Association of liquid-assisted grinding with aging accelerates the inherently slow slipping-on of a dibenzo-24-crown-8 over the N-hydroxysuccinimide ester of an ammonium-containing thread

Solvent-free and solvent-less slipping-on of the dibenzo-24-crown-8 (DB24C8) over the N-hydroxysuccinimide end of an ammonium-containing thread has been studied and compared to the same reaction operated in solution. Slippage proved to be possible in solvent-free conditions, but the fastest slippage was obtained under heating when preliminary Liquid-Assisted Grinding (LAG) conditions were applied to the reactants followed by aging under an atmosphere of acetonitrile.

Very efficient slipping-on of the dibenzo-24-crown-8 over the NHS end of an ammonium-containing molecular axle was carried out through a solvent-less procedure.

The recently awarded 2016 Nobel Prize in chemistry¹ has put a light on molecular machines.² Some of these machines benefit from their interlocked molecular architecture³ so that the relative displacement of one interlaced element among others becomes possible and controllable. Hence, the straightforward synthesis of interlocked molecules is appealing in order to access novel molecular machines. Using the slippage strategy,⁴ we recently reported the preparation of an insulated and storable, albeit activated, N-hydroxysuccinimide (NHS) ester-containing [2]rotaxane building block (Scheme 1 and entry 1 of 5 This compound is a valuable activated building block for post-interlocking elongation of the encircled axle using bulky amino compounds.⁶ As the mechanism of such aminolysis reactions preserves the mechanical bond, it allowed the efficient and straightforward preparation of more sophisticated interlocked compounds such as [2] and [3]rotaxane molecular shuttles.^5,6 Improving the access to the NHS ester-containing [2]rotaxane building block 2 is therefore of real interest. This is particularly justified since in acetonitrile solution, the slipping-on of the DB24C8 (3 equiv.) over the NHS extremity of an ammonium-containing thread (at a concentration of 3 × 10⁻² M) is very slow and necessitates heating (13 days and 333 K, respectively). In this paper, we wondered if this slipping-on process could be possible, nay improved, by drastically reducing the amount of solvent. Since solvent-free/solvent-less conditions are highly prone to induce mass transfer limitations, utilisation of ball-milling was envisaged. Indeed it was previously shown that ball-milling could improve the speed of inherently slow reactions.⁷ A few examples of solvent-free/solvent-less synthesis of rotaxanes have been reported to date,⁸ and to the best of our knowledge, only three of these examples are related to slippage process through a co-melting process⁹ or an immediate solvent evaporation method.¹⁰ Herein, different experimental procedures were considered to yield the activated [2]rotaxane 2: solvent-free grinding,¹¹ Liquid-Assisted Grinding (LAG),¹² and aging by heating with or without an acetonitrile atmosphere.¹³ LAG is defined as the use of small amounts of a non-reactive liquid during grinding.¹⁴ It has been shown by us and by other research groups to have a considerable effect on the course of reactions run under mechanical forces.¹⁵ Besides, aging is the action of letting the reaction take place in the absence of any mechanical agitation. This reactivity is based on the inherent mobility of molecules and can be accelerated by the presence of vapours and/or a slight heating in the presence, or not, of a catalyst.¹⁶ Both LAG and aging are processes that are using generally much lower quantities of solvents compared to traditional solvent-based syntheses, and therefore are generally qualified as “solvent-less” processes. The results of these slipping-on experiments are shown in Fig. 1 and Open in a separate windowScheme 1Slippage process of the NHS ester-containing molecular axle 1 by the DB24C8.Experimental conditions relative to the slippage of thread 1

Synthesis of trifluoromethyl-containing isoindolinones from tertiary enamides via a cascade radical addition and cyclization process

A radical trifluoromethylation reaction of tertiary enamides was investigated and trifluoromethyl-containing isoindolinones were prepared under mild conditions. Using TMSCF₃ as a radical source, PhI(OAc)₂ as an oxidant and KHF₂ as an additive, tertiary enamides were converted to isoindolinones via a cascade addition and cyclization process in moderate to good yields.

Radical trifluoromethylation and cyclization of tertiary enamides was developed and trifluoromethyl-containing isoindolinones were obtained in moderate to good yields.

In recent years, trifluoromethyl-containing azaheterocycles have attracted much attention for their potential application in the fields of pharmaceutical and agricultural chemistry.¹ Thus, lots of efforts have been devoted to the synthesis of trifluoromethyl azaheterocycles,² and among these developed methods, radical cascade addition and cyclization has emerged as a remarkable strategy due to its unique properties such as economy and high efficiency. Unsaturated amides are commonly used substrates for this type of transformation, which could be attacked by a CF₃ radical followed by intramolecular C–O, C–N, or C–C bond formation to give different kinds of trifluoromethyl azaheterocycles. Fu reported a metal-free trifluoromethylation of N-allyamides with CF₃SO₂Na for the synthesis of trifluoromethyl-containing oxazolines via oxytrifluoromethylation.³ In the presence of copper salts, N-acyl-2-allylaniline could be converted to trifluoromethylated indolines in moderate to good yields via aminotrifluoromethylation process.⁴ With Togni''s reagent,⁵ TMSCF₃,⁶ CF₃SO₂Na,⁷ CF₃SO₂Cl⁸ and other reagents⁹ as the CF₃ source, α, β-unsaturated amides, tosyl amides, or imides underwent a tandem conversion to give trifluoromethyl-containing oxindoles or isoquinoline-1,3-diones by trifluoromethylation/arylation reaction. On the other hand, as a special type of unsaturated amide containing an active double bond, enamide also exhibited excellent reactivity in radical reactions.¹⁰ In fact, trifluoromethylation of enamides has already been investigated, and in most cases trifluoromethylated alkenes were obtained as the main products.¹¹ To the best of our knowledge, the radical trifluoromethylation and cyclization of enamide still remains undeveloped.Isoindolinones are important N-heterocyclic compounds necessary in organic and pharmaceutical chemistry, and these compounds are used widely as anticoagulants and tranquilizers such as aristolactam, pagoclone, and zopiclone.¹² To introduce a CF₃ group into isoindolinones, Wang and co-workers explored a convenient way to the synthesis of trifluoromethyl-containing isoindolinones by radical aminotrifluoromethylation (Scheme 1a),¹³ but this transformation only occurred for N-methoxylbenzamides, and in case of N-alkylbenzamides trifluoromethylated alkenes were obtained as the major products. 1,1-disubstituted terminal alkenes were also not suitable substrates because of the competition between O-trapping and N-trapping process. Thus, development a new method for the synthesis of trifluoromethyl-containing isoindolinones is still in demand. Here in, as a continuation of our efforts on the radical modification of amide derivatives,¹⁴ we wish to present our work on the synthesis of trifluoromethyl-containing isoindolinones using enamides as the start materials by radical carbon trifluoromethylation (Scheme 1b).Open in a separate windowScheme 1Synthesis of trifluoromethyl-containing isoindolinones.Initially, N-n-butyl-N-(2-propenyl) benzamide 1a was chosen as the model substrate to optimize the reaction conditions of this radical carbontrifluoromethylation process. As shown in

N-Heterocyclic carbene (NHC)-catalyzed oxidation of unactivated aldimines to amides via imine umpolung under aerobic conditions

Herein, we disclose an NHC-catalyzed aerobic oxidation of unactivated aldimines for the synthesis of amides via umpolung of imines proceeding through an aza-Breslow intermediate. We have developed an eco-friendly method for the conversion of imines to amides by using molecular oxygen in air as the sole oxidant and dimethyl carbonate (DMC) as a green solvent under mild reaction conditions. Broad substrate scope, high yields and gram scale syntheses expand the practicality of the developed method.

A general NHC-catalyzed conversion of imines to amides proceeding through umpolung–oxidation under aerobic conditions in green solvent is reported.

NHCs have emerged as an important class of organocatalysts for unconventional organic transformations due to their unique property of umpolung i.e. essentially reversing the polarity of electrophilic carbon centers. NHC-catalyzed umpolung reactivity has been extensively exploited over the past two decades for the construction of carbon–carbon and carbon–heteroatom bonds.¹ NHC-catalytic transformations proceeding through umpolung reactivity, via Breslow intermediate, have been well established using aldehydes.^1,2 Despite imines being considered to be potentially important building blocks, the obvious use of imines as reactants for the same is still an under developed area, probably due their lower reactivity. The umpolung of imine came into existence after the isolation of a nitrogen containing Breslow intermediate (known as aza-Breslow intermediate) by the Douthwaite and Rovis groups from the reaction of stoichiometric amounts of NHC and imine or iminium salt, respectively.³ For the first time, our group⁴ and the Biju group,⁵ independently, reported the NHC-catalyzed imine umpolung transformations. Recently, a few other groups including our group,⁶ the Wei–Fu–Huang,⁷ Biju,⁸ Lupton⁹ and Tian–Zhang–Chi¹⁰ groups reported NHC-catalyzed imine C–H functionalization or oxidation of imines. In continuation of our ongoing research on NHC-catalyzed umpolung transformations,^4,6,11 herein, we present the development of NHC-catalyzed aerobic oxidation of aldimines to amides, via imine umpolung without using any additive. We became interested to access the amide functionality because amide is a very crucial functional group due its ubiquitous presence in life-processes in the form of peptide bond in protein molecules as well as its appearance in several of the drug molecules.¹² For example, imatinib^13a and ponatinib^13a are used in the chemotherapy treatment of chronic myelogenous leukemia (CML) in cancer disease (Fig. 1). Betrixaban containing two amide functional groups is an oral anticoagulant drug (Fig. 1).^13bOpen in a separate windowFig. 1Selected amide containing therapeutic molecules.The scientific community has been showing great interest to develop new and efficient methods for the construction of amide bond. Coupling of carboxylic acid with amine is one of the most common methods used for the construction of amide molecule.¹⁴ However, this method requires stoichiometric amounts of peptide coupling reagents such as carbodiimides and 1-hydroxy benzotriazoles or activated carboxylic acid derivatives.¹⁵ The Schmidt reaction¹⁶ and Beckmann rearrangement¹⁷ are classical examples for the synthesis of amides. However, there are considerably a few reports available for the oxidation of imine to amide. Palladium-catalyzed oxidation of imines to amides was reported by using excess tert-butyl hydroperoxide (TBHP) as an oxidant.¹⁸ Methods for the oxidation of imines to amides were reported by using peroxy acids in the presence of strong Lewis acid and Brønsted acid, which generate stoichiometric amount of by-products.¹⁹ Cheon and co-workers reported the oxidation of imines to amides by using sodium cyanide (NaCN) in stoichiometric amounts. High toxic nature of NaCN is the limitation of this methodology (Scheme 1a).^20a Recently, Fu and Huang group reported the oxidation of imines, limited to the imines derived from heteroaryl amines, to amides by using NHC catalysis with the assistance of excess lithium chloride as Lewis acid (Scheme 1b).^7a Recently, we reported an NHC-catalyzed tandem aza-Michael oxidation of β-carboline cyclic imines in the presence of external Michael acceptors (Scheme 1c).⁶ Besides the limitations associated with the above transformations, those were performed in non-green solvent media. However, to the best of our knowledge, there are no reports for the conversion of imines to amides under NHC-catalysis without using an external additive/assistance.²¹ On the other hand, the development of new methods to access amide functionality inclusive of green chemistry principles such as organocatalysis, air as the sole oxidant and use of green solvent medium under ambient conditions is highly desirable. Herein, we report an NHC-catalyzed conversion of aldimines to amides, proceeding through imine umpolung–oxidation, in the presence of air in a green solvent such as DMC²² under mild conditions.Open in a separate windowScheme 1Prior work and this work.Initially, we began our investigation with the reaction of aldimine 3a, derived from benzaldehyde 1a and aniline 2a, in the presence of NHC A1 catalyst under open air conditions at room temperature in a green solvent such as DMC. Gratifyingly, we observed the formation of the corresponding amide 4a in 53% yield († for an extensive optimization survey). We conducted an experiment in presence of LiCl (1.2 equiv.), and it did not help to improve the yield of the product.Optimization study

Direct access to multi-functionalized benzenes via [4 + 2] annulation of α-cyano-β-methylenones and α,β-unsaturated aldehydes

An efficient [4 + 2] benzannulation of α-cyano-β-methylenones and α,β-unsaturated aldehydes was achieved under metal-free reaction conditions selectively delivering a wide range of polyfunctional benzenes in high yields respectively (up to 94% yield).

