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

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

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

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

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

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.     

Synthesis of benzoxazoles via an iron-catalyzed domino C–N/C–O cross-coupling reaction

An eco-friendly and efficient method has been developed for the synthesis of 2-arylbenzoxazoles via a domino iron-catalyzed C–N/C–O cross-coupling reaction. Some of the issues typically encountered during the synthesis of 2-arylbenzoxazoles in the presence of palladium and copper catalysts, including poor substrate scope and long reaction times have been addressed using this newly developed iron-catalyzed method.

The synthesis of benzoxazoles via an iron-catalyzed cascade C–N and C–O coupling is described.

2-Arylbenzoxazoles are an important class of structures in natural products, and pharmaceuticals and has shown a wide range of biological activities, such as antitumor, antiviral, and antimicrobial activities.¹ In particular, they show a marvellous efficacy in the treatment of duchenne muscular dystrophy (DMD) which is one of the most common of the muscular dystrophies that is caused by a mutation in the gene DMD, located in humans on the X chromosome (Xp21).² So the synthesis of 2-arylbenzoxazoles has been intensively studied for use in organic and medicinal chemistry over the past few years.Numerous methods have been reported to synthesise this motif, one of the common methods is transition-metal-catalyzed (like Pd,³ Ni,⁴ Cu,⁵ Mn⁶etc.) cross-coupling from pre-existing benzoxazoles with aryl halide or arylboronic acid. And another method is the classic one employing a cyclocondensation approach between an aminophenol and either a carboxylic acid⁷ or benzaldehyde⁸ (Scheme 1, path a). In 2004, Frank Glorius'' group reported a domino copper-catalyzed C–N and C–O cross-coupling for the conversion of primary amides into benzoxazoles⁹ (Scheme 1, path b) which is a new reaction type for the synthesis of benzoxazoles. Bunch et al. apply this domino reaction in the synthesis of planar heterocycles in 2014.¹⁰ In addition the cyclization of o-halobenzenamides to benzoxazoles has been reported several times.^11,12 Nevertheless, some limitations in the reported methods need to be overcome, such as the use of palladium complexes and narrow substrate range.Open in a separate windowScheme 1Classic method of benzoxazole formation.In the last few years, there has been a significant increase in the number of reports pertaining to the development of iron-catalyzed reactions in organic synthesis, where iron has shown several significant advantages over other metals, such as being more abundant, commercially inexpensive, environmentally friendly and drug safety.¹³ Compared with palladium and copper, the use of iron is particularly suitable for reactions involving the preparation of therapeutic agents for human consumption. With this in mind, it was envisaged that an new method should be developed for the synthesis of benzoxazoles via an iron-catalyzed domino C–N/C–O cross-coupling reaction.The reaction of benzamide (1a) with 1-bromo-2-iodobenzene was used as model transformation to identify the optimum reaction conditions by screening a variety of different iron salts, bases, ligands and solvents (l-proline provided no product (14 high-purity Fe₂O₃ (99.999%) and K₂CO₃ (99.999%) were applied in the reaction ( EntryIron saltLigandBaseSolvent Y ^b (%)1FeCl₃DMEDAKO^tBuPhMeTrace2FeCl₂·4H₂ODMEDAKO^tBuPhMeTrace3FeSO₄·7H₂ODMEDAKO^tBuPhMe04Fe(acac)₃DMEDAKO^tBuPhMe05Fe₂O₃DMEDAKO^tBuPhMe156Fe₃O₄DMEDAKO^tBuPhMe07Fe₃O₄(nano)DMEDAKO^tBuPhMe108Fe₂O₃(nano)DMEDAKO^tBuPhMe09Fe₂(SO₄)₃DMEDAKO^tBuPhMe010Fe(NO₃)₃·9H₂ODMEDAKO^tBuPhMe011Fe₂O₃DMEDALiO^tBuPhMe012Fe₂O₃DMEDANa₂CO₃PhMe013Fe₂O₃DMEDANaOAcPhMe014Fe₂O₃DMEDAKOHPhMe015Fe₂O₃DMEDAK₂CO₃ (24 h)PhMe3716Fe₂O₃DMEDAK₂CO₃ (48 h)PhMe8717Fe₂O₃PhenK₂CO₃PhMeTrace18Fe₂O₃ l-ProlineK₂CO₃PhMe019Fe₂O₃DpyK₂CO₃PhMe020Fe₂O₃DMEDAK₂CO₃DMSO021Fe₂O₃DMEDAK₂CO₃DMF022Fe₂O₃DMEDAK₂CO₃PhMe₂023—DMEDAK₂CO₃PhMe024Fe₂O₃DMEDAK₂CO₃PhMe86^c25Fe₂O₃DMEDAK₂CO₃PhMe58^dOpen in a separate window^aReaction conditions: benzamides (0.5 mmol), 1-bromo-2-iodobenzene (1.5 eq.), iron salt (20% mol), base (1 eq.), ligand (20%) were added to a solvent (2 mL) and react at 110 °C for 48 h under N₂.^bIsolated yield based on 1a after silica gel chromatography.^cFe₂O₃ and K₂CO₃ were applied in purity of 99.999% from alfa.^dwith Fe₂O₃ in a dosage of 10 mmol%.At last, the dosage of Fe₂O₃ was reduce to 10 mmol%, but only 58% yield was obtained (Scheme 2.Open in a separate windowScheme 2The pathway of the reaction.With the optimized reaction conditions in hand, we proceeded to investigate the substrate scope of the reaction using a variety of different 1,2-dihalobenzene substrates and aryl formamide ( Open in a separate window^aReaction conditions: 1a (0.5 mmol), o-dihalo substrate (1.5 eq.), Fe₂O₃ (20% mol), K₂CO₃ (1 eq.), DMEDA (20%) were added to PhMe (2 mL) and react at 110 °C for 48 h under N₂.Based on the results observed in the current study and Goldberg reaction,¹⁵ we have proposed a reaction mechanism for this transformation, which is shown in Scheme 3. The initial transmetalation of benzamide with Fe₂O₃L_n in the presence of K₂CO₃ would give rise to the iron(iii) species A. Complex A would then undergo an oxidative addition reaction with 1-bromo-2-iodobenzene to give the iron(v) species B, which would undergo a reductive elimination reaction to give iron(iii) species C with the concomitant formation of a C–N bond. Followed the tautomerism of intermediate C to D, the intermediate iron(iii) species E was formed in the presence of K₂CO₃, which would undergo another oxidative addition reaction to afford iron(v) species F. Compound 3a would then be obtained via a reductive elimination reaction from iron(v) species F.Open in a separate windowScheme 3Possible catalytic cycle.In summary, we have demonstrated that the cheap and environmental friendly catalyst system composed of Fe₂O₃ and ligand DMEDA is highly effective for the synthesis of 2-arylbenzoxazoles. The new catalyzed system can be effective for both C–N coupling and C–O coupling.     

B(C6F5)3 catalyzed direct nucleophilic substitution of benzylic alcohols: an effective method of constructing C–O,C–S and C–C bonds from benzylic alcohols

An efficient and general method of nucleophilic substitution of benzylic alcohols catalyzed by non-metallic Lewis acid B(C₆F₅)₃ was developed. The reaction could be carried out under mild conditions and more than 35 examples of ethers, thioethers and triarylmethanes were constructed in high yields. Some bioactive organic molecules were synthesized directly using the methods.

An efficient and general method of nucleophilic substitution of benzylic alcohols catalyzed by non-metallic Lewis acid B(C₆F₅)₃ was developed.

Alcohols are ideal building blocks for high-value chemicals because of their high stability, low toxicity and wide availability.¹ However, due to the poor leaving ability of the hydroxyl group, in most cases, alcohol substitution requires hydroxyl preactivation or the use of excess Brønsted acids or stoichiometric amounts of Lewis acids. In 2005, the OH-activation for nucleophilic substitution was considered a central issue by the ACS Green Chemistry Institute² because the direct catalytic nucleophilic substitutions of alcohols are highly desirable in constructing high-value organic compounds such as ethers, thioethers and a variety of bioactive molecules. Furthermore, the reaction produces only H₂O as a byproduct, which meets the requirements of green chemistry and atom-economy.³In recent years, the direct catalytic nucleophilic substitution of alcohol has been explored, however, many urgent, difficult problems are still waiting to be solved. The catalytic nucleophilic substitutions of π-activated alcohols such as allylic/propargyl alcohols have been developed as well as the double bond or triple bond of the substrates being able to coordinate to the metal catalysts (Au, Bi, In, Al, Fe etc.), stabilizing the carbocations.⁴ In contrast, for benzylic alcohols, the catalytic substitution reactions are much less explored.⁵ Furthermore, harsh conditions and excess nucleophiles are two major defects in the existing reports, and for different nucleophiles, varied catalysts are always required. Therefore, a mild, green, efficient and general method of benzylic alcohol nucleophilic substitution is highly desirable (Scheme 1).Open in a separate windowScheme 1The difference between traditional method and catalytic method.In recent years, B(C₆F₅)₃ as a non-metallic Lewis acid has drawn notable attention because of its strong Lewis acidity, high-stability and environmental friendliness.⁶ Furthermore, the borane hydrate is also a strong Brønsted acid.⁷ And these inspired us that the borane may offer another chance to realize the direct substitution reaction of benzylic alcohols such as etherification, thioetherification and arylation (Scheme 2).Open in a separate windowScheme 2Catalytic substitution of alcohols.For the etherification of alcohols, the difficulty is that how to realize the high selectivity between cross-etherification and homo-etherification. Initially we chose diphenylmethanol 1a and BnOH as the model alcohol compounds. The reaction was carried out with 10 mol% B(C₆F₅)₃ in toluene at 60 °C (8 was formed between B(C₆F₅)₃ and THF. When the catalyst loading was decreased to 5 mol%, the yield had no erosion (entry 6), and a further decrease led to a longer reaction time and a slight lower yield (entry 7). Longer time was needed when the reaction was carried out at room temperature.Optimization conditions^a

DMSO-mediated palladium-catalyzed cyclization of two isothiocyanates via C–H sulfurization: a new route to 2-aminobenzothiazoles

DMSO was found to activate arylisothiocyanates for self-nucleophilic addition. A subsequent intramolecular C–H sulfurization catalyzed by PdBr₂ enables access to a wide range of 2-aminobenzothiazole derivatives in moderate to good yields. This is the first example of a DMSO-mediated Pd-catalyzed synthesis of 2-aminobenzothiazoles through cyclization/C–H sulfurization of two isothiocyanates.

