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

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

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

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

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

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

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

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

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

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

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

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

Fe-catalyzed esterification of amides via C–N bond activation

An efficient Fe-catalyzed esterification of primary, secondary, and tertiary amides with various alcohols for the preparation of esters was performed. The esterification process was accomplished with FeCl₃·6H₂O, which is a stable, inexpensive, environmentally friendly catalyst with high functional group tolerance.

An efficient Fe-catalyzed esterification of primary, secondary, and tertiary amides with various alcohols was performed. Esterification was accomplished with inexpensive, environmentally friendly FeCl₃·6H₂O, and with high functional group tolerance

The amide bond is not only employed as an important natural peptide skeleton in biological systems, but also as a versatile functional group in organic transformations.^1,2 Among amide transformations,^3,4 transamidation and esterification of amides have attracted widespread attention from organic chemists.^5–11 In contrast to transamidation of amides, esterification of amides is relatively difficult because of the low nucleophilicity of alcohols compared with amines.¹² To overcome this shortcoming, various processes for the esterification of amides have been developed, such as using an activating agent,⁶ employing twisted amides,⁷ and forming intramolecular assisted groups.⁸ For increasing the synthetic flexibility of esterification of amides, new catalytic systems Zn(OTf)₂ and Sc(OTf)₃ were developed by Mashima and Williams for the esterification of amides.⁹ Shimizu et al. reported CeO₂ catalyzed esterification of amides.¹⁰ Off late, progress of the significant Ni-catalyzed esterification of amides has gained precedence.¹¹ Although this approach produces satisfactory yield, the drawbacks such as the use of an expensive catalyst, generation of reagent waste, high temperature and the limited scope of the substrate still persists. Herein, under mild reaction conditions, we report a novel and efficient Fe-catalyzed esterification of amides for the synthesis of esters (eqn (1)). Compared to conventional methods, this esterification procedure is distinguished by using a stable, inexpensive, environment-friendly catalyst, i.e., FeCl₃·6H₂O with a low toxicity solvent. The catalytic system has wide functional group compatibility. The reactions of several primary, secondary, and tertiary amides with various alcohols have been well tolerated in this process. Moreover, esters were also as effective as esterification reagents for the esterification of amides by the acyl–acyl exchange process. In the course of our present study, a Co-catalyzed amide C–N cleavage to form esters was reported by Danoun et al.¹³ However, an additional additive (Bipy) and Mn (3 equiv.) were needed and the scope of the reaction was limited to only tertiary amides; primary or secondary amides were not compatible with this catalytic oxidation system.1We initially selected benzamide 1a and ethanol 2a as model substrates to screen the reaction conditions, and the results are summarized in EntryCatalyst (20%)Additive (40%)Yield^b1FeCl₂—312FeCl₃—313FeBr₃—254FeSO₄·7H₂O—205Fe(NO₃)₃·9H₂O—206FeCl₃·6H₂O—357CuCl₂—Trace8PdCl₂—Trace9Ni₂Cl·6H₂O—Trace10———12FeCl₃·6H₂OPyridineTrace13FeCl₃·6H₂O1,10-PhenanthrolineTrace14FeCl₃·6H₂OFormic acidTrace15FeCl₃·6H₂O l-ProlineTrace16FeCl₃·6H₂OH₂SO₄2217FeCl₃·6H₂OHNO₃2518FeCl₃·6H₂OHCl9119—HCl3520^cFeCl₃·6H₂OHClTrace21^dFeCl₃·6H₂OHCl3622^eFeCl₃·6H₂OHCl2823^fFeCl₃·6H₂OHCl40Open in a separate window^aReaction conditions: 1a (0.2 mmol), 2a (0.1 mL), catalyst (0.04 mmol, 20 mol%), H₂SO₄ (concentrated, 0.24 mmol), HNO₃ (concentrated, 0.24 mmol), HCl (0.24 mmol, 36–38%), n-hexane (1.0 mL), 80 °C, 14 h.^bGC yield using hexadecane as internal standard.^cDMF was used as a solvent.^d1,4-Dioxane was used as solvent.^eToluene was used as solvent.^fCH₃CN was used as solvent.The substrate scope of esterification with alcohols was investigated under the optimized reaction conditions. As shown in EntryAlcoholProductsYield^b1Ethanol 2a 3a, 85%2 n-Propanol 2b 3b, 88%3 n-Octanol 2c 3c, 82%4 i-Propanol 2d 3d, 91%5 t-Butyl alcohol 2e 3e, 81%6Cyclohexanol 2f 3f, 80%7Phenethanol 2g 3g, 83%8Phenethanol 2h 3h, 81%9Trifluoroethanol 2i 3i, 81%10Ethane-1,2-diol 2j 3j, 85%Open in a separate window^aReaction conditions: 1a (0.2 mmol), 2a (0.1 mL), 2b–2j (0.24 mmol), FeCl₃·6H₂O (0.04 mmol, 20 mol%), HCl (0.24 mmol, 36–38%), n-hexane (1.0 mL), 80 °C, 14 h.^bIsolated yield.We then examined the generality of amides and the results are compiled in EntryAmidesProducts and yield^b1 3k, 86%2 3l, 85%3 3m, 78%4 3n, 75%5 3o, 86%6 3p, 84%7 3q, 90%8 3r, 86%9 3s, 84%10 3t, 55%11 3u, 88%12 3v, 85%13 3w, 81%Open in a separate window^aReaction conditions: 1b–1n (0.2 mmol), 2a (0.1 mL), FeCl₃·6H₂O (0.04 mmol, 20 mol%), HCl (0.24 mmol, 36–38%), n-hexane (1.0 mL), 80 °C, 14 h.^bIsolated yield.In addition to alcohols, esters were also used as substrates for esterification of amides through the acyl–acyl exchange process under the optimal reaction conditions.¹⁴ As shown in EntryAmidesEstersProducts and yield^b11a 21a 31a 41a 51b 61c 71h Open in a separate window^aReaction conditions: 1a–1h (0.2 mmol), 2k, 2l (0.1 mL), 2m–2o (0.24 mmol), FeCl₃·6H₂O (0.04 mmol, 20 mol%), HCl (0.24 mmol, 36–38%), n-hexane (1.0 mL), 80 °C, 14 h.^bIsolated yield.The substrate scope of this iron-catalyzed esterification of secondary and tertiary amides with alcohols was investigated. Remarkably, when a secondary amide, viz., N-methylbenzamide (1o) and a tertiary amide, viz., N,N-diethylbenzamide (1p) were used as substrates, the corresponding esters 3a and 3v were afforded in high yield (Scheme 1).Open in a separate windowScheme 1Reaction of secondary and tertiary amides 1o and 1p with ethanol.In addition to aromatic primary, secondary and tertiary amides, the esterification of aliphatic primary, secondary and tertiary amides was also investigated under the optimal reaction conditions, the corresponding esters were afforded in good to excellent yield and the results are shown in Scheme 2. 2-Phenylacetamide (1q) participated in this catalytic reaction to form the ester 3y in 86% yield. N-Acetylaniline 1r and N,N-dimethylformamide 1s were also applicable to this catalytic system, and transformed into the corresponding esters 3z and 3z¹ in 79% and 82% yield respectively.Open in a separate windowScheme 2Reaction of aliphatic amides 1q, 1r and 1s with different alcohols.To demonstrate the effect of iron salt in the current catalytic system, several control experiments were carried out as shown in Scheme 3. When 1 equivalent FeCl₃·6H₂O was used as the catalyst in the absence of HCl, 3a was obtained in 90% yield. This result indicated that the catalytic cycle of the iron salt was hindered in the present reaction conditions. When the stronger bidentate ligands such as 2,2-bipyridine was used, 3a was not obtained and trace amounts of 3a were detected on using ferrocene as the catalyst, indicating that the iron salt catalyst showed low efficiency in the presence of the stronger ligand. Thus, it was deduced that free Fe(ii or iii) was effective for this reaction.Open in a separate windowScheme 3Control experiments.According to the reported literature^5d and our experimental results, the catalytic reaction pathways for the Fe-catalyzed esterification of amides by alcohols are proposed as shown in Scheme 4. The first step is the generation of the amidate complex A, which can be formed from free Fe(iii) and amide 1. The complex A reacts with alcohol 2 to produce an unstable intermediate B. The interaction between the alcohol oxygen and the carbonyl results in cyclic intermediate C, which is in equilibrium with its isomer D. Intermediate E can also be produced from Dvia C–N bond cleavage. Through the reaction of HCl and a new molecule amide, intermediate E produces the desired ester 3, ammonium chloride (colorless crystal, which was detected after the reaction), and the amidate complex A.Open in a separate windowScheme 4Plausible reaction mechanism for Fe-catalyzed esterification of amides by alcohols.     

Transition-metal-free regioselective C–H halogenation of imidazo[1,2-a]pyridines: sodium chlorite/bromite as the halogen source

A facile transition-metal-free regioselective halogenation of imidazo[1,2-a]pyridines using sodium chlorite/bromite as the halogen source is presented. The reaction has provided an efficient method for the formation of C–Cl or C–Br bonds to synthesize 3-chloro or 3-bromo-imidazo[1,2-a]pyridines which were then efficiently transformed into imidazo[1,2-a]pyridine core π-systems by Suzuki–Miyaura reactions.

We report highly efficient strategies for the synthesis of 3-Cl or 3-Br-imidazo[1,2-a]pyridines using sodium chlorite/bromite as the halogenic source.

