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

ortho-Naphthoquinone-catalyzed aerobic oxidation of amines to fused pyrimidin-4(3H)-ones: a convergent synthetic route to bouchardatine and sildenafil

A facile access to fused pyrimidin-4(3H)-one derivatives has been established by using the metal-free ortho-naphthoquinone-catalyzed aerobic cross-coupling reactions of amines. The utilization of two readily available amines allowed a direct coupling strategy to quinazolinone natural product, bouchardatine, as well as sildenafil (Viagra™) in a highly convergent manner.

Fused pyrimidin-4(3H)-one derivatives have been accessed by using the ortho-naphthoquinone-catalyzed aerobic cross-coupling reactions of amines.

N-Heterocyclic compounds with a pyrimidin-4(3H)-one core constitute a large number of natural products and biologically active molecules. For example, quinazolinone alkaloids possess a phenyl-fused pyrimidin-4(3H)-one structure and display a wide spectrum of pharmacological activities (Scheme 1a).¹ Sildenafil (Viagra™), a potent and selective inhibitor of type 5 phosphodiesterases on smooth muscle cell, is based on the pyrazole-fused pyrimidin-4(3H)-one structure and marketed for erectile dysfunction.² The synthetic approaches to the phenyl-fused pyrimidin-4(3H)-ones, quinazolinones, typically involve the condensation between anthranilamides and aldehydes to give aminal intermediates that in turn oxidized to quinazolinones under oxidation conditions (Scheme 1b). The oxidation catalysts include Cu,³ Fe,⁴ Ga,⁵ Ir,⁶ Mn,⁷ iodine,⁸ peroxide,⁹ however the aerobic oxidation of aminal intermediates is also known at 150 °C.¹⁰ The utilization of alcohols also effects the one-pot synthesis of quinazolinones through in situ oxidation to aldehydes in the presence of Fe,¹¹ Ir,¹² Mn,¹³ Ni,¹⁴ Pd,¹⁵ Ru,¹⁶ V,¹⁷ Zn,¹⁸ and iodine catalysts.¹⁹ Other precursors to aldehydes have been also identified using alkynes,²⁰ benzoic acids,²¹ indoles,²² α-keto acid salts,²³ β-keto esters,²⁴ styrenes,²⁵ sulfoxides,²⁶ and toluenes.²⁷ Non-aldehyde approaches to quinazolinones have been also demonstrated in the cross coupling of amidines,²⁸ amines,²⁹ benzamides,³⁰ isocyanides,³¹ and nitriles.³² In 2013, the Nguyen group disclosed the synthesis of four quinazolinones, utilizing the autooxidation of benzylamines to imines that subsequently condensed with anthranilamides.³³ While a closed system at 150 °C was necessary, the use of 40 mol% AcOH without solvent provided the quinazolinones in 46–75% yields. The Nguyen group also developed the FeCl₃·6H₂O-catalyzed condensation of 2-nitroanilines and benzylamines in the presence of 20 mol% of S₈, where six quinazolinones were obtained in 68–75% yields.³⁴ While the cross condensation of anthranilamides and benzylamines was accomplished, there exists a significant knowledge gap due to the limited substrate scope combined with less optimal reaction conditions (i.e. high reaction temperature, closed system in neat conditions and excess use of amines). In addition, it is not entirely clear if the cross condensation of amide-containing amines and benzylamines would work for other fused pyrimidin-4(3H)-one derivatives.³⁵ To address such shortcomings in the cross condensation of amines, the ortho-naphthoquinone (o-NQ)-catalyzed aerobic cross amination strategy was investigated (Scheme 1c).³⁶ Herein, we report a highly general approach to fused pyrimidin-4(3H)-one derivatives in the presence of o-NQ catalyst, culminating to the direct aerobic coupling of two amines to bouchardatine and sildenafil.Open in a separate windowScheme 1Biologically active fused pyrimidin-4(3H)-one derivatives and their synthetic methods.Given that the o-NQ-catalyzed aerobic cross coupling of benzylamines and aniline derivatives such as o-phenylenediamines provided a facile approach to heterocyclic compounds including benzoimidazoles,³⁷ the use of anthranilamide 1a and benzylamine 2a was examined as a model study (38 The reaction in DMSO lowered down the ratio of 1a and 2a from 1.0 : 1.5 to 1.0 : 1.2 (entry 12) and the catalyst loading to 5 mol% without affecting the overall reaction efficiency (entry 13). The control experiments confirmed the critical roles of both o-NQ1 and TFA (entries 15–18), and the reaction utilized molecular oxygen as a terminal oxidant (entries 19 and 20). Piecing together the experimental data, the employment of 5 mol% o-NQ1 and 20 mol% TFA in DMSO at 100 °C was selected for further studies.Optimization of o-NQ-catalyzed aerobic cross-coupling of amines to quinazolinone^a

Enantioselective synthesis of α-tetrasubstituted (3-indolizinyl) (diaryl)methanamines via chiral phosphoric acid catalysis

An enantioselective Friedel–Crafts reaction of cyclic α-diaryl N-acyl imines with indolizines catalyzed by a chiral spirocyclic phosphoric acid has been developed. The asymmetric transformation proceeds smoothly to afford α-tetrasubstituted (3-indolizinyl) (diaryl)methanamines in good yields with up to 98% ee under mild conditions.

Chiral phosphoric acid-catalyzed enantioselective synthesis of α-tetrasubstituted (3-indolizinyl) (diaryl)methanamines has been developed.

Chiral α-tetrasubstituted methanamines are frequently distributed in diverse bioactive natural products,¹ and extensive effort has been devoted to constructing these scaffolds in synthetic chemistry over the past decade.² Some excellent chiral organocatalysts³ and chiral metal salt catalysts⁴ have been developed in the asymmetric synthesis of chiral α-tetrasubstituted (diaryl)alkyl or (triaryl) methanamines. Despite these notable advances, to the best of our knowledge, there are currently no versatile protocols for the asymmetric preparation of chiral α-(3-indolizinyl)(diaryl) methanamines.Indolizines as an important class of N-containing heterocycles can be found in organic synthesis and numerous pharmaceuticals (Fig. 1).⁵ Many versatile strategies for the direct functionalization of indolizines have been developed.⁶ Moreover, some elegant examples toward the asymmetric synthesis of enantioenriched indolizine derivatives have been reported,⁷ as shown in Scheme 1. For instance, List and Coelho reported the first organocatalyzed asymmetric conjugate addition of indolizines to enones using the chiral BINOL-derived phosphoric acid (BINOL-PA) as a catalyst (Scheme 1a).^7a Zhang and Fu developed a copper-catalyzed enantioselective propargylation reaction of indolizines (Scheme 1b).^7b Later, Zeng''s group established a highly asymmetric allylic substitution reaction of indolizine derivatives catalyzed by chiral Ir complexes (Scheme 1c).^7c Ni and Song described an organocatalytic highly diastero- and enantioselective Friedel–Crafts conjugate addition of indolizines to prochiral cyclopentenediones catalyzed by BINOL-PA (Scheme 1d).^7dOpen in a separate windowFig. 1Indolizine-containing bioactive compounds.Open in a separate windowScheme 1Asymmetric functionalization of indolizines.Recently, Li and Gu realized the catalytic asymmetric conjugate addition of indolizines to unsaturated ketones catalyzed by chiral Rh complexes (Scheme 1e).^7e Very recently, Ni and Song reported BINOL-PA-catalyzed asymmetric atroposelective arylation of indolizines for the preparation of the axially chiral 3-arylindolizines (Scheme 1f).^7f Although these strategies enable direct access to asymmetric synthesis of chiral indolizine derivatives, development of new class indolizines is still a formidable target. To continue our efforts⁸ on the advancement of chiral phosphoric acid catalysis,⁹ we here present the chiral spirocyclic phosphoric acid (SPINOL-PA) catalyzed enantioselective Friedel–Crafts of indolizines with in situ generated cyclic α-diaryl N-acyl imines¹⁰ for the synthesis of chiral α-(3-indolizinyl)(diaryl) methanamines.An initial investigation for the asymmetric Friedel–Crafts reaction was carried out with methyl indolizine-2-carboxylate (1a) and 3-phenyl 3-hydroxyisoindolinone (2a) in the presence of 10 mol% chiral phosphoric acid (CPA), as shown in 8a were firstly screened in 1,2-dichloroethane (DCE) at room temperature to afford the desired chiral α-(3-indolizinyl)(diaryl) methanamine (3a) with acceptable yields but up to different enantioselectivities, and catalyst 4d gave the best reaction activity and enantioselectivity (89% yield, 74% ee) (entries 1–4). In addition, we also tested BINOL-derived phosphoric acids (5a–d) as catalysts, only low yields (37–72%) and poor enantioselectivities (12–53% ee) were observed (entries 5–8). We believe that the efficient catalytic activity of chiral spirocyclic phosphoric acid (SPA) is due to its special skeleton. Mostly the chiral backbone of the catalyst plays a vital role in attaining high stereoinduction by regulating electronic and structural properties of substrates. On the other hand, the dual hydrogen bonding network between the SPA and other two substrates plays a crucial role in terms of reactivity and selectivity. Moreover, the influence of solvent was investigated (entries 9–13). 1,2-Dichloroethane (DCE) was still the optimal solvent, and this reaction did not even proceed in toluene, THF or EtOAc. Next, the effect of additives was also investigated (entries 14–17). In the presence of 4 Å MS, the desired product 3a could be obtained in 91% yield with 87% ee (17). Lastly, we examined the temperature, and the reaction proceeded for 36 hours to afford the product 3a with 92% ee but in only 9% yield when the temperature was lowered to 0 °C (entry 18). Hence, the optimized reaction conditions employed 10 mol% (S)-4d in 1,2-dichloroethane at room temperature (entry 17).Optimization of the reaction conditions^a

Microwave-assisted iodine-catalyzed oxidative coupling of dibenzyl(difurfuryl)disulfides with amines: a rapid and efficient protocol for thioamides

An efficient protocol for synthesis of thioamides was developed via the microwave-assisted iodine-catalyzed oxidative coupling of dibenzyl(difurfuryl)disulfides with amines. This process is scalable and tolerates a wide spectrum of amines to deliver the corresponding products in moderate to excellent yields in 10 minutes, providing a cheap and rapid approach to thioamides.

Rapid and efficient protocol for thioamides via microwave-assisted iodine-catalyzed oxidative coupling of dibenzyl(difurfuryl)disulfides with amines.

Thioamides have become an attractive synthetic goal in organic chemistry,¹ because thioamide skeletons are widely present in drugs and natural products,² such as cycasthioamide,³ 6-thioyuanine,⁴ 2-thiocytidine⁵ and closthioamide^2a (Scheme 1), and their application as useful precursors and versatile building blocks for construction of a range of heterocyclic compounds has also been studied.^1a,6 In addition, thioamides also can be used as a synthetic isostere for amides in peptide backbones,⁷ and their application as directing groups has also been reported.^8,1c Furthermore, the application of thioamides in developing novel a fluorophore/quencher pair for monitoring the unfolding of a small protein was also explored.⁹Open in a separate windowScheme 1Structures of natural products bearing thiocarbonyl group.Because of their wide application, efforts are devoted toward their generation.¹⁰ The Willgerodt–Kindler reaction is a well-known method for construction of thioamides by using aldehydes and secondary amines as starting materials.¹¹ However, this thioamidation always suffers from the problems of low conversions and harsh conditions. Though, modified variations in Willgerodt–Kindler reaction were also reported,^1a,12 the use of excessive amounts of elemental sulphur makes it a less economical method. Lawesson''s reagent was also used as common sulfur reagent for synthesis of thioamides,¹³ however, this reaction was also occur under harsh conditions. Another thioamidation, where elemental sulfur was used as sulfur reagent, was also reported by Savateev''s groups via a photoinitiated reaction (Scheme 2a).^11a However, this transformation was only suitable for special thioamides with the same structure of amines. Thiols can also be used as sulfur reagent for construction of thioamides,^13b,c but its pungent smell makes this reaction difficult to carry out (Scheme 2b). Recently, Nguyen''s group described a novel process to thioamides by using sulfur as catalyst.¹⁴ This method was suitable for a large range of amines for giving the corresponding products in good to excellent yields at 80 °C for a long time of 16 h.Open in a separate windowScheme 2General methods for synthesis of thioamides.Other methods for thioamides were also reported,¹⁵ but challenges still exist in developing more convenient and efficient ways to these important scaffolds. In our previous work, thioamides were synthesized via the iodine-promoted thioamidation of several of amines.¹⁶ However, this reaction must be performed under high temperature, for a long time (100 °C, 8.0 h), and 0.5 equiv. of I₂ must to be used to promote the thioamidation effectively (Scheme 2c).As one of the efficient and clean procedures in modern synthetic organic chemistry, microwave-assisted organic synthesis (MAOS) has aroused wide interest among scientists, which are suited to the increased demands in industry with the advantages of short reaction times and expanded reaction range.¹⁷ Herein, we reported an efficient method for synthesis of thioamides via the microwave-assisted iodine-catalyzed oxidative coupling of dibenzyl(furan-2-ylmethyl) disulfides with amines (Scheme 2d).We initiated our studies with the reaction of dibenzyldisulfide (1a) with N-methylpiperazine (2a) catalyzed by 10 mol% of I₂ in DMSO under microwave radiation (100 °C) for 10 minutes, and the desired product (3a) was obtained in the yield of 36% ( EntryI₂ (mol%)SolventTemp. (°C)Time (min)Yield^b (%)1I₂ (10 mol%)DMSO1001036%2I₂ (10 mol%)DMSO1101048%3I₂ (10 mol%)DMSO1201065%4I₂ (10 mol%)DMSO1301088%5I₂ (10 mol%)DMSO1401088%6I₂ (10 mol%)DMSO1301588%7I₂ (10 mol%)DMF1301074%8I₂ (10 mol%)1,4-Dioxane1301067%9I₂ (10 mol%)THF1301065%10I₂ (10 mol%)CH₃CN1301070%11I₂ (10 mol%)HOAc1301062%12I₂ (10 mol%)Chlorobenzene1301074%13I₂ (10 mol%)Toluene1301063%14I₂ (10 mol%)Solvent-free1301021% 15 I ₂ (5 mol%) DMSO 130 10 88% (86%) ^c 16I₂ (3 mol%)DMSO1301073%17I₂ (3 mol%)DMSO1301578%18^dI₂ (5 mol%)DMSO1301088%19^eI₂ (5 mol%)DMSO1301018%Open in a separate window^aReaction conditions: dibenzyldisulfide 1a (0.2 mmol), N-methylpiperazine 2a (0.4 mmol), I₂, solvent (2.0 mL).^bGC yields based on dibenzyldisulfide 1a.^cIsolated yields based on dibenzyldisulfide 1a.^d0.6 mmol of N-methylpiperazine 2a was used.^eWithout microwave radiation.With the optimal conditions in hand, the scope of the amines and disulfides were investigated, and results were summarized in Open in a separate window^aReaction conditions: dibenzyldisulfide 1a (0.5 mmol), amines 2 (1.0 mmol), I₂ (0.025 mmol), DMSO (2.0 mL), 130 °C, 10 min.^bIsolated yields based on dibenzyldisulfide 1a.In subsequent studies, we examined the reaction of various amines with difurfuryl disulfide under the optimal conditions, and the results were summarized in Open in a separate window^aReaction conditions: difurfuryldisulfide (1b) (0.5 mmol), amines 2 (1.0 mmol), I₂ (0.025 mmol), DMSO (2.0 mL), 130 °C, 10 min.^bIsolated yields based on difurfuryldisulfide (1b).The thioamidation can also be carried out on a larger scale reaction, and the desired product (3a) were obtained in the yields of 87%, when 5 mmol of dibenzyldisulfide (1a) was treated with 10 mmol of N-methylpiperazine (2a) under the standard conditions (Scheme 3a). To shed light on the mechanism of the reaction, dibenzyldisulfide (1a) was treated with N-methylpiperazine (2a) under standard conditions by using 2.0 equiv. of TEMPO or BHT as radical scavengers (Scheme 3b), and desired product 3a was obtained in the yields of 86% and 80% respectively, suggesting that no single-electron transfer process was involved through the whole reaction. In addition, thioamides have been used as important intermediates for the construction of heterocycles and other compounds containing both nitrogen and sulfur in their backbones (Scheme 3c).¹⁸Open in a separate windowScheme 3(a) Larger-scale synthesis of 3a. (b) Control experimental for mechanism study. (c) Selected transformation of thioamides.On the basis of the above experimental results and previous works,^16,19 a possible mechanism has been depicted in Scheme 4. The first step of the thioamidation is the generation of the intermediate A by the reaction of dibenzyldisulfide (1a) with I₂, with concomitant loss of HI and BnS⁻. Then intermediate A react with N-methylpiperazine (2a) to yield intermediate B, which was converted to species Cvia coupling with BnS⁻ in the presence of DMSO. Finally, species C decomposed to desired product (3a) and BnSH, which was then converted to dibenzyldisulfide (1a) via oxidation reaction. During the whole reaction, the catalyst (I₂) was regenerated by the cycle of HI in the presence of DMSO, which catalyzed the thioamidation effectively.Open in a separate windowScheme 4Proposed mechanism of the thioamidation.     

