20 : 1.^c1.0 equiv. of base was used.^d2.0 equiv. of base was used.^e t = 3 h.After establishing the optimal reactions conditions for 2,3-dihydroindoles, the substrate scope was explored. As shown in Open in a separate window^aAll reactions were conducted with 1 (0.11 mmol), 2 (0.10 mmol), Cs₂CO₃ (1.5 equiv.), CH₃CN (1.5 mL). Yields are those of isolated products 3 after column chromatography.With the optimal one-pot reaction conditions in hand, we began to explore the substrate scope of this annulation reaction. The scope of bromomethyl ketones part was examined firstly and we were pleased to find that a wide range of bromomethyl aryl ketones 2 could readily react with ortho-tosylaminophenyl-substituted p-QM 1a to afford 4a–4o in good yields ( Open in a separate window^aAll reactions were conducted with 1 (0.11 mmol), 2 (0.10 mmol), Cs₂CO₃ (1.5 equiv.), DDQ (1.5 equiv.), CH₃CN (1.5 mL). Yields are those of isolated products 4 after column chromatography.Subsequently, the generality of this reaction was further evaluated by varying another reaction partner ortho-tosylaminophenyl-substituted p-QMs 1. It was found that p-QMs bearing different substituents on the benzene ring could be smoothly converted into the expected products 4r–4t in 67–77% yields, and the reaction efficiency was less affected by the electronic properties of substituents. The structure and relative configuration of 4d was determined based on its HRMS, NMR spectroscopy and single-crystal X-ray analyses (14After accomplishing the [4 + 1] annulation reaction of ortho-tosylaminophenyl-substituted p-QMs with bromomethyl ketones for the synthesis of 2,3-disubstituted indole derivatives, we further tried to apply this methodology for the synthesis of other nitrogen-containing heterocycles. We envisioned that assembly of 3,4-diaryl-substituted quinolinone derivatives could be realized by treating ortho-tosylaminophenyl-substituted p-QMs with arylacetyl halides followed by one-pot dehydrogenative oxidation with DDQ. To verify the feasibility of our hypothesis, an initial experiment was carried out by treating 1a with phenylacetyl chloride 5a (1.2 equiv.) in the presence of Cs₂CO₃ (2.2 equiv.) in CH₃CN for 1.5 h followed by the addition of DDQ (1.5 equiv.) and reaction for another 6 h. As expected, the desired product 6a was obtained in 87% isolated yield. Encouraged by this result, the substrate scope of this [4 + 2] annulation reaction was explored. As shown in Open in a separate window^aAll reactions were conducted with 1 (0.1 mmol), 5 (0.12 mmol), Cs₂CO₃ (2.2 equiv.), DDQ (1.5 equiv.), CH₃CN (1.5 mL). Yields are those of isolated products 6 after column chromatography.To evaluate the general utility and robustness of this novel protocol, we conducted a 1 mmol scale reaction under the standard conditions, and the products 4a and 6a could be isolated in 88% and 90% yields (Scheme 2a). Furthermore, the synthetic transformation of 6a was carried out by treating it with excess of AlCl₃ (10 equiv.) in toluene at 60 °C, and the expected de-tert-butylation product 7 was obtained in 78% yield (Scheme 2b).Open in a separate windowScheme 2Scale-up synthesis (a) and synthetic transformation (b).Finally, to understand the mechanism of this reaction, some control experiments were carried out (Scheme 3). Firstly, the reactions of phenyl substituted p-QM 8 with phenacyl bromide and phenylacetyl chloride were carried out individually under standard conditions. However, the corresponding products 9 and 10 were not detected, and the starting material 8 was not transformed in both cases. Further, in exploring the substrate scope of bromomethyl ketones, we obtained some by-products which may help explain the mechanism of this reaction. When treating 1a with 1-bromo-2-butanone under standard conditions, in addition to product 4p, N-alkylated product 11 was isolated in 20% yield. The similar phenomenon was observed when treating 1a with bromopinacolone, N-alkylated product 12 was isolated in 55% yield, while the corresponding 1,6-adduct was only obtained in 30% yield. Based on above results, a plausible mechanism was suggested as shown in Scheme 4. The reaction proceeds through N-alkylation followed by intramolecular 1,6-conjugate addition/cyclization to form 2,3-dihydroindoles, which underwent the in situ dehydrogenative oxidation for the one-pot synthesis of 2,3-disubstituted indoles (Scheme 4a). Also, we can speculate that quinolinone derivatives were formed through N-acylation followed by intramolecular cyclization and one-pot oxidation (Scheme 4b).Open in a separate windowScheme 3Control experiments.Open in a separate windowScheme 4The plausible reaction mechanism for the one-pot synthesis of 2,3-disubstituted indoles (a) and 3,4-diaryl-substituted quinolinones (b).In summary, we have developed an efficient and facile one-pot method for the synthesis of 2,3-disubstituted indoles and 3,4-diaryl-substituted quinolinones through alkylation/acylation of ortho-tosylaminophenyl-substituted p-QMs followed by intramolecular 1,6-conjugate addition/cyclization and oxidation sequence. This protocol could not only fulfill the task of developing new cyclization reactions of ortho-tosylaminophenyl-substituted p-QMs but also provide an easy access to structurally diverse nitrogen-containing heterocycles.