Aryl halides as a structural skeleton are present in a large number of natural products, pharmaceuticals, and biologically active compounds.¹ Significant drugs such as Aripiprazole, Chlortrimeton, Plavix and Zoloft all included the aryl chlorides motif (Scheme 1). Apart from this, aryl bromides have always been extremely important synthetic intermediates and building blocks in organic chemistry² for the construction of diverse and highly functionalized compounds. In the past few years, aryl halides have been used as substrates to form carbon–carbon and carbon–heteroatom bonds via transition-metal-catalyzed cross-coupling reactions. There are some classical methods: Heck, Suzuki, Negishi, Stille, Sonogashira, Ullmann, Buchwald–Hartwig, Kumada, etc.^3–10 Consequently, the development of a new route for the construction of these scaffolds is highly desirable, especially those based on assembling structures directly from readily available raw materials. In the last few years, several transition-metal-catalyzed halogenation transformations^11,12 have been developed, employing Pd, Rh or Cu as the catalysts and carboxylic acid, amide, nitrile, or pyridine as the directing groups (Scheme 1a). Recently, NH₄X, NaX and HX have been also employed as the halogen sources¹³ in transition-metal-free conditions for the halogenation of several arenes and heteroarenes (Scheme 1b). Nevertheless, directing groups and additional oxidants were usually needed in these transformations and the halogen sources were very limited.Open in a separate windowScheme 1Chlorine containing drugs.In order to expand the richness of green synthetic methods, we tried to hunt for other atom-economical and easy-to-obtain halogen sources. As we know, sodium chlorite or bromite are commodity chemicals that are widely used as main effective components of bleaches or desizing agents.¹⁴ On the other hand, imidazo[1,2-a]pyridines represent an important class of molecules and show unique bioactivities and chemical properties¹⁵ that lead them to broad applications in organic synthesis and pharmaceutical chemistry.¹⁶ Recent significant advances¹⁷ have been achieved in this field. We have also developed novel strategies for the construction of imidazo[1,2-a]pyridines.¹⁸ Herein, our current interest is focused on developing an efficient transition-metal-free selective halogenation of imidazo[1,2-a]pyridines without direct group, in which process sodium chlorite or bromite were used as both halogen sources and oxidants (Scheme 2c).Open in a separate windowScheme 2Selective halogenation reactions.Our initial investigation focused on the halogenation of imidazo[1,2-a]pyridine 1a. The results of the optimized reaction conditions are summarized in EntryNaClO₂ (equiv.)AdditiveSolventTemp (°C)Yield^b (%)12AcOHToluene606423AcOHToluene606231AcOHToluene604342CF₃COOHToluene604052PivOHToluene602962TsOHToluene603172—Toluene60Trace82AcOHDioxane606992AcOHNMP6045102AcOHCH₃CN6037112AcOHDMSO6063 12 2 AcOH DMF 60 87 132AcOHDCE6014142AcOHDMF4074152AcOHDMF808516^c2AcOHDMF60n.r.Open in a separate window^aReaction conditions: 1a (0.5 mmol), NaClO₂ (1–3 mmol), AcOH (2 mmol), solvent (2 mL), 40–80 °C for 10 h.^bDetermined by GC analysis.^cWithout NaClO₂.With the establishment of the optimal conditions, the scope of this transition-metal-free chlorination reaction was next investigated. And the results have been described in Scheme 3. A variety of 2-unsubstituted imidazo[1,2-a]pyridines were first employed under the optimized conditions. Different position substituted groups on the pyridine ring of imidazo[1,2-a]pyridine, having 6-CH₃, 6-Cl, 6-I, 7-CH₃, 8-CH₃ substitution, were well-tolerated under the optimized conditions. The results indicated that selective C-3 chlorination products 2a–2f were formed in good to excellent yields. This catalytic system was further found to be successfully applied to catalyze the chlorination of 2-CH₃, 2-C(CH₃)₃, and 2-Ph substituted imidazo[1,2-a]pyridines, generating the desired products in moderate to good yields (2g–2p). It was worth noting that when imidazo[1,2-a]pyridines substituted with sterically hindered 2-C(CH₃)₃ were employed as substrates, the transformation worked well and led to a beneficial effect on the reaction outcome.Open in a separate windowScheme 3Chlorination of imidazo[1,2-a]pyridines.We next examined the bromination of imidazo[1,2-a]pyridines derivatives in the presence of NaBrO₂ and AcOH in DMF at 60 °C for 10 h. The results were summarized in Scheme 4. As we expected, the optimal conditions could also be applied to bromination of imidazo[1,2-a]pyridines and afforded the brominated products 3a–3f in 70–88% yields. It was found that the reaction was also with great regioselective in the case of 2-unsubstituted imidazo[1,2-a]pyridines.Open in a separate windowScheme 4Bromination of imidazo[1,2-a]pyridines.The reactions of 2a or 3d with phenylboronic acid were conducted in the presence of Pd-catalyst (Scheme 5). The Suzuki–Miyaura reactions were performed very well, affording the product 5a or 6a in 74% or 79% yields, respectively.Open in a separate windowScheme 5Suzuki–Miyaura reactions of 2a or 3d with phenylboronic acid.In order to text whether this method is compatible with other aromatic species or not, we have tried to use indoles, 1-methyl-1H-indoles, benzofurans, N,N-dimethylaniline, N-phenylacetamide and 1,3,5-trimethoxybenzene to perform under the present reaction conditions, while no target products were obtained. We supposed that the specificity of this reported method is because of the rich electronic ethene-1,2-diamine moiety of imidazo[1,2-a]pyridine (Scheme 6).Open in a separate windowScheme 6Applications for other aromatic species.Gaining insight into the mechanism, control experiments were carried out for this transition-metal-free halogenation reaction. To prove a radical species involved in transformation, the reactions were conducted by adding radical-trapping reagent (TEMPO) or radical inhibitor (BHT) (Scheme 7, eqn (1)) in the reaction, and only trace amount of product 2a was observed. The result clearly showed that this reaction had been inhibited and a radical process was involved for this transformation, which was consistent with previous reported.¹⁷ To further investigated the chlorine source, NaClO and NaClO₃ were employed to react with imidazo[1,2-a]pyridine 2a under the standard conditions. The results showed that the chlorination products were obtained in yields of 47% or 63% respectively, which means chlorine ions having a charge of 1+ or 5+ can also proceed this transformation, albeit with low yields (Scheme 7, eqn (2)).Open in a separate windowScheme 7Control experiments for investigation of the mechanism.Base on the above results and previous works,¹⁹ a possible mechanism was proposed to account for this transition-metal-free regioselective halogenation reaction (Scheme 8). Firstly, oxidation–reduction reaction of sodium chlorite happened in the presence of AcOH to produce chlorine, NaOAc and H₂O. Subsequently, the chlorine radical was easily formed via homolysis of chlorine, which then attack the double bond between C2 and C3 of imidazo[1,2-a]pyridine, resulting in free radical intermediate I (more stable than II because of the p–π conjugation). Finally, the free radical intermediate I underwent an aromatization with chlorine free radical to give the target product 2a.Open in a separate windowScheme 8Possible mechanism.     

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

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

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

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

[3 + 2] cycloaddition of nonstabilized azomethine ylides and 2-benzothiazolamines to access imidazolidine derivatives

A simple and practical method for the construction of 1,3,5-trisubstituted imidazolidine derivatives via [3 + 2] cycloaddition reaction has been developed. This reaction could smoothly proceed between nonstabilized azomethine ylides generated in situ and 2-benzothiazolamines to deliver a wide scope of differently substituted imidazolidines in high yields (up to 98%). The structure of one example was confirmed by X-ray single-crystal structure analysis.

An effective method for the synthesis of functionalized imidazolidine derivatives via a [3 + 2] cycloaddition reaction from nonstabilized azomethine ylides generated in situ from 2-benzothiazolamines in high yields (up to 98%) has been developed.