An efficient [4 + 2] benzannulation of α-cyano-β-methylenones and α,β-unsaturated aldehydes was achieved under metal-free reaction conditions selectively delivering a wide range of polyfunctional benzenes in high yields respectively (up to 94% yield).

Multi-substituted benzenes are privileged structural units ubiquitous in pharmaceuticals,¹ natural products² and advanced functional materials.³ Various excellent methodologies have been investigated for the construction of functionalized aromatics including nucleophilic or electrophilic substitution,⁴ transition metal-catalyzed coupling reactions⁵ and directed metalation.⁶ However, the widespread application of these strategies established thus far suffer from the limitations of functional groups introduced on the pre-existing benzene and regioselectivity issues. Among various synthetic methods, tandem benzannulation reactions arguably represent an attractive alternative to classical methods for rapid construction of polysubstituted benzenes in an atom-economical fashion.⁷ This protocol featuring an efficient transformation of acyclic building blocks into structurally valuable benzene skeletons. In this context, α-cyano-β-methylenones has been employed as substrates to format six-membered ring in tandem cyclization reactions due to the activation of the pronucleophile methyl group. In 2015, Tong and co-workers developed a phosphine-catalyzed addition/cycloaddition domino reactions of β′-acetoxy allenoate with 2-acyl-3-methyl-acrylonitriles to give 2-oxabicyclo[3.3.1]nonanes (Scheme 1a).⁸ Soon after that, the construction of benzonitrile derivatives and 1,3,5-trisubstituted benzenes via N-heterocyclic carbene catalysis has been reported by the groups of Wang and Ye independently (Scheme 1b).⁹ Then the synthesis of 1,3,5-trisubstituted benzenes by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)-mediated annulation of α-cyano-β-methylenones and α,β-unsaturated carboxylic acids was also developed by Ye and co-workers (Scheme 1c).¹⁰ Shi et al. reported a base-promoted tandem cyclization reaction of α-cyano-β-methylenones and α,β-unsaturated enones, which have electron-withdrawing group (EWG), accessing to a wide range of benzonitriles in a different C–C bond formation process (Scheme 1d).¹¹ As part of our ongoing interest in harnessing enones for developing new methodologies for the construction of functionalized benzenes, we have recently demonstrated NHC-catalyzed convenient benzonitrile assembly in the presence of oxidant.^9a While the same reaction of enals and α-cyano-β-methylenones was conducted in the basic condition without NHC, a novel polyfunctionalized benzene product was obtained (Scheme 1e). The result inspired us to extend the synthetic potential of benzannulation strategy to access diverse benzonitriles, particularly from simpler, abundantly available starting materials.Open in a separate windowScheme 1α-Cyano-β-methylenones in cycloaddition domino reactions.At the outset, model reaction of 2-benzoyl-3-phenylbut-2-enenitrile 1a and cinnamaldehyde 2a was used to evaluate reaction parameters. Key results of condition optimization are summarized in 12 The configuration of products were assigned unambiguously by X-ray analysis of the product 3a. A quick solvent screening demonstrated that chloroform is the best choice to produce the benzannulation product 3a in a desirable yield (entries 10–13, †). Reducing the loading of the cinnamaldehyde or NaOH to 1.2 equivalence led to dramatical loss of the yield (entries 14 &15, EntryBaseSolventTime (h)Yield^b (%)1Cs₂CO₃Toluene24702Na₂CO₃Toluene24423K₂CO₃Toluene24384NaOHToluene12785NaOAcToluene24526KOHToluene12747K₃PO₄Toluene24588DBUToluene24339Et₃NToluene484610NaOHDCM1288 11 NaOH CHCI ₃ 12 94 12NaOHDCE128413NaOHH₂O48014^cNaOHCHCI₃128515^dNaOHCHCI₃128416^eNaOHCHCI₃1280Open in a separate window^aReaction conditions: 1a (0.1 mmol, 1.0 equiv.), 2a (0.15 mmol, 1.5 equiv.), base (0.2 mmol, 2.0 equiv.), and solvent (1 mL) for 12 h.^bIsolated yields.^c1a : 2a = 1 : 1.2.^dNaOH used 1.2 equiv.^e50 °C.Finally, the standard reaction conditions for the base-promoted synthesis of the multi-functionalized benzene derivatives identified as follows: 1.5 equivalence of NaOH and CHCl₃ as the solvent under an atmosphere of air for 12 hours at room temperature.With the optimized reaction conditions in hand, we explored the scope of the reaction. A series of enones were examined, variation of the electronic nature of the aromatic ring (R¹, including the substituted phenyl or thienyl) has little influence on the reaction efficiency (3b–f, 86–93% yields, Open in a separate window^aReaction conditions: 1a (0.1 mmol, 1.0 equiv.), 2a (0.15 mmol, 1.5 equiv.), NaOH (0.2 mmol, 2.0 equiv.), and CHCl₃ (1 mL) for 12 h.We next turned our attention to examine the scope of enals. Different substituents on the phenyl ring of cinnamaldehydes were tolerated even disregarding the position and properties, giving 4a–g in satisfying yields (82–92% yields, Open in a separate window^aReaction conditions: 1a (0.1 mmol, 1.0 equiv.), 2a (0.15 mmol, 1.5 equiv.), NaOH (0.2 mmol, 2.0 equiv.), and CHCl₃ (1 mL) for 12 h.To highlight the practicality of this mild and efficient method, the reaction of 2-benzoyl-3-phenylbut-2-enenitrile 1a at 4.0 mmol scale proceed well under the standard conditions to generate the desired product in 88% yield (Scheme 2).Open in a separate windowScheme 2Gram-Scale Synthesis of 3a.The formyl group could be easily reduced by using LiAlH₄ in THF at reflux, leading to the formation of the benzyl alcohol product 5 in 95% yield while keeping the CN group intact. Suzuki coupling of 3o with phenylboronic acid furnished derivative 6 in 90% yield¹³ (Scheme 3).Open in a separate windowScheme 3Synthetic transformation.To gain insight into the role of air in this reaction, a control experiment was designed and investigated (Scheme 4). When the reaction of 1a and 2a was carried out under an argon atmosphere, the desired product 3a was obtained in 10% yield and product 7 could be isolated in 82% yield. The results indicate that oxygen is necessary for the oxidation process and played a key role in this reaction.Open in a separate windowScheme 4Control experiment.A postulated reaction course is illustrated in Scheme 5. Briefly, α-deprotonation of enone 1a in the presence of bases, subsequent 1,4-addition of deprotonated enone I to enal 2a generates intermediate II, which undergoes an intramolecular aldol reaction to yield the adduct 7.¹⁴ Lastly, dehydration of 7 followed by spontaneous oxidative aromatization affords the polysubstituted benzonitrile 3a.Open in a separate windowScheme 5The proposed mechanism.     

Palladium-catalyzed cross-coupling reaction of alkenyl aluminums with 2-bromobenzo[b]furans

Highly efficient and simple cross-coupling reactions of 2-bromobenzo[b]furans with alkenylaluminum reagents for the synthesis of 2-alkenylbenzo[b]furan derivatives using PdCl₂ (3 mol%)/XantPhos (6 mol%) as catalyst are reported. Excellent yields (up to 97%) were obtained for a wide range of substrates at 80 °C for 4 h in DCE.

PdCl₂ (3 mol%)/XantPhos (6 mol%) complexes was found to be a highly efficient catalyst for the synthesis of 2-alkenylbenzo[b]furans from 2-bromobenzo[b]furans and alkenylaluminums. The reaction was also found to be effective in gram-scale synthesis.