Ligand-free copper-catalyzed C(sp3)–H imidation of aromatic and aliphatic methyl sulfides with N-fluorobenzenesulfonimide

A novel and efficient process has been developed for copper-catalyzed C(sp³)–H direct imidation of methyl sulfides with N-fluorobenzenesulfonimide(NFSI). Without using any ligands, various methyl sulfides including aromatic and aliphatic methyl sulfides, can be transformed to the corresponding N-((phenylthio)methyl)-benzenesulfonamide derivatives in good to excellent yields.

A novel and efficient process for ligand-free C(sp³)–H amination of aromatic and aliphatic methyl sulfides with N-fluorobenzenesulfonimide catalyzed by copper catalysts was developed.

Nitrogen-containing molecules are widely present in natural products, drug molecules, agrochemicals, and other chemical materials.¹ Among the large number of approaches developed for their synthesis,² the pathway through C–N bond formation has been of great interest to synthetic chemists. This is mainly due to the fact that the introduction of amino groups can facilitate the tuning of physicochemical properties of the molecules leading to biologically significant structures(Fig. 1).³ Typical methods for C–N bond formation include Buchwald–Hartwig, Ullmann–Goldberg and Chan–Evans–Lam imidations, which are mostly transition metal catalyzed, and require prefunctionalization of starting materials.⁴ Recently, a more concise and atom-economic alternative to such imidations has been investigated by direct C–H imidation of oxidized nitrogen reagents and carbon nucleophiles. This process is also transition metal-catalyzed, however avoids prefunctionalization of coupling partners, thus providing a more efficient and environmentally friendly approach for C–N bond formation.^5,6 However, the requirements of directing groups and a stoichiometric amount of oxidants have limited the wide application of these C–H imidation processes.Open in a separate windowFig. 1Representative examples of bioactive amides. N-Fluorobenzenesulfonimide (NFSI), a commonly used fluorination reagent and nitrogen source,^7–16 has been recently employed in a variety of aminative functionalization reactions, such as imidations of aromatic C–H bond,⁸ alkenes or unsaturated ketones,⁹ alkyne¹⁰ and benzylic or allylic C–H bond.^11–16 Various transition metals have been explored to catalyze direct imidation of C(sp³)–H bonds with NFSI (Scheme 1). In 2010, a pioneering work on remote amide-directed palladium-catalyzed intermolecular highly selective benzylic C–H imidation with N-fluorobenzenesulfonimide was disclosed by Zhang''s group.¹¹ Liu''s¹² group proposed a copper-catalyzed C(sp³)–H imidation strategy for synthesizing various benzylic amines from benzylic hydrocarbons. The first biocompatible iron-catalyzed benzylic C(sp³)–H imidation of methylarenes with NFSI have been achieved by Bao et al. (Scheme 1a).¹³ Using palladium as catalyst has also been reported by Muñiz et al.¹⁴ to catalyze intermolecular sequence consisting of the C–H activation, where amidation of methyl groups relied on NFSI as both oxidant and nitrogen sources. In addition, copper-catalyzed amidation of 8-methylquinolines with N-fluoroarylsulfonimides via C(sp³)–H activation has been examined by Zheng et al. (Scheme 1b).¹⁵ Furthermore, copper-catalyzed sequential C(sp²)/C(sp³)–H imidation of 2-vinylanilines has been performed with NFSI for the efficient synthesis of indole frameworks (Scheme 1c).¹⁶Open in a separate windowScheme 1Methodologies for C(sp³)–H imidation using NFSI.Despite considerable progress in studying transition metal catalyzed C(sp³)–H imidation reactions, limited effort has been made in the methyl C(sp³)–H imidation of thioanisoles with NFSI. Xu and co-workers¹⁷ reported the direct imidation of the methyl C(sp³)–H bond of thioanisoles. However, the scope of substrates was limited to thioaromatics with low product yields. Recently, our group has developed a novel method for copper-catalyzed direct imidation of thiophene with NFSI, demonstrating a convenient and complementary approach to synthesizing the gem-thiazamethylene structural motifs exist in biologically active structures (Scheme 1d).^8h Built on this development, the present study was extended to the direct C(sp³)–H imidation of methyl sulfides with NFSI catalyzed with ligand-free copper catalysts (Scheme 1e), where both aromatic and aliphatic methyl sulfides were investigated. This strategy provides a facile and efficient process for transition metal-catalyzed C(sp³)–H direct imidation of methyl sulfides.Initially, the reaction of methyl(phenyl)sulfane 1a with NFSI was carried out successfully by using CuI as a catalyst and NaHCO₃ as a base. In the presence of 10 mol% CuI and 2 equiv. of NaHCO₃, 1a and with NFSI were under stirring in a reaction medium of 1,2-dichloroethane (DCE) at room temperature for 8 h, and the desired product 3a was obtained in 55% yield ( EntryCatalystBase (2 equiv.)SolventTemperature (°C)Yield ^b(%)1CuINaHCO₃DCE25552CuINaHCO₃DCE40763CuINaHCO₃DCE60854CuINaHCO₃DCE80815CuINaHCO₃DCE100736CuClNaHCO₃DCE60767CuBrNaHCO₃DCE60808CuOAcNaHCO₃DCE60569—NaHCO₃DCE604910CuINa₂CO₃DCE601011CuINaOtBuDCE601512CuIK₂CO₃DCE601813CuICs₂CO₃DCE602014CuI—DCE60n. r.^c15CuINaHCO₃CH₃CN604516CuINaHCO₃DCM605517CuINaHCO₃DMSO60n. r.^c18CuINaHCO₃DMF60n. r.^cOpen in a separate window^aReactions were carried out on a 0.5 mmol scale in 3.0 mL of solvent with 1 equiv. of 1a, 1.2 equiv. of 2, 2 equiv. of base and 10 mol% of catalyst at 60 °C for 8 h.^bIsolated yield after column chromatography.^cn. r. = No reaction.By applying the optimized reaction conditions, the generality and limitations of this ligand-free C–N bond formation were further investigated. The results are presented in Scheme 2. The reaction of NFSI and a variety of methyl(phenyl)sulfane derivatives 1 afforded the desired imidation products 3 in a range of 72–93% either electron electron-donating (1b, 1c) or electron-withdrawing groups (1d–1g) at the para-position of the benzene ring, such as methy, OMe, halogens, or CN, reacted with NFSI effectively to give the desired benzenesulfonamides 3b–3g in moderate to good yields (72–90%). Thioanisole substrates bearing methoxyl, bromo and chloro substituents at meta-position of the benzene ring were found to be good candidates for the imidation, where the corresponding products (3h–3j) were obtained in satisfactory yields (79–93%). Interestingly, (3,5-dichlorophenyl)(methyl)sulfane also afforded target product 3k in a good yield (76%). Substrates bearing methoxyl (1l) or halogen (1m–1p) groups at ortho-position of the benzene ring were also successfully imidated with high yields (3l–3p). Both heterocyclic substrates 2-(methylthio)pyridine (1q) and 2-(methylthio)thiophene (1r) also worked nicely to deliver the imidation products with good to excellent yields (3q–3r, 83–84%). Likely due to the steric effect, ethyl(phenyl)sulfane 1s did not provide imidated product under the optimized reaction conditions. Unfortunately, largely associated with the electronic effect, anisole 1t also failed to afford the desired product.Open in a separate windowScheme 2Substrate Scope of Thioanisoles.^{a,b a}Reactions were carried out on a 0.5 mmol scale in 3.0 mL of solvent with 1.0 equiv. of 1, 1.2 equiv. of 2, 2 equiv. of base and 10 mol% of catalyst at 60 °C for 8h. ^b Isolated yield after column chromatography.To further extend the scope of the imidation reaction, various alky methyl sulfides were also explored as the reactants (Scheme 3). It was demonstrated that both short chain methyl(propyl)sulfane (4a) and long chain dodecyl(methyl)sulfane (4b) reacted well to afford the desired products in satisfactory yields (5a and 5b). Moreover, cyclohexyl(methyl)sulfane (4c) smoothly participated in this reaction to give the desired imidated product in good yields (5c).Open in a separate windowScheme 3Substrate scope of alkyl methyl sulfides.^{a,b a}Reactions were carried out on a 0.5 mmol scale in 3.0 mL of solvent with 1.0 equiv. of 1, 1.2 equiv. of 2, 2 equiv. of base and 10 mol% of catalyst at 60 °C for 8h. ^b Isolated yield after column chromatography.In order to demonstrate the synthetic utility of the reaction we developed, this imidation reaction was performed on a 7.0 mmol scale in the presence of 10 mol% of CuI catalyst, giving 2.9 g of the desired product 3i in 83% yield under standard conditions (Scheme 4). Notably, 3i could undergo an oxidation process in the presence of 3.0 equivalents of m-chloroperoxybenzoic acid (m-CPBA) to provide the sulfone 6 in 95% yield.Open in a separate windowScheme 4Scaled-up study and application of 3i.Based on the results and discussion above, a possible reaction pathway has been proposed as illustrated in Scheme 5, involving the formation of Cu(i), Cu(ii), and Cu(iii) complexes,^2d,17 although the exact reaction mechanism still remains to be elucidated. Initially, NFSI 2 oxidizes CuI to provide a Cu(iii) species A. Next, the substrate 1 can attack A forming the key methylenethionium ions C and the Cu(ii) species B. Finally, the methylenethionium ions C is oxidized by the Cu(ii) species B to form the imidation product 3 and regenerate CuI for the next catalytic cycle. In this circle system, the addition of chemical equivalent base can clearly enhance increasing the product yield, where the neutralization of HF by NaHCO₃ is likely to accelerate the transformation from substrate 1 to intermediate C.Open in a separate windowScheme 5Plausible reaction pathway.     

Catalytic enantioselective intramolecular Tishchenko reaction of meso-dialdehyde: synthesis of (S)-cedarmycins

The first successful example of a catalytic enantioselective intramolecular Tishchenko reaction of a meso-dialdehyde in the presence of a chiral iridium complex is described. Chiral lactones were obtained in good yields with up to 91% ee. The obtained enantioenriched lactones were utilized for the first synthesis of (S)-cedarmycins A and B.

The first successful example of a catalytic enantioselective intramolecular Tishchenko reaction of a meso-dialdehyde in the presence of a chiral iridium complex is described.