Heterocyclic compounds are important structural motifs that are frequently discovered in natural products and biologically active molecules, with wide applications and potency in the field of medicinal chemistry.¹ Among them, the 2-aminobenzothiazole scaffolds, which contain a core of isothiourea motifs as a privileged scaffold, are ubiquitous in natural products, drugs and bioactive compounds.² Some examples of biologically active molecules and pharmaceuticals containing benzothiazoles are shown in Fig. 1. These compounds display a variety of important biological activities, such as anti-HIV, anticancer, antineoplastic and anticonvulsant activity, and so on.³Open in a separate windowFig. 1Selected examples of biologically active compounds containing a 2-aminobenzothiazole scaffolds.Due to their momentous and potent biological activities and structural diversifications, more organic and medicinal chemists have been significantly attracted to developing effective and advanced methodologies for the construction of benzazole scaffolds.⁴ The 2-benzothiazolamines could serve as alternative C4 synthons with various reaction partners in [4 + 2] cycloadditions for the straightforward and convenient access to 2-aminobenzothiazole scaffolds, and this type of reaction has been well established (Scheme 1a).⁵ By contrast, the 2-benzothiazolamines which acted as C2 synthons in cycloaddition reactions have been very limited.⁶ Therefore, the development of efficient cycloaddition between the 2-benzothiazolamines as C2 synthons and suitable reaction partners to provide diverse functionalized heteroarenes molecules is always in great demand.Open in a separate windowScheme 1Previous reports and our protocol.On the other hand, the 1,3-dipole cycloaddition is recognized one of the most efficient and powerful methods for building five membered heterocyclic rings from simple starting materials.⁷ In particular, the nonstabilized azomethine ylides generated in situ from N-benzyl-substituted compounds were a highly reactive intermediate with unsaturated compounds, such as activated alkenes,⁸ aromatic ketones,⁹ aromatic aldehydes,¹⁰ phthalic anhydrides,¹¹ imines,¹² cyano compounds¹³ or stable dipoles,¹⁴ to build various N-containing heterocycles via [3 + 2] or [3 + 3] cycloaddition reactions (Scheme 1b). Despite the progress were well developed via 1,3-dipolar cycloadditions employing nonstabilized azomethine ylides as the substrates, challenges still remain. Herein, we would like to present an effective process to furnish functionalized 1,3,5-trisubstituted imidazolidine derivatives via [3 + 2] cycloaddition strategy from 2-benzothiazolamines with nonstabilized azomethine ylides generated in situ (Scheme 1c). In contrast, the desired product was not obtained via [4 + 3] cycloaddition reaction.Initially, we used 2-benzothiazolimine 1a and N-(methoxymethyl)-N-(trimethylsilyl-methyl)-benzyl amine 2a which could in situ form azomethine ylide in the presence of acid as model substrates to optimize the reaction conditions. The results were shown in EntryAdditiveSolventTimeYield of 3a^b (%)1AcOHCHCl₃12482TfOHCHCl₃12513TFACHCl₃3904HClCHCl₃12205TFACH₂Cl₂1986TFADCE3827TFAEtOAc6758TFAToluene12709TFAMeOH123110TFACH₃CN37111TFADioxane125912TFAEt₂O124613TFATHF1262Open in a separate window^aReaction conditions: 2-benzothiazolimine 1a (0.1 mmol, 1.0 equiv.), N-(methoxymethyl)-N-(trimethylsilyl-methyl)-benzyl-amine 2a (0.12 mmol, 1.2 equiv.), addition (0.01 mmol, 0.1 equiv.) and solvent (1.0 mL) in a test tube at room temperature.^bYield of the isolated product.After establishing the optimal reaction conditions, the scope and limitations of this [3 + 2] cycloaddition reaction for formation of 1,3,5-trisubstituted imidazolidines were examined. The results were shown in †)¹⁵ was unequivocally confirmed by X-ray crystallographic analysis (see ESI^†). On the other hand, when the R² groups were heteroaromatic substituted group, such as 2-furanyl, 3-thienyl, 1-naphthyl and 2-naphthyl, the cycloaddition reaction were well tolerated and could also proceed smoothly without obvious interference to produce corresponding pyrazoles 3k–3n in 92–96% yields. Meanwhile, substituted substrates at the C4 or C6-position of the 2-aminobenzothiazole, such as Me and Cl were also reacting smoothly to afford the corresponding products in 95%, 96% yields (3o–3p), respectively. Notably, the 2-benzoxazolimine as substrate also reacted smoothly with azomethine ylides 2a to deliver the corresponding product 3q in high yield (94%). Especially, when using (R)-nonstabilized azomethine ylide as the chiral substrate in the cycloaddition reaction, the reaction could proceed smoothly under the standard conditions to afford the corresponding chiral product 3r in 95% yield as single diastereomer only. The chiral center was determined by NOESY analysis (see ESI^†). Nevertheless, as for the R² group, when it was changed from an aryl group to an alkyl group, the reaction did not take place (3s). The possible reason may be due to the low activity of alkyl substituted substrate.Substrate scopes for the formation of 1,3,5-trisubstituted imidazolidine derivatives 3^a

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

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

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

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

Photoinduced successive oxidative ring-opening and borylation of indolizines with NHC–boranes

A facile photoinduced successive oxidative ring-opening and borylation of indolizines with NHC–boranes via a one-pot method has been unveiled. This photo-promoted strategy enables the formation of unsaturated NHC–boryl carboxylates under transition metal-free and radical initiator-free conditions. A wide array of pyridine-containing NHC–boryl carboxylates were directly prepared in moderate to good yields. This work contributes to a better understanding of the reactivity and photo-behavior of both indolizines and NHC–boranes.

A facile photoinduced successive oxidative ring-opening and borylation of indolizines with NHC–boranes via a one-pot method has been unveiled. This photo-promoted strategy enables the formation of unsaturated NHC–boryl carboxylates under transition metal-free conditions.

Organoboron compounds are of vital significance in modern organic synthesis, and they also show great promise in luminescent materials, covalent organic frameworks, and pharmaceutical industries.^1–3N-Heterocyclic carbene (NHC)–boranes have recently gathered a lot of attention in building various C–B bonds.⁴ In fact, as an increasingly popular and reliable boron source, NHC–boranes have the typical characteristics of being: (1) weaker B–H bonds compared to other LB·BH₃; (2) stable solids under ambient conditions; (3) easily prepared on the gram scale. Owing to these advantages, many borylation methods via NHC–boryl radicals have been extensively exploited.⁵ Among them, photochemical borylations with high efficiency have become a powerful, practical, and economic strategy.⁶ For example, Xie and Zhu reported a photoinduced inverse hydroboration of imines and alkenes with NHC–boranes.⁷ Visible-light-induced selective defluoroborylation of fluorinated alkenes have been well established by Wu, Wang, Yang, and co-workers (Scheme 1a).⁸ Recently, Curran reported an Ir-catalyzed 1,4-hydroboration of electron-deficient arenes with NHC–BH₃ under CFL irradiation (Scheme 1b).⁹ Very recently, Wang, Liang, and Zhu disclosed a photoinduced regio- and stereoselective fluorocarboborylation of alkenes.¹⁰ However, direct C–H borylation of N-heterocycles especially for indolizines utilizing NHC–boranes have not been successfully developed.Open in a separate windowScheme 1Visible light-induced borylation with NHC–BH₃.Indolizines, which contain 10 π-electrons, are isoelectronic with indole. So, they represent an important class of N-heterocycles and are widely applied in the field of material science.¹¹ We have long been committed to developing green and sustainable new methods for C–H bond functionalization of indolizines to synthesize indolizines derivatives.¹² In 2019, we disclosed visible-light-induced intermolecular [3 + 2] alkenylation–cyclization of indolizines to obtain pyrrolo[2,1,5-cd]indolizines.¹³ Very recently, we successfully constructed pyrrolo[2,1,5-cd]indolizine rings via visible-light-induced intermolecular [3 + 2] cycloaddition of indolizines and alkynes.¹⁴ Considering the great value of organoboron compounds, we expected that direct C–H borylation of indolizines with NHC–boranes would be realized via a clean photoredox system (Scheme 1c). However, the desired borylated indolizines were not observed via photoinduced C(sp²)–H borylation of indolizines and NHC–boranes. It turned out that sequence photooxygenation–borylation of indolizines occurred, delivering the deconstructive NHC–boryl carboxylates, and this type of borane compound is rarely reported.¹⁵ Herein, we disclose our unexpected findings that successive oxidative ring-opening and borylation of indolizines with NHC–boranes was accomplished under the irradiation of visible light. A variety of NHC–boryl carboxylates could be afforded through this manner (Scheme 1c).To optimize the conditions, we employed 2-phenylindolizine 1a and NHC–borane 2a as the model substrates for reaction development ( EntryPhotocatalystAdditiveSolventYield^b (%)1Rose bengal—CH₃CN362Eosin Y—CH₃CN183Rhodamine 6G—CH₃CNn. d.4Fluorescein—CH₃CNn. d.5Ir(ppy)₃—CH₃CN236Rose bengalCs₂CO₃CH₃CN517Rose bengalK₂CO₃CH₃CN388Rose bengalDBUCH₃CN219Rose bengalDABCOCH₃CN14 10 Rose bengal NaOAc CH ₃ CN 72 11Rose bengalNaOAcTHF6812Rose bengalNaOAcDCE6013Rose bengalNaOAcToluene4514Rose bengalNaOAcDMSO5115—NaOAcCH₃CNn. d.16^cRose bengalNaOAcCH₃CNn. d.17^dRose bengalNaOAcCH₃CN7018^eRose bengalNaOAcCH₃CNn. d.19^fRose bengalNaOAcCH₃CNn. d.20^gRose bengalNaOAcCH₃CNn. d.Open in a separate window^aStandard conditions: 1a (0.2 mmol), 2a (0.4 mmol), photocatalyst (5 mol%), additive (0.4 mmol), solvent (2 mL), and irradiation with a 20 W blue LED for 12 h, air, n. d. = not detected.^bIsolated yields.^cWithout light.^dUnder O₂.^eUnder N₂.^fCuI (5 mol%).^gCu(OAc)₂ (5 mol%).Then, we turned our attention to examining the effect of different additives, such as Cs₂CO₃, K₂CO₃, DBU, DABCO, and NaOAc (i) or Cu(ii) salts (Scheme 2). The reaction proceeded well under the standard reaction conditions and afforded the corresponding NHC–boryl carboxylates 3a–3aa in 56–75% yields. For example, alkyl substituents (–Me or –Et) and electron-donating substituents (–OMe), electron-withdrawing substituents (–Br) substituted on the indolizine ring did not affect the reactivity, and they were effective to afford NHC–boryl carboxylates under the optimized conditions (3b–3g). A series of various functional groups substituted on the ortho, para and meta position of benzene ring were compatible too (3h–3r). We next tested the reactivity of the substrates that are dichlorosubstituted on benzene rings, and the desired products 3s and 3t were obtained in 70% and 72% yields. Furthermore, when the model substrate 1a was replaced by 2-(4-fluorophenyl)-8-methylindolizine 1u, 2-(4-chlorophenyl)-8-methylindolizine 1v, and their analogues(1w–1z), respectively, the corresponding products (3u–3z) were obtained in good yields as well. The molecular structure of the product 3w was determined by X-ray crystallography (CCDC number: 2116778) (Scheme 3). In addition, the reaction of 2-(naphthalen-2-yl)indolizine 1aa with 2a was also performed to give the desired NHC–boryl carboxylate 3aa in 70% yield.Open in a separate windowScheme 2Substrate scope of 2-phenylindolizine^a. ^aReaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), RB (5 mol%), NaOAc (0.4 mmol), MeCN = 2 mL, irradiation with a 20 W blue LED for 12 h, air, isolated yield.Open in a separate windowScheme 3Crystal structure of compound 3w.Next, we further turned our attention to exploring the NHC–borane of this photoinduced successive oxidative ring-opening and borylation reaction. We employed (1-isopropyl-3-methyl-1H-imidazol-3-ium-2-yl) trihydroborate 2b instead of 2a to participate in photoinduced transformation (Scheme 4). It was pleased to find that the desired NHC–boryl carboxylate 4a was obtained in 71% yield under the standard reaction conditions.Open in a separate windowScheme 4Substrate scope of NHC–borane^a. ^aReaction conditions: 1a (0.2 mmol), 2b (0.4 mmol), RB (5 mol%), NaOAc (0.4 mmol), MeCN (2 mL), and irradiation with a 20 W blue LED for 12 h. Isolated yield.After the substrate scope exploration of this transformation, the scale-up experiment was studied. We enlarged the model substrate 1a to 1.0 mmol with 2a (2 mmol) under the irradiation with a 20 W blue LED for 12 h, and we found that boryl carboxylate product 3a was still produced though the yield has a small decrease (49%) (Scheme 5).Open in a separate windowScheme 5Scale-up experiment^a. ^aReaction conditions: 1a (1.0 mmol), 2a (2.0 mmol), RB (5 mol%), NaOAC (2 mmol), MeCN (10 mL), and irradiation with a 20 W blue LED for 12 h.To gain some insight into the mechanism of this transformation, several controlled experiments were designed and carried out (Scheme 6). The yield of 3a dropped sharply when the reaction of 1a with 2a was conducted in the presence of a radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or 2,6-di-tert-butyl-4-methylphenol (BHT).Open in a separate windowScheme 6Control experiment.Based on our experimental results and literature reports,^13,16 the possible mechanisms for this reaction of the ring-opening and borylation of indolizines have been depicted in Scheme 7. Under visible-light irradiation, the ground state of RB is converted to the excited RB* via the energy transfer, which interacts with ³O₂ to give the ¹O₂ and RB to realize the photoredox cycle. In the presence of singlet oxygen, 1a readily forms the perepoxide exciplex A which is easily transferred to peroxidic zwitterion intermediate B. Subsequently, the intermediate B produced the intermediate C by intramolecular electron transfer. Then the trace amount of water in the solvent attack at C3 of intermediate C and cleavage the C–N bond to give the intermediate D, which would get rid of a molecule of water to generate acrylic acid intermediate E. Finally, the intermolecular reaction of acrylic acid intermediate E to NHC–borane 2a furnishes the target product 3a.Open in a separate windowScheme 7Plausible mechanistic pathway.     