2-Substituted benzo[b]furans are important structural scaffolds found in many natural products and pharmaceutical products.¹ Some of these compounds have been known to exhibit anti-inflammatory,² antitumor,³ anticancer,⁴ and anti-fungal,⁵ antiplasmodial,⁶ antioxidant,⁷ anti-HIV,⁸ and estrogenic activities.⁹ In addition, they serve as building blocks for many organic transformations.¹⁰ Thus, their synthesis and applications have attracted considerable attention in the chemical and pharmaceutical industries over the past decades.¹¹ Until now numerous effective synthetic methodologies of synthesis 2-substituted benzo[b]furans have been reported.^12,13 Among these methods hitherto developed, the metal-catalyzed 2-halobenzo[b]furans coupling with organometallic nucleophiles is one of the most effective methods (Scheme 1).¹³ However, in most cases generally suffer from one or more drawbacks such as requirement co-catalyst like Cu salts, limited substrate scope, high catalyst loading, high temperature and poor chemoselectivity etc. Therefore, the development of more efficient and atom economical approaches for the preparation of 2-substituted benzo[b]furans remains as desirable work. Previous studies show that organoaluminum reagents are highly efficient nucleophiles for cross-coupling reactions with aromatic halides¹⁴ or benzylic halides,¹⁵ and the investigations have demonstrated that palladium is a good catalytic metal.¹⁶Open in a separate windowScheme 1Palladium-catalyzed cross-coupling reactions of 2-halobenzo[b]furans derivatives with organometallic nucleophiles.At present, a variety of methods have been developed to prepare compounds containing olefin functional groups through hydrocarbon activation of olefins.¹⁷ To continue our effort to develop coupling reactions using reactive organoaluminum reagents,¹⁸ we herein report a palladium(ii)-catalyzed, base free cross-coupling reactions of 2-bromo benzo[b]furans with alkenylaluminum reagents at 80 °C in short reaction time with good to excellent isolated yields for 2-alkenyl benzo[b]furans. The process was simple and easily performed, and it provides an efficient method for the synthesis of 2-alkenyl benzo[b]furans derivatives. Notably, in our procedure palladium is used as the single catalyst and base free.Our initial studies used 2-bromo-6-methoxybenzo[b]furan (2e) with diethyl(oct-1-enyl)aluminum (1a) as model substrates. Treatment of compound 2e with the alkenylaluminum (1a) using PdCl₂ (3 mol%)/XantPhos (6 mol%) as catalyst in toluene at 60 °C for 4 h, the coupled product 6-methoxy-2-(oct-1-enyl)benzo[b]furan (3ae) was obtained in 46% isolated yield ( EntryPd salt.1a (equiv.)Base (x equiv.)Solvent3ae^b yield (%)1PdCl₂1.0—Toluene462Pd(OAc)₂1.0—Toluene193Pd(acac)₂1.0—Toluene104PdCl₂1.0Et₃N (2.0)Toluene275PdCl₂1.0K₂CO₃ (2.0)TolueneNR6PdCl₂1.0TMEDA (2.0)TolueneNR7PdCl₂1.0—Hexane478PdCl₂1.0—THF519PdCl₂1.0—DCE7410^cPdCl₂1.0—DCE8511^cPdCl₂0.8—DCE8412^cPdCl₂0.6—DCE5313^c,dPdCl₂0.8—DCE49Open in a separate window^a1a/2a/PdCl₂/XantPhos = 1.0/0.5/0.03/0.06 mmol, 60 °C, 3 mL solvent, 4 h, Ar₂.^bIsolated yield of 3ae.^c80 °C.^d1a/2a/PdCl₂/XantPhos = 0.8/0.5/0.02/0.04 mmol.Under the optimized conditions, coupling reactions of aliphatic alkenylaluminum reagents, such as di-sec-butyl(oct-1-enyl)aluminum (1a) and di-sec-butyl(dec-1-enyl)aluminum (1b), proceed with electron-neutral, electron rich and electron-deficient 2-bromo benzo[b]furans derivatives affording the products in good yields ( Open in a separate window^a1/2/PdCl₂/XantPhos = 0.8/0.5/0.03/0.06 mmol, 80 °C, 4 h. Isolated yield of 3, two runs.The reaction was also found to be effective in gram-scale synthesis, which indicated its potential for practical application (Scheme 2). 2-Substituted benzo[b]furans derivatives 3ah was synthesized in 1.31 gram using this methodology.Open in a separate windowScheme 2Preparative scale synthesis of compound 3ah.In order to further explore the reaction mechanism, control experiments were carried out (see the ESI^†). We performed the reaction between 2-bromobenzo[b]furan (2a, 0.5 mmol) with di-sec-butyl(oct-1-enyl)aluminum (1a, 0.8 mmol) in the presence of PdCl₂ (3 mol%)/XantPhos (6 mol%) in DCE at 80 °C for 4 h. The reaction mixture was analyzed by ³¹P NMR, it was found that the characteristic peak of ³¹P NMR appeared around at 22.98 ppm and 30.98 ppm. However, ³¹P NMR peak of pure XantPhos is −18.03 ppm. The results show that XantPhos work as a ligand of the palladium center. Thus, a proposed possible reaction mechanism for the cross-coupling reaction is shown in Scheme 3. The first step is the oxidative addition of 2-bromobenzo[b]furans (2) to Pd(0) phosphine complex (4) (which in turn from PdCl₂ and RAlMe₂ (1) reagents) to form the organopalladium(ii) bromide intermediate (5). Transmetalation of RAlMe₂ (1) with complex 5 gives R''PdR(ii) intermediate (6) and Me₂AlBr. Finally, complex 6 under goes reductive elimination to afford the desired coupling product of 2-alkenylbenzo[b]furans (3) and regenerate the active Pd(0) species for the next catalytic cycle.Open in a separate windowScheme 3The proposed mechanism for the formation of coupled product 3.     

Highly dispersed Ni nanoparticles on mesoporous silica nanospheres by melt infiltration for transfer hydrogenation of aryl ketones

Nickel-based catalysts have been applied to the catalytic reactions for transfer hydrogenation of carbonyl compounds. In the present work, highly dispersed nickel particles located at the pores of mesoporous silica spheres (Ni@mSiO₂) were prepared via an optimized melt infiltration route. The nickel nanoparticles of 10 wt% in the Ni@mSiO₂ catalyst could be uniformly loaded with high dispersion of 36.3%, resulting excellent performance for catalytic transfer hydrogenation of aryl ketones.

Nickel-based catalysts have been applied to the catalytic reactions for transfer hydrogenation of aryl ketones.

The reduction of carbonyl compounds has received steady interest as a common transformation in organic synthetic chemistry. Corresponding alcohols are important building blocks for the manufacture of chemicals, pharmaceuticals, and cosmetics.^1,2 The transfer hydrogenation (TH) reaction of ketones has lots of advantages owing to its low cost, simple process, easy handling, and mild conditions.³ Isopropyl alcohol both as a solvent and hydrogen donor provides safe reaction conditions.⁴ Until now, many catalysts have been developed for TH reactions.⁵Among the catalysts for TH reactions, nickel-based catalysts are representative, due to the metallic nickel surface can absorbs hydrogen and easily activates hydrogen in the atomic state.^6–11 In addition, nickel compounds could be the significant catalyst candidate because of the low price, accessibility, and high reactivity.^12,13 Therefore, several works used nickel nanocatalysts for TH reactions.^{14–17,44–51} However, developing the new supported catalyst with the high metal dispersion and narrow particle size distribution is still required, because it can enhance the reactant conversion and improve product yield.¹⁸ Recently, melt infiltration process has been exploited to prepare supported nanocatalysts as a fast and convenient route with no solvent use.^19–21The method which uses highly porous supports with regular porosity and hydrated metal salts with mild melting temperatures, allowed the metal salts to permeate inside the porous support via capillary forces. High performance nanocatalysts based on well-dispersed nanoparticles could be obtained through uniform infiltration of metal precursors and sequential thermal treatment.²² The obtained nanoparticles have narrow size distributions as well as small sizes, enlarging active sites.^23,24Mesoporous silica nanosphere (mSiO₂) as a porous support can be an outstanding platform for the synthesis of metal nanoparticle, owing to the good thermal stability, high surface area, and large pore volume as well as uniform pore structures.^25–29 Herein, we report a new catalyst with highly dispersed Ni nanoparticles at mesoporous silica sphere nanostructures (Ni@mSiO₂) for catalytic TH reactions, which was synthesized through a melt infiltration of hydrated nickel salts and a sequential thermal reduction (Scheme 1). First, mSiO₂ supports could be prepared by a sol–gel method based on a modified Stöber process. More details were described in the ESI.^† The mesopores were formed in the silica nanospheres using the cationic surfactant C₁₆TAB as a self-assembly template. The TEM images show mesoporous silica spheres with an average diameter of 417 ± 20 nm (Fig. 1a and b). Ordered mesoporous channels were generated by removing the long carbon chains of C₁₆TAB by calcination at 500 °C. The corresponding Fourier-transform (FT) pattern showed a ring pattern of polycrystalline (inset of Fig. 1c). The inverse fast Fourier-transform (IFFT) image, calculated by Micrograph TM Gatan software, also demonstrated the existence of hexagonal lattice planes (Fig. 1c).Open in a separate windowScheme 1A brief synthetic scheme of Ni@mSiO₂ nanocatalyst.Open in a separate windowFig. 1(a and b) TEM images, (c) FT pattern for (b) (inset of c) and IFFT image, (d) HRTEM image, (e) N₂ adsorption/desorption isotherms, and (f) pore size distribution diagrams of mSiO₂. The bars represent 1 mm (a), 100 nm (b), and 20 nm (d).The brightest of the rings originated from a two-dimensional hexagonal (p6mm) structure with d100 spacing. The interplanar spacing computed from the brightest FFT diffraction ring was approximately 3 nm, corresponding to the pore sizes shown in the TEM image (Fig. 1d).N₂ sorption experiments for the mSiO₂ nanosphere exhibited type IV adsorption–desorption hysteresis with H4 type hysteresis loop (Fig. 1e). The Brunauer–Emmett–Teller (BET) surface area and pore volume of the mSiO₂ nanosphere were 1501 m² g⁻¹ and 0.70 cm³ g⁻¹, respectively. The average pore size was estimated to be approximately 2 nm from the adsorption/desorption branches of N₂ isotherms by using the Barrett–Joyner-Halenda (BJH) method (Fig. 1f). Scheme 1 illustrated the simple procedure for the synthesis of the Ni@mSiO₂ nanocatalyst. Based on the small pore size (3 nm) of mSiO₂ nanospheres, very tiny nickel nanoparticles (∼2 nm) could be generated via a melt-infiltration process and thermal treatment under hydrogen flow. Using a 0.55 g_{nickel salt}/g_silica support ratio, the hydrated nickel salt (melting point = 56.7 °C) was successfully incorporated in the mSiO₂ nanosphere during the melt infiltration process, driven by the capillary forces. The Ni-loading content after the final thermal treatment was calculated to be nominally 10 wt% on the basis of Ni converted from the nickel nitrate salt. First, the hydrated nickel salt was melt-infiltrated into the mesoporous silica pores of the mSiO₂ nanospheres by physical mixing at room temperature with subsequent aging at 60 °C for 24 h in a tumbling oven. Then, tiny nickel nanoparticles were generated by thermal reduction of the confined hydrated Ni salt in the small pores at 500 °C under hydrogen flow.The low-resolution TEM images of the Ni@mSiO₂ nanostructure show Ni nanoparticles as black dots (Fig. 2a and b). The high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) image showed bright dots of a very small size (average 2.0 nm), which indicates uniform incorporation of the Ni nanoparticles in the porous silica (Fig. 2c and S1 in the ESI^†). In the elemental mapping of silica (green color) and nickel (red color), high dispersion of nickel nanoparticles was observed (Fig. 2d). HRTEM analysis showed lattices of a single Ni nanoparticles in the mSiO₂ pores (Fig. 2e). The inner particle size was observed to be around 2 nm. The Fourier-transform pattern represented a single crystal of metallic nickel with a distance of 0.2 nm between neighboring fringes, which corresponded to the (111) planes of face centered-cubic nickel (Fig. 2e).Open in a separate windowFig. 2(a and b) TEM and (c) HAADF TEM images, (d) scanning TEM image with elemental mapping and (e) HRTEM images, and (f) XRD spectrum of Ni@mSiO₂ nanostructure. The bars represent 200 nm (a), 20 nm (b–d), and 2 nm (e).The X-ray diffraction (XRD) spectrum of Ni@mSiO₂ nanocatalyst has a broad peak at 2θ = 44.5°, which is assigned to the reflections of the (111) plane in the fcc-nickel phase (Fig. 2f, JCPDS No. 04-0850). The average crystal size of the nickel particle was estimated to be 1.8 nm, from the broadness of the (111) peak using the Debye–Scherrer equation, which is well-matched with that observed in the TEM images. The other intense peak around 23° of the Ni@mSiO₂ nanocatalyst indicates the presence of amorphous silica.Using a H₂ chemisorption experiment, the active nickel surface area and average nickel particle size of the Ni@mSiO₂ nanocatalyst could be analyzed, and measured 242 m² g⁻¹ and 2.78 nm, respectively. The obtained Ni dispersion was very high, and was calculated to be 36.3%.The XPS spectrum analysis was carried out to probe the chemical states of Ni@mSiO₂ (Fig. S2^†). The Ni 2p peak of Ni@mSiO₂ showed NiO and Ni peak. The four peaks at 853.9, 855.6, 860.7, and 863.5 eV are assigned to NiO, and the other peak at 852.1 eV is assigned metallic Ni peak. The metallic Ni surface of the small nanoparticles (∼2 nm) was easily oxidized under an ambient condition.N₂ sorption experiments for the Ni@mSiO₂ nanocatalyst showed a type IV isotherm with type H4 hysteresis (Fig. 3a). The BET surface area was calculated to be 636 m² g⁻¹. The total pore volume was found to be 0.3 cm³ g⁻¹, which is about 43% of the initial mSiO₂ nanosphere (0.7 cm³ g⁻¹). The significant decrease in pore volume was attributed to inner nickel nanoparticle occupancy. Applying the BJH method, small pore sizes were obtained by the adsorption/desorption branches (Fig. 3b). Because of the occupancy of tiny nickel particles in the pristine silica pores, the pore size of the Ni@mSiO₂ nanocatalyst was also slightly decreased, and was observed to be 1.8 nm.Open in a separate windowFig. 3(a) N₂ adsorption/desorption isotherms and (b) pore size distribution diagrams of Ni@mSiO₂ nanocatalyst.The Ni@mSiO₂ nanocatalyst was applied to the hydrogen-transfer reaction of acetophenone. Acetophenone is an ideal substrate in the hydrogen transfer reaction, and is generally used as a hydrogen acceptor.³⁰ Among the various products of acetophenone reduction, only 1-phenylethanol resulted from the catalyzed reaction. The metallic Ni on the catalyst surface is the active species and the reaction was promoted by base.¹⁷ The dihydride species referred in this catalyst system to make alcohol from the transfer of the two hydrogen atoms of the donor to the surface of the metal.³¹ However, small amount of various byproduct including hemiacetals and condensation products which is occurred between ketone and alcohol were produced due to basic conditions.³² For optimization, the reaction parameters, such as amount of catalyst and base, temperature, and time, are adjusted. The TH reaction results of acetophenone are summarized in EntryCat. (mol%)Temp. (°C)Time (min)Base (eq.)Conv.^b (%)Yield^b (%)TON1111045110095952111060176737331100602100999941100601100929251100600.562595961906011009696718045158555581806017268689180751100979710180901676565110.58075110096192120.25807511095380130.1807516260603140.05100602806262Open in a separate window^aRxn. condition: acetophenone (2 mmol), i-PrOH (solvent, 10 mL), base (NaOH).^bDetermined by GC-MS spectroscopy.^cnickel-aluminium alloy purchased from Lancaster (10034177) was applied.First, we studied the effect of the base and determined the amount of base required (Entries 3–6, 33,34 Although no reaction was observed without bases, a small amount of base was sufficient to trigger the reaction (Entry 5, 6,15,35 The optimized conditions were applied to extend the scope.To verify the general applicability of Ni@mSiO₂, various aromatic ketones were tested (†).^36–43Catalytic transfer hydrogenation reactions of various aromatic carbonyl compounds with Ni@mSiO₂^a