DMSO-initiated coupling of two isothiocyanates; Pd-catalyzed C–H sulfurization.

2-Aminobenzothiazole derivatives are privileged scaffolds which have been widely used in medicine and agricultural chemicals (Scheme 1a).¹ Significant effort has been devoted to the development of synthetic methodologies for the preparation of such species.² Thioureas,^3,4 isothiocyanates,^5,6 and benzothiazoles⁷ are effective reaction partners for the synthesis of 2-aminobenzothiazole derivatives via cross-coupling reactions or C–H functionalization. Intramolecular C–H sulfurization of N-arylthioureas is an effective strategy for the synthesis of 2-aminobenzothiazoles. Such a transformation can be achieved through metal-catalyzed C–H activation³ or via radical reactions.⁶ For example, Doi and coworkers reported a Pd-catalyzed intramolecular C–H sulfurization of arylthiourea using O₂ as an oxidant.^3c Metal-free iodine-catalyzed intramolecular C–H sulfurization also provides an effective pathway to 2-aminobenzothiazoles.^6e Zhu et al. developed an efficient oxidative radical strategy for the synthesis of 2-aminobenzothiazoles via an aminyl radical addition to aryl isothiocyanates followed by C–H sulfurization in the presence of n-Bu₄NI and TBHP.^6c Interestingly, Lei et al. reported a “green” synthesis of 2-aminobenzothiazoles by employing electro-catalysis technology for an external oxidant-free intramolecular C–H sulfurization.^6d In terms of metal-catalyzed C–H sulfurization,⁸ palladium-catalyzed C–H sulfurization has not been widely reported because thioureas are often strong metal-chelating species that may lead to poisoning of palladium catalysts. Thus, only a few examples of Pd-catalyzed protocols have been reported (Scheme 1b).^3b,c,e Therefore, the development of novel palladium-catalyzed C–H sulfurization reaction is of great interest. As a continuation of our interest in sulfur chemistry and C–H sulfurization,⁹ we attempted to transform isothiocyanates into sulfur-containing compounds.¹⁰ Unexpectedly, a newly formed 2-aminobenzothiazole was observed for the reaction of a phenylisothiocyanate. Encouraged by this discovery, we developed a new, facile and efficient DMSO-mediated palladium-catalyzed C–H sulfurization/cyclization of two isothiocyanates for the synthesis of 2-aminobenzothiazoles (Scheme 1c).Open in a separate windowScheme 1Biological application and synthetic methods for the preparation of 2-aminobenzothiazoles.Our study began with the reaction of phenyl isothiocyanate (1a) with PdCl₂ in different solvents ( EntryCatalystSolventYield^b (%)1PdCl₂Toluene02PdCl₂Chlorobenzene03PdCl₂DCE04PdCl₂CH₃CN05PdCl₂DMF126PdCl₂NMP167PdCl₂DMSO728^cPdCl₂DMSO329^dPdCl₂DMSO5810PdBr₂DMSO8211Pd(OAc)₂DMSOTrace12Pd(PPh₃)₂Cl₂DMSOTrace13^ePdBr₂DMSO7014—DMSO015^fPdBr₂DMSO/CH₃CN5516^gPdBr₂DMSO/CH₃CN2317^hPdBr₂DMSO/H₂O6118ⁱPdBr₂DMSO/H₂O75Open in a separate window^aReaction conditions: 1a (0.4 mmol), [Pd] (10 mol%), stirred at 80 °C in solvent (2 mL) for 24 h.^bIsolated yield.^cAt 100 °C.^dAt 60 °C.^ePdBr₂ (5 mol%).^fDMSO/CH₃CN = 1 : 1.^gDMSO/CH₃CN = 1 : 4.^hDMSO/H₂O = 10 : 1.ⁱDMSO/H₂O = 20 : 1.With the optimized reaction conditions in hand, the reaction scope was investigated ( Open in a separate window^aReaction conditions: 1 (0.4 mmol), PdBr₂ (10 mol%), stirred at 80 °C in DMSO (2 mL) for 24 h. Ortho-substituents, such as methyl, methoxy, methylthio, and phenyl, which increase steric hindrance, still performed well to give their corresponding products in moderate to good yields (products 12–20). For reactions involving ortho-substituted substrates, a small amount of brominated by-product similar to compound 19 was observed; however, the majority of these by-products were obtained in far lower yield than 19. To our delight, a naphthyl isothiocyanate also underwent reaction smoothly to give product 22 in 77% yield. 3-Isothiocyanatopyridine was also subjected to the reaction conditions. However, no cyclization/C–H sulfurization occurred; the electron-deficient pyridine ring is not reactive enough for C–H sulfurization. The reaction of meta-substituted methyl phenylisothiocyanates provided two isomers which could not be easily purified.To prove the feasibility of the cyclization of two different aryl isothiocyanates, a cross-reaction between 4-methyl-phenylisothiocyanate and 4-nitro-phenyliso-thiocyanate was conducted. The cross-reaction product 23, was obtained in 27% yield with compound 3 being formed as the main product in 52% yield (Scheme 2). The strong electron-withdrawing nitro group greatly reduces the electron density of the benzene ring, thus C–H sulfurization is disfavored; C–H sulfurization only occurred on the methyl-substituted benzene ring.Open in a separate windowScheme 2PdBr₂-catalyzed cross-reaction of two different isothiocyanates.To gain insight into the reaction mechanism, control experiments were conducted, as shown in Scheme 3. In the absence of PdBr₂, thiourea 24 was obtained in 35% yield for the reaction of 4-methyl phenylisothiocyanate in DMSO at 80 °C over 24 hours (Scheme 3, eqn (1)). This suggested that the thiourea may be the reaction intermediate; however, when thiourea 24 was subjected to reaction with PdBr₂, product 3 was obtained in only 16% yield (Scheme 3, eqn (2)). Aryl isothiocyanate may decompose to aniline, and react with isothiocyanate for C–H sulfurization. However, only a trace amount of product 25 was observed in the reaction between 4-methylphenyl isothiocyanate and aniline (Scheme 3, eqn (3)). None of the target product 26 was observed for the reaction of benzothiazole with 4-methyl phenylisothiocyanate, suggesting that benzothiazole is not a reaction intermediate (Scheme 3, eqn (4)). To our delight, a mass peak corresponding to intermediate 27 was observed with real-time ESI-MS when phenylisothiocyanate was stirred in DMSO at 60 °C (Scheme 3, eqn (5)) (see the ESI, Fig. S1^†). Based on theoretical calculations,¹¹ the dipole moment of the DMSO molecule is 3.9274 debye (gas) or 5.1281 debye in solvent form. Natural bond orbital analysis shows the differences in the charge distribution on the O and S atoms. Obviously, the polarity of the S–O bond increases and a greater distribution of the negative charge on the O atom leads to an improvement in its nucleophilic character. The oxygen atom attacks the carbon atom with the most positive NBO charge in PhNCS (see the ESI, Fig. S2 and S3^†). These results indicate that DMSO acts as a nucleophilic agent for the activation of arylisothiocyanates for C–H sulfurization.Open in a separate windowScheme 3Control experiments.Based on the above results and previous work,³ a possible reaction mechanism has been proposed and is shown in Scheme 4. Firstly, the polarized DMSO undergoes a nucleophilic addition with phenylisothiocyanate to afford the active intermediate A, which then reacts with another equivalent of phenylisothiocyanate to produce an intermediate B. Intermediate B chelates with PdBr₂ to form an intermediate C. Subsequent elimination of HBr leads to the formation of intermediate D, which undergoes reductive elimination to afford the desired product 2. The Pd(0) is oxidized by DMSO to PdBr₂ for the next catalytic cycle.Open in a separate windowScheme 4A possible mechanism.     

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

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

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

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

Solvent-free and room temperature microwave-assisted direct C7 allylation of indolines via sequential C–H and C–C activation

A Ru or Rh-catalyzed efficient and atom-economic C7 allylation of indolines with vinylcyclopropanes was developed via sequential C–H and C–C activation. A wide range of substrates were well tolerated to afford the corresponding allylated indolines in high yields and E/Z selectivities under microwave irradiation. The obtained allylated indolines could further undergo transformations to afford various value-added chemicals. Importantly, this reaction proceeded at room temperature under solvent-free conditions.