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

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

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

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

Base-promoted highly efficient synthesis of nitrile-substituted cyclopropanes via Michael-initiated ring closure

A convenient and efficient annulation reaction has been developed for the general synthesis of dinitrile-substituted cyclopropanes in moderate to excellent yields. A variety of 2-arylacetonitriles and α-bromoennitriles were compatible under the standard conditions. The reaction was achieved through tandem Michael-type addition followed by intramolecular cyclization. The preliminary application of this method was confirmed by the synthesis of the 2,4-dioxo-3-azabicyclo[3.1.0]hexane scaffold.

An efficient base-promoted synthesis of nitrile-substituted cyclopropanes from 2-arylacetonitriles and α-bromoennitriles under mild conditions via Michael-initiated ring closure.

Substituted cyclopropanes, as attractive structural units, are commonly found in a variety of natural products and biologically active compounds.¹ The strained structure, interesting bonding characteristics, and value as an internal mechanistic probe of the cyclopropane subunit have attracted the attention of the physical organic community.² As a consequence, considerable efforts have been made to develop new and effective approaches toward cyclopropane derivatives.³ Classical approaches to cyclopropane synthesis are the Simmons–Smith cyclopropanation.⁴ Transition-metal-catalyzed cyclopropanation of alkenes with diazo compounds represents a direct protocol for their preparation.⁵ Furthermore, the new types of cyclopropanation reactions based on nucleophilic addition-ring closure sequence were well documented (Scheme 1a and b).⁶ Nitrile-substituted cyclopropanes are of great interest as they are versatile templates for the rapid formation of biologically active and synthetically useful functionalized cyclopropane derivatives.⁷ Recently, nitrile-substituted cyclopropanes were synthesized via transition-metal-catalyzed olefin functionalization with diazoacetonitriles.⁸ Despite the significant advancement, the development of complementary strategy toward functionalized cyclopropanes by using readily available substrates and cheap agents with high efficiency would be highly desirable.Open in a separate windowScheme 1Methods for synthesis of cyclopropane derivatives.α-Bromoennitrile is a class of readily available intermediate in organic synthesis.⁹ However, this intermediate is rarely used in organic synthesis compared to its analog α-bromoenal.¹⁰ Recently, our group has reported a series of functionalization of 2-arylacetonitriles and their derivatives.¹¹ We hypothesized five-membered nitrogen containing heterocycles could be formed from 2-pyridylacetonitrile and α-bromoennitriles via [3 + 2] annulation. However, dinitrile-substituted cyclopropanes were afforded through a novel Michael-initiated ring closure procedure (Scheme 1c). Herein, we present a base-promoted synthesis of dinitrile-substituted cyclopropanes from 2-arylacetonitriles and α-bromoennitriles under mild conditions via Michael-initiated ring closure (Scheme 1d).Initially, (Z)-2-bromo-3-phenylacrylonitrile 1a and 2-pyridylacetonitrile 2a were selected as the model substrates for the condition optimization. As illustrated in EntryBaseSolventTemp.Yield^b (%)1DABCOMeCNrtTrace2DBUMeCNrt383TEAMeCNrtnp4DMAPMeCNrtnp5Cs₂CO₃MeCNrt956K₂CO₃MeCNrt677NaOAcMeCNrt428K₃PO₄MeCNrt899KO^tBuMeCNrt8410—MeCNrtnp11Cs₂CO₃DMFrt8712Cs₂CO₃DMSOrt3613Cs₂CO₃H₂Ortnp14Cs₂CO₃DCErt6715Cs₂CO₃THFrtnp16Cs₂CO₃Dioxanert5317Cs₂CO₃MeCN06218Cs₂CO₃MeCN50npOpen in a separate window^aReaction conditions: 1a (0.2 mmol), 2a (0.2 mmol) and base (1.5 equiv.) in solvent (1.0 mL) for 12 h.^bYields of isolated cis-3a and trans-3a are given. Cis refers the two nitriles positioned on the same face of the cyclopropane; trans refers the two nitriles positioned on the opposite face of the cyclopropane.Having the developed optimal conditions for the Michael-initiated ring closure reaction, the substrate scope was investigated. As illustrated in Scheme 2, a wide range of 2-arylacetonitriles were tolerated with (Z)-2-bromo-3-phenylacrylonitrile 1a to render dinitrile-substituted cyclopropanes in moderate to excellent yields (3a–3u). Except for 2-pyridylacetonitrile, 3-pyridyl and 4-pyridyl derivatives also reacted smoothly to generate the products in good yields (3a–3c). The annulation with 2-pyridylacetonitrils bearing electron-donating groups and withdrawing groups in the pyridine ring worked well to deliver the products in satisfactory yields (3d–3h). Thienyl derivatives were reactive to afford the corresponding products, but exhibited lower reactivity compared with pyridyl (3i–3j). In addition to heteroaryl-substituted substrates, various 2-arylacetonitriles were further tested. The reaction conditions were compatible with an array of substituents, such as alkyl, methoxy, phenyl, chloro, bromo, trifluoromethyl, fluoro, and cyano groups (3k–3u). In particular, the aryl bromide could be further functionalized in metal-catalyzed cross-coupling reactions and hold the enormous potential application in pharmaceutical and materials science (3p–3q). To our delight, nitrile-containing substrate could provide the product 3u in 86% yield. Significantly, the annulation reaction could be carried out on large-scale synthesis and formed the product 3a in 87% yield. The structure of cis-3a was verified by X-ray crystal analysis (CCDC: 2141258^†).Open in a separate windowScheme 2Substrate scope of 2-arylacetonitriles^a. ^aReaction conditions: 1a (0.2 mmol), 2 (0.2 mmol), Cs₂CO₃ (1.5 equiv.) and CH₃CN (1.0 mL) at room temperature for 12 h; isolated yields are given unless otherwise noted. Cis refers the two nitriles positioned on the same face of the cyclopropane; trans refers the two nitriles positioned on the opposite face of the cyclopropane. ^b2 mmol scale.Continuing to examine the generality and scope of the annulation reaction, we explored various α-bromoennitriles under the standard conditions (Scheme 3). α-Bromoennitriles bearing electron-rich or electron-deficient groups on the benzene ring reacted successfully with 2-pyridylacetonitrile to achieve the desired products in good yields (4a–4h). The substrates bearing a methyl at the ortho- and meta-positions of the benzene ring were suitable substrates for the transformation, thus indicating the steric hindrance is negligible (4a–4b). The bulky tert-butyl group was accommodated in this transformation (4c and 4j). The disubstituted α-bromoennitrile proved to be good substrate under the same reaction conditions (4d). The reaction of the fused ring system also yielded the products in satisfactory yields (4f). Finally, phenylacetonitriles also worked well with α-bromoennitriles to obtain the corresponding product in good yields (4i–4m). The structure of trans-4b was further confirmed by X-ray crystal diffraction measurements (CCDC: 2142244^†). It implied that this Michael-initiated ring closure reaction can be effective for the construction of dinitrile-substituted cyclopropane library.Open in a separate windowScheme 3Synthesis of nitrile-substituted cyclopropanes^a. ^aReaction conditions: 1 (0.2 mmol), 2 (0.2 mmol), Cs₂CO₃ (1.5 equiv.) and CH₃CN (1.0 mL) at room temperature for 12 h; isolated yields are given unless otherwise noted. Cis refers the two nitriles positioned on the same face of the cyclopropane; trans refers the two nitriles positioned on the opposite face of the cyclopropane. ^bThe cis/trans (isomer) ratio was determined by crude ¹H NMR.To illustrate the applicability of this reaction, further transformation of product cis-3a was carried out as depicted in Scheme 4. 2,4-Dioxo-3-azabicyclo[3.1.0]hexane scaffold is known to be an important pharmacology agent and synthons for synthesis of functionally substituted cyclopropanes and various spirocompounds.¹² The target compound 5a can be readily accessible in excellent yield via a simple hydrolysis reaction. It is worth noting that similar result was obtained for trans-3a.Open in a separate windowScheme 4Synthetic application.A tentative mechanism for cyclopropane formation was proposed and outlined in Scheme 5 on the basis of aforementioned results as well as our experimental observations. Initially, carbanion intermediate B was produced via the sequential extraction of hydrogen proton and Michael-type addition process. Then the intermediate B was converted into intermediate C through 1,3-hydride transfer. Finally, the dinitrile-substituted cyclopropane 3a was formed through intramolecular nucleophilic substitution. The diastereomer 3a is the favored product due to steric effects, in which the two aryl groups are located on the opposite face of the plane of the cyclopropane moiety.Open in a separate windowScheme 5Possible reaction mechanism.In summary, we have explored a convenient and highly efficient annulation reaction of 2-arylacetonitriles and α-bromoennitriles. A wide range of dinitrile-substituted cyclopropanes were obtained in moderate to excellent yields through a novel Michael-initiated ring closure procedure. The advantages of this transformation include readily accessible substrates, transition-metal-free conditions, good functional group tolerance, simple operation, etc. In addition, nitrile-substituted products have potential applications in synthetic and pharmaceutical chemistry. Further synthetic utilization and asymmetric transformations are currently ongoing in our laboratory.     