Catalytic N-methyl amidation of carboxylic acids under cooperative conditions

Amide is a fundamental group that is present in molecular structures of all domains of organic chemistry and the construction of this motif with high atom economy is the focus of the current research. Specifically, N-methyl amides are valuable building blocks in natural products and pharmaceutical science. Due to the volatile nature of methyl amine, the generation of N-methyl amides using simple acids with high atom economy is rare. Herein, we disclose an atom economic protocol to prepare this valuable motif under DABCO/Fe₃O₄ cooperative catalysis. This protocol is operationally simple and compatible with a range of aliphatic and (hetero)aromatic acids with very good yields (60–99%). Moreover, the Fe₃O₄ can be easily recovered and high efficiency is maintained for up to ten cycles.

The generation of N-methyl amides using simple acids with high atom economy is rare owning to the volatile nature of methyl amine. Herein, an atom economic protocol was disclosed to prepare this valuable motif under DABCO/Fe₃O₄ cooperative catalysis.

Amide is a fundamental group that is present in molecular structures of all domains of organic chemistry.¹ It is widely distributed in natural products, synthetic drugs and functional polymers, and is also the key chemical connection in proteins.² It has been shown that amide bond formation alone accounts for 65% of all preliminary screening reactions in the pharmaceutical industry.³ This means the generation of amide bonds with high atom efficiency is of high practical importance. And not surprisingly, ‘amide formation avoiding poor atom economy reagents’ was voted as the top challenge for organic chemistry by the ACS Green Chemistry Institute in 2007.³From synthetic point of view, the ideal way to produce amide bonds would be the direct coupling of readily available carboxylic acids and amines, but this process is thermodynamically unfavourable due to the formation of the corresponding carboxylate-ammonium salt,⁴ therefore, stoichiometric amount of coupling reagents, such as DCC, DIC, EDCI, HATU, HBTU, HCTU, SOCl₂, BOP, acid chloride etc, are generally required to sidestep thermal conditions for amide bond formation.⁵ These reagents are highly successful, but the process generally suffers from poor atom economy and side products removal issue especially in the large-scale applications.⁵ To overcome these drawbacks, “nonclassical” amide bonds formation routes were investigated.⁶ In these processes, the catalyst takes the role of a coupling reagent in generating an active ester suitable for amidation in a waste-free manner. However, these processes have not been applied in the preparation of N-methyl amides, probably because the methyl amine was delivered in its hydrochloride salt, alcoholic or aqueous form due to its volatile nature.On a different note, N-methyl amides are extensively presented in numerous natural products and pharmaceutical molecules, as shown in Fig. 1,⁷ and the methylation of amides is a promising way to improve the pharmacological property of molecules.⁸ However, the synthesis of N-methyl amides compounds relies heavily on non-catalytic approaches.^5,9 Catalytic approaches were also investigated by Hisaeda,¹⁰ Kundu,¹¹ Li,¹² Guo,¹³ Yu,¹⁴ Maruoka,¹⁵ Wang,¹⁶ Chen,¹⁷ Lamaty¹⁸ and their co-workers starting from nitriles, primiary amides, aldoximes, aldehydes, lignin, carbamoylsilane and alcohols. Until recently, Thakur,¹⁹ Marce,²⁰ Sadeghzadeh²¹ and their co-workers developed elegant N-methyl amidation approach starting from carboxylic acids under nano-MgO, diatomite Earth@IL/ZrCl₄ and Mg(NO₃)₂·6H₂O catalysis respectively, while limitations like poor substrate scope or sophisticated tailored catalyst still persist. Mindful of all the above issues, developing an N-methyl amidation process of simple carboxylic acids, which is still of great challenge in synthesis, and establishing a broad (hetero)aryl scope with high atom economy from commercial available reagents and catalysts were critical considerations in this study. Moreover, the significance of N-methyl amides combined with our interests in the development of green synthetic approaches motivated us to explore the direct coupling of the carboxylic acids and isothiocyanates. To the best of our knowledge, this is the first successful work using isothiocyanatomethane to prepare N-methyl amides.Open in a separate windowFig. 1Marketed drugs bearing N-methyl amide group.Our initial investigation begins with phenylacetic acid and isothiocyanatomethane as model substrate for condition optimization. Using acetonitrile as solvent, only trace amount of product was detected under catalyst free or p-toluenesulfonic acid (PTSA) catalysis conditions ( EntryAdditiveTime (h)CatalystYield (%)1—24—52—24PTSA—3—48TEA174—48DBU455—48DMAP436—48DBN517—48DABCO658LiBr48DABCO719Mn(OAc)₂48DABCO7510MnO48DABCO7911MgO48DABCO8812Al₂O₃48DABCO8513Fe₃O₄48DABCO9814Fe₃O₄24DABCO7515^bFe₃O₄48DABCO80Open in a separate window^aReactions were run on 1 mmol 1a and 1.1 mmol 2a with 10 mol% catalyst and 10 mol% additive in 1 mL of MeCN at 85 °C for 48 hours unless otherwise noted.^bReaction was conducted at 60 °C.Firstly, different acids were employed to react with isothiocyanatomethane and the results were summarized in Open in a separate window^aReactions were run on 1 mmol 1 and 1.1 mmol 2 with 10 mol% DABCO and 10 mol% Fe₃O₄ in 1 mL of MeCN for 48 hours at 85 °C unless otherwise noted.Subsequently, aromatic and heteroaromatic acids were tested for their compatibility with current reaction conditions and the results were summarized in Fig. 1) respectively, and all could be convenient prepared using current procedure with excellent yields.Substrate scope for the amidation reaction^a

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

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

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

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

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

[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

A formal intermolecular [4 + 1] cycloaddition reaction of 3-chlorooxindole and o-quinone methides: a facile synthesis of spirocyclic oxindole scaffolds

Herein, we developed an efficient and straightforward method for the rapid synthesis of spirocyclic oxindole scaffolds via the [4 + 1] cyclization reaction of 3-chlorooxindole with o-quinone methides (o-QMs), which were generated under mild conditions. The products could be obtained in excellent yields with numerous types of 3-chlorooxindole. This methodology features mild reaction conditions, high atom-economy and broad substrate scope.

Herein, we developed an efficient and straightforward method for the rapid synthesis of spirocyclic oxindole scaffolds via the [4 + 1] cyclization reaction of 3-chlorooxindole with o-quinone methides (o-QMs), which were generated under mild conditions.