A Ru or Rh-catalyzed direct C7 allylation of indolines with vinylcyclopropanes via sequential C–H/C–C activation under microwave irradiation has been disclosed.

The development of sustainable methodologies is attractive for access to complex molecular architectures in organic chemistry.¹ In recent years, various non-conventional techniques, such as microwave irradiation, sonochemistry, mechanical grinding and photochemistry, have achieved remarkable success.² In particular, microwaves have shown unique advantages with regards to reaction times, energy efficiency, temperature, and reaction media.³ On the other hand, transition-metal-catalyzed activation of C–H⁴ and C–C⁵ bonds has been considered as an ideal method for the formation of C–C and C–X bonds. Nevertheless, transition-metal-catalyzed C–H or C–C bond activation under the above non-conventional techniques remains to be explored. It is thus highly imperative to develop a practical strategy in combination of C–H or C–C activation and microwave irradiation.⁶Recently, there have significant advances in C–H activation technology by merging C–H functionalization with challenging C–C cleavage strategies.⁷ Since the pioneering work by Bergman and co-workers⁸ on the sequential C–H and C–C bond activation, many research groups, including Dong,⁹ Ackermann,¹⁰ Li,¹¹ Cramer,¹² and others¹³ have contributed to C–H/C–C activation. In this content, certain small strained rings are often utilized as an effective synthons to undergo ring-opening reactions driven by strain-release energy.¹⁴ Very recently, VCPs (vinylcyclopanes) have been reported as allyl reagents to access various (hetero)aromatic derivatives through sequential C–H and C–C activation (Scheme 1a–d).¹⁵Open in a separate windowScheme 1Sequential C–H/C–C activations using VCPs.As a continuation of our interest in chelation-directed reactions and novel methods for C–H functionalization,¹⁶ we herein report a Ru or Rh-catalyzed C-7 allylation of indolines under microwave irradiation using VCPs as the allylating agents (Scheme 1e). This transformation possesses great synthetic potential from the viewpoint of green and sustainable chemistry. Notable features of our protocol include (1) C–H/C–C activation with VCPs by microwave irradiation, (2) broad substrate scope with good regio- and E/Z selectivities, (3) high atom economy, and (4) high efficiency (2 h) at room temperature under solvent-free conditions.We initiated our investigation by choosing indoline 1a and VCP 2a as model substrates under microwave irradiation conditions ( EntryCatalyst (mol%)Additive (mol%) T (°C)Yield (%)1[Ru(p-cymene)Cl₂]₂AdCOOH90402RuCl₃·3H₂OAdCOOH90N.R3[Cp*RuCl₂]₂AdCOOH90N.R4[Ru(p-cymene)Cl₂]₂MesCOOH90475[Ru(p-cymene)Cl₂]₂AcOH90406[Ru(p-cymene)Cl₂]₂NaOAc90207[Ru(p-cymene)Cl₂]₂PivONa·H₂O90218[Ru(p-cymene)Cl₂]₂DABCO90Trace9^b[Ru(p-cymene)Cl₂]₂MesCOOH905710^b[Ru(p-cymene)Cl₂]₂MesCOOH706811^b[Ru(p-cymene)Cl₂]₂MesCOOH508312^b[Ru(p-cymene)Cl₂]₂MesCOOH256513^b,c[Ru(p-cymene)Cl₂]₂MesCOOH2587 (>20 : 1)^e14^c,d[Cp*Rh(CH₃CN)₃](SbF₆)₂AdCOOH8078 (10 : 1)^eOpen in a separate window^aReaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), [Ru(p-cymene)Cl₂]₂ (5 mol%), additive (30 mol%), MW, 1 h, 90 °C.^bMesCOOH (50 mol%).^c t = 2 h.^d[Cp*Rh(CH₃CN)₃](SbF₆)₂ (8 mol%).^eThe E : Z ratio was determined by ¹H NMR analysis. MW = microwave irradiation.Under the optimized reaction conditions with the ruthenium catalyst, the substrate scope of indolines 1 was investigated (†). While 3b′a was obtained in 84% yield, others failed to give the coupling products. Overall, indolines with a variety of functionalities ranging from C2 to C6 positions could react with VCP 2a to afford the allylated products in good yields with high E/Z selectivities under the [Ru(p-cymene)Cl₂]₂ catalytic system. On the other hand, when [RhCp*(CH₃CN)₃](SbF₆)₂ was employed as the catalyst instead of Ru analogue, decreased yields accompanied with lower E/Z selectivities was observed in most cases.Substrate scope of indolines^a,b

Copper(ii)-catalyzed tandem cyclization for the synthesis of benzo[d][1,3]thiazin-2-yl phosphonates involving C–P and C–S bond formation

A copper(ii)-catalyzed, high-efficiency and atom-economical synthesis of valuable organophosphorus compounds via tandem cyclization of o-alkynylphenyl isothiocyanates with phosphites is described. This protocol, having a good functional-group compatibility, provides a simple and direct pathway to organophosphorus heterocycles in good yields under mild conditions. The method could be efficiently scaled up to gram scale, thus providing a potential application of this cascade cyclization strategy in synthesis.

A simple and highly efficient cascade cyclization of o-alkynylphenyl isothiocyanates with phosphites has been developed, affording a series of 4H-benzo[d][1,3]thiazin-2-yl phosphonates in moderate to good yields.

As the valuable precursors of many biologically active molecules,¹ organophosphorus compounds have wide applications in the field of materials science,² medicinal chemistry,³ organic synthesis,⁴ natural products,⁵ and ligand chemistry.⁶ For example, α-amino and α-hydroxy phosphonic acids have been found to act as antibiotics,⁷ antitumor agents,⁸ and enzyme inhibitors.⁹ Therefore, the synthesis of these organophosphorus compounds is still appealing. The construction of a C(sp²)–P bond on heterocycles is one of the most fundamental methods to synthesize the organophosphorus compounds. Through the efforts of many chemists, several extensively valuable methods have been established and developed.¹⁰ For instance, the Duan group and the Ackermann group developed an Ag-mediated C–H/P–H functionalization method to construct a Csp²–P bond by using arylphosphine oxides and internal alkynes as the substrates (Scheme 1a).¹¹ At the same time, Studer and co-workers reported a novel Ag-catalyzed radical cascade reaction for the synthesis of 6-phosphorylated phenanthridines from 2-isocyanobiphenyls and diphenylphosphine oxides (Scheme 1b).¹² Recently, Liang and co-workers also developed two cases of cascade functionalization of N-(p-methoxyaryl)-propiolamides and alkynol substrates with diphenylphosphine oxides to construct phosphorylated heterocycles (Scheme 1c and d).¹³ Although various utilized methods for the construction of Csp²–P bond on heterocycles have been established, the development of a new synthetic strategy from easily prepared starting materials is still a challenging task.Open in a separate windowScheme 1Synthesis of P-containing heterocycles through Csp²–P bond formation. (a) Previous report through C–H/P–H functionalization. (b) Previous report through radical process. (c) and (d) Previous reports through cascade functionlization. (e) This work: copper-catalyzed cyclization of o-alkynylphenyl isothiocyanates with phosphites.Recently, transition-metal-catalyzed cascade cyclization of o-alkynylphenyl isothiocyanates with various nucleophiles provides a new and powerful synthetic strategy to synthesize different heterocycles. o-Alkynylphenyl isothiocyanates have extensively been used as versatile organic synthons for the construction of different compounds such as indoles,¹⁴ quinoline,¹⁵ thiazine¹⁶ due to its high reactivity and easy preparation. Encouraged by this fascinating research and our continuing interest in the transformation of o-alkynylphenyl isothiocyanates,¹⁷ we herein report an efficient copper-catalyzed cyclization of o-alkynylphenyl isothiocyanates with phosphites for the synthesis of phosphorylated heterocycles and related derivatives (Scheme 1e).According to the literature procedure,^14c,18 the starting o-alkynylphenyl isothiocyanates were prepared via the Sonogashira coupling of 2-iodoanilines with terminal alkynes,¹⁹ followed by reacting with thiophosgene. At the outset, we used o-phenylethynylphenyl isothiocyanate 1a and diethyl phosphonate 2 as the substrates in a model reaction to optimize the conditions, and the results are summarized in EntryCatalystBaseSolventYield^b (%)1CuICs₂CO₃MeCN252CuBrCs₂CO₃MeCN353CuClCs₂CO₃MeCN394Cu(OTf)₂Cs₂CO₃MeCN205Cu(OAc)₂Cs₂CO₃MeCN156CuOCs₂CO₃MeCNTrace7CuCl₂Cs₂CO₃MeCN418CuBr₂Cs₂CO₃MeCN399—Cs₂CO₃MeCNTrace10CuCl₂—MeCNNR11CuCl₂K₃PO₄MeCN4512CuCl₂ t-BuOKMeCN2813CuCl₂NaOHMeCN3214CuCl₂Et₃NMeCNTrace15CuCl₂DBUMeCN5016CuCl₂DBUDMF3117CuCl₂DBU1,4-Dioxane4518CuCl₂DBUTHF4919CuCl₂DBUToluene4220CuCl₂DBUDCM6021CuCl₂DBUDCE4522^cCuCl₂DBUDCM2523^dCuCl₂DBUDCM7524^eCuCl₂DBUDCMTraceOpen in a separate window^aReaction was performed with 1a (0.2 mmol), 2a (0.6 mmol), catalyst (0.04 mmol), base (0.6 mmol), in solvent (2 mL) at 80 °C for 18 h.^bIsolated yield based on o-phenylethynylphenyl isothiocyanate 1a.^cThe temperature is 100 °C.^dThe temperature is 45 °C.^eThe temperature is 25 °C.In order to further demonstrate the substrate scope, different o-alkynylphenyl isothiocyanates and phosphites were then explored; the results are summarized in †). Due to a kinetic effect according to Baldwin''s rules and a smaller steric effect compared to the E-isomer, all products were uniformly formed as the Z-isomer.²⁰ It is worth mentioning that all these reactions could be efficiently scaled up to gram scale under the optimal conditions, providing a potential application in the synthesis industry.Substrate scope of different o-alkynylphenyl isothiocyanates and phosphites^a,b