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

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

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

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

1,1-Difluoroethyl chloride (CH3CF2Cl), a novel difluoroalkylating reagent for 1,1-difluoroethylation of arylboronic acids

1,1-Difluoroethylated aromatics are of great importance in medicinal chemistry and related fields. 1,1-Difluoroethyl chloride (CH₃CF₂Cl), a cheap and abundant industrial raw material, is viewed as an ideal 1,1-difluoroethylating reagent, but the direct introduction of the difluoroethyl (CF₂CH₃) group onto aromatic rings using CH₃CF₂Cl has not been successfully accomplished. Herein, we disclose a nickel-catalyzed 1,1-difluoroethylation of arylboronic acids with CH₃CF₂Cl for the synthesis of (1,1-difluoroethyl)arenes.

1,1-Difluoroethylated aromatics are of great importance in medicinal chemistry and related fields.

Organic fluorine compounds have attracted extensive attention in recent years, since the introduction of fluorine atom(s) into organic molecules often results in dramatic changes in physical, chemical and biological properties.^1,2 Among them, aromatic compounds containing the difluoroethyl (CF₂CH₃) group are of great importance, because it mimics the steric and electronic features of a methoxy group, which makes it a significant group for drug design.³ For instance, a triazolopyrimidine-based dihydroorotate dehydrogenase (DHODH) inhibitor⁴ shows remarkable advantage in terms of potency due to the replacement of a methoxy group by a difluoroethyl group (Scheme 1A). LSZ102,⁵ a clinical agent, is currently applied in phase I/Ib trials for the treatment of estrogen receptor alpha-positive breast cancer (Scheme 1A). Thus, the invention of reagents or methods for the synthesis of (1,1-difluoroethyl)arenes is a very appealing and pretty meaningful task.Open in a separate windowScheme 1(A) Difluoroethyl-containing bioactive and drug molecules; (B) strategies for synthesis of (1,1-difluoroethyl)arenes. M = metal; (C) application of 1,1-difluoroethyl chloride.The synthesis of such compounds are generally accomplished by two strategies:⁶ one is the transformation of a functional group to a difluoromethylene (CF₂) group or a CF₂CH₃ moiety, such as nucleophilic fluorination of ketones or their derivatives,⁷ dihydrofluorination of terminal arynes,⁸ and benzylic C–H fluorination;⁹ the other is the direct introduction of a CF₂CH₃ moiety onto aromatic rings, including nucleophilic,¹⁰ electrophilic¹¹ and radical 1,1-difluoroethylation¹² (Scheme 1B). In spite of these important accomplishments, it is still a key challenge to develop low-cost and easily available difluoroalkylating reagents for synthesis of (1,1-difluoroethyl)arenes.1,1-Difluoroethyl chloride (CH₃CF₂Cl; HCFC-142b; bp = −9.5 °C), a cheap and abundant industrial raw material used for vinylidene fluoride (VDF),¹³ is viewed as an ideal source to prepare difluoroethylated derivatives.¹⁴ We envisioned that the direct introduction of CF₂CH₃ onto aromatic rings could be through transition-metal-catalyzed 1,1-difluoroethylation of arylboronic acids with CH₃CF₂Cl (Scheme 1C). Although transition-metal-catalyzed difluoroalkylation of aromatics using activated difluoroalkyl halides (RCF₂X, R = π system) has been successfully reported,¹⁵ the use of unactivated RCF₂X (R = alkyl) for synthesis of difluoroalkylarenes was rarely reported.^11,16 To the best of our knowledge, the use of CH₃CF₂Cl to prepare Ar–CF₂CH₃ compounds through a Suzuki-type cross-coupling reaction has not been reported and remains challenges because of the difficulties in activating the inert C–Cl bond of CH₃CF₂Cl and in suppressing homo-coupling and deboronation of arylboronic acids. Herein, we wish to disclose a nickel-catalyzed 1,1-difluoroethylation of arylboronic acids with CH₃CF₂Cl.At the onset of our investigation, 4-biphenylboronic acid (2a) was chosen as the model substrate for the nickel-catalyzed 1,1-difluoroethylation reaction (†), we next investigated the influence of additives and solvent. As previously reported,^16,17 pyridine derivatives could promote Ni-catalyzed Suzuki–Miyaura cross-coupling reactions. Thus, we attempted the current reaction in the presence of pyridine and its derivatives. As expected, the use of 4-(N,N-dimethylamino)pyridine (DMAP) afforded a higher yield of 3a (†), it was found that 1,4-dioxane and DMF were inferior to DME ( EntryLigand (mol%)Additive (mol%)SolventYield^b (%)1bpy (5)—DME52L1 (5)—DME153L2 (5)—DME74L3 (5)—DME75Phen (5)—DMETrace6L1 (5)Py (10)DMETrace7L1 (5)4-CNPy (10)DMETrace8L1 (5)DMAP (10)DME309L1 (5)DMAP (50)DME4910L1 (5)DMAP (70)DME6111L1 (5)DMAP (100)DME5912^cL1 (3)DMAP (70)DME70 (69)^d13^c—DMAP (70)MMETrace14^cL2 (3)DMAP (70)DME2415^cL3 (3)DMAP (70)DME6116^cL1 (3)DMAP (70)1,4-Dioxane3117^cL1 (3)DMAP (70)DMF21Open in a separate window^aReaction conditions: 2a (0.2 mmol, 1.0 equiv.), 1a (2.0–2.6 mmol), NiCl₂(PPh₃)₂ (5 mol%), K₂CO₃ (2.0 equiv.), solvent (2 mL), 110 °C, N₂, 5 h.^bIsolated yield.^cNiCl₂(PPh₃)₂ (3 mol%).^dThe reaction was conducted for 12 h. bpy = 2,2′-bipyridine, phen = 1,10-phenanthroline, DME = 1,2-dimethoxyethane, DMAP = 4-(N,N-dimethylamino)pyridine.With the optimised conditions in hand, we further explored the substrate scope of the 1,1-difluoroethylation of arylboronic acids with CH₃CF₂Cl (Scheme 2). The reaction can tolerate a variety of functional groups, such as methyl, methoxyl, trifluoromethyl, trifluoromethoxy and substituted morpholine (Scheme 2, 3d–3h). Generally, the substituent group of arylboronic acids with π-system showed good reactivity toward CH₃CF₂Cl, affording the desired product in moderate to good yields (Scheme 2, 3a, 3b, 3m–3o). It was found that the reaction afforded slightly low yields with sterically hindered arylboronic acids under the standard conditions (Scheme 2, 3c, 3k, 3l). In addition, this transformation was also applicable to 4-(9H-carbozol-9-yl)phenylboronic acid and the 1,1-difluoroethylated product was obtained in 62% yield (Scheme 2, 3j).Open in a separate windowScheme 2Scope of 1,1-difluoroethylation of arylboronic acids with CH₃CF₂Cl. Reaction conditions (unless otherwise specified): 2 (0.2 mmol, 1.0 equiv.), 1a (1.3 M in DME, 2.6 mmol, 13.0 equiv.), DME (2 mL), 110 °C, N₂, 5 h. Isolated yields. ^aYields were determined by ¹⁹F NMR spectroscopy using PhCF₃ as an internal standard.To investigate the substituent effect of fluoroalkyl chlorides on the Suzuki-type reaction, we conducted comparative experiments using HCF₂Cl (1b), PhCF₂Cl (1c) and CF₃CF₂Cl (1d) under the standard conditions (Scheme 3A). When arylboronic acids and 1b were subjected to the standard conditions, the reaction provided difluoromethylated products (4a–4c) in moderate yields. However, the use of 1c and 1d gave poor yields of the corresponding products 4d and 4e, respectively. These results indicate that the reactivity of RCF₂Cl in the reaction with 2a decreases in the following order: CH₃CF₂Cl > HCF₂Cl > CF₃CF₂Cl ≈ PhCF₂Cl. Next, we intended to explore the fluorine effect on the reaction. Comparative experiments by the use of H₂CFCl (1e) and ClCH₂CH₂Cl (1f) were conducted under the standard conditions (Scheme 3B). It was found that the reaction of 1e with 2a afforded monofluoromethylated product 4f in a low yield, while β-chloroethylarenes (4g, 4h) were obtained in good yields under the standard conditions. These results indicate that the reactivity of RCl in the reaction with 2a decreases in the following order: ClCH₂CH₂Cl ≈ CH₃CF₂Cl > H₂CFCl.Open in a separate windowScheme 3Ni-catalyzed cross-coupling of arylboronic acids with alkyl halides. Reaction conditions: 2 (0.2 mmol, 1.0 equiv.), 1 (2.0 mmol, 10 equiv.), DME (2 mL). Isolated yields. ^a1 (1.0 mmol, 5.0 equiv.). ^b1 (0.2 mmol, 1.0 equiv.), 2 (0.3 mmol, 1.5 equiv.).To examine the role of DMAP in the reaction, we prepared nickel complexes NiCl₂(diOMebpy) and NiCl₂(DMAP)₄. Both of them could serve as precatalysts and offered 3a in 50% and 15% yield, respectively (Scheme 4A and B). However, NiCl₂(diOMebpy) provided 3a in a low yield (5%) in the absence of DMAP (Scheme 4A) and the use of NiCl₂(DMAP)₄ resulted in no product without diOMebpy (Scheme 4B). It was noted that the additional DMAP did enhance the yield from 15% to 50% (Scheme 4C). These results demonstrate that one of the roles of DMAP may function as a co-ligand in the Ni-catalyzed reaction. Apparently, the combination of diOMebpy as a bidentate ligand with 70 mol% of DMAP facilitates the Ni-catalyzed 1,1-difluoroethylation of arylboronic acids with CH₃CF₂Cl.Open in a separate windowScheme 4The role of DMAP. Isolated yields.In order to obtain some insight into the mechanism of the current reaction, radical inhibition and radical clock experiments were conducted (Scheme 5). In the presence of 2,2,6,6-tetramethylpiperidine-1-oxy (TEMPO) as a radical scavenger, the reaction was readily inhibited and compound 5 was detected by ¹⁹F NMR and GC-MS. Furthermore, when diallyl ether was added to the reaction under the standard conditions, a ring-closing product 6 was formed (determined by ¹⁹F NMR and GC-MS), along with 9% yield of 3a (for details, see ESI^†). These results demonstrate that a 1,1-difluoroethyl radical is indeed generated in the reaction.Open in a separate windowScheme 5Radical trapping experiments. ^aThe yield was determined by ¹⁹F NMR spectroscopy using PhCF₃ as an internal standard.On the basis of these results and previous reports,^16,18 a plausible mechanism involving Ni(i)/Ni(iii) catalytic cycle was proposed for the 1,1-difluoroethylation reaction (Scheme 6). The L_nNi(i)Cl intermediate (A) is supposed to be generated via the comproportionation of initially formed L_nNi(0) species and the remaining L_nNi(ii)Cl₂,¹⁹ followed by transmetalation with arylboronic acids. The formed L_nNi(i)Ar species (B) reacts with CH₃CF₂Cl through a SET pathway to produce 1,1-difluoroethyl radical and L_nNi(ii)(Ar)(Cl) species (C). Subsequently, the resulting L_nNi(iii)(Ar)(CF₂CH₃)(Cl) species (D) undergoes reductive elimination to give the coupling product 3 and regenerates L_nNi(i)Cl to complete the catalytic cycle. It is noted that DMAP may not only function as a co-ligand to coordinated to the nickel center,^16,20 but also activate the arylboronic acids to facilitate the transmetalation.^17aOpen in a separate windowScheme 6Proposed reaction mechanism.In conclusion, the first transition-metal-catalyzed 1,1-difluoroethylation of arylboronic acids with the cheap and easily available CH₃CF₂Cl has been successfully developed. This method can tolerate methyl, methoxyl, trifluoromethyl and heteroarenes, affording 1,1-difluoroethylated products in moderate to good yields. The reactivity of different alkyl chlorides in the reaction was also investigated. Initial mechanism study showed the nickel-catalyzed 1,1-difluoroethylation probably involves a Ni^I/III process. Current efforts are to develop catalytic system for improving yields and novel reactions with CH₃CF₂Cl as cheap fluorine source.     