The structural diversity of spirocyclic oxindole scaffolds is a reason for their frequent occurrence in many relevant natural products and medicinal agents (Fig. 1).¹ In particular, natural spirocyclic-2-oxindole scaffolds have been proven to exhibit a broad range of biological activities and have attracted increasing attention in the synthetic field. For instance, XEN 907 is a novel pentacyclic spirooxindole with excellent activities as sodium channel blockers.² Due to their unique structure and intriguing biological activity, numerous methodologies have been developed for the construction of these privileged frameworks.³ For example, in the past few years, transition-metal catalyzed or organocatalytic [3 + 2] cycloaddition reactions have been developed for the synthesis of spirocyclic oxindole scaffolds.⁴ Despite the emergence of these elegant approaches, exploiting new strategies for the construction of spirocyclic oxindole derivatives is still highly desirable.Open in a separate windowFig. 1Examples of biologically active spirocyclic oxindole scaffolds. Ortho-quinone methides (o-QMs) as highly reactive versatile intermediates have been of great interest to the chemical and biological community.⁵o-QMs react with various classes of reagents by three typical reaction pathways: 1,4-addition of nucleophiles, [4 + 2] cycloaddition with dienophiles and oxa-6π-electrocyclization.⁶ Because most o-QMs are unstable, these reactions generally depend on the reaction conditions used for the generation of o-QMs in situ. Rokita et al. reported that o-silylated phenols when exposed to fluoride could also produce o-QMs under mild reaction conditions.⁷Because of the dual nature (nucleophilic/electrophilic) of the C-3 position, 3-chlorooxindole serves as a highly reactive starting material in the synthesis of spirocyclic oxindole scaffolds. The introduction of a chloro group at the C-3 position of indoles serves as an excellent leaving group in favour of the subsequent cyclization. In addition, this also increases the acidity of the C–H bond for directly entering the C-3 quaternary centers.⁸ Inspired by this reactivity profile, 3-chlorooxindoles have been successfully utilized for [2 + 1]⁹ and [4 + 1]¹⁰ cyclization to synthesize spirocyclic oxindole scaffolds (Fig. 2).Open in a separate windowFig. 2Representation of the synthesis and applications of 3-chlorooxindoles.We designed an efficient and straightforward method for the rapid synthesis of spirocyclic oxindoles via the [4 + 1] cyclization reaction of 3-chlorooxindole with o-QMs, which were generated under mild conditions. In this study, using TBAF as the fluoride source and base ensures that the one-pot domino reaction will occur in mild reaction conditions, with high atom-economy and broad substrate scope.Initially, we carried out optimization studies by examining the reaction between O-silylated phenol 2a and 3-chlorooxindole 1a. Indeed, when TBAF was employed as the fluoride source, a smooth [4 + 1] cyclization reaction occurred, affording the spirocyclic oxindole product 3a with 75% yield (entry 1, EntryF⁻ source X Y SolventTemp (°C)Yield^b1TBAF^c1.24.0DCMrt75%2TBAF1.54.0DCMrt87%3TBAF2.04.0DCMrt85%4CsF1.54.0DCMrt11%5TBAF1.53.0DCMrt80%6TBAF1.54.0CHCl₃rt83%7TBAF1.54.0THFrt94%8TBAF1.54.0Toluenert90%9TBAF1.54.0DMFrt72%10TBAF1.54.0MeCNrt84%11TBAF1.54.0MeOHrtNDOpen in a separate window^aReaction conditions: 1a (0.3 mmol), solvent (3.0 mL), 6 h.^bIsolated yield.^cTBAF (1 M in THF solution).With the optimal conditions known, we next investigated the substrate scope of substituted 3-chlorooxindole 1 using O-silylated phenol 2a as a representative ( Open in a separate window^aReaction conditions: 1 (0.3 mmol), 2a (1.5 eq.), TBAF (4.0 eq.), THF (3.0 mL), 6 h.^bIsolated yields.Next, we also explored the substrate scope of substituted 3-chlorooxindole 1 using O-silylated phenols 2a′ ( Open in a separate window^aReaction conditions: 1 (0.3 mmol), 2a′ (1.5 eq.), TBAF (4.0 eq.), THF (3.0 mL), 6 h.^bIsolated yields.On the basis of above-mentioned results, a plausible mechanism for this formal [4 + 1] cycloaddition reaction is depicted in Scheme 1. Initially, the highly reactive o-QMs are generated via the desilylation/elimination reaction. Then, 3-chlorooxindole 1a as a nucleophile attacks the external carbon of o-QMs, affording zwitterion Int-1. Finally, the zwitterion Int-1 loses one molecular HCl through a nucleophilic attack, yielding the spirocyclic oxindole product 3a.Open in a separate windowScheme 1Possible mechanism.     

Catalyst- and solvent-free approach to 2-arylated quinolines via [5 + 1] annulation of 2-methylquinolines with diynones

A novel route for the synthesis of 2-arylated quinolines through a [5 + 1] annulation directly from 2-methylquinolines and diynones under catalyst-free and solvent-free conditions was disclosed. This synthetic process was atom-economic, with good tolerance of a broad range of functional groups, and with great practical worth.

A novel route for the synthesis of 2-arylated quinolines through a [5 + 1] annulation directly from 2-methylquinolines and diynones under catalyst-free and solvent-free conditions was disclosed.

Nitrogen-containing heterocyclic compounds are ubiquitous in natural molecules and exhibit a wide array of biological activities.¹ Among various N-heterocycles, quinoline nuclei are privileged scaffolds that occupy an important role in many medicinally relevant compounds.² 2-Arylated quinolines are found in many medicinal compounds including etoricoxib,³ rosuvastatin,⁴ and gleevec,⁵ as well as molecules designed for other purposes including P, N ligands, such as QUINAP.⁶ Because of their unique biological activity and wide application, the functionalized 2-arylated quinoline elicited considerable synthetic interest, and a variety of synthetic routes have been established.⁷ In addition, some classical synthetic methods such as Kumada,⁸ Suzuki,⁹ Negishi,¹⁰ or Stille^9b are usually used to efficiently prepare these compounds, but these methods require the preparation of cross-coupling reagents such as Grignard reagents, boronic acids, organozincs, and organostannanes in advance and these cross-coupling reagents are unstable or toxic or can''t be isolated as solids.¹¹ More recently, much research has been directed toward the synthesis of 2-arylated quinolones and their derivatives via transition-metal-catalyzed C–H arylation¹² and many other methods also have been developed by transitional-metal-catalyzed cross-couplings.¹³ These transition metals included Co, Cu or Pd. Moreover, 2-arylated quinolines synthesis via direct C–H arylation of quinolones with various aryl bromides, arylboronic acid, or arylzinc reagents catalyzed by transition metal catalyst, such as Rh, Fe, or Ni, have been investigated by Bergman,¹⁴ Maiti,¹⁵ and Tobisu.¹⁶ Ru¹⁷ or Mn¹⁸ also was used to catalyze indirect Friedländer synthesis to obtain 2-arylated quinolines that involved oxidative cyclization of 2-aminobenzyl alcohol with either ketones or alcohols. Although these processes were highly efficient and significance, none of these procedures could directly provide the final products with a low content of the heavy metal impurities which are strict restrictions in drugs and pharmaceuticals.¹⁹ Thus, an alternative, general, solvent-free, and environmentally sustainable procedure is urgently required for the quick synthesis of 2-arylated quinolines.Recently, as our continuous study on the C(sp³)–H activation of 2-methylquinolines, which provided a facile synthetic approach to access substituted pyrrolo[1,2-a]quinolones (Scheme 1),²⁰ we had found that the methyl of 2-methylquinolines has very high reactivity. Based on this, herein we reported the catalyst-free and solvent-free [5 + 1] annulation of 2-methylquinolines and diynones to access 4-(quinolin-2-yl)-phenols. To the best of our knowledge, there were none of the group that reported direct construction of six-member aromatic-ring at the methyl of 2-methylquinolines with diynones to give 4-(quinolin-2-yl)-phenols. The present novel construction protocol for 4-(quinolin-2-yl)-phenols had several significant advantages: (1) this chemistry provided a novel and simple strategy for the synthesis of highly valuable 4-(quinolin-2-yl)-phenols under very simple conditions; (2) according to the atom economy concept, this protocol was carried out under catalyst-free and solvent-free conditions, without the addition of any acid, base, or other reagents, which provided the final products without heavy metal impurities and improved its potential utility; (3) the method featured high functional group tolerance, high yields, and broad substrate scopes. Particularly, this route could directly introduce two different substituent groups on the newly formed of six-member aromatic-ring (see Open in a separate windowScheme 1C–H bond activation of 2-methylquinolines and 2-methylpyridine.Synthesis of 4-(quinolin-2-yl)phenol derivatives^a,b,c

1,3-Dipolar cycloaddition of isatin N,N′-cyclic azomethine imines with α,β-unsaturated aldehydes catalyzed by DBU in water

A simple and green procedure was established by [3 + 3] cycloaddition reaction of isatin derived cyclic imine 1,3-dipoles with α,β-unsaturated aldehydes, giving the desired spiro heterocyclic oxindoles with aza-quaternary centers in good yields and diastereoselectivities. It should be noted that water can be employed as a suitable solvent for the improvement of diastereoselectivity.

A simple and green procedure was established by [3 + 3] cycloaddition reaction of isatin derived cyclic imine 1,3-dipoles with α,β-unsaturated aldehydes, giving spirooxindoles with aza-quaternary center in good yields and diastereoselectivities.

Aza-quaternary centers are pivotal structural units, which exist in a variety of bioactive molecules and natural products.¹ In particular, spirooxindoles at the C3 position bearing a quaternarized N-heterocycle have attracted considerable attention because of their privileged structural units with attractive bioactivities,² for example, antimalarial,³ anti-HIV,⁴ antitumor,⁵ anticancer,⁶ inhibitor at the vanilloid receptor,⁷ antituberculosis,⁸etc. (Fig. 1). Due to their remarkable biological importance, great efforts have been made to access spiro heterocyclic oxindoles with aza-quaternary centers. These methods include cycloaddition of imines,⁹ 1,3-dipolar cycloaddition,¹⁰ multicomponent cyclization reaction¹¹ and metal-catalyzed cycloaddition.¹² Among them, 1,3-dipolar cycloaddition is one of the most powerful tools for the construction of diverse spirooxindole fused N-heterocyclic scaffolds. Of these, N,N′-cyclic azomethine imines were widely studied for constructing various types of N-heterocyclic skeletons with spirooxindole as a stable and easily accessed 1,3-dipoles. In 2013, Wang''s group reported their pioneering studies on Et₃N-catalyzed diastereoselective [3 + 3] annulation of N,N′-cyclic azomethine imines with isothiocyanatooxindoles to build 3,3′-triazinylspirooxindoles. In 2017, Wang et al. developed a new isatin-derived N,N′-cyclic azomethine imine 1,3-dipoles, and successfully applied in the [3 + 2] cycloaddition reaction for the construction of spirooxindoles bearing N-heterocycles (Scheme 1a).^10c Very recently, Jin''s group reported a Cs₂CO₃-catalyzed [3 + 4] annulation of isatin-derived 1,3-dipole with aza-oQMs (Scheme 1b).^10d Furthermore, Moghaddam and coworkers developed an efficient method for the synthesis of pyridazine-fused spirooxindole scaffolds by 1,3-dipolar [3 + 3] cycloadditions (Scheme 1c).^10e On the other hand, α,β-unsaturated aldehydes and their analogs as readily available substrates are also important building blocks in the synthesis of heterocyclic compounds which are widely applied in N-heterocyclic carbenes catalysis and other organocatalysis.¹³ Inspired by these great works and our continuing efforts towards green synthesis of spirooxindole skeletons. We envisioned a quick and efficient way of [3 + 3] cyclization reaction of α,β-unsaturated aldehydes with the new isatin N,N′-cyclic azomethine imine 1,3-dipoles via oxindole C3 umpolung. We wish to disclose herein that a green and practical access to synthesize pharmacologically interesting spirooxindole derivatives by involving isatin N,N′-cyclic azomethine imine 1,3-dipole as nucleophiles and various α,β-unsaturated aldehydes in water using DBU as organocatalyst. Our initial examinations were carried out using isatin derivated cyclic imine 1,3-dipole 1a (0.1 mmol) and α,β-unsaturated aldehyde 2a (0.12 mmol) as the model substrates, the results of condition optimization are shown in Open in a separate windowFig. 1Selected bioactive products of C3-spirooxindoles with aza-quaternary centers.Open in a separate windowScheme 1Isatin-derived N,N′-cyclic azomethine imine 1,3-dipoles participated in the construction of N-heterocyclic skeletons with C3-spirooxindole.Optimization of the reaction conditions^a

Iodine-catalyzed sulfonylation of sulfonyl hydrazides with tert-amines: a green and efficient protocol for the synthesis of sulfonamides

This study provides a direct, sustainable and eco-friendly method for the synthesis of various sulfonamides via the sulfonylation of sulfonyl hydrazides with tert-amines. The method utilizes sulfonyl hydrazides to oxidize and couple with tertiary amines through selective cleavage of C–N bonds. In this reaction, molecular iodine was used as the catalyst and t-butyl hydroperoxide was used as the oxidant.