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

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

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

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

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

Visible light-induced photocatalytic C–H ethoxycarbonylmethylation of imidazoheterocycles with ethyl diazoacetate

A visible light-mediated regioselective C3-ethoxycarbonylmethylation of imidazopyridines with ethyl diazoacetate (EDA) was achieved under mild reaction conditions. In contrast to the carbene precursors from α-diazoester a first C3-ethoxycarbonylmethylation of imidazopyridines via a radical intermediate has been established. The present methodology provides a concise route to access pharmacologically useful esters with wide functional group tolerance in high yields.

A visible-light-promoted regioselective ethoxycarbonylmethylation of imidazoheterocycles has been developed using an α-diazoester via a radical pathway.

Ester groups are a most powerful and versatile synthetic building block in natural products as well as in organic synthesis since they can be derivatized to diverse functional groups such as carbonyl, hydroxymethyl, and amide, etc.¹ Beside the traditional methods of using xanthates for ethoxycarbonylmethylation,² the introduction of diazoesters represents a very important strategy for the synthesis of acetate derivatives.³ Generally, thermal,^4a photoinduced,^4b or metal catalyzed^4c reactions of diazo compounds produce reactive carbene precursors which further undergo an addition reaction, insertion reaction, cyclopropanation, Wolff rearrangement, etc. (Scheme 1a).⁴ In contrast to the carbene precursors from α-diazoester, a new methodology is always highly desirable especially with a significantly different mode of activation under a distinct mechanism.⁵ In this context, a new strategy for installation of alkyl radicals from diazo compounds under photoredox-catalysis is very important.⁶ Recently, visible light-mediated photoredox catalyzed direct C–H bond functionalization reactions have come to the forefront in synthetic organic chemistry⁷ where Ru(ii)-polypyridyl complexes have been extensively used as photoredox-catalysts due to their unique photo-physical properties.⁸Open in a separate windowScheme 1Visible light-mediated ethoxycarbonylmethylation. (a) Previous reports through carbene pathway. (b) This work: visible-light mediated radical reaction of diazoacetate with imidazopyridine.Imidazo[1,2-a]pyridines, an important class of nitrogen-based privileged structural motifs widely found in a variety of natural products and alkaloids.⁹ In pharmaceutical chemistry, it possesses large number of biological activities like antitumor, antibacterial, antifungal, antipyretic, analgesic, antiinflammatory, etc.^10a It is also important in material sciences due to its unique excited state intramolecular proton transfer phenomena (ESIPT).^10b In particular, ethoxycarbonylmethylated imidazopyridines are the core structure of several marketed drugs such as alpidem, zolpidem, saripidem, etc.¹¹ Therefore, practical methodologies for the synthesis of alkylated ester substituted imidazoheterocycles are highly desirable and will be of great interest to the synthetic chemists.¹¹ However, to the best of our knowledge there is no such method for the direct photo-initiated ethoxycarbonylmethylation reaction of imidazoheterocycles with diazo compounds through distinct radical pathway.^11–13 As part of our ongoing research on photoredox-catalyzed C–H functionalization reactions,¹³ herein we describe an environmentally benign visible light-promoted ethoxycarbonylmethylation for the synthesis of alkyl substituted imidazopyridines by the coupling between imidazopyridines and ethyl diazoacetate using Ru(bpy)₃Cl₂ as photoredox-catalyst under argon atmosphere at room temperature (Scheme 1b).To begin, the reaction was carried out using 2-phenylimidazo[1,2-a]pyridine (1a) and ethyl diazoacetate (EDA) (2) (2.0 equiv.) in presence of 0.2 mol% of Ru(bpy)₃Cl₂ as a photoredox-catalyst under the irradiation of 34 W blue LED lamp in methanol at room temperature. To our delight, 49% yield of the ethyl 2-(2-phenylimidazo[1,2-a]pyridin-3-yl)acetate (3a) was obtained after 36 h under argon atmosphere. However, no desired product was formed in aerobic conditions ( EntryPhotocatalyst (0.2 mol%)SolventYield (%)1Ru(bpy)₃Cl₂MeOH49, NR^b2Ru(bpy)₃Cl₂EtOH213Ru(bpy)₃Cl₂DCM434Ru(bpy)₃Cl₂MeCN475Ru(bpy)₃Cl₂TolueneNR6Ru(bpy)₃Cl₂MeOH : H₂O (1 : 1)767Ru(bpy)₃Cl₂MeOH : H₂O (2 : 1)898Ru(bpy)₃Cl₂MeOH : H₂O (1 : 2)Trace9Ru(bpy)₃Cl₂H₂ONR10Ru(bpy)₃Cl₂EtOH : H₂O (2 : 1)6811Ir(ppy)₃MeOH : H₂O (2 : 1)Trace12Rose bengalMeOH : H₂O (2 : 1)NR13Eosin YMeOH : H₂O (2 : 1)NR14Eosin BMeOH : H₂O (2 : 1)NR15Rhodamine BMeOH : H₂O (2 : 1)NR16—MeOH : H₂O (2 : 1)NR^c17Ru(bpy)₃Cl₂MeOH : H₂O (2 : 1)NR^d18Ru(bpy)₃Cl₂MeOH : H₂O (2 : 1)NR^e19Ru(bpy)₃Cl₂MeOH : H₂O (2 : 1)45^f, 84^g20Ru(bpy)₃Cl₂MeOH : H₂O (2 : 1)56^h, NRⁱOpen in a separate window^aReaction conditions: all reactions were carried out with 0.25 mmol of 1a, 0.5 mmol of 2, and 0.2 mol% of photocatalyst in 2.0 mL of solvent for 36 h at room temperature under argon atmosphere and irradiation with 34 W blue LED. NR = no reaction.^bIn aerobic condition.^cAbsence of Ru(bpy)₃Cl₂.^dWithout light source at rt.^eReaction at 60 °C without light scource.^f1.5 equiv. EDA.^g2.5 equiv. EDA.^hIrradiation with 20 W blue LED.ⁱ30 W white LED.With the optimized reaction conditions in hand we explored the substrate scope of this methodology with various substituted imidazopyridines. At first we checked the effect of various substituents on the pyridine ring of imidazopyridine derivatives and the results are summarized in Scheme 2. Imidazopyridine containing various electron-donating groups (8-Me and 7-OMe) efficiently reacted with ethyl diazoacetate to provide the desired products in good yields (3b and 3c). It is important to note that substrates bearing electron-withdrawing groups did not afford alkylated products under the optimized reaction condition. However, addition of 10 mol% N,N-dimethyl-m-toluidine as a redox-active additive gave a satisfactory yield of the desired products (see ESI^†). Therefore in modified reaction conditions, halogens containing imidazopyridines like –F, –Br, –I and strong electron-withdrawing group such as –CF₃, –CN containing substrates were successfully afforded the desired products in 67–90% yields (3d–3h). Next, we examined the substrate scope with various substitutions in phenyl part of imidazo[1,2-a]pyridine. Imidazopyridine with electron-releasing (4-Me, and 4-OMe), halogens (4-F, 4-Cl, and 3-Br) and strong electron-withdrawing group (4-CF₃, and 4-CN) containing substrates produced the desired products with good to excellent yields (3i–3p). 