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

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

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

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

Copper-catalyzed aerobic oxidative radical alkoxycyclization of tryptamines to access 3-alkoxypyrroloindolines

We report a copper-catalyzed alkoxycyclization of tryptamine derivatives with O₂ as the sole oxidant, leading to a variety of C3a-alkoxypyrroloindolines in good yields with high diastereoselectivities. This reaction involves an interesting double catalytic cycle in which copper-catalyzed carboamination cyclization is favored to form the C-3 radical pyrrolidinoindoline intermediate, then a copper-catalytic radical alkoxylation reaction proceeds smoothly.

An oxazoline/copper-catalyzed cascade carboamination alkoxylation of substituted tryptamine under mild eco-friendly O₂ oxidation conditions was reported.

Pyrrolidino[2,3-b]indoline is an important heterocyclic core skeleton that exists in numerous biologically active natural products and pharmaceutical molecules.¹ Cyclotryptamine type molecules which are oxygenated at the C3a position are especially outstanding due to their prominent bioactivity profiles,² various applications in biological probes³ and chiral catalysts.⁴As direct access to these complex products, the development of C3a-oxygenation/cyclization reactions of tryptamine or tryptophan derivatives has attracted extensive interest from synthetic chemists. Recently, some remarkable efforts have contributed to the one-step assembly of 3-hydroxyl,⁵ acetoxyl,⁶ peroxyl⁷ and other oxygenated⁸ pyrroloindolines through oxidative cyclization of tryptophan substrates. However, by utilizing a similar strategy, the direct synthesis of 3-alkoxyl pyrroloindolines remains less developed. In 2020, Zhong et al.⁹ reported the first example of alkoxycyclization of tryptamine derivatives using molecular iodine catalyst with tert-butyl hydroperoxide as the oxidant. None of the other studies, like using transition-metal catalysts, have been described yet.Copper salts, which are inexpensive and easily accessible, have been widely used in organic synthesis as catalysts. Copper(ii)-promoted radical intramolecular carboamination of alkene has proven to be an effective means toward the synthesis of N-fused heterocycles.¹⁰ Recent reports have utilized this strategy toward the cyclization and radical alkylation, aromatization and aminooxygenation of alkene.¹⁰ However, due to the difficulty in homolytic breakage of the oxygen–hydrogen bond in alcohols with a high bond dissociation energy (BDE is ca.105 kcal mol⁻¹),¹¹ the related direct cyclization and radical alkoxylation of carbon–carbon double bond with copper catalysts is still unknown. Inspired by the relevant research of copper-catalyzed radical alkoxylation reaction,¹² we assume that if the catalytic carboamination and radical alkoxylation tandem reaction could be realized by a single copper catalyst, which will represent as a new effective protocol for the direct construction of alkoxyl-containing N-fused heterocycles. Herein, we report an oxazoline/copper-catalyzed cascade carboamination alkoxylation of substituted tryptamine under mild eco-friendly O₂ oxidation conditions, which facilitate the construction of the 3-alkoxyl pyrroloindolinese motif in good yield with good to excellent levels of diastereoselectivity (Scheme 1).Open in a separate windowScheme 1Copper-catalyzed cyclization and alkoxylation of tryptamines.In our studies, the commercial easily available N-methyl tryptamine 1a was chosen as model substrate. Initially, 10 mol% of metal salt CuBr₂ was used as catalyst, the 3-alkoxylation product 2a was obtained as 38% yield with 14/1 dr ( EntryMetal saltsLigandYield^b (%)Dr^c1CuBr₂—3814/12CuBr₂L128>20/13CuBr₂L245>20/14CuBr₂L32413/15CuBr₂L4358/16Cu(OTf)₂L2Trace—7CuOL2nr—8Cu(OAc)₂L2nr—9Cu(ClO₄)₂L2nr—10CuCl₂L2158/111^dCuBr₂L271>20/112^d,eCuBr₂L246>20/1Open in a separate window^aCarried out under oxygen atmosphere: metal salt (0.02 mmol, 10 mol%), 1a (0.2 mmol), 2 mL MeOH.^bIsolated yields.^cdr was determined by ¹H NMR.^d4 mL methanol was used.^eAir atmosphere; nr: not reaction.With the optimized reaction conditions in hand, we continued to investigate the substrate scope of the reaction ( Open in a separate windowIn order to gain insight into the mechanism of the methodology, several control experiments were carried out. As shown in Scheme 2, the radical scavenger, 2,2,6,6-tetramethylpiperidine1-oxyl (TEMPO), inhibited the alkoxycyclization process completely, suggesting that a radical process might be involved in this reaction (Scheme 2: eqn (1)).¹³ When the nucleophilic substrate 1-methyl indole was involved in the standard conditions (Scheme 2: eqn (2)), trace amount of 3-indole pyrrolidinoindoline adduct 4 was detected by HRMS, suggesting that the exposed carbocation intermediate may be the precursor for the formation of the 3-alkoxylation product. Besides, the amidyl radical addition process has been ruled out by the substrate scope investigation of 1n (Scheme 2: eqn (3)), which indicated that this reaction proceeded via an intramolecular collaborative tandem process.Open in a separate windowScheme 2Control experiments.Combining with the previous reports about copper-catalyzed carboamination,¹⁰ alkoxylation¹² of alkene, a possible reaction pathway is proposed in Scheme 3. Initially, a ligand–exchange reaction of Cu(ii) species with substrate 1a proceeds to form the chelation intermediate A. Subsequent nitrogen intramolecular addition–cyclization forms the C3a Cu(ii) pyrrolidinoindoline intermediate B, Then, homolytic cleavage of carbon–Cu(ii) bond to generate the Cu(i) species and C3a radical intermediate C. The C3a radical could be oxidized by Cu^II species to generate the C3a cation intermediate D. Subsequent nucleophilic attack of alcohol delivers the product 2a. Meanwhile, Cu^II complex was produced in situ through the reaction of Ln–Cu^I complex with O₂ on the basis of the previous reports,¹⁴ completing the catalytic cycle.Open in a separate windowScheme 3Plausible reaction pathway.In conclusion, we have successfully developed copper-catalyzed alkoxycyclization of tryptamine under mild O₂ oxidation conditions, affording C3a-alkoxylation pyrrolidinoindolines in good yields with high diastereoselectivities. This protocol was proved practicable and useful by the rapid concise total synthesis of natural product CPC-1. Mechanistic studies illustrated that the copper-catalyzed carboamination cyclization was favored to form the C-3 radical pyrrolidinoindoline intermediate, then a copper-catalyzed radical alkoxylation reaction proceeded to deliver the desired product. The extension of the present catalytic protocol to other useful reactions and biological evaluation of these products are undergoing in our laboratory.     