Sustainable and eco-friendly method for the synthesis of various sulfonamides.

Sulfonamides commonly serve as synthetic intermediates to produce various drugs and industrial compounds (Scheme 1).¹ They also commonly act as a N-sulfonyl protecting group for easy removal under mild conditions.² There have been many efforts devoted to synthesizing these compounds. Among the methods developed, nucleophilic substitution of an amine with a sulfonyl chloride or sulfonamides with organic halides in the presence of a base is frequently utilized.³ Over the past few years, transition metal catalysis has been proved a powerful tool to synthesize sulfonamides. For example, a cross-coupling reaction of primary sulfonamides with aryl halide or boronic acids,⁴ a Chan-Lam type coupling reaction of sulfonyl azides with boronic acids,⁵ or an oxidative coupling reaction of sulfinate salts with amines were developed.⁶ However, the use of non-stable, hazardous and mutagenic starting materials and toxic high boiling polar solvents in these reactions resulted in a larger amount of toxic waste. Furthermore, the use of stoichiometric amounts of bases or transition metals makes reactions with a slow reactivity and poor functional group tolerability. Therefore, a novel, sustainable, efficient, and eco-friendly method is desired to synthesize sulfonamides.Open in a separate windowScheme 1Examples of important sulfonamide drugs in top 200 pharmaceuticals of 2018.Iodine and its salts have been reported as very efficient catalysts in CDC reactions in which transition metals are used as catalysts.⁷ In recent years, many methods have been reported for synthesis of sulfonamides under metal-free conditions.⁸ As a source of sulfonyl groups, sulfonyl hydrazides are readily accessible solid. They are stable in air and under moisture conditions, and can be easily prepared and stored. Most importantly, only water and nitrogen were obtained as by-products during the reactions using sulfonyl hydrazides as starting materials. Iodine catalyzed oxidative coupling of sulfonyl hydrazides with secondary amines have been developed (Scheme 2(a)).⁹Tert-amines can donate an amine group via a C–N cleavage in place of primary or secondary amines. Compared to the high reactivity of primary or secondary amines, tert-amines are less nucleophilic and non-destructive for some amine-sensitive functional groups. Recently, Yuan et al. and Gui''s have developed a new method to sulfonamides using I₂-mediated or catalyzed C–N bond cleavage of tert-amines (Scheme 2(b)).¹⁰ Meanwhile, Sheykhan et al. reported a novel electrochemical oxidative sulfonylation¹¹ of tert-amines (Scheme 2(c)).¹² Moreover, catalytic reactions in the aqueous phase have also been recently developed,¹³ and sulfonylation of sulfonyl hydrazides has caused wide interest recently.¹⁴ In this study, we will report a new method to synthesize sulfonamides using iodine-catalyzed oxidative coupling of sulfonyl hydrazides with tert-amines (Scheme 2(d)). This approach avoids use of metal catalysts and hazardous regents; the materials, sulfonyl hydrazides and tert-amines, are versatile intermediates in commercial.Open in a separate windowScheme 2Methods for the synthesis of sulfonamides.Commercially available sulfonyl hydrazide 1a was selected as a sulfonyl source to synthesize sulfonamides. When 1a was mixed with 1 equiv. of N-ethyl pyrrolidine under various solvents at 80 °C, an 80% yield of the corresponding sulfonamide 3a was obtained after 4 hours in the aqueous phase (Scheme 3).Optimization of the reaction conditions^a

Oxidative bridgehead functionalization of (4 + 3) cycloadducts obtained from oxidopyridinium ions

Treatment of selected (4 + 3) cycloadducts derived from oxidopyridinium ions with N-iodosuccinimide (NIS) in hexafluoroisopropanol (HFIP) resulted in the formation of bridgehead ethers via a net oxidative C–H activation.

Selected azabicyclo[4.3.1]deca-3,8-dienes react with NIS in HFIP to form bridgehead ethers via a net oxidative C–H activation.

Since their beginnings in the mid-1970s, the (4 + 3) cycloaddition reactions of N-substituted oxidopyridinium ions have provided an attractive and facile method for the construction of nitrogenous, heterocyclic seven-membered rings (Scheme 1).^1,2 While N-aryl and N-alkenyl substitution of the pyridinium nitrogen have largely dominated the literature, to the best of our knowledge, there had been only one example of a (4 + 3) cycloaddition reaction of N-alkyl oxidopyridinium ions reported prior to 2017.^2a Our recent reports of the reaction of N-methyl oxidopyridinium ions with conjugated dienes expanded the scope of the (4 + 3) process, due to the incorporation of an ester functional group at the 5-position of the hydroxypyridine starting material.³ Cycloadducts are formed in good to excellent yields, and the reactions of select dienes proceed in high regioselectivity. Furthermore, the cycloaddition process can be steered towards a high preference for the endo diastereomer when the starting diene bears a bulky trialkylsilyl groups at C2, as we have recently reported (Scheme 2).⁴Open in a separate windowScheme 1Example of a (4 + 3) cycloaddition of an oxidopyridinium ion.Open in a separate windowScheme 2 Endo selective (4 + 3) cycloaddition of an oxidopyridinium ion.Upon our initial exploration into the chemistry of the latter (4 + 3) cycloadduct products, our intentions were the replacement of the trialkylsilyl group with a halogen atom such as iodine or bromine. We were particularly inspired by a report from the Zakarian group, who showed that vinylsilanes react with N-iodosuccinimide in hexafluoroisopropanol to afford iodoalkenes stereospecifically and in good yield (Scheme 3).⁵ However, when our (4 + 3) cycloadducts were exposed to such reaction conditions, the replacement of the C–Si bond by a C–I bond was not observed. Thus, when a mixture of 3a–c was treated with NIS in hexafluoroisopropanol (HFIP),⁶ a vinyl iodide was not formed. Instead, functionalization of the bridgehead carbon as a hexafluoroisopropyl ether was observed, a formal oxidative C–H activation process, affording 4a (Scheme 4).⁴ This communication reports further examples of this process and other results that provide some insights for future studies.Open in a separate windowScheme 3Zakarian''s vinyl iodide synthesis.Open in a separate windowScheme 4First example of the bridgehead oxidation of a (4 + 3) cycloadduct.The substrates for the process are known compounds, produced in our laboratories using methodology we developed for the (4 + 3) cycloaddition of oxidopyridinium ions with dienes.⁴ From the very first example of the process, we noted an interesting phenomenon. For example, entry 1 of Scheme 4) makes use of an inseparable mixture of diastereomers as the starting material. All three of the diastereomers are detectable by ¹H NMR in the mixture. Nevertheless, the product of the oxidation is a single diastereomer. The structure of 4a was supported by ¹H NMR data. The fate of the minor diastereomers of the starting material is unknown at this time, as nothing else could be isolated from the reaction mixture. This is also true for similar entries in EntrySubstrate^aTime^a (h)ProductYield^b (%)1 1 522 23 543 1.5 524 22 515 21 446 23 387 23 168 5.5 339^c 2 3510^c 3 5911 4 3112 23 64Open in a separate window^aThe major diastereomer/regioisomer of the mixture is shown.^bYields are based on the entire mass of the starting material, including isomers that may not have given rise to the product observed.^cThe substitution pattern of the major isomer is given in parentheses.In general, the reactions were conducted with 0.25 mmol of substrate dissolved in 4 mL of hexafluoroisopropanol (HFIP). The stirred solution was cooled to 0 °C in an ice bath. After addition of N-iodosuccinimide (1.5 equiv.), the mixture was allowed to slowly warm to the room temperature. The reaction was monitored by TLC until starting material was completely consumed.The substrates that contained an alkyl substituent at C-2 and a trialkylsilyl group at C-4 afforded product in about 50% yield (entries 1–4, 8Not all substrates bearing an alkyl substituent at C-2 and a trialkylsilyl group at C-4 afforded product in the 50% range. The lower yield of 24a from 23a–b, is perhaps due to the phenyl group on the silicon being sufficiently reactive to cause side product formation (entry 11, Fig. 1 shows substrates that did not afford bridgehead oxidation product and led to complex reaction mixtures when treated with NIS. It does appear that the silyl group provides protection to the alkene, but the effect is clearly not universal.Open in a separate windowFig. 1Substrates that did not lead to oxidation.We attempted to modify the reaction conditions in the hope of obtaining different products or limit the need for HFIP as solvent using 3a–c as a model substrate. When LiI, NaI, or NaBr was added to the reaction mixture, oxidation products were obtained in low yield. No halogen incorporation was observed, though such products might be expected to be labile in any case, as they would likely be readily solvolyzed. Attempts to reduce the amount of HFIP used in the process (2–30 equiv. in MeCN) gave bridgehead substitution products in 5–46% yield with recovered starting material isolated in yields ranging from 29–64%. Addition of small amounts of trifluoroacetic acid to the standard reaction mixture led to decomposition. Excess NIS (15 equiv.) gave decomposition and NBS was not effective at all in producing the oxidation product under the standard reaction conditions.Our working mechanism for this reaction is shown in Scheme 5. Reaction of 3a with NIS activated by HFIP through hydrogen bonding produces the iminium ion 27a.⁷ Deprotonation of this intermediate with succinimide anion affords the bridgehead iminium species 28a, which is trapped with HFIP to produce the product 4a (Scheme 5). Inclusion of allyltrimethylsilane in the reaction to trap 28a led to a complex product mixture.Open in a separate windowScheme 5Proposed mechanism of the oxidation.In conclusion, we report a unique bridgehead oxidation process of selected (4 + 3) cycloadducts derived from oxidopyridinium ions. While this process will certainly possess limitations, it raises questions about mechanism and what other reagents might be used to effect such an oxidation in a more general way, and whether more general bridgehead functionalization might be possible through such a mechanism. We plan on addressing these questions. Results will be reported in due course.     