2-Hydroxy substituted imidazo[1,2-a]pyridine was also worked well in this transformation (3k). In addition, disubstituted imdazopyridines with different substituents at both the phenyl and pyridine ring underwent the reaction very smoothly (3q, and 3r). Heteroaryl and naphthyl substituted imidazopyridines produced the desired products without any difficulties (3s–3u). However, unsubstituted imidazo[1,2-a]pyridine did not produce the desired product in this protocol. To highlight the applicability of the present protocol a gram-scale reaction was carried out taking 1a in 6.0 mmol scale under normal laboratory setup. The yield of ethyl 2-(2-phenylimidazo[1,2-a]pyridin-3-yl)acetate (3a) was slightly diminished to 70% after 36 h along with the recovery of excess starting material.Open in a separate windowScheme 2Substrate scope of imidazopyridines.^a aReaction conditions: 0.25 mmol of 1, 0.5 mmol of 2 in presence of 0.2 mol% of Ru(bpy)₃Cl₂ in 2.0 mL of MeOH : H₂O (2 : 1) at room temperature under 34 W blue LED and argon atmosphere for 36 h. ^b10 mol% N,N-dimethyl-m-toluidine was added as an additive. ^c6.0 mmol scale.Next, to show the generality of this present methodology, we investigated the reaction taking other imidazoheterocycles like imidazo[2,1-b]thiazole and benzo[d]imidazo[2,1-b]thiazoles (Scheme 3). 6-Phenylimidazo-[2,1-b]thiazole reacted smoothly to afford 5a in 66% yield. Benzo[d]imidazo[2,1-b]thiazole containing –Me, –OMe, and –Cl substituted derivatives were well tolerable under the present reaction conditions (5b–5e). The structure of ethyl 2-(7-methoxy-2-phenylbenzo[d]imidazo[2,1-b]thiazol-3-yl)acetate (5c) was confirmed by X-ray crystallography.¹⁴ In addition, thiophene substituted benzo[d]imidazo[2,1-b]thiazole furnished the corresponding alkylated product in good yield (5f).Open in a separate windowScheme 3Substrate scope.^a aReaction conditions: 0.25 mmol of 4, 0.5 mmol of 2 in presence of 0.2 mol% of Ru(bpy)₃Cl₂ in 2.0 mL of MeOH : H₂O (2 : 1) at room temperature under 34 W blue LED and argon atmosphere for 36 h. ^b10 mol% N,N-dimethyl-m-toluidine was added as an additive.After that, we have directly modified the synthesized ethoxycarbonylmethylated product (3q) to amide derivative (6q) in 56% yield using benzylamine in the presence of La(OTf)₃ as a catalyst under ambient air at rt to 70 °C as shown in Fig. 1.Open in a separate windowFig. 1Modification of ester group via direct amidation process.A few control experiments were performed to understand the mechanistic insights of the present protocol (Scheme 4). The alkylation reaction did not proceed in the presence of 3.0 equiv. radical scavengers like 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO), 2,6-di-tert-butyl-4-methyl phenol (BHT), 1,1-diphenylethylene (DPE), and p-benzoquinone (BQ) which suggest the reaction probably proceeds through radical pathway (Scheme 4, eqn (A)). Moreover, 3-phenylimidazo[1,2-a]pyridine (1v) did not produce the C-2 alkylated product that signifies the regioselectivity of the present protocol (Scheme 4, eqn (B)). Taking 2-(2-(vinyloxy)phenyl)imidazo[1,2-a]pyridine we also performed this reaction with ethyl diazoacetate under this standard reaction conditions. Desired C-3 alkylated product (8a) was formed in 35% yield (Scheme 4, eqn (C)). But cyclopropanation product was not formed in the alkene part of the allyl group via carbene pathway. From this experimental result strongly imply that the present strategy only proceeds through radical mechanistic pathway.Open in a separate windowScheme 4Control experiments.Based on the above mechanistic studies and previous literature reports,^7,8,13 a possible radical mechanism was proposed for the formation of ethyl 2-(2-phenylimidazo[1,2-a]pyridin-3-yl)acetate (3a) as presented in Scheme 5. Initially, photo-catalyst Ru(bpy)₃²⁺ is transformed to its excited-state *Ru(bpy)₃²⁺ under blue LED irradiation. In the presence of MeOH/H₂O, diazo compounds are in equilibrium with their protonated form (A). Then cationic diazoester involves single-electron transfer (SET) process with excited photocatalyst *Ru(bpy)₃²⁺ leading to the formation of alkyl radical intermediate (B) and Ru(bpy)₃³⁺.^6b,c Next, alkyl radical intermediate (B) effectively reacts with imidazopyridine (1a) to produce imidazole radical intermediate (C) which is successively transformed to imidazolium radical cation intermediate (D) along with the generation of ground state photocatalyst. Finally, C-3 alkylated imidazopyridine (3a) is obtained through deprotonation of intermediate D. It is worthy to mention that Meggers et al.^7h did not observe quenching of *Ru(bpy)₃²⁺ whereas Gryko et al.^6c did observe the quenching of *Ru(bpy)₃²⁺ by ethyl diazoacetate that was accelerated in the presence of protic sources.Open in a separate windowScheme 5Proposed mechanistic pathway.In case of halogen or electron-withdrawing substituted imidazoheterocycles a possible mechanism for the radical alkylation reaction is illustrated in Scheme 6.^6b,c Reductive quenching of *Ru(bpy)₃²⁺ by SET oxidation of aniline derivatives affords radical cation E and Ru(bpy)₃⁺. Then reduced photocatalyst Ru(bpy)₃⁺ comes back to ground state with the generation of radical intermediate Bvia the elimination of N₂. Subsequently, radical intermediate B reacts with imidazopyridine 1 to produce radical intermediate C′. Finally, the desired product 3′ is produced through the hydrogen atom transfer (HAT) process between radical cation E and radical intermediate C′.Open in a separate windowScheme 6Mechanistic pathway for electon-deficient substrates.     