The catalytic dimerization of aldehydes giving the corresponding esters was first discovered by Claisen in 1887,¹ and is now well known as the “Tishchenko reaction” (Scheme 1).Open in a separate windowScheme 1Tishchenko reaction.Claisen''s method utilizing sodium alkoxides, however, could only be applied to nonenolizable aldehydes like benzaldehyde, because enolizable aldehydes undergo aldol reactions when treated with strong bases such as sodium alkoxides.¹ In 1906, a Russian chemist, Tishchenko, reported that aluminum alkoxides were superior to sodium alkoxides in the reaction, because they were more Lewis acidic and less basic.² The transformation of acetaldehyde into ethyl acetate is the representative application of the Tishchenko reaction in the chemical industry.³ So far, a number of homogeneous catalysts exhibiting high catalytic performance for the Tishchenko reaction have been developed to compensate for the drawback of the classical aluminum alkoxide catalysts.⁴ In 2005, we reported a mild Tishchenko dimerization using a Ir catalyst.⁵ The reaction proceeds at room temperature and is effective with a wide range of aldehydes. We also reported the enantioselective oxidative lactonization⁶ of meso-diols for the preparation of chiral lactones.⁷ Although asymmetric aldol-Tishchenko reactions⁸ for chiral 1,3-diols are known, there is no report of an asymmetric intramolecular Tishchenko reaction of meso-dialdehydes for chiral lactones. We envisaged that the asymmetric borrowing hydrogen methodology⁹ could be applied to achieve an enantioselective intramolecular Tishchenko reaction of meso-dialdehydes (Scheme 2).Open in a separate windowScheme 2Strategies for enantioselective intramolecular Tishchenko reaction.The initial enantioselective reduction of meso-dialdehyde 1 could occur by a chiral 18 electron Ir hydride complex to afford chiral hydroxy aldehyde 2. The hydroxy aldehyde-lactol equilibrium would generate lactol 3. Finally, irreversible oxidation of 3 would produce the desired lactone 4.With this hypothesis in mind, we began the investigation of the intramolecular Tishchenko reaction using o-phthalaldehyde as a model substrate (10ⁱPrOH, and K₂CO₃ (6a : 5a : ⁱPrOH : K₂CO₃ = 100 : 1 : 20 : 20 mol ratio) was stirred at 30 °C for 7 h, lactone (7a) was obtained in 97% yield (entry 1). The reaction did not proceed at all in the absence of Ir catalyst (entry 2). Interestingly, the reaction without the additional hydrogen donor, ⁱPrOH, also gave the lactone, but the yield was low (entry 3). To enhance the reactivity, the addition of a base was necessary.^5a Without base or with a lower amount of base, the reaction proceeded in less than 28% yield (entries 4, 5). The reaction of 2,3-naphthalene dicarboxaldehyde 6b also proceeded similarly under optimized conditions (entry 6).Intramolecular Tishchenko reaction of aromatic dialdehydes^a

A simple and efficient copper-catalyzed three-component reaction to synthesize (Z)-1,2-dihydro-2-iminoquinolines

A operationally simple synthesis of (Z)-1,2-dihydro-2-iminoquinolines that proceeds under mild conditions is achieved by copper-catalyzed reaction of 1-(2-aminophenyl)ethan-1-ones, sulfonyl azides and terminal ynones. In particular, the reaction goes through a base-free CuAAC/ring-opening process to obtain the Z-configured products due to hydrogen bonding.

The synthesis of (Z)-1,2-dihydro-2-iminoquinolines via a base free CuAAC/ring-opening procedure and obtaining the Z-configured products.

Nitrogen-containing polyheterocycles are present in a wide variety of bioactive natural products¹ and biological molecules that may be good drug candidates.² Specifically, quinoline-based compounds represent a medicinally and pharmaceutically important class of heterocyclic motifs that are found as the core structural skeletons in a variety of potential candidates.³ 2-Aminoquinolines are found to be antagonists for the hormone 1-receptor (MCH1-R),⁴ as targets for JNK phosphorylation,⁵ as potent and selective neuronal nitric oxide synthase inhibitors,⁶ and as new inhibitors of protein kinase CK₂.⁷ Therefore, the development of novel methods for the synthesis of these quinoline derivatives is important in the field of synthetic organic and pharmaceutical chemistry.In the past few years, utilizing the annulation reactions of Cu,⁸ Pd,⁹ Ni,¹⁰ Ag,¹¹ Ru,¹² and a few other catalysts^13–15 have provided attractive and valuable routes for the construction of 2-aminoquinolines. As an isomer of 2-aminoquinolines, the synthesis of 2-iminoquinoline skeletons has still rarely been investigated. To the best of our knowledge, only two examples of the nickel¹⁶ or copper-catalyzed¹⁷ cascade reaction have been developed, leading to 2-iminoquinolines. However, these two examples have been limited to the use of a base or obtained the E-configured products (Scheme 1a and b).Open in a separate windowScheme 1Synthesis of 2-iminoquinolines.Previous studies reported on the copper-catalyzed multicomponent reactions (MCRs) of sulfonyl azides and terminal alkynes with other components that generated N-heterocycles and related compounds (CuAAC/ring-opening reaction),^18,19 and have also been used in the synthesis of 2-aminoquinolines²⁰ and 2-iminoquinolines.¹⁷ However, the reaction was generally carried out under strong basic conditions. This limited the application of some substrates, such as terminal ynones, which would undergo self-condensation under the basic conditions.²¹ Thus, neutral or weak acidic conditions have been developed in our previous study, and the terminal ynones were successfully used in the CuAAC/ring-opening reaction to form highly active intermediate α-acyl-N-sulfonyl ketenimines.²² Herein, we report the base-free copper-catalyzed reaction of 1-(2-aminophenyl)ethan-1-ones, sulfonyl azides and terminal alkynes, leading to Z-configured 2-iminoquinolines (Scheme 1c).Our investigations began with an examination of the synthesis of the parent and previously unreported system, N-(3-acetyl-4-methylquinolin-2(1H)-ylidene)-4-methylbenzene sulfonamide (4a), from 1-(2-aminophenyl)ethan-1-one (1a), but-3-yn-2-one (2a) and p-tosyl azide (3a). Initial screenings involved using CuI as a catalyst in a range of standard solvents. These screenings revealed that the desired conversion could be achieved in many solvents ( EntryCat.SolventYield^b (%) 4a1CuICHCl₃722CuIDCE813CuIToluene79 4 CuI MeCN 96 5CuITHF856CuI1,4-Dioxane947CuIDMSO208CuIDMF469CuIEtOH4010CuClMeCN8811CuBrMeCN8412CuBr₂MeCN7813Cu(OAc)₂MeCN8014Cu(OTf)₂MeCN2215AgOAcMeCNnd^c16CuIMeCN90^d17CuIMeCN86^eOpen in a separate window^aReaction conditions: 1a (0.5 mmol), cat. (10 mol%) in the solvent (3 mL) was added 2a (1.5 equiv.) and 3a (1.5 equiv.) stirring at 80 °C for 4 h.^bIsolated yields.^cnd = not detected the target product.^dThe reaction temperature was 70 °C.^eThe temperature was 90 °C.With optimized reaction conditions for the formation of the “parent reaction” having been defined, the capacity of these to affect the coupling of a range of different substrates was investigated. As shown in Open in a separate window^aUnless otherwise noted, the reaction conditions were as follows: 1 (0.5 mmol), CuI (10 mol%) in the MeCN (3 mL) was added 2 (1.5 equiv.), 3 (1.5 equiv.) with stirring at 80 °C for 4 h.^bGram-scale synthesis of compound 4a: magnify by 10 times.Except for 4m, none of the products 1,2-dihydro-2-iminoquinolines 4a–4v have been reported previously, which were subject to full spectroscopic characterization (see ESI for details^†) and the derived data were in complete accordance with the assigned structures. Furthermore, 4a and 4s were confirmed by single-crystal X-ray analysis (Fig. 1). These analyses revealed that both incorporate Z-configured imine residues due to the hydrogen bonding (Fig. 1, the red dotted line). Thus, it has been assumed that all the other products formed during the course of this study possess the same geometry about the C N bond.Open in a separate windowFig. 1Single-crystal X-ray analysis of 4a (CCDC 2092343) and 4s (CCDC 2092351).In order to further explain the effect of hydrogen bonding on the spatial structure of products, we synthesized N1 substituted product 4w through 1-(2-(methylamino)phenyl)ethan-1-one (1i), but-3-yn-2-one (2a) and p-tosyl azide (3a) under the standard condition. The single crystal analyses revealed that the product 4w gave the E-configured imine residues without the hydrogen bonding (Fig. 2).Open in a separate windowFig. 2Single-crystal X-ray analysis of 4w (CCDC 2092350).Products 4a–4v are all relatively stable species that survive chromatographic purification under conventional conditions. However, the 2-iminoquinolines skeletons were easy hydrolysis to 2-aminoquinolines. For example, upon treatment with 1.5 equivalents of 30% H₂SO₄ in water under reflux for 6 h, compound 4a is converted into 2-iminoquinolines product 5a of yield 98% (Scheme 2).Open in a separate windowScheme 2Hydrolysis of 2-iminoquinolines.A possible reaction pathway for the formation of N-(3-acetyl-4-methylquinolin-2(1H)-ylidene)-4-methylbenzenesulfonamide (4a) from precursors 1a, 2a and 3a is shown in Scheme 3. Thus, in keeping with earlier proposals,²² substrates 2a and 3a are expected to react in the presence of the copper(i) catalyst, so as to form the metallated triazole A that fragments with the accompanying loss of nitrogen to form a highly active intermediate, α-acyl-N-sulfonyl ketenimine B. Then, B is captured by 1a to generate the adduct C, which can transfer to the isomer D that undergoes aldol condensation to deliver the observed product 4a.Open in a separate windowScheme 3Plausible reaction mechanism.In summary, we have developed an operationally simple and effective means for preparing (Z)-1,2-dihydro-2-iminoquinolines from a mixture of the corresponding 1-(2-aminophenyl)ethan-1-ones, sulfonyl azides and terminal ynones through the base-free CuAAC/ring-opening process, and obtain the Z-configured products. This methodology is quite flexible and offers the capacity to generate forms of the title products that will be particularly useful in, for example, building more 2-iminoquinolines block facility.     

Total synthesis of pyrano[3,2-e]indole alkaloid fontanesine B by a double cyclization strategy

The regioselective synthesis of pyrano[3,2-e]indole alkaloid fontanesine B by two different cyclizations is described. The complete regioselectivity is controlled by the C4 Pictet–Spengler cyclization, in which an iminium ion acts as a transient directing (TDG) group. Furthermore, carbolines were constructed by a new Bischler–Napieralski-type cyclization, in which an unprecedented trichloromethyl carbamate serves as a reactive group.

The regioselective synthesis of pyrano[3,2-e]indole alkaloid fontanesine B have been accomplished by C4 Pictet–Spengler cyclization and Bischler–Napieralski-type cyclization of a trichloromethyl carbamate.

Fontanesines A (1), B (2), and C (3) were isolated from the stem bark and leaf fractions of Conchocarpus fontanesianus by Queiroz and co-workers in 2016 (Fig. 1).¹ These compounds have a characteristic pyrano[3,2-e]indole moiety fused with quinazolinone. A crucial challenge in the synthesis of fontanesines is the regioselective formation of the pyrano[3,2-e]indole core. Although the structures were unique and unprecedented, there are no reports on their partial preparation or total synthesis.Open in a separate windowFig. 1Fontanesines A (1), B (2), and C (3).The importance of a pyrano[3,2-e]indole framework in medicinal chemistry had encouraged Macor,² Pandit,³ May,⁴ and Conforti⁵ to develop efficient methods for the regioselective construction of this framework. The majority of these methods relied on the thermal Claisen rearrangement,^2–4 and Pt-mediated cyclization.⁵ To keep the pyran intact from earlier stage of total synthesis is difficult due to its instability.⁶In our continuing efforts in the synthesis of indole alkaloids,⁷ we developed a novel strategy for the synthesis of azepinoindoles by C4 Pictet–Spengler reaction of serotonins⁸ or 5-hydroxytryptophans⁹ and aldehydes. This approach proved useful in the one-pot regioselective synthesis of pyrano[3,2-e]indoles.¹⁰ We considered the above facts and envisioned that the synthesis of pyrano[3,2-e]indoles by C4 Pictet–Spengler reaction would allow a rapid and regioselective formation of fontanesines, keeping the pyran intact. Herein, we report the results of our efforts to synthesize 2.The retrosynthetic analysis of fontanesine B (2) is shown in Scheme 1. The quinazolinone moiety in 2 might be forged by a deprotection followed by condensation of anthranilic acid (11a) with carboline 9. One of the key steps in the synthetic route involved the carbonylative cyclization of pyrano[3,2-e]indole 8 to afford carboline 9. The pyrano[3,2-e]indole 8 could be accessible from aldehyde 5 and benzyl protected 5-hydroxytryptamine 4 using our developed C4 Pictet–Spengler/allylic transposition via the iminium intermediate 6 and azepinoindole 7.Open in a separate windowScheme 1Retrosynthetic analysis of fontanesine B (2).Before synthetic studies, we could predict the difficulty of removing the protecting group on the nitrogen atom at the late stage. Therefore, we decided to prepare the several tryptamines 4 with different protecting groups. The synthesis was started from the benzyl protected 5-hydroxytryptamine 4 (Scheme 2). It was reacted with 3-methyl-2-butenal (5) in 2-propanol/Et₃N under reflux to produce the desired pyrano[3,2-e]indole 8 in a one-pot reaction. Normal Pictet–Spengler reaction occurs at the C2 position of the indole ring under the acidic conditions. All steps of this one-pot sequence take place under basic conditions, which is presumably key to its success.Open in a separate windowScheme 2Synthesis of substrates 8.To test the feasibility of our approach, we resorted to the carbonylative cyclization of 8. According to the previous report on the reaction using triphosgene,^11–13 which is a bench-stable solid and easy to handle,¹⁴ we investigated the conversion of 8 into 9 through intermediate 13 (ref. 15) (Scheme 3). Numerous attempts including screening of bases to achieve this have resulted in the polymerization and halogenation¹³ of 8 over the carbonylative cyclization.¹² Upon exposure of 8c to triphosgene in the presence of Et₃N followed by addition of HBr,¹² the desired product 9c was obtained in low yield along with unstable brominated product 12. The acid lability of a pyrano[3,2-e]indole afforded troublesome, with polymerized materials being the major spot observed. As this polymerization presumably arises from activated urea intermediate 16, which was generated from less electrophilic acid chloride 14 (ref. 14 and 16b) or more electrophilic intermediate 15 by addition/elimination process by HBr and Et₃N,¹⁶ it was clear that the Et₃N^14b and HBr would require to be dismissed at the cyclization step in our synthetic route.Open in a separate windowScheme 3Attempted synthesis of 9. ^a12 was obtained in 14% yield.Because the product yield was not sufficient (up to 6% yield), further investigations were carried out. After intensive investigations, it was serendipity that we found that the treatment of 8 with triphosgene in the presence of Et₃N at room temperature afforded a trichloromethyl carbamate intermediate 13b in 88% yield (Scheme 4).¹⁷ Then, after aqueous work-up to remove Et₃N in the reaction media, 13b was heated in DMSO to afford 9b in 86% yield. Furthermore, by employing a stepwise method, we obtained 9 from 8 in good yield through the carbamoyl ion 17 (ref. 18) using a single column chromatography. To the best of our knowledge, this is the first time that an unstable trichloromethyl carbamate intermediate has been applied to the C–C bond formations.^11–17 In contrast to the mild Bischler–Napieralski-type cyclization developed by Saikawa and Nakata,¹⁹ and Clayden,²⁰ our protocol does not require additives to promote the cyclization.Open in a separate windowScheme 4Improved synthesis of β-carbolines 9 from 8via interrupted phosgene cyclization and Bischler–Napieralski-type cyclization.Numerous attempts were made in case of benzyl-substituted lactam 9a; however, all of them led to rapid decomposition (Scheme 5). On the other hand, treatment of 9b with p-toluenesulfonic acid (p-TsOH)²¹ afforded the deprotected lactam 10 in 17% yield. As expected, lactam 9c could also be deprotected under the same conditions to afford 10 in 67% yield. In general, 2,4-DMB group is more easily removed than PMB group.²¹Open in a separate windowScheme 5Removal of benzyl substituents on the nitrogen atoms in 9.With the synthetic access to 9, we were set to answer whether 9 could be deprotected keeping the alkene, pyran, and indole intact. Finally, the condensation of 10 and anthranilic acid (11a) in the presence of POCl₃ (ref. 22) generated the final product 2 (Scheme 6), whose structure was determined by spectroscopic experiments. All the physical data of synthetic 2 were in good agreement with those reported for the natural product (1Open in a separate windowScheme 6Completion of total synthesis of fontanesine B.Comparison of ¹H and ¹³C NMR data of synthetic compound 2 and natural fontanesine B

I2-mediated Csp2–P bond formation via tandem cyclization of o-alkynylphenyl isothiocyanates with organophosphorus esters

A novel, I₂-mediated tandem cyclization of o-alkynylphenyl isothiocyanates with organophosphorus esters has been developed under mild conditions. Different kinds of 4H-benzo[d][1,3]thiazin-2-ylphosphonate could be synthesized in moderate to excellent yields. This method has the advantages of easy access to raw materials, free-metal catalyst, simple operation, high yield and high functional group tolerance.