Simple and efficient synthesis of bicyclic enol-carbamates: access to brabantamides and their analogues

A novel synthetic approach towards the formation of the unusual bicyclic enol-carbamates, as found in brabantamides A–C, is reported. The bicyclic oxazolidinone framework was obtained in very good yield and with high E/Z selectivity from a readily available β-ketoester under mild reaction conditions using Tf₂O and 2-chloropyridine tandem. The major E isomer was used in the synthesis of the brabantamide A analogue.

A simple and short synthesis of bicyclic enol-carbamates with high E/Z selectivity and the synthesis of brabantamide A analogue are presented.

Brabantamides A–C (1–3) (Fig. 1) were first isolated in 2000 from the culture extracts of Pseudomonas fluorescens.¹ They displayed nanomolar inhibitory activity towards lipoprotein-associated phospholipase A₂ (Lp-PLA₂) and therefore they could be used in the treatment of the inflammatory diseases such as atherosclerosis.^1–3 It was found that the sugar moiety is not necessary for the biological activity against Lp-PLA₂. In contrast, deglycosylated brabantamides A and C showed improved inhibitory activity compared to their natural counterparts.³ Moreover, simplified brabantamide analogues with amide functional group and long alkyl side chains showed even higher inhibitory effect.⁴ Brabantamides A–C also exhibit significant activity against Gram-positive bacteria, fungi, and oomycetes.^5,6 A recent study confirmed that the bicyclic scaffold and the long lipophilic side chain are essential for the antibacterial activity.⁷Open in a separate windowFig. 1Structures of brabantamides A–C (1–3). Rha = rhamnose.Surprisingly, only five reports concerning the synthesis of the bicyclic oxazolidinone with an exocyclic double bond have been reported to date.In 2000, Pinto et al. prepared a series of analogues of brabantamide A where the enol-carbamate 5 was first obtained by direct iodocyclization from acetylene derivative 4 and then converted into key ester 6 by carbonylation of the corresponding vinyl iodide in the presence of 2-(trimethylsilyl)ethanol and PdCl₂ (Scheme 1a).⁴ Another synthesis of the related esters 9 has been reported by Snider et al. in 2006, employing Wittig reaction between stabilized ylides and bicyclic oxazolidindione 8 synthesized from l-proline 7 (Scheme 1b).⁸ Shortly after, bicyclic enol-carbamate 10 with an exocyclic methylene group was synthesized in one step from acetylene derivative 4 using gold(i) catalysts (Scheme 1c).⁹ Very recently, Witte et al. reported the synthesis of series of Z-analogues of brabantamides 12 by cyclization of β-ketoamides 11 using CDI (Scheme 1d).⁷ As a part of our ongoing research program aimed at the utilization of trifluoromethanesulfonic anhydride (Tf₂O)/2-halopyridine (2-XPy) tandem in the synthesis of bioactive natural products and their analogues, we envisioned that similar reaction conditions could be effectively used to form the bicyclic oxazolidinone framework as found in brabantamides.Open in a separate windowScheme 1Literature syntheses of bicyclic enol-carbamates and method proposed herein.The combination of Tf₂O/2-XPy was extensively and successfully used in the amide activation^10,11 as well as in generating isocyanate species from N-Boc and N-Cbz protected amines.¹² We anticipated that the N-Boc-protected β-ketoester 13 could react in its enolate form with in situ generated isocyanate ion by intramolecular 5-endo-dig cyclization to give bicyclic enol-cyclocarbamate 14 (Scheme 1e).At the start of our investigation, model β-ketoester 15, prepared from N-Boc-l-proline,⁷ was chosen as the model substrate to identify optimal reaction conditions (12c the initial using of 1.5 equivalents of Tf₂O and 3 equivalents of 2-ClPy led to a full conversion of the substrate 15 in 15 minutes (monitored by TLC) (13 Any variation of the amount of 2-ClPy did not have any positive impact on the reaction ( EntryTf₂OBaseTime (min)16a : 16b^aYield^b (%)11.5—60—–^c21.5Et₃N60—–^c31.5DMAP60—–^c41.5Pyridine60—–^c51.5^d2,6-Lutidine60—–^c61.5^dDBU6090 : 1041^e,f71.52-ClPy1593 : 753^e 8 1.1 2-ClPy 15 85 : 15 80 ^e 91.12-ClPy (1.5 equiv.)4085 : 1575^e101.12-ClPy (5 equiv.)1587 : 1364^e111.12-FPy1589 : 1171^e121.12-BrPy7086 : 1473^e131.12-IPy9086 : 1468^e14Witte''s protocol^gOvernight50 : 5036^eOpen in a separate window^aRatio determined by ¹H NMR of the crude reaction mixture.^bIsolated combined yield.^cTraces of products.^dReactions performed with 1.1 equiv. of Tf₂O did not lead to full conversion of ester 15.^eReactions were performed on 1 mmol of ester 15.^fReaction mixture contained a large amount of unidentified by-products.^gReaction conditions: (1) TMSOTf (2 equiv.), CH₂Cl₂, 0 °C, 1 h. (2) CDI (1.5 equiv.), CH₂Cl₂, 0 °C – rt, overnight.⁷It is noteworthy that the reaction can be performed on a gram scale without affecting the yield and both isomers are easily separable by FCC (see the ESI^†).The ¹H and ¹³C NMR data of the major E isomer 16a were consistent with those published previously.⁸ Possible racemization in the course of the reaction was dismissed based on the comparing specific optical rotation with the published data for 16a ([α]²²_D = −261.1 (c 1.01, MeOH); ref. 8: [α]²²_D = −207 (c 1.0, MeOH)). Most importantly, X-ray crystallographic analysis of 16a (Fig. 2; see the ESI^† for further details)¹⁴ confirmed its absolute configuration on the C-7a carbon atom.Open in a separate windowFig. 2Molecular structure of the enol-carbamate E-16a confirmed by X-ray crystallographic analysis.The minor Z isomer 16b was isolated for the first time as the pure compound and was fully characterized. Its structure was assigned on the basis of its ¹H, ¹³C, COSY, HSQC, and HMBC NMR spectra.A plausible mechanism of the cyclization of β-ketoester 15 was based upon previous works^12a–c and it is depicted in Scheme 2. Isocyanate cation II, as a key intermediate, can be formed directly from iminium triflate I (path A) or through the formation of carbamoyl triflate III with subsequent elimination of triflate ion spontaneously (path B). Ester enolate moiety IV then reacts as O-nucleophile via 5-endo-dig cyclization and leads predominantly to the formation of the enol-carbamate 16a.Open in a separate windowScheme 2Plausible mechanism of the cyclization β-ketoester 15.Next, the optimized conditions were briefly applied in the synthesis of the brabantamide A analogue 21 (Scheme 3). Starting β-ketoester 18 was synthetized in two steps in a 70% yield using both commercially available N-Boc-d-proline 17 and 2-(trimethylsilyl)ethanol. It ought to be mentioned that previously examined hydrolysis of the corresponding methyl ester 16a under acidic as well as basic conditions failed due to the instability of the bicyclic enol-carbamate.^3,8Open in a separate windowScheme 3Synthesis of the brabantamide A analogue 21.Subsequent cyclization of ester 18 using optimized reaction conditions afforded enol-carbamate 19 in 76% yield as a mixture of E and Z isomers in a ratio of 89 : 11. After isolation of the major isomer E-19a, it was treated with TBAF, providing free acid 20 in 89% yield. Finally, an amidation of 20 with tetradecylamine in the presence of EDCI gave amide 21 in moderate 40% yield. Both free acid 20 and amide 21 were fully characterized for the first time and their structures were assigned on the basis of its ¹H, ¹³C, COSY, HSQC, and HMBC NMR spectra. Moreover, their structures were unambiguously confirmed by X-ray crystallographic analysis (Fig. 3; see ESI^† for further details).¹⁴Open in a separate windowFig. 3Molecular structures of acid 20 (top) and amide 21 (bottom) confirmed by X-ray crystallographic analysis.     

Metal-free synthesis of 1,4-benzodiazepines and quinazolinones from hexafluoroisopropyl 2-aminobenzoates at room temperature

Herein, we describe the novel reactivity of hexafluoroisopropyl 2-aminobenzoates. The metal-free synthesis of 1,4-benzodiazepines and quinazolinones from hexafluoroisopropyl 2-aminobenzoates has been developed at room temperature. These procedures feature good functional group tolerance, mild reaction conditions, and excellent yields. The newly formed products can readily be converted to other useful N-heterocycles. Moreover, the products and their derivatives showed potent anticancer activities in vitro by MTT assay.

A metal-free synthesis of 1,4-benzodiazepines and quinazolinones from hexafluoroisopropyl 2-aminobenzoates has been developed at room temperature.