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.     

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

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

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

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

Acetonitrile and benzonitrile as versatile amino sources in copper-catalyzed mild electrochemical C–H amidation reactions

A mild, efficient electrochemical approach to the site-selective direct C–H amidation of benzene and its derivatives with acetonitrile and benzonitrile has been developed. It has been shown that joint electrochemical oxidation of various arenes in the presence of a copper salt as a catalyst and nitriles leads to the formation of N-phenylacetamide from benzene and N-benzylacetamides from benzyl derivatives (up to 78% yield). A favorable feature of the process is mild conditions (room temperature, ambient pressure, no strong oxidants) that meet the criteria of green chemistry.

Different pathways of C–H transformation depending on the substrate nature and oxidation potential.

Direct functionalization of C–H bonds is one of the most popular tools in organic synthesis and allows formation of complex molecules from structurally simple starting substrates in one step.¹ The direct functionalization of carbon–hydrogen bonds catalyzed by transition metals is currently one of the main ways of constructing carbon–element bonds (C–N, C–C, C–P, C–R_fetc.).² Catalysed by transition metals, C–N bond building reactions are of particular importance in biology, pharmaceuticals and materials science.³ There are many examples of C–N bond formation reactions using organic (pseudo) halides such as aryl iodides, bromides, chlorides, triflates and sulfonates, that react with amines or their precursors. Ullmann and Goldberg were the first to report on the N-arylation of aryl halides using a copper mediator,⁴ and later Pd, Cu and Rh catalyzed C–N bond formation with suitable ligands was developed (Scheme 1, reaction 1).⁵Open in a separate windowScheme 1Strategies for the synthesis of N-arylamides and N-benzylamides.However, as a rule, such catalytic reactions have limited practical application due to the requirements for stoichiometric amounts of reagents and harsh reaction conditions (high temperature, high pressure, excess amount of strong oxidants, etc.). In addition these reactions involve strong chemical oxidants that are expensive, reduce the atomic economy of the process and lead to the formation of by-products. To address those limitations, reactions of C–H functionalization catalysed by transition metals by means of electrochemical oxidation⁶ and photoelectrochemistry⁷ have been developed relatively recently.Electrocatalytic approaches have been shown to be effective methods for building C–P, C–C, C–R_f and C–N bonds.⁸ In particular, the synthesis of N-arylamides is of particular interest for organic chemists, since amides are important structural frameworks presented in natural products, biological compounds, pharmaceuticals and synthetic materials.⁹ Therefore, the search for the new methods to synthesize N-arylamides, including electrochemical approach, is of current interest. The synthesis of N-arylamides could be more accessible while using nitriles as amidation agents instead of amides.It is known that certain alkanes can be oxidized at sufficiently high electrode potentials in acetonitrile with functionalization of C(sp³)–H bonds. Koch and Miller studied the electrochemical acetamidation reaction of adamantanes in acetonitrile at a platinum anode.¹⁰ The anodic oxidation of adamantine was performed potentiostatically producing N-(1-adamanty1)acetonitrilium ions as the major product. Further aqueous work-up was leading to the formation of 1-adamantylacetamide in 65–90% yields.Ji group developed an efficient and practical methodology for the synthesis of N-arylamides via copper catalyzed amidation of diaryliodonium salts with nitriles (Scheme 1, reaction 2).¹¹N-Arylated amides were obtained in moderate to good yields (up to 88%) and various substituted aryl nitriles and aliphatic nitriles could be applied in this reaction.Ley and coworkers reported on the preparation of benzyl amides from a number of aromatic hydrocarbons by a stable and continuous flow anodic oxidation using Bu₄NPF₆ as electrolyte and Brønsted acid additives (Scheme 1, reaction 3).¹² The amide derivatives of various para-, meta- and ortho-substituted benzene derivatives were obtained in good yields (64%). However the continuous flow electrolysis could not be carried out in pure acetonitrile and limited to certain substrates.In Vecchio group the series of acetamides was obtained in high yields under solvent- and catalyst-free conditions using isopropenyl acetate as reagent for acetylation of amines.¹³ Although this protocol is not suitable for unsubstituted arenes.Just recently Shen and Lambert reported on electrophotocatalytic convert benzylic C–H bonds to acetamides with the use of hard-to-find and expensive trisaminocyclopropenium (TAC) ion as catalyst (Scheme 1, reaction 4).¹⁴ The protocol is compatible with many functional groups and was demonstrated on complex substrates although no examples of aromatic ring amidation reaction were provided.Anodic oxidation of 1-(trifluoromethyl)benzene in dry acetonitrile/Bu₄NBF₄ under constant potential conditions leading to 2-(trifluoromethyl) acetanilide was proposed by Barba et al.¹⁵ No other substrates were demonstrated in this protocol.Inspired by the literature data in this area we report on the optimized conditions of the cross-coupling reaction between unsubstituted arenes (e.g. benzene) and different nitriles. Relying on the previously obtained experience of Cu-catalyzed electrochemical amination reactions,^8g copper acetate salt was chosen as a catalyst. Thus, electrooxidation of benzene in MeCN in the presence of catalytic amount of copper acetate leaded to the formation of acetanilide as only product with a yield of 70% ( No.CatalystAdditiveSolventYield^b15%, Cu(OAc)₂—MeCN54210%, Cu(OAc)₂—MeCN703——MeCN—41 eq., Cu(OAc)₂—MeCN425^c10%, Cu(OAc)₂—DCM/MeCN—610%, Cu(OAc)₂NH₂COOMeMeCN61710%, Cu(OAc)₂K₃PO₄MeCN30810%, Cu(OAc)₂Et₃NMeCN239Co(BF₄)₂·6H₂O—MeCN—10^d10%, Cu(OAc)₂—MeCN211110%, Mn(OAc)₂—MeCN—1210%, Pd(OAc)₂—MeCN—Open in a separate window^aReaction conditions: benzene (1 mmol), catalyst (0.1 mmol, 10 mol%), H₂O (1 mmol), rt, divided cell, 2F electricity (80 mA h).^bIsolated.^cDCM : MeCN (40 : 1).^dWithout H₂O.Aromatic ring Ritter reaction also proceeds when bromobenzene, p-dibromobenzene and trifluormethylbenzene are used as substrates (Scheme 2). In the case of using bromobenzene, N-(4-bromophenyl)acetamide (2b) is formed as a major isomer. This is most likely due to the steric factor of the bulky bromine substituent presence. While using trifluormethylbenzene as a substrate, the major product is N-(2-(trifluoromethyl)phenyl)acetamide (4a) probably due to strong inductive effect of the trifluoromethyl group what makes the adjacent positions assailable to nucleophilic attack.Open in a separate windowScheme 2Electrocatalytic amidation of benzene and benzyl derivatives. Reaction condition: substrate (1 mmol), Cu(OAc)₂ (0.1 mmol, 10 mol%), H₂O (1 mmol), MeCN (40 mL), Pt–Pt, divided cell, constant current, isolated yield.In the presence of copper salt, further reactions were carried out with methyl-substituted arenes such as toluene, xylenes, 2-bromtoluene, mesitylene, 2-bromomesitylene, etc. The results obtained from the electrocatalytic oxidation of arenes in R–CN (MeCN, PhCN) are summarized in Scheme 2. In case of a methyl group presents in the aromatic ring of a substrate, the reaction proceeds with the participation of a methyl fragment. When substrates have several methyl groups (xylene, mesitylene), amidation products with one substituted methyl group are obtained as the main product even while passing more electricity (4F).Molecular weight of the amidation products were verified via GC-MS analysis. According to GC-MS data amidation product with three acetamide fragments is also formed when 2-bromomesitylene is used as a substrate. The presence of bromine substituent in the aromatic ring probably affects the reactivity so the yield of the main product decreases due to the formation of dimers that are also observed via GC-MS analysis. In case of using o-bromotoluene as a substrate we also registered the formation of a small amount of o-bromobenzaldehyde as a byproduct that wasn''t observed while using other substrates. In case of 2,6-dimethyllutidine, only a trace amount of the desired product is observed. This is probably due to the coordination properties of 2,6-dimethyllutidine itself and the formation of a copper complex.When naphthalene, 2,6-dimethylnaphthalene, 2-phenylpyridine, p-bromoanisole and anisole were tested in electrooxidation reaction, formation of the C–C bond (dimer formation) was observed instead of the expected C–N bond (Scheme 3) according to GC-MS data. Passing 2F is sufficient to form dimers of anisole, p-bromoanisole and phenylpyridine. In the case of p-bromoanisole and anisole, di-, tri-, and tetradimers are formed. Conversion of naphthalene reaches 90% after passing 4F electricity, in this case 2,2′-binaphthyl is formed. When using coumarin, 7-methylcoumarin, benzonitrile and caffeine the products of cross-coupling with CH₃CN or dimers were not formed.Open in a separate windowScheme 3Electrocatalytic homo-cross-coupling of aromatics.On the basis of the preparative electrolysis and cyclic voltammetry data and the previous studies on anodic oxidation of investigated molecules,^8g,16 the general scheme of possible C–H transformations depending on the substrate nature (aromatic or heteroaromatic, presence of substituents) and oxidation potentials of using substrates can be represented as follows Scheme 4.Open in a separate windowScheme 4Different ways of C–H transformation depending on the substrate nature and oxidation potentials.It is obvious that the one of the criteria of success and selectivity of the amidation reaction, either an aromatic C–(sp²)–H or a benzyl C–(sp³)–H bond, is determined by the electrolysis potential, namely, by the oxidation potentials of the reaction participants (Table S2^†). Amidation of the aromatic ring occurs only in the case of difficult oxidizable substrates (benzene, bromobenzene, p-dibromobenzene, trifluormethylbenzene) according to the following possible scheme (Scheme 5):Open in a separate windowScheme 5Plausible mechanism for the amidation of benzene.The presence of a methyl substituent on the benzene ring leads to selective amidation of the benzyl fragment and the reaction is already proceeding through the oxidation of methyl group. However, no radical intermediates were detected by EPR. Heteroarenes (e.g. 2-phenylpyridine) have the ability to coordinate with metals; thus, during electrooxidation of heteroarenes the dimers are formed instead of acetylamides.Thus, depending on the substrate nature (aromatic or heteroaromatic, presence of methyl or other substituents) and the oxidation potentials of aromatics, the reaction proceeds in different way under the same conditions.     

Access to 1-amino-3,4-dihydroisoquinolines via palladium-catalyzed C–H bond aminoimidoylation reaction from functionalized isocyanides

Efficient access to 1-amino-3,4-dihydroisoquinolines, through palladium-catalyzed intramolecular C–H bond aminoimidoylation of α-benzyl-α-isocyanoacetates, has been developed. Consecutive isocyanide insertion and C–H bond activation were realized with C–N and C–C bonds formation in one step under redox neutral conditions, employing O-benzoyl hydroxylamines as electrophilic amino sources.

Efficient and practice access to 1-amino-3,4-dihydroisoquinolines, through palladium-catalyzed intramolecular C–H bond aminoimidoylation of α-benzyl-α-isocyanoacetates, has been developed.