A highly efficient molecular-iodine-catalyzed cascade cyclization reaction has been developed, creating a series of 4H-benzo[d][1,3]thiazin-2-yl phosphonates in moderate to excellent yields. This approach benefits from metal-free catalysts and available raw materials.

As an important class of organic products, organophosphorus compounds have received considerable attention because they have broad application in the field of materials science,¹ medicinal chemistry,² organic synthesis,³ natural products,⁴ and ligand chemistry.⁵ Phosphorus-containing compounds are valuable precursors of many biologically active molecules which can act as antibiotics,⁶ anti-tumor agents⁷ and enzyme inhibitors.⁸ Traditionally, the preparation of organophosphorus compounds relies on a transition-metal-catalyzed cross-coupling of phosphine reagents with electrophilic aryl halides (Ar-X),⁹ aryl boronic acids (Ar-B),¹⁰ aryl diazonium salts (Ar-N),¹¹ and so on.¹² Recently, the construction of a Csp²–P bond on heterocycles is another powerful method to synthesize the organophosphorus compounds.¹³ For instance, the Duan group and the Ackermann group reported a Ag-mediated C–H/P–H functionalization method to construct a Csp²–P bond by using arylphosphine oxides and internal alkynes as the substrates^13a,b (Scheme 1a). In 2014, Studer and co-workers reported a pioneering radical cascade reaction for the synthesis of 6-phosphorylated phenanthridines from 2-isocyanobiphenyls and diphenylphosphine oxides (Scheme 1b).^13c Before long, Ji and Lu''s group described two similar radical process with excess of PhI(OAc)₂ or K₂S₂O₈ as the oxidant (Scheme 1c).^13d,e Recently, Liang and co-works developed two cases of cascade functionalization to construct phosphorylated heterocycles via the ionic pathway (Scheme 1d and 1e).^13f,g Meanwhile, Li and coworkers reported a Mn(ii)-promoted tandem cyclization reaction of 2-biaryl isothiocyanates with phosphine oxides which went through the same mechanism(Scheme 1f).^13h Despite the usefulness of the above methods, common problems, such as complex reaction substrates, relatively high temperature, excess amounts of oxidants, limited their applications. Furthermore, transition metals are required in these reactions, thereby resulting in limitations in reactants. Therefore, the development of a simple and transition-metal-free method for the formation of the Csp²–P bond from easily prepared starting materials is highly desirable.Open in a separate windowScheme 1Synthesis of P-containing heterocycles through Csp²–P bond formation. o-Alkynylphenyl isothiocyanates are easily prepared organic synthons with versatile chemical reactivity,¹⁴ and they could be used as electrophiles,¹⁵ nucleophiles,¹⁶ and radical receptors¹⁷ due to the N C S moiety in the structure. Recently, the rapid development of the transition-metal-catalyzed cascade cycloaddition of o-alkynylphenyl isothiocyanates with various nucleophiles provides a new and powerful synthetic strategy to synthesize different heterocycles. Very recently, we have developed a tandem cyclization process for the synthesis of 4H-benzo[d][1,3]thiazin-2-yl)phosphonates by using this strategy.¹⁸ As part of our continuing interest in the transformation of o-alkynylphenyl isothiocyanates,¹⁹ we describe herein a novel I₂-promotedtandem reaction to construct Csp²–P bond from o-alkynylphenyl isothiocyanates and phosphine oxides(Scheme 1g).The starting o-alkynylphenyl isothiocyanates were prepared via the Sonogashira coupling of 2-iodoanilines with terminal alkynes,²⁰ followed by the treatment with thiophosgene according to the literature procedure.²¹ We commenced our studies with the reaction of o-phenylethynylphenyl isothiocyanate (1a, 0.2 mmol) and diethyl phosphonate (2a, 0.6 mmol) in the presence of I₂ (0.5 equiv.) as the catalyst, 8-diazabicyclo[5,4,0]undec-7-ene (DBU, 3.0 equiv.) as the base, in dichloromethane (DCM, 2 mL) at 0 °C for 12 h in air atmosphere. Gratifyingly, the desired product diethyl (Z)-(4-benzylidene-4H-benzo[d][1,3] thiazin-2-yl)phosphonate 3a was obtained in 75% yield (Schemes 1–4)Optimization of the reaction conditions^a

Highly efficient construction of an oxa-[3.2.1]octane-embedded 5–7–6 tricyclic carbon skeleton and ring-opening of the bridged ring via C–O bond cleavage

We report herein a highly efficient strategy for construction of a bridged oxa-[3.2.1]octane-embedded 5–7–6 tricyclic carbon skeleton through [3 + 2] IMCC (intramolecular [3 + 2] cross-cycloaddition), and the substituents and/or stereochemistries on C-4, C-6, C-7 and C-10 fully match those in the rhamnofolane, tigliane and daphnane diterpenoids. Furthermore, ring-opening of the bridged oxa-[3.2.1]octane via C–O bond cleavage was also successfully achieved.

We reported a highly efficient construction of an oxa-[3.2.1]octane-embedded 5–7–6 tricyclic carbon skeleton with a full match of the substituents and stereochemistries on C-4/-6/-7/-10 with those in the rhamnofolane/tigliane/daphnane diterpenoids.

Rhamnofolane, tigliane, and daphnane are three families of diterpenoids displaying a broad range of biological activities such as antiviral, anticancer, anti-HIV, immunomodulatory and neurotrophic activities.¹ Three representative members are neoglabrescin A² and curcusones I/J.³ The unique structural features of these three compounds include a 5–7–6 tricyclic carbon skeleton with a trans-fused 5–7 bicyclic skeleton, a 4,7-bridged oxa-[3.2.1]octane skeleton and a methylene (methyl) group at C-6 (Fig. 1). Some other related natural products include crotophorbolone,⁴ phorbol,⁵ prostratin,⁶ resiniferatoxin⁷ and curcusone A.⁸Open in a separate windowFig. 1Representative rhamnofolane/tigliane/daphnane diterpenes with a trans-fused 5–7 bicyclic skeleton, a 4,7-bridged oxa-[3.2.1]octane skeleton (corresponding structures with a ring-opening of the oxa-[3.2.1]octane via C–O cleavage) and a methylene (methyl) group at C-6.Due to their remarkable biological activities and unique and complex structures, these types of diterpenoids have drawn considerable attention from organic chemists, and many creative strategies have been developed for construction of the 5–7–6 tricycles with desirable substituents and stereochemistries on C-4, C-6, C-7 and C-10.⁹ Dai et al. reported the total syntheses of curcusones I and J by using an intramolecular Au-catalysed [4 + 3] cycloaddition for construction of the oxa-[3.2.1]octane-embedded 5–7-fused carbon skeleton and Diels–Alder [4 + 2] cycloaddition for construction of the additional 6-membered carbocycle (Scheme 1).^10a Some other natural products have been reported by the groups of Wender (phorbol, resiniferatoxin and prostratin),¹¹ Cha (phorbol),¹² Baran (phorbol),¹³ Xu/Li (prostratin),¹⁴ Liu (crotophorbolone),¹⁵ Inoue (crotophorbolone, resiniferatoxin, prostratin and related molecules)¹⁶ and Dai/Adibekian (curcusones A–D).^10b The groups of West^9c and Maimone^9h have reported attempts toward the total syntheses of related molecules through construction of a 4,7-bridged oxa-[3.2.1]octane skeleton respectively (Scheme 2).Open in a separate windowScheme 1Representative total syntheses of rhamnofolane/tigliane/daphnane diterpenes containing a 5–7–6 tricyclic carbon skeleton with a trans-fused 5–7 bicyclic skeleton and a 4,7-bridged oxa-[3.2.1]octane skeleton.Open in a separate windowScheme 2Representative synthetic strategies for construction of a bridged oxa-[3.2.1]octane-embedded 5–7–6 tricyclic carbon skeleton with desirable substituents and stereochemistries.We have previously reported a highly efficient construction of 5–7–6 tricyclic carbon skeleton with an intramolecular [4 + 3] IMPC (intramolecular [4 + 3] parallel-cycloaddition) of cyclopropane with dendralene/Diels–Alder [4 + 2] cycloaddition strategy.¹⁷ With this strategy, the fused 5–7 bicycle was efficiently constructed which matched the trans-stereochemisty, however a C-4 oxygen atom was not be direct. Following our previously developed [3 + 2] IMCC strategy,^18a–h we have recently reported a novel and efficient construction of a bridged aza-[3.2.1]octane-embedded 5–7–6 tricyclic carbon skeleton with desirable substituents and stereochemistries toward total syntheses of calyciphylline D-type Daphniphyllum alkaloids (Scheme 3).¹⁸ⁱ Herein, we report the application of the [3 + 2] IMCC strategy for efficient construction of the bridged oxa-[3.2.1]octane-embedded 5–7–6 tricycle with stereochemistries on C-4, C-7 and C-10, as well as a methylene (methyl) group at C-6 matching those in neoglabrescin A, curcusones I/J and related rhamnofolane/tigliane/daphnane diterpenes.Open in a separate windowScheme 3Proposed [3 + 2] IMCC strategy for construction of the bridged oxa-[3.2.1]octane-embedded 5–7–6 tricycle with suitable substituents and stereochemistries on C-4, C-6, C-7 and C-10.We started the research from benzyl bromide 2 which was prepared from a known compound 1 according to our recently reported method (Scheme 4).¹⁸ⁱ Compound 2 was then oxidized with NMO to afford aldehyde 3 which was used directly in the next step without further purification. Under catalysis of Sc(OTf)₃ (0.2 equiv.), the [3 + 2] IMCC of aldehyde 3 was successfully carried out to afford compound 4 in 82% yield over two steps. The structure of 4 was confirmed by X-ray crystal structure analysis.¹⁹ Hereto, the bridged oxa-[3.2.1]octane-embedded 5–7–6 tricycle have been successfully constructed, the substituents and stereochemistries on C-4, C-6, C-7 and C-10 fully match those in the corresponding natural products.Open in a separate windowScheme 4Construction of the bridged oxa-[3.2.1]octane-embedded 5–7–6 tricycle.With compound 4 in hand, we started to investigate the ring-opening of the bridged oxa-[3.2.1]octane via C–O bond cleavage (Scheme 5). Krapcho decarboxylation of 4 afforded monoester 5 in 88% yield as a mixture of two diastereoisomers in a ratio of nearly 1 : 1. Reduction of 5 with DIBAL-H at −78 °C afforded aldehyde 6 in 85% yield. To our delight, the oxa-bridge was opened under catalysis of TMSOTf²⁰ at −5 °C and a dehydration product 7 was obtained in 16% yield (brsm 53%) (21 conditions (Open in a separate windowScheme 5Ring-opening of the oxa-[3.2.1]octane via C–O bond cleavage.Ring-opening of the compound 6

PhI(OAc)2-mediated intramolecular oxidative C–N coupling and detosylative aromatization: an access to indolo[2,3-b]quinolines

A PIDA mediated intramolecular oxidative C–N coupling and subsequent detosylative aromatization to afford indolo[2,3-b]quinoline derivatives has been developed. This tandem reaction provided an efficient method for the synthesis of valuable indolo[2,3-b]quinoline derivatives.

Under mild conditions, PIDA mediated oxidant C–N coupling to afford indolo[2,3-b]quinoline derivatives has been developed with a decent substrate scope.

Indolo[2,3-b]quinolones are a kind of important poly-fused heterocycle, commonly occurring in many natural products and synthetic drugs (Fig. 1).¹ These compounds usually display diverse biological activities² such as anticancer,³ antiplasmodial,⁴ molluscicidal,⁵ and antimalarial activity⁶etc. Due to their importance, their efficient synthesis attracts chemists'' interest and many synthetic methods have been developed.⁷ Among these established methods, indolo[2,3-b]quinolones are usually prepared through construction of a pyridine cycle with indole derivatives as the starting materials catalysed by transition metals.⁸ The more attractive metal-free methods avoiding the metal contamination of products have also been reported.⁹ Initially, indole-3-aldehydes or o-amino benzaldehydes were used; these compounds were usually unstable and difficult to prepare. In 2012, Liang and co-authors reported an efficient synthesis from indoles and o-sulfamidoaryl ketones.¹⁰ This reaction is a two-step process involving iodine-promoted amination/intramolecular cyclization and subsequent detosylation in 12 M HCl. The direct intramolecular cyclization of indole derivatives through oxidative C–N coupling and detosylative aromatization was also reported. In 2016, Sekar and co-authors pioneering used Ts (4-benzenesulfonyl) as the activating group for amino group under heat (Scheme 1A).¹¹ In this reaction, 1.2 equiv. sublimed and corrosive I₂ was used as the oxidant and 2 equiv. Cs₂CO₃ as the base, only 5 examples were demonstrated. Very recently, using the special Ns (4-nitrobenzenesulfonyl) to activate the amino group, Ishihara and co-authors achieved the reaction at room temperature through iodine catalysis (Scheme 1B).¹² This reaction required 3–5 equiv. hazardous TBHP as the oxidant and relatively long reaction time (12–48 h).Open in a separate windowFig. 1Selected examples of bioactive indolo[2,3-b]quinoline derivatives.Open in a separate windowScheme 1Metal-free intramolecular cyclization for preparing indolo[2,3-b]quinolones.PhI(OAc)₂ is a common oxidant used in annulation reactions due to its easy operation and environmental benignity.¹³ With our continuing interest in exploding synthesis of heterocyclic compounds,¹⁴ we envisioned that this reaction might also be achieved with the use of PhI(OAc)₂ as the oxidant. Indeed, it worked well under the mild reaction conditions with the amino group being activated by 4-chlorobenzenesulfonyl group (Scheme 1C).Stirring a mixture of 1a and 1.2 equiv. PhI(OAc)₂ in DCM at room temperature for 12 h under an Ar atmosphere gave the product 2a in 10% yield († for details).Optimization of the reaction conditions^a

Regio- and stereoselective thiocyanatothiolation of alkynes and alkenes by using NH4SCN and N-thiosuccinimides

A highly regioselective thiocyanatothiolation of alkynes and alkenes assisted by hydrogen bonding under simple and mild conditions is developed. Our thiocyanatothiolation reagents are readily available ammonium thiocyanate and N-thiosuccinimides. This metal-free system offers good chemical yields for a wide range of alkyne and alkene substrates with good functional group tolerance.