Benzodiazepines (BDZs), especially 1,4-benzodiazepines, are privileged motifs in pharmaceuticals.¹ For examples, oxazepam is used to treat anxiety disorders or alcohol withdrawal symptoms; triazolam is used to treat insomnia (Scheme 1). Until now, some synthetic approaches to 1,4-benzodiazepine skeletons have been developed include isocyanide-based multicomponent reactions,² cycloadditions,³ metal-catalyzed tandem reactions,⁴ and redox-neutral [5+2] annulation with o-aminobenzaldehydes.⁵ However, these procedures have some limitations involving unavailable materials, several steps, harsh reaction conditions and low yields. α-Haloamides are widely used to synthesize N-heterocycles.⁶ Recently, some groups reported the synthesis of 1,4-benzodiazepines with α-haloamides.⁷ Kim and coworkers developed a [4+3]-annulation reaction between α-haloamides and isatoic anhydrides for 1,4-benzodiazepines, but the reaction required 80 °C reaction temperature and provided an unsatisfactory yield.^7a Singh''s group reported a two-step method to construct 1,4-benzodiazepines from α-haloamides and anthranils, but the anthranils are not readily available substrates and the second step also required 80 °C reaction temperature.^7b Quinazolinones are a significant class of heterocycles that widely occur in natural products and pharmaceuticals (Scheme 1).⁸ These compounds exhibit a range of biological activities including anticancer, antibacterial, antiinflammatory, antifungal, etc. Due to their significant value, the synthesis of quinazolinones has attracted considerable attention. The reported synthetic methods can be summarized as: (i) condensation of 2-aminobenzamides with carbonyl compounds;⁹ (ii) oxidative cyclization of primary alcohols with 2-aminobenzamides or 2-aminobenzonitriles;¹⁰ (iii) metal-catalyzed coupling/cyclization reactions;¹¹ and (iv) palladium-catalyzed carbonylation reactions.¹² But these synthetic methods also had some disadvantages. Thus, it is highly desirable to develop new available reagents for synthesizing the useful N-heterocycles such as benzodiazepines and quinazolinones with good yields under mild reaction conditions.Open in a separate windowScheme 1Structures of representative 1,4-benzodiazepine and quinazolinone drugs.In the past few years, 2-aminobenzoates have been used for the synthesis of N-heterocycles via [4+n] cyclization (Scheme 2a).¹³ However, harsh reaction conditions such as high reaction temperatures and strong bases or acids were required to effect alkoxy leaving. When we tried to synthesize benzodiazepines or quinazolinones with methyl or tert-butyl 2-aminobenzoates, we failed. Recently, hexafluoroisopropanol (HFIP) has attracted a lot of attention when used as solvent or substrate, due to its special properties.¹⁴ When we used isatoic anhydrides as substrates and NEt₃ as base in HFIP at room temperature, we unexpectedly discovered that hexafluoroisopropyl 2-aminobenzoates were completely formed. We supposed hexafluoroisopropyl 2-aminobenzoates were good synthons for the synthesis of N-heterocycles. Herein, we report metal-free procedures for the synthesis of 1,4-benzodiazepines and quinazolinones from hexafluoroisopropyl 2-aminobenzoates at room temperature with excellent yields (Scheme 2b).Open in a separate windowScheme 2Synthesis of N-heterocycles from 2-aminobenzoates.We examined the annulation reaction with hexafluoroisopropyl 2-aminobenzoate (1a) and α-bromoamide (2a) as the model substrates. Initially, when the reaction was performed with 1 equiv. of Et₃N in HFIP at room temperature for 0.5 h, 3a was formed, but cyclization product 4a was not obtained. We thought the transformation from 3a to the product 4a needing to release one molecule of HFIP, and the transformation maybe be inhibited when HFIP was used as solvent. So we removed the solvent HFIP under vacuum and added 2.0 mL DMF to react for 0.5 h. Pleasingly, the desired product 4a was obtained in 68% yield ( EntryBaseSolvent ASolvent BYield (%)1Et₃NHFIPDMF682Cs₂CO₃HFIPDMF973NaHCO₃HFIPDMFn.d.4K₂CO₃HFIPDMFn.d.5DBUHFIPDMF616NaOHHFIPDMF937DIPEAHFIPDMF638—HFIPDMF09Cs₂CO₃DMSO—010Cs₂CO₃DMA—011Cs₂CO₃MeCN—012Cs₂CO₃Toluene—013Cs₂CO₃HFIPDMA7114Cs₂CO₃HFIPDMSO4115Cs₂CO₃HFIPMeCN4016Cs₂CO₃HFIPDioxane3817Cs₂CO₃HFIPNMPn.d.18Cs₂CO₃HFIPToluenen.d.19^bCs₂CO₃HFIPDMF92Open in a separate window^aReaction conditions: unless otherwise noted, all reactions were performed with 1a (0.3 mmol), 2a (0.3 mmol), and base (0.3 mmol) in solvent A (3.0 mL) at room temperature for 0.5 h, then the solvent A was removed under vacuum and solvent B (2.0 mL) added to react for 0.5 h. Isolated yield.^bYield on a 3.0 mmol scale.After determining the optimized reaction conditions, the scope of the cyclization reaction for 1,4-benzodiazepines was examined ( Open in a separate window^aReaction conditions: 1 (0.3 mmol), 2 (0.3 mmol), and Cs₂CO₃ (0.3 mmol) in solvent HFIP (3.0 mL) at room temperature for 0.5 h, then the HFIP was removed under vacuum and added DMF (2.0 mL) to continue to react for 0.5 h. Isolated yield.When hexafluoroisopropyl 2-aminobenzoates reacted with amidines hydrochloride in the presence of base, quinazolinones were produced. Then, we optimized the reaction conditions to enhance the yields of the quinazolinones (see the ESI^† for more details). With optimum conditions in hand, substrate scope for the synthesis of quinazolinones was next investigated ( Open in a separate window^aReaction conditions: 1 (0.3 mmol), 5 (0.36 mmol), K₃PO₄ (0.45 mmol), DMF (2.0 mL) at room temperature for 10 h. Isolated yields.To probe the reaction mechanism, several preliminary experiments were conducted (Scheme 3). Under standard reaction conditions, methyl 2-aminobenzoates 7 reacted with 2a to provide compound 8 in 92% yield, and 4a was not detected. This control experiment indicated the importance of hexafluoroisopropyl (Scheme 3, eqn (1)). Treatment of methyl 2-aminobenzoates 7 with 5a in the presence of K₃PO₄ did not furnish any product 6a, and 3a did not convert at all (Scheme 3, eqn (2)). On the basis of the control experiments and previous reports, we propose a possible mechanism. First, aza-oxyallyl cation A is formed from α-bromoamide with Cs₂CO₃.¹⁵ Whereafter, aza-oxyallyl cation A combines with 1a to produce compound 3a.^15b The product 4a is obtained via intramolecular nucleophilic substitution, releasing a molecule of hexafluoroisopropanol. The nucleophilic attack of 5a onto 1a provides the intermediate B. Subsequently, product 6a is formed by intramolecular nucleophilic addition/deamination cyclization.Open in a separate windowScheme 3Control experiments and possible reaction mechanism.In order to address the potential synthetic application of our methods, the transformations of the obtained 1,4-benzodiazepines and quinazolinones were performed (Scheme 4). Compound 9 was formed from 4a through cleavage of the N–O bond with Mo(CO)₆ (Scheme 4, eqn (1)). The quinazolinones can be transformed into substituted quinazolines with anilines or phenols as nucleophilic reagents in the presence of BOP and DBU (Scheme 4, eqn (2) and (3)).Open in a separate windowScheme 4Derivatization of products.We next investigated the cytotoxicity of the products and their derivatives against cancer cell lines (A549, HCT116 and MCF7) by MTT assay, with 5-fluorouracil (5-FU) as the positive control. To our delight, some products and their derivatives exhibited potent inhibitory activities, and some of them showed better inhibitory activities than 5-Fu (CompoundsIC₅₀ (μM)A549HCT116MCF74e64.69 ± 7.3533.27 ± 5.8440.32 ± 0.496c35.11 ± 3.4026.61 ± 1.2658.12 ± 3.456d52.32 ± 2.8523.58 ± 1.5081.32 ± 2.806f82.89 ± 10.3459.59 ± 1.6038.52 ± 1.836g67.00 ± 8.2432.90 ± 0.6042.54 ± 3.796l19.56 ± 1.1617.73 ± 2.3225.00 ± 5.3010a14.79 ± 1.1526.31 ± 3.9529.70 ± 0.0910b5.98 ± 0.4215.41 ± 4.4121.12 ± 1.0611a68.54 ± 3.7017.84 ± 3.1375.84 ± 2.5011b94.76 ± 1.1425.14 ± 5.3167.13 ± 3.655-Fu>10013.03 ± 2.8029.58 ± 12.86Open in a separate windowIn summary, we have developed novel and simple approaches for the synthesis of 1,4-benzodiazepines and quinazolinones from hexafluoroisopropyl 2-aminobenzoates with α-bromoamides or amidines hydrochloride. These protocols feature readily available starting materials, mild reaction conditions, good functional group tolerance, and excellent yields. In addition, the newly obtained products and their derivatives showed potent anticancer activities in vitro by MTT assay. Further studies on the synthesis of other N-heterocycles from hexafluoroisopropyl 2-aminobenzoates are in progress.     

Enantioselective amination of 4-alkylisoquinoline-1,3(2H,4H)-dione derivatives

A mild and efficient enantioselective amination of 4-alkylisoquinoline-1,3(2H,4H)-dione derivatives was established, which is compatible with a broad range of substrates and delivers the final products in excellent yields (up to 99%) and ee values (up to 99%) with low catalyst loading (down to 1 mol%). The synthetic potential of this methodology was also demonstrated in the gram scale level.

A mild and efficient enantioselective amination of 4-alkylisoquinoline-1,3(2H,4H)-dione derivatives was established and a broad range of amination products were prepared in excellent yields and ee values with low catalyst loading.

Isoquinolinedione, bearing the carbon skeleton of tetrahydroisoquinoline (THIQ), is an important structural motif present in bioactive compounds and natural products with a broad array of biological properties.¹ However, the construction of isoquinolinedione, particularly the chiral version, is currently underdeveloped,² and the reported methods heavily rely on the radical-initiated addition–cyclization of activated alkenes to prepare this structural motif that hard to be further diversified.³ From a pharmaceutical point of view, the presence of heteroatoms (such as nitrogen) is essential for their biological activity (Fig. 1).⁴ Therefore, the introduction of other functional groups or heteroatoms into this framework is a pressing issue to be addressed.Open in a separate windowFig. 1Bioactive compounds bearing isoquinolinedione or tetrahydroisoquinoline core structure.On a different note, amine attached to a stereogenic center is a ubiquitous structure in natural products and bioactive compounds and becomes impetus for continuous exploration.⁵ Using azodicarboxylates or nitrosoarenes as electrophilic amine sources,⁶ activated substrates such as 1,3-dicarbonyl compounds and pyrazolones could be readily transformed into the corresponding amination products in high ee and yields.⁷ With the pioneering work of List and Jørgensen, the α-amination of aldehydes could be realized through enamine activation.⁸ The α-amination of less activated substrates such as nitroisoxazole derivatives could be realized via phase-transfer catalysis.⁹ Recently, cyclic ketones or vinyl ketones were transformed into the corresponding amination products via organo- or metal catalysis.¹⁰ Surprisingly, reports on the amination of heterocyclic compounds are very limited, and they majorly focus on the oxindole scaffold.¹¹ Therefore, the construction of other pharmaceutical relevant α-amination heterocyclic compounds would be a meaningful work.¹² In addition, the organo-catalyzed asymmetric amination reactions generally require relatively high catalyst loading to achieve the optimal yields and enantioselectivities; for this reason, the development of an efficient amination protocol would still be highly desirable.Recently, our group reported the amination of 4-arylisoquinolinedione via organo-catalysis.¹³ However, due to the attenuated reactivity at low temperatures, high catalyst loading is required for satisfactory yields and enantioselectivities, and the substrate scope is limited to 4-aryl substituents. To further expand the scope of this reaction, we tried to extend this amination methodology to 4-alkylisoquinolinedione derivatives.Our study commenced with 2-benzyl-4-butylisoquinoline-1,3(2H,4H)-dione 4a and di-tert-butyl azodicarboxylate 5 as model substrates for condition optimization ( Entry^a7 (mol%)SolventYield 6a^b (%)ee^c (%)1^d10CHCl₃5098210CHCl₃7197310Toluene8274410Ether9580510THF9921610DCM9990710Chlorobenzene8594810CH₂ClCH₂Cl999895CH₂ClCH₂Cl979710^e2CH₂ClCH₂Cl999711^f,g1CH₂ClCH₂Cl839512^f,g1CH₂ClCH₂Cl8893Open in a separate window^aAll reaction was conducted with 0.2 mmol compound 4a, 0.44 mmol compound 5, in 0.5 mL solvent and reacted at 25 °C for 24 h.^bIsolated yield.^cThe ee was determined by HPLC analysis.^dReaction was conducted at 5 °C and reacted for 24 h.^eReaction was run for 35 h.^fReaction was reacted for 72 h.^gReaction was conducted at 40 °C.Further solvent optimization reveals that DCM gives the best yield along with very good ee (14Substrate scope for the amination reaction

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