As a class of cyclic amidine compounds, 1-amino-3,4-dihydroisoquinolines are essential six-membered heterocycles which can be found in numerous natural products, functional chemicals and pharmaceutical agents (Scheme 1).¹ For example, piperazine tethered dihydroisoquinoline and benzocyclic amide I was found to be an efficient cardiovascular agent.^1a Phenylalanine-derived and arylamine or cyclic aliphatic-amine-containing 1-amino-3,4-dihydroisoquinolines (II–V) show outstanding BACE-1 inhibition, kinase VEGFR-2 inhibition, phosphodiesterase IV inhibition and hydrogen ion-sodium exchanger NHE-3 inhibition activities, respectively.^1b–e Traditional preparation of such 1-amino-3,4-dihydroisoquinoline scaffolds is mainly based on nucleophilic substitution of readily prepared 3,4-dihydroisoquinolines² and Bischler-Napieralski reaction starting from urea.³ Most of these methods suffer from multiple-step synthesis, harsh conditions or the use of toxic reagents. Thus, developing an efficient and practical method for the construction of 1-amino-3,4-dihydroisoquinoline derivatives remain an attractive synthetic task.Open in a separate windowScheme 1(a) Representative bioactive molecules containing the 1-amino-3,4-dihydroisoquinoline moiety. (b) Traditional synthetic methods.In recent decades, isocyanides have been extensively studied in multicomponent reactions,⁴ imidoyl radical-involved transformations⁵ and transition-metal-catalyzed insertion reactions⁶ due to their diverse and unique reactivities. A variety of acyclic imine derivatives were synthesized via palladium-catalyzed imidoylation reactions.⁷ For the construction of biorelevant nitrogen-containing heterocycles via Pd-catalyzed non-functionalized isocyanide insertion reactions, a nucleophilic group is usually preinstalled to the substrates containing C–X (C–H) bonds, followed by Pd-catalyzed oxidative addition (C–H bond activation)/isocyanide insertion/ligand substitution/reductive elimination sequence.⁸ For example, Maes and coworkers developed an efficient palladium-catalyzed synthesis of 4-aminoquinazolines from N-(2-bromoaryl)amidines using amidine as an internal nucleophile.^8a Access to the same scaffold through palladium-catalyzed amidine-directed C–H bond imidoylation/cyclization reaction was reported by Zhu group.^8c Isocyanide acted as a C1 synthon in these cyclization reactions, with the terminal carbon of isocyanide being used in the ring formation.⁹ Considering the diversity of R group on the nitrogen atom of isocyanide, the so-called functionalized isocyanide strategy was widely developed as well, with various N-heterocycles such as oxazoles,¹⁰ indoles,¹¹ phenanthridines,¹² 9H-pyrido[3,4-b]indoles¹³ and nonaromatic azepines¹⁴ being synthesized efficiently. Zhu and coworkers developed the first asymmetric C–H bond imidoylation reaction from easily accessible α,α-dibenzyl-α-isocyanoacetates with chiral quaternary-carbon-containing 3,4-dihydroisoquinolines being generated (Scheme 2a).¹⁵ Recently, a catalytic system controlled regioselective C–H bond imidoylation was realized for the selective synthesis of 5 or 6-membered cyclic imines (Scheme 2b).¹⁶ Aryl halides were mostly used in these transformations while N–O compounds were rarely reported as electrophiles in Pd-catalyzed isocyanide insertion reactions.¹⁷ Zhu group reported the synthesis of phenanthridin-6-amine derivatives from O-benzoyl hydroxylamines and commonly used biaryl isocyanides.^17c However, a methyl or methoxyl carbonyl group was needed at the ortho position of isocyano group, which critically limited the application of the reaction. Herein, we developed an efficient and practical synthesis of 1-amino-3,4-dihydroisoquinolines, through palladium-catalyzed intramolecular C–H bond aminoimidoylation reaction of α-benzyl-α-isocyanoacetates. Consecutive isocyanide insertion and C–H bond activation were realized with C–N and C–C bonds being constructed in one step, employing O-benzoyl hydroxylamines as electrophilic amino sources.Open in a separate windowScheme 2Palladium-catalyzed imidoylative cyclization of α-benzyl-ethylacetates.The reaction conditions were optimized with ethyl 2-benzyl-2-isocyano-3-phenylpropanoate (1a) and morpholino benzoate (2a) as model substrates, and ethyl 3-benzyl-1-morpholino-3,4-dihydroisoquinoline-3-carboxylate (3a) was obtained in 34% yield in the presence of Pd(OAc)₂ (1.5 equiv.), PPh₃ (20 mol%), Cs₂CO₃ (1.0 equiv.) and PivOH (0.6 equiv.) in toluene at 80 °C (entry 1, EntryCatalystLigandSolventYield^b1Pd(OAc)₂PPh₃Toluene342Pd(OAc)₂PPh₃THFTrace3Pd(OAc)₂PPh₃DCE294Pd(OAc)₂PPh₃Dioxane765Pd(OAc)₂PPh₃MeCNTrace6Pd(OAc)₂PPh₃DMSOTrace7Pd(OPiv)₂PPh₃Dioxane318Pd(TFA)₂PPh₃Dioxane269PdCl₂(MeCN)₂PPh₃Dioxane3811Pd(PPh₃)₄Dioxane5612Pd(OAc)₂BINAPDioxane3013Pd(OAc)₂dppbDioxane2614Pd(OAc)₂dpppDioxane2815Pd(OAc)₂XantPhosDioxane4216Pd(OAc)₂SPhosDioxane3417Pd(OAc)₂XPhosDioxane2418^cPd(OAc)₂PPh₃Dioxane84 (80)^d19^cNonePPh₃Dioxane020^cPd(OAc)₂NoneDioxane5621^c,ePd(OAc)₂PPh₃Dioxane022^c,fPd(OAc)₂PPh₃Dioxane4123^c,gPd(OAc)₂PPh₃Dioxane2424^c,hPd(OAc)₂PPh₃Dioxane3125^c,iPd(OAc)₂PPh₃Dioxane61Open in a separate window^aReaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), Pd-catalyst (0.01 mmol, 10 mol%), ligand (0.02 mmol, 20 mol%), Cs₂CO₃ (0.1 mmol, 1.0 equiv.), PivOH (0.06 mmol, 0.6 equiv.), 80 °C, Ar. A solution of 1a was added via a syringe pump within 1 h.^bNMR yield with 1-iodo-4-methoxybenzene as an internal standard.^c T = 110 °C.^dIsolated yield.^eWithout Cs₂CO₃ and PivOH.^fCsOPiv was used as the base.^gK₂CO₃ was used as the base.^hNa₂CO₃ was used as the base.ⁱ5 mol% of catalyst was used.With the optimized conditions in hand, the scope of functionalized isocyanide was investigated first, using morpholino benzoate 2a as the coupling partner (Scheme 3). Both electron rich and withdrawing substituents such as Me, t-Bu, F, Cl, CF₃, CO₂Me and NO₂ at the para position of aromatic ring can tolerate the reaction conditions, and generate the corresponding products in good to excellent yields (3a–3h). Isocyanides bearing ortho substituents on the phenyl ring underwent the reaction smoothly, generating the products 3i and 3j in 58% and 82% yields respectively. Even substrates bearing two substituents were well suited to the reaction conditions, affording the aminoimidoylation products without loss of efficiency (3k–3l). Compound 3m was delivered with excellent regioselectivity in 63% yield when m-Cl substituted starting material was employed in the reaction, which indicated the hindrance sensitivity of this reaction. Modifying the ester moiety in 1 to a methyl ester or an amide did not impede the reaction, giving 3n and 3o with excellent yields. Changing one of the benzyl groups to alkyl substituents didn''t decrease the reaction efficiency, generating products 3p and 3q in moderate yields.Open in a separate windowScheme 3Scope of isocyanides. Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol), Pd(OAc)₂ (0.01 mmol, 10 mol%), PPh₃ (0.02 mmol, 20 mol%), Cs₂CO₃ (0.1 mmol, 1.0 equiv.), PivOH (0.06 mmol, 0.6 equiv.), 110 °C, Ar. A solution of 1 was added via a syringe pump within 1 h. Isolated yields.Then we moved our attention to the investigation of substrate scope of aminating partners (Scheme 4). It was found that various O-benzoyl hydroxylamines derived from piperidines could be smoothly employed in the reaction (4a–4e). Substituents such as Me, CO₂Et, OMe and ketal group on the piperidines were well tolerated (4b–4e). Aminating reagent derived from Boc-protected piperazine was also compatible with this reaction, generating the product 4f in 99% yield. Fortunately, acyclic aminated product 4g was obtained as well in moderate yield.Open in a separate windowScheme 4Substrate scope of aminating agents. Reaction conditions: 1a (0.1 mmol), 2 (0.15 mmol), Pd(OAc)₂ (0.01 mmol, 10 mol%), PPh₃ (0.02 mmol, 20 mol%), Cs₂CO₃ (0.1 mmol, 1.0 equiv.), PivOH (0.06 mmol, 0.6 equiv.), 110 °C, Ar. A solution of 1a was added via a syringe pump within 1 h. Isolated yields.When ethyl 2-isocyano-2,3-diphenylpropanoate was conducted in the reaction with 2a, the 3,4-dihydroisoquinoline product 6 was generated exclusively, albeit in only 37% yield (Scheme 5a). To examine if isoindoline could be afforded by this aminoimidoylation reaction, ethyl 2-isocyano-4-methyl-2-phenylpentanoate (7) was selected as the substrate with 2a (Scheme 5b). However, no desired product was generated under the standard conditions, showing different site-selectivity with the previous imidoylation reaction developed by Zhu and coworkers.¹⁶Open in a separate windowScheme 5Reaction conditions: 5(7) (0.1 mmol), 2a (0.15 mmol), Pd(OAc)₂ (0.01 mmol, 10 mol%), PPh₃ (0.02 mmol, 20 mol%), Cs₂CO₃ (0.1 mmol, 1.0 equiv.), PivOH (0.06 mmol, 0.6 equiv.), 110 °C, Ar. A solution of 5(7) was added via a syringe pump within 1 h. Isolated yields.Gram-scale preparation of 3a was carried out smoothly under standard conditions (Scheme 6a). The reduction reaction of 3a was carried out using LiAlH₄ and the corresponding product 8 was generated in 70% yield (Scheme 6b). The ester group was successfully transformed to tertiary alcohol (9) in moderate yield with Grignard reagent.Open in a separate windowScheme 6Gram-scale preparation and diversifications of 3a.In order to get further insight into the reaction mechanism, a radical trapping reaction with 0.1 equivalents of TEMPO was carried out (Scheme 7a). The product 3a was generated without loss of efficiency, which indicated that the radical-involved pathway could be ruled out. A plausible mechanism was then proposed in Scheme 7b. The reaction was initiated with oxidative addition of O-benzoyl hydroxylamine 2a to the in situ generated Pd(0) species. Migratory isocyanide insertion to intermediate B afforded aminoimidoyl Pd(ii) intermediate C. The following intramolecular C–H bond activation and reductive elimination viaE yielded the final product 3a and regenerated Pd(0) to complete the catalytic cycle.Open in a separate windowScheme 7Proposed mechanism.In conclusion, we have developed an efficient and practical method to prepare 1-amino-3,4-dihydroisoquinolines via palladium-catalyzed intramolecular C–H bond aminoimidoylation of α-benzyl-α-isocyanoacetates under redox-neutral conditions. Consecutive isocyanide insertion and C–H bond activation were realized with C–N and C–C bonds formation in one step, employing O-benzoyl hydroxylamines as electrophilic amino sources. A broad range of substrates were applicable to the reaction in good to excellent yields.     