A highly regioselective thiocyanatothiolation of alkynes assisted by hydrogen bonding under simple and mild conditions is developed.

Sulfur-containing molecules are ubiquitous structural motifs and widely exist in natural products,^1,2 pharmaceuticals^3,4 and agrochemicals.^5–7 Examples include the nonsteroidal anti-inflammatory drug Sulindac,⁸ the basal-cell carcinoma treatment drug Vismodegib,⁹ and drugs for the treatment of Parkinson''s disease.¹⁰ Therefore, efficient introduction of sulfur into organic molecules has drawn much attention.^11–15 And numerous approaches for the formation of C–S bonds have been developed.^16–20 The most used organosulfur sources for the formation of C–S bonds are thiols and thiophenols, which have an unpleasant smell. Recently, inorganic metal sulfides have been extensively used to construct C–S bonds, such as sodium metabisulfite,²¹ K₂S,²² Na₂S²³ and Na₂S₂O₃.²⁴ Compared to thiols and thiophenols, inorganic metal sulfides are cheaper and generally stable. Thus, introduction of sulfur-containing groups into molecules by using inorganic metal sulfides is one of the desired approaches. Among them, thiocyanates commonly serve as important precursors for the preparation of thioethers,²⁵ trifluoromethyl sulfides,²⁶ heteroaromatic compounds.²⁷ In general, the sources of SCN used to introduce a sulfur-containing group into molecules are thiocyanate salts^28–35 such as KSCN, NaSCN, AgSCN and NH₄SCN. For example, thiocyanate salts were employed in thiocyanation of bromoalkenes via photocatalysis (Scheme 1a).³⁶ Besides, the vinyl thiocyanates could be also obtained by thiocyanation of haloalkynes (Scheme 1b),³⁷ iodothiocyanation of alkynes (Scheme 1c).³⁸ Obviously, difunctionalization of alkynes is the most straightforward protocol to prepare vinyl thiocyanates.Open in a separate windowScheme 1Methods for thiocyanatothiolation of alkynes and alkenes.Recently, our group has focused on hydrogen-bonding network or cluster³⁹ assisted transformations such as hydrofluorination of ynamides⁴⁰ and alkenes,⁴¹ the addition of sulfonic acids to haloalkynes,⁴² fluorothiolation of alkenes,²⁰ dihalogenation of alkynes⁴³ and hydrochlorination of alkynes,^44–46halothiolation of alkynes.⁴⁷ Along this line, herein, we are glad to report a hydrogen bond network-enabled regio- and stereoselective thiocyanatothiolation of alkynes using NH₄SCN and N-thiosuccinimides.Initially, according to the previous report,²⁰ we started the investigation of thiocyanatothiolation protocol using NH₄SCN and N-(phenylthio)succinimide as thiolation reagents in DCM under air and carried out the reaction at 60 °C (48 In order to enhance the H-bond interaction between the hydroxyl and 2, so AcOH was chosen to compare with HFIP ( Entry^a[SCN]SolventTemp. (°C)Yield^b (%)1NH₄SCNDCM60422NH₄SCNDCE60473NH₄SCNTHF6004NH₄SCNAcetone6005NH₄SCNDMF6006NH₄SCNiPrOH6007NH₄SCNAcOH60248NH₄SCNTFE6018 9 NH ₄ SCN HFIP 60 87 10LiSCNHFIP603611NaSCNHFIP604212KSCNHFIP604913NH₄SCNHFIP256314NH₄SCNHFIP8083Open in a separate window^aReaction conditions: 1 (0.1 mmol), 2 (0.12 mmol), NH₄SCN (0.2 mmol), solvent (0.5 mL), under air for 12 h at 60 °C.^bDetermined by GC.With the optimized conditions in hand, we next turned our attention to explore the substrate scope (d-glucose (l-menthol ( Open in a separate window^aReaction conditions: 1 (0.1 mmol), 2 (0.12 mmol), NH₄SCN (0.2 mmol), HFIP (0.5 mL), under air for 12 h at 60 °C.^bIsolated yield.^cAr = Ph.^dDetermined by NMR.Next, we started to explore the scope of N-arylsulfenylsuccinimides. Various N-arylsulfenylsuccinimides can be obtained easily by the method in ESI.^† To our delight, the introduction of electron-donating groups or halide substitutes to the phenyl ring of N-arylsulfenylsuccinimides had little influence on this reaction, providing the corresponding products in 57–90% yields ( Open in a separate window^aReaction conditions: 4 (0.1 mmol), 2 (0.12 mmol), NH₄SCN (0.2 mmol), DCE (1.0 mL), under air for 12 h at 60 °C.^bIsolated yield.To demonstrate the scalability of this protocol, a gram-scale reaction of 1,1′-biphenyl-4-ethynyl (6 mmol) with N-(4-bromo thio)succinimide was carried out, and the corresponding product 3aq was obtained in 62% yield (Scheme 2).Open in a separate windowScheme 2Gram-scale preparation of 3aq.To identify the configuration, the single crystal of product 3aq was cultivated by solvent evaporation. And the regio- and stereoselectivity of products were further confirmed the X-ray crystallographic analysis of the obtained product 3aq (Fig. 1).Open in a separate windowFig. 1Single crystal structure of 3aq.Based on our previous work,⁴⁷ a plausible reaction pathway was proposed in Scheme 3. The interaction of HFIP hydrogen bonding linear aggregates⁴⁸ with sulfenylation reagent 2a may strongly activate the sulfenylation reagent, which generates the active intermediate B (Scheme 3). Sequentially, a sulfonium C is produced from intermediate B with an alkyne, followed by a nucleophilic attack of SCN anion to obtain the products 3.Open in a separate windowScheme 3Plausible mechanism.     

An expeditious and efficient bromomethylation of thiols: enabling bromomethyl sulfides as useful building blocks

A facile and highly efficient method for the bromomethylation of thiols, using paraformaldehyde and HBr/AcOH, has been developed, which advantageously minimizes the generation of highly toxic byproducts. The preparation of 22 structurally diverse α-bromomethyl sulfides illustrates the chemo-tolerant applicability while bromo-lithium exchange and functionalization sequences, free radical reductions, and additions of the title compounds demonstrate their synthetic utility.

A new method for the bromomethylation of thiols using paraformaldehyde and HBr/AcOH, minimizes the generation of toxic byproducts. Synthetic utility of α-bromomethyl sulfides was demonstrated through umpolung and free radical chemistry.

Heteroatom halomethylations¹ have proven to be extremely useful for the generation of valuable synthetic intermediates.² Halomethylation of thiols provides synthetically valuable chloromethylated intermediates (chloromethyl sulfides), which are typically prepared by condensation with bromochloromethane in basic media,³ or with HCl and a formaldehyde source (paraformaldehyde, polyoxymethylene, etc.).⁴ While chloromethyl sulfides have been traditionally used as alkylating reagents, the analogous bromomethyl counterparts offer superior electrophilicity, recognized since the earliest report describing their syntheses using hydrogen bromide and paraformaldehyde,⁵ yet they are often overlooked in this role. Moreover, the reactivity scope of bromomethyl thiol derivatives remains largely unexplored, despite a potentially broader synthetic range (e.g. for the generation of organometallics by metal–halogen exchange).⁶Other methods for the generation of bromomethylated thiol derivatives consist of replacing hydrogen bromide gas with concentrated aqueous hydrobromic acid, along with a formaldehyde source (usually paraformaldehyde),⁷ or by using dibromomethane⁸ in basic media.⁹ Two or three-step procedures consisting of hydroxymethylation followed by substitution have also been developed.¹⁰ A desilylative rearrangement of α-TMS sulfides has also been used for the generation of bromomethylsulfides.¹¹As part of our interest in the preparation and application of structurally diverse sulfur-based building blocks,¹² we investigated the preparation of benzyl(bromomethyl)sulfane (2a), previously used as an olefination reagent.¹³ However, several attempts to prepare 2a through exposure of benzylmercaptan (1a) to paraformaldehyde and hydrobromic acid,^7b led to a ca. 1.5 : 1 mixture of 2a (32%) and bis(benzylthio)methane 3a (21%, Scheme 1a). Iterations of the experiment always delivered important and variable amounts of the dithioacetal by-product 3a. On the other hand, an alternate approach to the bromomethylation of a cyclohexanethiol bromomethyl derivative 2b, using dibromomethane and K₂CO₃, resulted in trace amounts of the dithioacetal derivative 3b only (Scheme 1b).¹⁴Open in a separate windowScheme 1Attempts for the bromomethylation of 1a or 1b under (a) acidic or (b) basic media. (c) and (d) A highly efficient and direct approach for thiol bromomethylation (this work).HBr/AcOH is a convenient hydrogen bromide source that minimizes exposure to risky set-ups and has been employed as a surrogate to highly corrosive and toxic hydrogen bromide gas in numerous applications.¹⁵ Although this reagent has been used previously in the generation of bromomethyl sulfides, installation of the methylene bridge required first a S-pivaloxymethylation of a mercaptan, followed by cleavage by HBr/AcOH.¹⁶Surprisingly, sequential exposure of thiols 1a or 1b to paraformaldehyde and HBr/AcOH,¹⁷ rapidly delivered bromomethylated derivatives 2a and 2b with outstanding yields (Scheme 1). The simple experimental setup and straightforward purification procedure offer methodological utility; in most cases extraction with a low-boiling point hydrocarbon such as pentane or hexanes is sufficient to recover the material in high purity (>95%).¹⁸ Traces of impurities can be easily discarded through bulb-to-bulb vacuum distillation.The reaction scope was explored with a series of structurally diverse thiols (19 was prepared satisfactorily in 76% yield. Fluorinated bromomethyl 2e has been used for the preparation of fluorinated surfactants,^10a,20 which some exhibit antimicrobial activity. As a previous method involves a 2-step sequence involving thiol hydroxymethylation and substitution by PBr₃, our method directly delivered 2e in 88% yield.Thiol bromomethylation with HBr/paraformaldehyde^a

Dual C–H activation: Rh(iii)-catalyzed cascade π-extended annulation of 2-arylindole with benzoquinone

A rhodium-catalyzed, N–H free indole directed cyclization reaction of benzoquinone via a dual C–H activation strategy is disclosed. This protocol has a good functional group tolerance and affords useful indole-fused heterocylces. Besides, it is insensitive to moisture, commercially available solvent can be directly used and work quite well for this transformation.

A Rh-catalyzed cascade annulation of N–H free 2-arylindole with benzoquinone via dual C–H activation strategy was reported.

Quinones are widely distributed in nature, and commonly occur in bacteria, flowering plants and arthropods (Fig. 1). They have a wide range of applications, including diverse important pharmacological properties, involvement in redox reactions and development for advanced electrochemical energy storage.¹ Among varied reported quinones, benzoquinone (BQ) is the simplest and most important one. It has been well reported that BQ has a significant and unique role in oxidative palladium(ii)-catalyzed coupling reactions.² The chemistry of benzoquinone has been extensively explored in detail, including nucleophilic addition and cycloaddition reactions, photochemistry and oxidative coupling.^1b,c,2 Although great achievements have been obtained, only a few examples are disclosed about BQ as a reactant applying to transition-metal catalyzed C–H functionalization.^1e Among the examples reported, cyclization or BQ direct functionalization products were mainly afforded (Scheme 1a).Open in a separate windowFig. 1Selected examples of bioactive molecules containing the benzoquinone moiety.Open in a separate windowScheme 1Transition-metal catalyzed C–H functionalization of BQ.Transition-metal catalyzed C–H functionalization has undergone great progresses in the past two decades.³ In order to get a better reactivity and controlled selectivity, a directing group is usually needed for this process. Therefore, various directing groups have been developed.⁴ However, many of them (e.g. various nitrogen-containing heterocycles) remained parts of products after reaction, therefore increasing the procedures and difficulty for structure further modification and manipulation.⁵ As a result, it is highly demanded to explore traceless or easily removable directing groups.⁶ In this context, N–H free indole moiety has gradually emerged as a versatile functionalizable directing group in transition-metal catalyzed cyclization reaction.⁷On the other hand, although the above-mentioned great breakthrough obtained in C–H functionalization, there are few examples reported for dual C–H activation reactions.⁸ During our research program exploring transition-metal catalysis and heterocyclic synthesis,⁹ we intended to prepare the indole-containing heterocycles based on the consideration of their potential biological activity. Herein, we report a rhodium-catalyzed N–H free indole directed annulation reaction with BQ through dual C–H activation strategy (Scheme 1b).Our initial study was carried out by examining 2-phenyl indole 1a and benzoquinone 2a in the presence of [{Cp*RhCl₂}₂] and Cu(OAc)₂·H₂O in commercial available N,N-dimethylformamide under argon atmosphere. To our delight, the desired 9H-dibenzo[a,c]carbazol-3-ol product 3a was isolated in 55% yield ( EntrySolventCatalystAdditiveYield1DMF[Cp*RhCl₂]₂Cu(OAc)₂·H₂O55%2DMF[Cp*RhCl₂]₂—<5%3DMF—Cu(OAc)₂·H₂O—4 t-Amyl-OH[Cp*RhCl₂]₂Cu(OAc)₂·H₂O—5DMAc[Cp*RhCl₂]₂Cu(OAc)₂·H₂O<5%6DMSO[Cp*RhCl₂]₂Cu(OAc)₂·H₂OTrace7DMF[RuCl₂(p-cymene)]₂Cu(OAc)₂·H₂O—8DMFPd(OAc)₂Cu(OAc)₂·H₂O—9DMFRhCl(PPh₃)₃Cu(OAc)₂·H₂O<5%10DMF[Cp*RhCl₂]₂AgOAc—11DMF[Cp*RhCl₂]₂Ag₂O—12DMF[Cp*RhCl₂]₂Cu(acac)₂Trace 13 ^{bb , cc} DMF/DCE[Cp*RhCl₂]₂Cu(OAc)₂·H₂O 84% Open in a separate window^aReaction on a 0.2 mmol scale, using 1a (1.0 equiv.), 2a (1.0 equiv.), additive (2.0 equiv.), CsOAc (2.0 equiv.), [TM] (5 mol%), solvent (1.0 mL), under N₂, isolated yield.^b1a (1.5 equiv.), solvent (0.3 M).^cNaOAc was used instead of CsOAc.With the optimized conditions in hand, we next tend to examine the substrates scope of this reaction. Various 2-aryl indoles with electron-rich substituted groups were tested and worked well for this reaction (10 Finally, an interesting S, N-fused heterocycle 3m was obtained when 2-thienyl indole was employed. Other derivatives of benzoquinone such as 1,4-naphthaquinone or methyl-p-benzoquinone currently failed to produce the related cyclization products with proper yields.Substrates scope^a

LiCl-promoted amination of β-methoxy amides (γ-lactones)

An efficient and mild method has been developed for the amination of β-methoxy amides (γ-lactones) including natural products michelolide, costunolide and parthenolide derivatives by using lithium chloride in good yields. This reaction is applicable to a wide range of substrates with good functional group tolerance. Mechanism studies show that the reactions undergo a LiCl promoted MeOH elimination from the substrates to form the corresponding α,β-unsaturated intermediates followed by the Michael addition of amines.