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

Enantioselective bromination of axially chiral cyanoarenes in the presence of bifunctional organocatalysts

Enantioselective bromination of axially chiral cyanoarenes bearing high intrinsic rotational barriers via dynamic kinetic resolution using bifunctional organocatalysts is reported. Sequential addition of a brominating reagent in several portions at an optimized temperature was effective in accomplishing high enantioselectivities.

Enantioselective bromination of axially chiral cyanoarenes bearing high intrinsic rotational barriers via dynamic kinetic resolution using bifunctional organocatalysts is reported.

Axially chiral biaryls are privileged structures in pharmaceuticals,¹ asymmetric catalysts,² functional materials,³etc. Thus, the development of efficient methods for their synthesis is desirable to advance research in these scientific fields. Among recent accomplishments on catalytic atroposelective transformations⁴ toward the synthesis of densely substituted axially chiral biaryls, powerful strategies include organocatalytic dynamic kinetic resolution involving ortho-functionalization of existing biaryls via the introduction of additional rotational barriers.⁵ In this method, substrates should in principle have rotational barriers low enough to enable fast rotation about the biaryl axis, leading to their rapid racemization. Therefore, it is difficult to employ biaryl substrates bearing intrinsic rotational barriers, which impede their racemization. In 2015, the Miller group reported an elegant example of this type of dynamic kinetic resolution via bromination of 3-arylquinazolin-4(3H)-ones, the rotational barrier of which is ∼19 kcal mol⁻¹, by slow addition of a brominating agent.^5e Here, we present enantioselective bromination of axially chiral cyanoarenes bearing intrinsic rotational barriers exceeding 18 kcal mol⁻¹ (Scheme 1). To the best of our knowledge, there has been no report of a catalytic asymmetric reaction affording axially chiral cyanoarenes,⁶ despite their prevalence in bioactive agents⁷ and the rich chemistry of cyano compounds as synthetic intermediates.⁸Open in a separate windowScheme 1Enantioselective bromination of axially chiral cyanoarenes using bifunctional organocatalysts. 9 Other catalysts 3d and 3e, bearing a cyclohexanediamine framework, and 3f, bearing a binaphthyl framework, resulted in poor enantioselectivities (10 Using 3a and 3c, lower reaction temperatures were investigated (Fig. 1) were also investigated; NBA (4a) still afforded the best enantioselectivities ( EntryCatalystBrominating reagentSolventTemp. (°C)Yield^b (%)ee (%)13aNBA (4a)CH₂Cl₂25812623bNBA (4a)CH₂Cl₂2587633cNBA (4a)CH₂Cl₂25891843dNBA (4a)CH₂Cl₂2583653eNBA (4a)CH₂Cl₂2585363fNBA (4a)CH₂Cl₂2579373aNBA (4a)CH₂Cl₂−40822083aNBA (4a)CH₂Cl₂−60<1—93cNBA (4a)CH₂Cl₂−408341103cNBA (4a)CH₂Cl₂−60<1—113cNBA (4a)CHCl₃−402154123cNBA (4a)Toluene−4018−10133cNBA (4a)THF−4013−2143cNBA (4a)Et₂O−4046−20153cNBA (4a)EtOAc−4068−4163cNBA (4a)EtOH−40<5—173cDBH (4b)CH₂Cl₂−40791183cNBS (4c)CH₂Cl₂−408220193cNBP (4d)CH₂Cl₂−4079−520^c,d3cNBA (4a)CH₂Cl₂−40854921^c,e3cNBA (4a)CH₂Cl₂−40515922^c,f3cNBA (4a)CH₂Cl₂−40336623^c,g3cNBA (4a)CH₂Cl₂−401771 Open in a separate window^aReactions were run using 1a (0.10 mmol), the brominating reagent (0.30 mmol), and the catalyst (0.010 mmol) in the solvent (10 mL).^bIsolated yields.^cReactions were run using 3c (0.0050 mmol).^dReaction was run for 48 h.^eReaction was run for 24 h.^fReaction was run for 12 h.^gReaction was run for 6 h.Open in a separate windowFig. 1Brominating reagents.Subsequently, to improve the efficiency of dynamic kinetic resolution by retarding the enantiodetermining bromination,^5e4a was added sequentially in five portions (Fig. 2).¹¹ Although the procedure hardly affected the results at −40 °C, the enantioselectivity was greatly improved for reactions carried out at −20 °C and −30 °C. Such effects were smaller at temperatures above −10 °C.Open in a separate windowFig. 2Investigations of temperatures and procedures. Blue bar: reactions were run with 4a added in 1 portion. Red bar: reactions were run with 4a added in 5 portions. Green values represent yields of 2a isolated after silica gel column chromatography. At 0, −10, −20, and −30 °C, reactions were run for 24 h; at −40 °C, reactions were run for 72 h.Next, at −30 °C and −40 °C, respectively, the relationships between enantioselectivity and yield were investigated (Fig. 3). Reactions were carried out using various amounts of 4a. At both temperatures, the enantioselectivity decreased as the yield increased; however, the quantitative reactions also exhibited some enantioselectivity (−30 °C: 99% yield, 50% ee; −40 °C: 99% yield, 47% ee), implying the presence of the characteristics of dynamic kinetic resolution. In addition, although the enantioselectivity was better at −40 °C than −30 °C when the yield was low, the relationship became reversed as the yield increased; hence, the efficiency of dynamic kinetic resolution was revealed to be better at −30 °C than at −40 °C. Furthermore, when 1.5 equiv. of 4a were used at −30 °C affording 2a in 22% yield with 65% ee, the ortho-monobrominated product 1a-Br (Fig. 4) was also obtained with 75% ee (see Scheme S1 in the ESI^† for details). It shows that the bromination at one of the ortho-positions introduces a rotational barrier high enough to set the chiral axis, which is consistent with the rotational barriers calculated at the M06-2X/6-311++G(2d,3p)//B3LYP/6-31+G(d,p) level of theory (Fig. 4).Open in a separate windowFig. 3Relationships between ee and yield. Red line: reactions were run at −30 °C for 24 h with 4a added in 5 portions. Blue line: reactions were run at −40 °C for 72 h with 4a added in 5 portions. Red and blue values represent amounts of 4a used for each reaction.Open in a separate windowFig. 4Rotational barriers of substrate, intermediate, and product calculated at the M06-2X/6-311++G(2d,3p)//B3LYP/6-31+G(d,p) level of theory.Under the conditions of using 3c as the catalyst at −30 °C with 3 equiv. of 4a added sequentially in five portions, other substrates bearing substituted phenols were also investigated (Scheme 2).¹² First, substrates 1b–1e bearing a substituent at the meta-position were investigated. While the electron-deficient substrate 1b resulted in poor enantioselectivity, 1c and 1d bearing aliphatic substituents gave improved enantioselectivities; however, substrate 1e with a methoxy group resulted in low enantioselectivity. In addition, substrates 1f–1i bearing substituents at the para-positions of the biaryl axis were then examined; phenol 2h bearing a methyl group resulted in higher enantioselectivities than phenols 2f and 2g bearing electron-withdrawing groups and 2i bearing a methoxy group. These results suggest that aliphatic substituents might efficiently facilitate the racemization of 1 during bromination, leading to dynamic kinetic resolution with greater enantioselectivity. Utilizing this methodology with the characteristics of dynamic kinetic resolution, the reactions of 1c and 1g were also carried out using a sub-stoichiometric amount of 4a (Scheme 3); higher enantioselectivities were accomplished albeit with lower yields.¹³ The absolute configuration of 2c was determined by X-ray crystallography (see the ESI^† for details), and the configurations of all other products were assigned analogously.Open in a separate windowScheme 2Reactions of substrates with substituted phenols. ^aReaction was run for 72 h.Open in a separate windowScheme 3Reactions with a substoichiometric amount of 4a.In summary, we present enantioselective bromination of axially chiral cyanoarenes bearing high intrinsic rotational barriers via dynamic kinetic resolution using bifunctional organocatalysts. The sequential addition of 4a in several portions at the optimized temperature was effective in improving the enantioselectivity. Although the enantioselectivities are still moderate using the current catalytic system, the guidelines for designing catalytic asymmetric syntheses of axially chiral cyanoarenes were established. Further studies on the additional optimization and application of this methodology to the construction of densely substituted axially chiral biaryls are currently underway.     