The amination of β-methoxy amides (γ-lactones) including natural products michelolide, costunolide and parthenolide derivatives were first developed by using lithium chloride.

The formation of carbon–nitrogen bonds remains one of the most fundamental and widely practiced reactions in organic synthesis, due to the prevalence of this functionality in the preparations of functional molecules in pharmaceutical chemistry, biochemistry and material sciences.¹ Various synthetic methodologies have been developed to form C(sp²)-N bonds, including the Goldberg reaction,² Buchwald–Hartwig reaction,³ imine reduction⁴ and the nucleophilic addition of carbon-nucleophiles to imine derivatives.⁵ Meanwhile, the formations of C(sp³)-N bonds can be achieved by reductive amination, which involves the conversion of a carbonyl group to an amine via an imine intermediate, such as Eschweiler–Clarke reaction⁶ and Borch reductive amination.⁷ Nucleophilic substitution of alkyl(pseudo)halides with amines (amine alkylation) serves as one direct strategy for the preparation of alkylamines, while the necessity of pre-installation of the halogen atoms and the production of stoichiometric inorganic salt wastes are considered as two main drawbacks for its application in large scale industrial synthesis.⁸Methoxy as the leaving group in the amination reactions has recently attracted the attention of organic chemists. For instance, Chiba and coworkers reported a method for the nucleophilic amination of methoxy arenes,⁹ which was achieved by using sodium hydride (NaH) in the presence of lithium iodide (LiI) through a concerted nucleophilic aromatic substitution pathway (Fig. 1a).¹⁰ Kondo and coworkers demonstrated that the organic superbase t-Bu-P4 efficiently catalyzes the amination of methoxy(hetero)arenes with the amine nucleophiles (Fig. 1b).¹¹ The t-Bu-P4 is also suitable to catalyze the amination of β-(hetero)arylethyl ethers with amines to synthesize β-(hetero)arylethylamines (Fig. 1c).¹² Sun and coworkers reported that C–S bond cleavage to access N-substituted acrylamide and β-aminopropanamide(Fig. 1d).¹³Open in a separate windowFig. 1Amination reactions of methyl ethers.Recently, we described the application of a CuBr–LiCl composite for the short-chain alkoxylation of aryl bromides.¹⁴ During that course of study, the single-shell lithium ion was found to embrace a unique affinity for oxygen and can be used as an additive to activate C–O bond and facilitate the nucleophilic reaction. On the basis of this study, we herein present the synthesis of β-amino amides (γ-lactones) via the elimination of methoxy group followed by Michael addition of an amine, that was promoted by LiCl in good yields under conventional conditions.We initiated our study with the reaction of 3-methoxy-N-phenylpropanamide 1a and piperidine 2a in the presence of lithium salts ( EntryAdditive (equiv.)Solvent T (°C)Time (h)Yield^b (%)1LiCl (2.0) ⁱPrOH12012702LiBr (2.0) ⁱPrOH12012303LiI (2.0) ⁱPrOH12012434LiOTf (2.0) ⁱPrOH12012385Li₂CO₃ (2.0) ⁱPrOH1201266NaCl (2.0) ⁱPrOH12012N. R.7LiCl (2.0)DMF12012468LiCl (2.0)Toluene12012219LiCl (1.0) ⁱPrOH120123810^c— ⁱPrOH12012N. R.11LiCl (2.0) ⁱPrOH80122312LiCl (2.0) ⁱPrOH120649Open in a separate window^aReaction conditions: 1a (0.45 mmol), 2a (0.90 mmol) and additive (2.0 equiv.) in solvent (3.0 mL) at 120 °C in sealed tube.^bYield of isolated product.^cNo LiCl was used.With the optimized condition in hand, the substrate scope and functional group tolerance of the transformation was then examined (Scheme 1). It was found that the 3-methoxy-N-arylpropanamides without substitution or substituted with electron-donating (–OMe) or electron-withdrawing (–Cl, –Br) groups at the para-position of the N-aryl ring exhibit good tolerance under the present conditions, giving good yields of 70–77% (3aa–3da). Moreover, the diversity of amines was studied, including pyrrolidine, diethyl amine, dimethyl amine, morpholine and methyl amine solution, and the amination products were formed in moderate to good yields in all cases (3ab–3db, 3ac–3dc, 3ad–3dd, 3ae–3de, 3af). However, when using anilin (2g) as the starting material, no reaction took place. Replacement of the N-phenyl substituent with a benzyl group (1e) led to an increased yield of 83% (3ed). Remarkably, challenging 3-methoxypropanoyl piperazine derivatives also worked well under the optimized conditions, producing the desired products in good yields (3fa–3fe). Promoted by the successful amination of the amide, we then extended this transformation to β-methoxy γ-lactones. It was noteworthy to find that 3-methoxymethyl γ-lactones 4a also worked for this reaction with the high yield of 85% 5ad.Open in a separate windowScheme 1Evaluation of the substrate scope of β-methoxy amides and amines. ^aReactions were carried out with 1a (1.0 equiv.), 2a (2.0 equiv.) and LiCl (2.0 equiv.) in ⁱPrOH (0.15 M) at 120 °C for 12 h in sealed tube. Yields of isolated products are given.Encouraged by the above results, our research was then extended to perform this transformation between the natural product michelolide derivatives 4b with β-methoxy γ-lactone subunit and various amines 2 (Scheme 2).¹⁵ Due to a high tolerance and compatibility of function groups, this strategy can be applied to 4b possessing both hydroxy group and carbon–carbon double bond. Both cyclic amines (2a, 2b, 2e, 2h) and linear amines (2d, 2i, 2f, 2j) gave the corresponding products in moderate to excellent yields. Additionally, the structure of product 5bb was unambiguously identified by X-ray crystallography.Open in a separate windowScheme 2Evaluation of the substrate scope of amines with michelolide derivatives. ^aReactions were carried out with 4b (1.0 equiv.), 2 (2.0 equiv.) and LiCl (2.0 equiv.) in ⁱPrOH (0.15 M) at 120 °C for 5 h in sealed tube. Yields of isolated products are given. ^bReaction was conducted for 10 h. ^cReaction was conducted for 20 h. ^dReaction was conducted for 15 h.Meanwhile, it is well demonstrated that amine substituted natural products is an efficient hydrophilic modification strategy used in medicinal chemistry.¹⁶ Therefore, this system was then extended to the amination of other natural product derivatives (4c–4g) containing β-methoxy γ-lactone subunit (17 Arglabin derivative 4c underwent the amination to give the product (5cd) in 99% yield, which is equivalent to the commercially available antitumor agent Arglabin-DMA.^16a,18 Michelolide derivative (4d and 4e) gave similarly good yields, in which the epoxy subunit does not affect the yield under the optimized conditions.¹⁹ The costunolide derivative 4f was converted to the corresponding product 5fd in 60% yield, while the reaction based on the parthenolide derivative 4g gave the desired product 5gd in 48% yield.Evaluation of the substrate scope of β-methoxy γ-lactones of natural products^a

Rh(iii)-catalyzed C-7 arylation of indolines with arylsilanes via C–H activation

Site-selective synthesis of C-7 arylated indolines has been achieved via oxidative arylation of indolines with arylsilanes under Rh(iii)-catalyzed C–H activation of indolines by using CuSO₄ as a co-oxidant. This transformation has been explored for a wide range of substrates under mild conditions.

Site-selective synthesis of C-7 arylated indolines has been achieved via oxidative arylation of indolines with arylsilanes under Rh(iii)-catalyzed C–H activation of indolines.

The indole and indoline ring systems represent ubiquitous structural motifs as natural alkaloids and biologically active compounds as well as in functional materials.^1,2 With the development of C–H bond functionalization,³ a great deal of effort has been devoted to the formation C-2 and C-3 functionalized indoles.⁴ Nevertheless, only a few methods have been explored for the direct C–H bond functionalization of indoles at the C-7 position,⁵ in which the unique work for the direct Pd-catalyzed C–H arylation of indoles with arylboronic acids at the C-7 position was developed by the Shi group using a designed di-tert-butylphosphine oxide (TBPO) directing-group.^5b In general, the C-7 arylated indolines can be conveniently oxidized to transform into C-7 arylated indoles. So far, transition metals such as Pd,⁶ Rh,⁷ Ru,⁸ Ir,⁹etc.,¹⁰ have been employed as catalysts for the C-7 C–H bond functionalization of indolines, among which the C–H arylation in the C-7 position of indoline was mainly established by using Pd complexes as catalysts (Scheme 1a).¹¹ In 2016, we also reported the Pd-catalyzed C-7 arylation of indolines with arylsilanes via C–H bond activation.¹² Recently, the Punniyamurthy group developed the site-selective C-7-arylation of indolines with arylboronic acids by using low-cost and earth-abundant cobalt(ii)-PCy₃ as a catalyst.¹³ Even so, in view of the importance of indole and indoline scaffolds, it is still highly desirable to develop more convenient and efficient approaches for the synthesis of C-7 arylated indolines and C-7 arylated indoles.Open in a separate windowScheme 1C-2 arylation of indoles with arylsilanes and C-7 arylation of indolines.Meanwhile, recent years have witnessed tremendous developments in the area of Rh(iii)-catalyzed C–H bond functionalization,¹⁴ which has allowed effective construction of various C–C bonds. The major advantages of Rh(iii) catalysis are (i) high functional-group tolerance, (ii) broad substrate scope, (iii) low catalyst loading, high activity, and high catalytic efficiency.Since the Hiyama cross-coupling reaction had been first reported in 1988,¹⁵ as one of the most useful and reliable synthetic methods for the construction C–C bonds, the Hiyama cross-coupling reaction has drawn increasing attention.¹⁶ As attractive organometallic coupling partners with many unique advantages such as low toxicity, high stability and environmental benignity, organosilicon reagents were used as coupling partners for the C–H arylation of indoles and indolines (Scheme 1b).¹⁷ Zhang group reported the Pd-catalyzed C-2 arylation of indoles with arylsilanes in acidic medium in 2010. In 2014, Loh group developed the Rh(iii) catalyzed C-2 C–H arylation of indoles with arylsilanes in aqueous media.¹⁸ Very recently, Szostak group developed the Ru(ii) catalyzed arylation of indoles with arylsilanes via C–H activation,¹⁹ it is worth noting that the reaction was carried out in water. However, the methods for the synthesis of C-7 arylated indolines and C-7 arylated indoles are very limited by using arylsilanes as the coupling partners. To the best of our knowledge, the Rh(iii) catalyzed C-7 arylation of indolines with arylsilanes has not been achieved. Due to our continuous interest in the arylsilanes-based coupling reaction,^12,20 we herein would like to report a Rh(iii)-catalyzed regioselective C-7 arylation of indolines with arylsilanes via C–H activation (Scheme 1c), the reaction provides a facile access to C-7 arylated indolines.At the outset of the investigation, various N-protecting indolines (iii)-catalyzed C-7 arylation of indolines with arylsilane^a

Entry	Substrates	Co-oxidant	F source	Solvent	Yieldb (%)
1	1a–1d	Ag2CO3	AgF	Dioxane	0
2	1e	Ag2CO3	AgF	Dioxane	0
3	1f	Ag2CO3	AgF	Dioxane	81
4	1f	Ag2CO3	CsF	Dioxane	0
5	1f	Ag2CO3	KF	Dioxane	0
6	1f	Ag2CO3	TBAF	Dioxane	0
7	1f	—	AgF	Dioxane	72
8	1f	AgOAc	AgF	Dioxane	89
9	1f	Cu(OAc)2	AgF	Dioxane	85
10	1f	CuSO4	AgF	Dioxane	98
11	1f	CuSO4	AgF	DMF	62
12	1f	CuSO4	AgF	DMSO	0
13	1f	CuSO4	AgF	iPrOH	81
14	1f	CuSO4	AgF	H2O	Messy
15	1f	CuSO4	AgF	Dioxane/H2O = 1/10	47
16c	1f	CuSO4	AgF	Dioxane	87

Open in a separate window^aUnless otherwise noted, the reaction conditions are as follows: 1 (0.3 mmol), 2a (0.9 mmol), [Cp*Rh(iii)Cl₂]₂ (1 mol%), Co-oxidant (0.6 mmol), F resource (0.9 mmol), solvent (3.0 mL).^bIsolated yield after purification by flash column chromatography on silica gel, n.d.p or trace product was determined by TLC.^cThe reaction temperature was 60 °C.With the optimized reaction conditions in hand, we then proceeded to explore the scope of the direct C-7 C–H arylation of N-(2-pyrimidyl)-indoline with a series of arylsilanes (iii)-catalyzed the direct C-7 arylation of indoline 1f with various phenyltriethoxysilane 2^a,bOpen in a separate window^aUnless otherwise noted, the reaction conditions are as follows: 1f (0.3 mmol), 2 (0.9 mmol), dioxane (3.0 mL).^bAll the yields refer to isolated yields.^cPhenyltrimethoxysilane was used.To further evaluate the substrate scope, various substituted N-(2-pyrimidyl)-indolines were used to test the reaction with the phenyltriethoxysilane 2a under the optimized reaction conditions. The results are summarized in iii)-catalyzed the direct C-7 arylation of various indolines 1 with phenyltriethoxysilane 2a^a,bOpen in a separate window^aUnless otherwise noted, the reaction conditions are as follows: 1 (0.3 mmol), 2a (0.9 mmol), dioxane (3.0 mL).^bAll the yields refer to isolated yields.To explore the utility of this transformation, we tried to explore direct C-8 C–H arylation with N-(2-pyrimidyl)-tetrahydroquinoline 5 and phenyltrimethoxy-silane 2a under the standard condition, to our delight, the desired C-8 C–H arylated product was obtained in 48% yield (Scheme 2).Open in a separate windowScheme 2Rh(iii)-catalyzed the direct C-8 arylation of N-(2-pyrimidyl)-tetrahydroquinoline 5 with phenyltriethoxysilane 2a.To further demonstrate the synthetic utility of the method, the transformation of C-7 arylated indoline into C-7 arylated indole was studied.^13,21 As shown in Scheme 3, the transformation was begun with the oxidation of C-7 arylated N-(2-pyrimidyl)-indoline 3fa by the use of DDQ (2,3-dicyano-5,6-dichlorobenzoquinone), followed by removing pyrimidyl group in the present of base. Finally, 83% yield of the C-7arylated indole product 7a was successfully obtained.Open in a separate windowScheme 3Transformation of C-7-arylated indoline 3fa to the corresponding indole 7a.To gain some preliminary mechanistic insights, kinetic isotope experiments were conducted. The parallel reactions of 1f and deuterio-1f with 2a resulted k_H/K_D = 0.80 (Scheme 4), which suggested that the C–H cleavage was not the rate-determining step in the catalytic cycle. On the basis of previous literatures, ^18,22,23 a plausible mechanism is proposed as shown Scheme 5. The process is likely to be initiated by the coordination of the nitrogen atom of 2-pyrimidyl group of 1f to the rhodium catalyst, leading directly to cyclometalation process via C–H bond activation to afford the five-membered rhodacycle A.²⁴ The Ph–Ag species can be generated via the C–Si activation by the nucleophilic attack of a fluoride ion on silicon,^20c,25 followed by the transmetalation with intermediate A to afford the Rh(iii) intermediate B, from which reductive elimination would provide C-7 arylated indolines 3fa and regenerate the Rh(i) catalyst, which is reoxidized to Rh(iii) species by Ag(i) or Cu(ii) salts to complete the catalytic cycle.Open in a separate windowScheme 4Parallel kinetic isotope experiment.Open in a separate windowScheme 5Plausible catalytic cycle for Rh(iii)-catalyzed the direct C-7 arylation of indolines with phenyltriethoxysilane.In summary, we have demonstrated a Rh(iii)-catalyzed oxidative arylation of indolines with arylsilanes via C–H activation by using CuSO₄ as an co-oxidant. This general transformation exhibits excellent reactivity and broad substrate scopes, various functional groups are well tolerated under the mild reaction conditions. This reaction constitutes a complement method for the synthesis the desired C-7 arylated indolines up to excellent yields, which can be conveniently transformed into C-7 arylated indoles.     

A green metal-free “one-pot” microwave assisted synthesis of 1,4-dihydrochromene triazoles

The synthesis of several 4-aryl-1,4-dihydrochromene-triazoles was achieved via a metal-free “one-pot” procedure using PEG400 as the sole solvent in an eco-friendly process. Using microwave irradiation, the triazole derivatives were obtained in good yields and short reaction times starting from readily accessible building blocks.

A straightforward metal-free “one-pot” microwave procedure using PEG400 as the sole solvent in an eco-friendly process for the synthesis of 4-aryl-1,4-dihydrochromene-triazoles is described.

Novel green technologies play a pivotal role in modern society economics and way of life, and are being considered an important engine of transformation by directly affecting people''s daily lives.¹ In this sense, the “Click Chemistry” philosophy encompasses several features within the “Twelve Principles of Green Chemistry”, including mild reaction conditions, simple operation, simple product isolation procedures, solvent-free conditions, readily available starting materials and reagents, high yields and selectivity.²Among the “Click” reaction arsenal, the formation of 1,2,3-triazoles emerged as a reliable approach for the synthesis of novel compounds, being present in several fields of science, particularly in biomedical chemistry and drug design.³ 1,2,3-Triazoles are useful building blocks in organic chemistry owing to their stablily to moisture, oxidation, and metabolism in organisms.⁴ Moreover, these moieties are powerful pharmacophores, playing an important role in bio-media.⁵ Mainly represented by the Cu(i) catalyzed Huisgen cycloaddition over the last years, the majority of reports englobes the use of sodium/organic azides and alkynes.⁶Green and sustainable triazole synthesis approaches have gained the attention of chemists more recently, with highlights to metal-free conditions,⁷ heterogeneous reactions employing an immobilized catalyst⁸ and microwave irradiation.⁹ Regarding green protocols that use nitroolefins as dipolarophiles,¹⁰ the metal-free acid-catalyzed approach by Guan et al.¹¹ as well as the use of palladium- and copper-supported mesoporous polyaromatic hydrocarbons by Banerjee et al.¹² represent important advances in this field. However, due the lack of solubility of azides, DMSO and DMF are the solvents of choice for those transformations.The use of water as a benign solvent in organic reactions is always appreciated as it is one of the most abundant, cheapest, and greener solvents.¹³ As another important green alternative, polyethylene glycol 400 (PEG400) has been used to enhance the solubility of organic compounds. An important feature of PEG400 is its ability to act as a crown ether,¹⁴ enhancing the solubility of metal-based salts such as sodium azide (Scheme 1A).Open in a separate windowScheme 1Previously reported procedures and novel microwave assisted “one-pot” metal-free reaction.Kumar and Varma demonstrated that aqueous PEG400 is an excellent solvent for Cu(i)-catalysed Huisgen cycloadditions (Scheme 1A).¹⁵ In the same year, Yao et al. reported the synthesis of 4-aryl-1,4-dihydrochromene-triazoles from 3-nitrochromens in DMSO (Scheme 1B).¹⁶ In recent years, nitroolefins have been efficiently explored, allowing the direct obtention of 1H-1,2,3-triazoles using sodium azides with concomitant aromatization,^10–14,16 and HNO₂ release, which assists in the decomposition of residual NaN₃.^10f Aiming for a more sustainable process, based on microwave irradiation and sequential metal-free “one-pot” reactions, we developed a methodology starting from simple building blocks such as substituted benzaldehydes and nitromethane, avoiding the manipulation of potentially toxic nitroalkenes, and using PEG400 as the sole solvent for the synthesis of aryl-1,4-dihydrochromene 1H-1,2,3-triazoles (Scheme 1C). We believe that this novel procedure can open new possibilities for the synthesis of such an important scaffold in medicinal chemistry.Our study began with the optimization of a reaction model consisting of 1a, sodium azide and PEG400 as the solvent under microwave irradiation conditions (300 W) (11 catalytic amounts of acids were employed, aiming at reducing the formation of 1,3,5-triphenylbenzene. The addition of p-toluene sulfonic acid (PTSA) resulted in a slightest yield improvement, while the use of camphor sulfonic acid (CSA) led to a decrease in yield (entries 3–4). Although an increase in the yield was not observed by increasing the concentration of the reaction medium (entry 5), a better result was observed when catalytic amounts of several acids were used under the same conditions (entry 6–9), and the best result was found for benzoic acid (62%, entry 9), with a minor increase in the reaction time. Previous results showed similar performance for acetic acid as the solvent.^10f Next, an increase in the amount of benzoic acid led to a decrease in the yield (entries 10–11) and attempts of using mixtures of solvents resulted in the reaction inhibition (entries 12–13). Furthermore, doubling the reaction concentration, decreasing the reaction temperature and raising the reaction time led to unsatisfactory results (entries 14–15).Selected optimization results

PIDA-mediated intramolecular oxidative C–N bond formation for the direct synthesis of quinoxalines from enaminones

A intramolecular oxidative C(sp²)–N bond formation mediated by hypervalent iodine(iii) to obtain quinoxalines from readily available N-(2-acetaminophenyl)enaminones was developed. A tandem process involving PIDA-mediated intramolecular condensation cyclization and a subsequent elimination was postulated, which was highly efficient and metal-free under mild conditions. Moreover, flexible structural modifications of quinoxalines bearing carbonyl groups are of interest for further transformations as building blocks in organic synthesis.

An expedient hypervalent iodine(iii)-mediated approach to obtain substituted quinoxalines from readily available enaminones has been developed under mild conditions.

Quinoxaline represents one of the most prevalent heterocycles in natural products.¹ It has enjoyed extensive applications in pharmaceuticals due to its various biological activities such as antimicrobial, antiviral, antidiabetic, anti-inflammatory, anticancer, and antidepressant properties.^2,3 Moreover, quinoxalines are the building blocks used in the preparation of porphyrins,⁴ dyes,⁵ electroluminescent materials,⁶ cavitand and salen ligands.⁷ Among these, quinoxalines bearing carbonyl groups are important structural motifs in bioactive molecules (Fig. 1), such as compounds a and b, which are used as potential photoprotective drugs and anticancer and hypoxia-selective agents.⁸ They are also the building blocks of some quinoxaline metal complexes, such as compounds c and d, which possess significant antimicrobial and anticancer activities.⁹Open in a separate windowFig. 1Selected bioactive molecules with quinoxaline bearing a carbonyl group moiety.Consequently, a variety of strategies have been developed to prepare such a core. The conventional procedure for the synthesis of quinoxalines involves the condensation of o-disubstituted benzene with two-carbon synthons such as 1,2-dicarbonyl compounds,¹⁰ α-hydroxy ketones,¹¹ vicinal diols,¹² phenacyl bromides,¹³ epoxides,¹⁴ and alkynes.¹⁵ Recently, transition metal-catalyzed domino cyclization reactions¹⁶ have been found to be efficient. However, there are still some respective limitations such as the use of problematically available or dangerous starting materials, harsh reaction conditions, poor regioselectivity, and the requirement of noble metals as catalysts, which may lead to potential contamination in products and impede their applications, especially in the pharmaceutical industry. Therefore, the development of an efficient and metal-free route to obtain quinoxalines under mild reaction conditions remains highly desirable.Owing to the didentate nucleophilicity and electrophilicity of enaminones, various heterocycles can be synthesized from enaminones.^17,18 In 2016, a convenient regiospecific synthesis of quinoxalines involving base-promoted C-α-CH₂-extrusion from enaminones under metal-free conditions was developed by our group.¹⁹ Due to our continued interest in the development of new strategies for the synthesis of heterocycles based on enaminones under metal-free conditions,^20a−h we recently reported the preliminary results of a simple, mild and highly atom-efficient synthesis of 2-hydroxy-benzo[b][1,4]oxazins from N-(2-hydroxylaryl) enaminones via a hypervalent iodine(iii)-promoted intramolecular iminoenol trapping reaction (Scheme 1a).^20g,21 As an extension of this methodology and the synthesis of versatile quinoxalines, N-(2-acetaminophenyl)enaminones as starting materials under appropriate hypervalent iodine(iii)-mediated conditions were explored (Scheme 1b). It was proven to be an expedient and simple strategy to access quinoxalines.Open in a separate windowScheme 1Hypervalent iodine(iii)-mediated synthesis of heterocycles from enaminones.Initially, N-(2-acetaminophenyl)enaminone 1a was used as the standard substrate to search for suitable reaction conditions. We were pleased to find that the reaction of 1a with PIDA (iodobenzene diacetate) in EtOH at 80 °C successfully afforded the desired product quinoxaline 2a in 58% isolated yield ( EntrySolvent T (°C)[O] (equiv.)Additive (equiv.)Yields^b (%)1EtOH80PIDA (1.1)—582DCE80PIDA (1.1)—7231,4-Dioxane80PIDA (1.1)—624DMF80PIDA (1.1)—345Toluene80PIDA (1.1)—796Toluene80PIFA (1.1)—677Toluene80PhI (10 mol%) + m-CPBA (2)—Trace8Toluene80PIDA (0.3)—369Toluene60PIDA (1.1)—7510Toluene100PIDA (1.1)—7011Toluene80PIDA (1.1)AcOH (1.0)5912Toluene80PIDA (1.1)TsOH (1.0)21 13 Toluene 80 PIDA (1.1) PhCOOH (1.0) 90 14Toluene80PIDA (1.1)Et₃N (1.0)4915Toluene80PIDA (1.1)K₂CO₃ (1.0)7216Toluene80PIDA (1.1)PhCOOH (2.0)9217Toluene80PIDA (1.1)PhCOOH (0.1)8018^cToluene80PIDA (1.1)PhCOOH (1.0)8819^dToluene80PIDA (1.1)PhCOOH (1.0)25Open in a separate window^aReaction conditions: 1a (0.2 mmol) and iodine compound in solvent (2 mL) at a corresponding temperature for 12 h under air atmosphere.^bIsolated yields.^cUnder O₂.^dUnder N₂. PIFA = phenyliodine(iii) bis(trifluoroacetate), m-CPBA = 3-chloroperoxybenzoic acid.Under the optimized reaction conditions (Scheme 2, R¹ and R² in substrate 1 can be either electron-rich or electron-deficient aryl groups and provide the corresponding quinoxalines in 44–93% yields (2b–2k, 2n–2r). N-(2-Acetaminophenyl)enaminones 1 with electron-donating groups at the para position of the phenyl ring reacted smoothly to afford the expected quinoxalines in desirable yields (2d, 2f, and 2g), while the yields for the substrates bearing electron-withdrawing groups were relatively lower (2h, 2i). Due to steric hindrance, the substrates with para-substituents (2d) gave slightly higher yields than those with ortho- and meta-substituents (2b, 2c). Halogens, including F, Cl, and Br, worked well (2i–2k, 2p–2r, 53–73% yields), which could be further extended to subsequent transition metal-catalyzed coupling reactions. Heteroaryl groups, such as furyl and thienyl groups, were also suitable and gave the desired products in 42% and 43% yields, respectively (2l, 2m). Moreover, when the R² group was a cyclopropyl group, this transformation could still proceed smoothly, giving the desired product in 35% yield (2s). A trace amount of the desired product was obtained when R² was an aliphatic group and enamino esters were used as the substrate.Open in a separate windowScheme 2Substrate scope of enaminones. ^aReaction conditions: 1a (0.2 mmol), PIDA (0.22 mmol), PhCOOH (0.2 mmol) in toluene (2 mL) at 80 °C for 12 h. ^bIsolated yields.The flexible structural modification of quinoxalines bearing carbonyl groups indicates their further transformations to useful molecules.²² For example, the reduction of 2a with KBH₄ furnished 3a in 85% yield, which showed some activity to prevent brain damage and neurodegenerative diseases (Scheme 3a).²³ Subsequent cyclization in the presence of concentrated H₂SO₄ afforded the condensed quinoxaline 4a, which is a pharmacophoric structure motif with antifungal activity (Scheme 3b).²⁴Open in a separate windowScheme 3Further transformations of 2a.To probe the possible reaction mechanism, some control experiments were carried out (Scheme 4). The radical scavengers TEMPO (2,2,6,6-tetramethylpiperidine, 1-oxy) and DPE (1,1-diphenylethylene) resulted in yields of 68% and 55%, respectively (eqn (1)), which indicated that a radical pathway might not be involved in this reaction. When N-(2-acetaminophenyl)enaminone 1a was reacted under the standard conditions for 2 h, intermediate 5a was isolated in 32% yield, which could be transformed into the desired product 2a in 93% yield (eqn (2)). As expected, the intermediate 5a could be transformed into the desired product 2a in 41% yield under standard conditions without PIDA and PhCOOH (eqn (3)), while a higher yield (84%) was obtained in the presence of PhCOOH (eqn (4)), indicating that PhCOOH could promote the process from intermediate 5a to the desired product 2a.Open in a separate windowScheme 4Control experiments.A plausible mechanism is proposed in Scheme 5 according to the aforementioned results and reported literatures.²⁵ The initial reaction of 1a and PIDA afforded α-iodo iminoketone A. Then, intramolecular condensation cyclization of A with the concomitant release of PhI and CH₃COOH afforded 5a. Subsequently, the oxidation of 5a provided B, which was detected by HRMS (ESI, Fig. S1^†) in the presence of O₂. Finally, the elimination of CH₃COOH from B generated the final product 2a.Open in a separate windowScheme 5Proposed reaction mechanism.In conclusion, an efficient hypervalent iodine(iii)-mediated approach to substituted quinoxalines from readily available N-(2-acetaminophenyl)enaminones was developed. This reaction tolerated a wide range of functional groups in moderate to excellent yields under mild and metal-free conditions. Due to the importance of quinoxalines, this protocol can be further expanded to the synthesis of biologically and medicinally relevant compounds.     