Sequential cycloaddition and ring expansion reaction of arynes and methylenebenzothiopheneones: synthesis of a benzo-fused eight-membered ring via sulfonium ylides

A sequential cycloaddition and ring expansion of arynes and methylenebenzothiopheneones has been disclosed. This strategy proceeds through a sulfonium ylides intermediate and allows for the efficient synthesis of a sulfur-containing benzo-fused eight-membered ring.

Efficient construction of benzo-fused eight-membered ring containing sulfur. New reaction profile with sulfonium ylides.

As leading biologically relevant structural components, organosulfur compounds are widely present in many pharmaceuticals and bioactive compounds.¹ Accordingly, sulfur-containing compounds have found their medical applications including as antibacterials, anti-inflammatories, dermatologics, and cancer treatments. A survey of the structures of compounds among the top 200 brand name drugs by U.S. retail sales (RS) in 2011 revealed that 24.8% of the drugs contain sulfur. The list included the famous Plavix (blood thinner, no. 2) and Seroquel (antipsychotic drug, no. 6).² In addition, the benzothiazepine-containing drug diltiazem (calcium channel blocker) is used in the treatment of hypertension and angina (Scheme 1).³ On the other hand, Et743 as a sulfur-containing marine natural product was also used as an effective drug for the treatment of advanced soft tissue sarcoma.⁴ As a consequence, many efforts have been devoted to the synthesis of such skeletons.Open in a separate windowScheme 1Representative natural products and bioactive molecules with sulfur-containing ring.Arynes are recognized as one of the most reactive intermediates in organic synthesis. The past years have witnessed a great progress with respect to the carbon–carbon and carbon-heteroatom bond-forming reactions involving arynes.^5,6 A careful literature screening revealed that reactions involving the insertion of aryne into C–C, C–N, C–O, C–S, and other bonds have been well documented.^7–9 Furthermore, the aryne-based Diels–Alder reaction, [2 + 5], nucleophilic addition and annulation reactions.^8,9 Among [2 + 8] and many other pericyclic reactions have been intensively investigated for the construction of various benzo-fused frameworks.¹⁰ Remarkably, the reactions between arynes and organosulfur compounds have been widely investigated. As such, arynes can react with a variety of organosulfur compounds including S(ii), S(iv), and S(iv) valence state, thus allows for the diversity-oriented synthesis of aromatic organosulfurs that are difficult to access by conventional methods.^11,12 Among them, we are particularly interested in those reactions involves sulfonium ylides, a neutral 1,2-dipolar species consisting of electron-rich carbon atom and an adjacent electro-positive sulfur atom. For example, nucleophilic attack of alkyl thioether towards aryne followed by intramolecular 1,4-proton shift contribute an elegant strategy for the formation of sulfonium ylides (Scheme 2a), which can be further applied to various conversions.¹³ Remarkably, this strategy has been established from various modes of trapping of HDDA-generated benzynes with sulfides by Hoye and co-workers.¹⁴ Recently, Studer and co-workers have disclosed that vinyl thioethers lacking α-CH protons reacted with benzyne through direct [3 + 2] cycloaddition to give cyclic sulfonium ylides. This methods eventually enables the preparation of corresponding tetrasubstituted alkenes with high stereoselectivity (Scheme 2b).¹⁵ In the past years, we have paid much attention to the aryne chemistry and the heterocycle synthesis.^16,17 As a continuation, herein we report that the unprecedented reaction of arynes and methylenebenzothiopheneones enables the synthesis of structurally unusual benzo-fused eight-membered ring.Open in a separate windowScheme 2Representative examples involving sulfonium ylide.We commenced our investigation using benzyne precursor 1 and 2-methylenebenzothiophene-3-ones 4a as the model substrates. As shown in EntryF sourceEquiv. of 1SolventTemp. (°C)Yield^b (%)1CsF1.5CH₃CN40482CsF1.5THF40633CsF1.5Toluene40624CsF1.5Dioxane40595CsF1.5DCMReflux^c876CsF1.5DCMrt657CsF1.5DCM60^d798CsF2.0DCMReflux829CsF1.0DCMReflux7510TBAF1.5DCMReflux4711KF/18-c-61.5DCMReflux6712KF/18-c-61.5THFReflux71Open in a separate window^aUnless otherwise noted, all reactions were carried out with 1.0 mmol 2-methylenebenzothiophene-3-one 4a, fluorine source, in 3 mL solvent.^bIsolated yield.^cBp of DCM: 39.8 °C.^dSealing reaction temperature.After the best conditions were obtained in hand, the feasibility of substituted 2-methylenebenzothiophene-3-ones 4 was next evaluated. As shown in Scheme 3, a variety of 2-methylenebenzothiophene-3-ones 4 having substituents including methyl, tert-butyl, halo, and methoxyl groups at the position 7, 6, 5 of the aromatic ring were used to react with benzyne precursor 1. All reactions worked well to produce the desired products (5a–5h). Additionally, when the ester moiety in substrate 4 was changed from OEt to OMe, OBn, or O^tBu, the corresponding products 5i–5k were afforded in high performance. It was also worthy to note that when the electron-withdrawing groups such as cyano, and substituted carbonyl groups were employed instead of ester unit, the corresponding products 5l–5s were isolated in satisfactory yields. Furthermore, the structure of compounds 5j and 5n was unambiguously characterized by single-crystal X-ray analysis.¹⁸Open in a separate windowScheme 3Substrate scope of the reaction with respect to the methylenebenzothiopheneone. Reaction condition: 1.5 mmol benzyne precursor 1, 1.0 mmol 2-methylenebenzothiophene-3-one 4, CsF (3.0 mmol), in 3 mL DCM. Isolated yields are reported.After a broad substrate scope with benzyne precursor was established, reactions of naphthyne precursor 6 and substituted 2-methylenebenzothiophene-3-ones were subsequently tested. As shown in Scheme 4, reactions with 2-methylenebenzothiophene-3-ones 4 bearing different electron-withdrawing groups proceeded smoothly to produce products 9a–9e in satisfactory yield.Open in a separate windowScheme 4Reaction conditions: 1.5 mmol naphthyne precursor 6, 1.0 mmol 2-methylenebenzothiophene-3-one 4, CsF (3.0 mmol), in 3 mL DCM. Isolated yields are reported.To gain more insight into the present reaction, several control experiments and preliminary mechanistic experiments were next conducted. As shown in Scheme 5, benzyne precursor ortho-(trimethylsilyl)aryltriflate 10a and 10b were proven to be compatible reaction partners to react with 2-methylenebenzothiophene-3-ones 4 (Scheme 5, eqn (1) and (2)). After that, reactions with unsymmetrical benzyne precursor 10c and 10d were also examined (Scheme 5, eqn (3) and (4)). Pleasingly, only one isomer was detected when 3-methyl-2-(trimethylsilyl)phenyl trifluoromethanesulfonate 10c was used. The isotope-labelling experiment with 10a and 4i also revealed that deuterium was incorporated in the product to produce [D]-11e (Scheme 5, eqn (5)). This result suggested that water was also involved in present transformation.Open in a separate windowScheme 5Control experiments and preliminary mechanistic studies.Based on the aforementioned results and previous reports, a plausible reaction mechanism is described in Scheme 6. Firstly, the [3 + 2] cycloaddition between 2-methylenebenzothiophene-3-ones 4 and aryne yields a sulfonium ylide intermediate B. In the presence of water, B is further protonated to deliver sulfonium salt C. After that, the in situ generated hydroxide ion serves as a base to facilitate the following intramolecular β-elimination, thus providing a quick access to the product.Open in a separate windowScheme 6Possible mechanism.To further explore the application of present reaction, an oxidation reaction of the products was also attempted. In the presence of H₂O₂,¹⁹ the resultant sulfide products 5k and 5s experienced oxidation to corresponding functionalized sulfones 12a and 12b in an efficient and environmentally friendly manner (Scheme 7, eqn (1) and (2)).Open in a separate windowScheme 7Further application of the products.In conclusion, we have described an unprecedented reaction from in situ generated aryne and 2-methylenebenzothiophene-3-ones. This strategy allows for a new approach to benzo-fused eight-membered ring containing sulfur, which was difficult to be synthesized by traditional methods. Mechanistically, this reaction proceeds through cycloaddition, proton shift, intramolecular β-elimination, and the formation of sulfonium ylide. Further study and application of the present reaction including the biological detection are still underway in our laboratory.     

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

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

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

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