Copper-catalyzed three-component reaction to synthesize polysubstituted imidazo[1,2-a]pyridines

An efficient three-component one-pot and operationally simple cascade of 2-aminopyridines with sulfonyl azides and terminal ynones is reported, providing a variety of polysubstituted imidazo[1,2-a]pyridine derivatives in moderate to excellent yields. In particular, the reaction goes a through CuAAC/ring-cleavage process and forms a highly active intermediate α-acyl-N-sulfonyl ketenimine with base free.

Three-component one-pot synthesis of polysubstituted imidazo[1,2-a]pyridine derivatives through a base free CuAAC/ring-cleavage process.

Polysubstituted imidazo[1,2-a]pyridines are well established as privileged scaffolds which are commonly encountered in many bioactive natural products and biological molecules that may be good drug candidates.¹ Most imidazo[1,2-a]pyridines possess various biological activities, like antibacterial,² antiinflammatory,³ antiviral,⁴ and anticancer.⁵ Some of the imidazo[1,2-a]pyridine derivatives are commercially available drugs, including Saripidem,⁶ Alpidem,⁷ Zolpidem,⁸ Zolimidine,⁹ Miroprofen¹⁰ and drug candidates GSK812397 (Fig. 1).¹¹ Therefore, the development of novel methods for the synthesis of these imidazo[1,2-a]pyridines is important in the field of synthetic organic and pharmaceutical chemistry.Open in a separate windowFig. 1Some imidazo[1,2-a]pyridine drugs or drug candidates.In the past few years, reactions utilizing Cu,¹² Pd,¹³ Mn,¹⁴ TEMPO-mediated,¹⁵ I₂ (ref. 16) and a few other catalysts¹⁷ have provided attractive and valuable routes for the construction of imidazo[1,2-a]pyridines. However, most reactions can only produce monosubstituted imidazo[1,2-a]pyridines or halogenated intermediates (Scheme 1a)¹⁸ which can undergo one more steps of coupling reaction leading to polysubstituted products. Therefore, developing one-pot synthetic reactions will provide a direct and powerful tool to meet these challenges. To the best of our knowledge, imidazo[1,2-a]pyridines can be synthesized from 2-aminopyridines, terminal alkyne and aldehyde in a three-component coupling reaction, catalyzed by copper, in one pot (Scheme 1b).¹⁹ However, aldehydes are unstable and easily oxidized. They are environmentally unfriendly for synthesis or complex procedures. Under this background, the development of multicomponent one-pot synthetic strategies for the preparation of polysubstituted imidazo[1,2-a]pyridines still remains highly desirable.Open in a separate windowScheme 1Synthesis of polysubstituted imidazo[1,2-a]pyridines.Previous studies reported that the copper-catalyzed multicomponent reactions (MCRs) of sulfonyl azides, terminal alkynes and other components (CuAAC/ring-cleavage reaction) has been applied to synthesize numerous oxygen- and nitrogen-containing heterocyclic compounds.²⁰ However, the reaction generally carried out under strong base conditions, and limited the application of some substrates, such as terminal ynones, which will take a self-condensation under the base conditions.²¹ Thus, the neutral or weak acidic conditions have developed by our group and the terminal ynones successfully used in CuAAC/ring-cleavage reaction to form a highly active intermediate α-acyl-N-sulfonyl ketenimines.²² Accordingly, an efficient one-pot and operationally three-component reaction of 2-aminopyridines, sulfonyl azides and terminal ynones is reported (Scheme 1c).Our initial study began with an examination of the synthesis of imidazo[1,2-a]pyridine 4a from 2-aminopyridine (1a), ethyl propiolate (2a) and p-tosyl azide (3a). Initial screenings involved using CuI as catalyst and no additive with a variety of solvents in a range of standard solvents. These results revealed that the desired conversion could be effected in most solvents ( EntryCat.SolventYield^b (%) 4a1CuICHCl₃742CuIDCE773CuIToluene784CuIMeCN805CuITHF626CuI1,4-Dioxane447CuIDMSO268CuIDMF359 CuI EtOH 83 10CuClEtOH7511CuBrEtOH7312CuBr₂EtOH7013Cu(OAc)₂EtOH5014Cu(OTf)₂EtOH3215AgOAcEtOHnd^c16CuIEtOH80^d17CuIEtOH76^eOpen in a separate window^aReaction conditions: 1a (1.0 mmol), cat. (10 mol%) in the solvent (3 mL) was added 2a (1.5 mmol) and 3a (1.5 mmol) stirring at 80 °C for 6 h.^bIsolated yields.^cnd = not detected the target product.^dThe reaction temperature was 70 °C.^eThe temperature was 90 °C.Under the optimized conditions ( Open in a separate window^aUnless otherwise noted, the reaction conditions were as follow: 1 (1.0 mmol), CuI (10 mol%) in the MeCN (3 mL) was added 2 (1.5 mmol), 3 (1.5 mmol) stirring at 80 °C for 6 h.Next, the scope and limitation of the terminal ynone 2 and sulfonyl azide 3 substrates were tested. It is noteworthy that the sulfonyl azide substrates showed slight influences on this reaction. With R³ changed by aromatic or aliphatic substituents, such as –Ph, –(4-ClC₆H₄), –(4-CF₃C₆H₄), –(4-OMeC₆H₄), –Me and –n-Bu, the reaction could smoothly give the anticipated products (4f–4n) in comparable yields. The substrates R² bearing the –OMe, –O^tBu, –Me and other alkyl group also can obtain 4o–4r in good yields.In order to broaden the suitability of substrates, we also investigated other terminal alkynes, such as aryl acetylenes. The experiments revealed that some aryl acetylene such as 3-methyl phenylacetylene can obtain imidazo[1,2-a]pyridine 4u with low yield of 26% and an uncyclized linear product 4v (Scheme 2a). Most aryl acetylenes such as 4-methoxy phenylacetylene only obtain uncyclized products (Scheme 2b). It shows that the reactivity of terminal ynones is higher than that of traditional terminal alkyne.Open in a separate windowScheme 2Investigation the reaction of 2-aminopyridine (1a), aryl acetylenes (2f, 2g) and p-tosyl azide (3a).None of the product imidazo[1,2-a]pyridines 4a–4r have been reported previously, which were subject to full spectroscopic characterization (see ESI^† for details) and the derived data were in complete accord with the assigned structures. And 4a was confirmed by single-crystal X-ray analysis (Fig. 2).Open in a separate windowFig. 2Single-crystal X-ray analysis of 4a (CCDC 2121234).^†A possible reaction pathway for the formation of imidazo[1,2-a]pyridine (4a) from precursors 1a, 2a and 3a is shown in Scheme 3. Thus, in keeping with earlier proposals,^19,21 the substrates 2a and 3a are expected to react, in the presence of the copper(i) catalyst to form the metallated triazole A through the CuAAC procedure. Then, the complex A undergo a ring-cleavage rearrangement leading to a highly active intermediate N-sulfonyl-α-acylketenimine B. This last species B is captured by 1avia nucleophilic addition to generate the intermediate C, which deliver the observed product 4a by intramolecular oxidative coupling similar to literature.²³ Otherwise, due to the poor activity, most of the traditional terminal alkynes involved in the reaction will stop in the intermediate C leading the uncyclized products.Open in a separate windowScheme 3Plausible reaction mechanism.In summary, we have developed an original approach for the synthesis of polysubstituted imidazo[1,2-a]pyridines from a mixture of the corresponding 2-aminopyridines, sulfonyl azides and terminal ynones, through CuAAC/ring-cleavage process and generated a highly active intermediate α-acyl-N-sulfonyl ketenimines. More detailed novel reactions and the investigation of new applications of this intermediate are now being undertaken in our laboratory.     

Catalyst-free synthesis of tetrahydropyrimidines via formal [3+3]-cycloaddition of imines with 1,3,5-hexahydro-1,3,5-triazines

A practical and environmentally benign synthesis of poly-substituted tetrahydropyrimidines from readily available starting materials has been developed. This process features an unprecedented intermolecular formal [3+3]-annulation of imines and 1,3,5-hexahydro-1,3,5-triazines under catalyst-free conditions. Importantly, differing from previous transformations, the 1,3,5-triazines are firstly utilized as formal 1,3-dipoles in cycloaddition reactions.

A practical and environmentally benign synthesis of poly-substituted tetrahydropyrimidines via formal [3+3]-annulation of imines and 1,3,5-hexahydro-1,3,5-triazines under catalyst-free conditions has been developed.

Tetrahydropyrimidines are important heterocycles which have been widely explored in various biologically active molecules and advanced materials, possessing unique properties such as antiviral activity, anti-inflammatory, muscarinic agonist activity, and sensitivity to protein–DNA interactions.¹ However, efficient methods for tetrahydropyrimidine synthesis are rare² and some of them suffer from poor practicability with low yields, harsh reaction conditions and lack readily available starting materials. Therefore, to develop simple but efficient methodologies for the direct synthesis of polysubstituted tetrahydropyrimidines is highly demanded.As stable and readily available intermediates, 1,3,5-trisubstituted-hexahydro-1,3,5-triazines (simply as 1,3,5-triazines in this text) have been previously utilized as imine equivalents in various Lewis acid promoted [n+2]-cycloaddition reactions (Scheme 1a).³ They also have been employed as precursors of N-aryl formaldimines in hydroaminomethylation of π-unsaturated reactants pioneered by the Krische group,⁴ and as suitable reagents in asymmetric Mannich reaction subsequently reported by the groups of Feng⁵ and Kang⁶ (Scheme 1b). Recently, inspired by Krische''s work, we found that 1,3,5-triazines could be utilized as formal 1,4-dipoles in gold-catalyzed formal [4+1] and [4+3]-cycloaddition reactions to synthesize five- and seven N-heterocycles.^7a Afterwards, we have successfully developed a series of 1,3,5-triazines involved [2+2+2],^7b [2+1+2]^7c,d and formal [4+3] annulations^7e (Scheme 1c). Concurrently, the groups of Hashmi⁸ and Xu⁹ also described the gold-catalyzed cycloaddition of 1,3,5-triazines with activated alkynes to produce six- and seven-membered heterocycles. Just recently, Werz and co-worker reported an elegant formal [4+3]-cycloaddition of 1,3,5-triazines with donor–acceptor cyclopropanes to prepare seven-membered ring system.¹⁰ Although the great advances, the former reports focused on the use of 1,3,5-triazines as formal 1,2- or 1,4-dipoles. In continuation with our ongoing interest, we want to report here the first use of 1,3,5-triazines as formal 1,3-dipoles to react with imines, providing tetrahydropyrimidines in moderate to excellent yields under catalyst-free reaction conditions.Open in a separate windowScheme 1Previous reports and our protocol.Initially, the reaction of imine 1a and 1,3,5-triazine 2a was performed in various solvents at room temperature ( EntrySolventTemp (°C)Time (h)Conv.^b (%)Yield^c (%)1Toluenert10100842CH₂Cl₂rt1094793CHCl₃rt1092784DCErt1098805THFrt10100816MeCNrt10907871,4-Dioxanert1093778MeOHrt1092789EtOHrt10876710DMFrt10786011DMSOrt10816412Toluene4071008413Toluene6061008614Toluene80610086Open in a separate window^aReaction conditions: 1a (0.3 mmol), 2a (0.33 mmol), solvent (6 mL).^bDetermined by GC analysis.^cIsolated yields.With the optimal conditions in hand, we started to examine the scope of substrates (11Substrate scope^a,b