Palladium-catalyzed dehydrogenative C–H cyclization for isoindolinone synthesis

In this paper Pd-catalyzed intramolecular dehydrogenative C(sp³)–H amidation for the synthesis of isoindolinones is described. This method features the use of a Pd/C catalyst and the addition of a stoichiometric amount of oxidant is not necessary. A mechanistic study suggested the possible formation of H₂ gas during the reaction.

Pd-catalyzed intramolecular dehydrogenative C(sp³)–H amidation for the synthesis of isoindolinones was developed. Use of Pd/C as a catalyst enables the desired cyclization to proceed smoothly without adding any stoichiometric oxidants.

The isoindolinone scaffold occurs frequently in numerous biologically active compounds ranging from designed medicinal agents to natural products, thus constituting an extremely important class of heterocycles.^1,2 Although a number of synthetic methods exist for the preparation of isoindolinones,³ the development of more general, versatile, and efficient procedures to construct the isoindolinone framework is still an ongoing, intensive research area.Among a variety of synthetic strategies for isoindolinones, methods that make use of transition metal-catalyzed C–H functionalization represent a remarkable approach.⁴ In this research area, catalytic oxidative annulation of N-substituted benzamides and appropriate coupling partners (e.g. alkenes, alkynes, isocyanides, diazo compounds) has been extensively studied, most of which employ transition metals such as rhodium,^4d,g,h,n,o ruthenium,^4l cobalt,^4a,i,j,k and palladium.^4b,m These precedents often require the use of stoichiometric oxidants or prefunctionalized coupling partners to make the process catalytic.On the other hand, an approach that involves intramolecular C–H cyclization of benzamide derivatives exploiting a transition metal catalyst could provide another efficient, facile, and direct access to isoindolinones, although less attention has been paid to such a process (Scheme 1). Kondo et al. previously reported C(sp³)–H aminative cyclization of 2-methyl-N-arylbenzamides in the presence of a copper catalyst along with a stoichiometric amount of di-tert-butyl peroxide as an oxidant, which resulted in the formation of 3-unsubstituted isoindolinones (Scheme 1a).^4c Bedford''s group also developed a copper-based catalytic system composed of 20 mol% of Cu(OTf)₂ and 2 equiv. of PhI(OAc)₂ that successfully effected the intramolecular benzylic C–H sulfamidation of 2-benzyl-N-tosylbenzamides for the synthesis of isoindolinones (Scheme 1b).^4f In both cases, the choice of an oxidant should be crucial for the successful construction of the isoindolinone ring.Open in a separate windowScheme 1C–H cyclization strategies for isoindolinone synthesis.Herein, we describe a catalytic system that enables cyclization of 2-benzyl-N-mesylbenzamides leading to isoindolinone derivatives, in which benzylic C(sp³)–H functionalization in the presence of a palladium catalyst smoothly occurs. It is particularly noteworthy to mention that any stoichiometric oxidants are not necessary for our isoindolinone synthesis. The key to success is the use of Pd/C as a catalyst. In this dehydrogenative process, an only detectable by-product was H₂, which should also be an appealing feature of the process.Based on our fruitful results of the heterocycles synthesis via transition metal-catalyzed C–H cyclization,⁵ our investigation began by examining the conversion of N-tosyl-protected benzamide 1a to the corresponding isoindolinone 2a. During the screening studies utilizing a range of transition metal catalysts as well as various oxidants, it was found that 2a did produce even in the absence of an oxidant when Pd/C was used as a catalyst. Indeed, the use of 10 mol% of Pd/C along with 20 mol% of KOAc enabled the desired cyclization process, providing 2a in 42% yield (6Effect of protecting group^a,b

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

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

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

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

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

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

Synthesis of six-membered spirooxindoles via a chiral Brønsted acid-catalyzed asymmetric intramolecular Friedel–Crafts reaction

By means of the direct condensation of N-aminoethylpyrroles and isatins, followed by a chiral phosphoric acid-catalyzed asymmetric intramolecular Friedel-Crafts reaction, a new class of valuable chiral 3′,4′-dihydro-2′H-spiro[indoline-3,1′-pyrrolo[1,2-a]pyrazin]-2-ones bearing a quaternary carbon stereocenter were successfully synthesized in good to excellent yields and with moderate to good enantioselectivities under mild reaction conditions.

A chiral phosphoric acid-catalyzed asymmetric intramolecular Friedel–Crafts reaction for the synthesis of 3′,4′-dihydro-2′H-spiro[indoline-3,1′-pyrrolo[1,2-a]pyrazin]-2-ones.

Spirooxindoles, containing a spirocyclic system, are unique structural motifs found in a wide range of natural products and bioactive compounds.¹ For instance, Spirotryprostatin B (Fig. 1) was isolated from the fermentation broth of Aspergillus fumigatus and was shown to completely inhibit the G2/M progression of cell division in mammalian tsFT210 cells.²Gelsemium alkaloids (e.g. gelsenicine, gelsedine and gelsedilam) were isolated from the ancient medicine Yakatsu stored in the Shosoin Repository and exhibit a wide range of biological activities, including analgesic, anti-inflammatory, and antitumor effects.³ Besides, a considerable number of spirooxindoles display anticancer activity. For example, APG-115 and MI77301, which can effectively block the MDM2-p53 protein–protein interaction in cells as MDM2 inhibitors, are under clinical trials as promising anticancer drugs.⁴Open in a separate windowFig. 1Selected examples of natural and artificial spirooxindoles.Consequently, the unique structure of those compounds has attracted much attention from synthetic chemists.⁵ Some investigated strategies to access this skeleton include intramolecular reactions of imines via Pictet–Spengler reaction synthesized from tryptamines or tryptophans with isatin (Scheme 1a),⁶ oxidative rearrangement of tetrahydro-β-carbolines prepared via Pictet–Spengler reaction (Scheme 1b),⁷ metal or small-molecule catalyzed 1,3-dipolar cycloaddition of imino esters with methyleneindolinones (Scheme 1c),⁸ Rh-catalyzed [4 + 1] cycloaddition of azocompound with vinyl isocyanates (Scheme 1d),⁹ chiral iodoarene catalytic oxidative spirocyclization (Scheme 1e),¹⁰ Pd-catalyzed intramolecular addition and domino spirocyclization,¹¹ intramolecular nucleophilic addition¹² and so on.¹³ Despite of several methods developed for the construction of this skeleton, however, less work finished catalytic asymmetric synthesis and preparation of novel chiral spirooxindoles are warmly anticipated. Herein, we report an efficient protocol via an intermolecular condensation/intramolecular Friedel–Crafts reaction to synthesize a new class of 3′,4′-dihydro-2′H-spiro[indoline-3,1′-pyrrolo[1,2-a]pyrazin]-2-ones in an asymmetric way.Open in a separate windowScheme 1Catalytic synthesis of spirooxindoles.At the outset of this study, we envisaged that reaction of N-aminoethylpyrroles with isatins catalyzed by chiral phosphoric acids might undergo direct condensation, followed by intramolecular Friedel–Crafts reactions under very mild reaction conditions.¹⁴ We first began our investigation with 1-benzylindole-2,3-dione (1.0 equiv.) and N-aminoethylpyrrole (1.2 equiv.) as the substrates, BINOL-derived chiral phosphoric acid 4a as the catalyst, dichloromethane (DCM) as the solvent, 4 Å MS as a desiccant. The reaction was performed at room temperature (20 °C). To our delight, the cascade reaction proceeded smoothly providing 3′,4′-dihydro-2′H-spiro[indoline-3,1′-pyrrolo[1,2-a]pyrazin]-2-one 3aa in 99% yield but with a poor enantioselectivity (5% ee, 15 we turned to employ another kind of spiro catalysts¹⁶ and investigated their function. Delightingly, catalyst (R)-PA 5a was found to significantly improve the ee from 49% to 88% and product 3aa was given in 85% yield under mild reaction conditions in DCM. Then we evaluated the feasibility of the reaction in other solvents ( EntrySubstrate(R)-PASolventTemp. [°C]Yield^b [%]ee^c [%]11a4aDCMr.t.99521a4bDCMr.t.99031a4cDCMr.t.72541a4dDCMr.t.99051a4eDCMr.t.992161a4fDCMr.t.99071a4gDCMr.t.99081a4hDCMr.t.97091a4iDCMr.t.9649 10 1a5a DCM r.t. 85 88 111a5bDCMr.t.7019121a5aTHFr.t.9980131a5aMeCNr.t.6862141a5aDMFr.t.2844151a5aEt₂Or.t.8179161a5aCHCl₃r.t.9078171a5a1,4-Dioxaner.t.8383181a5aDCEr.t.8487191b5aDCMr.t.8939201c5aDCMr.t.6868211d5aDCMr.t.9774221e5aDCMr.t.8474231f5aDCMr.t.9269241a5aDCM07179251a5aDCM309080Open in a separate window^aReaction conditions: 1a (0.2 mmol), 2a (1.2 equiv.), (R)-PA (10 mol%), 4 Å MS (50 mg), 2.0 mL of solvent, r.t. = 20 °C, overnight.^bIsolated yield.^cee was determined by chiral HPLC.With the set of optimized reaction conditions in hand, we focused our attention on the substrate scope of this catalytic asymmetric intramolecular Friedel–Crafts reaction. At first, substituted isatin derivatives were screened as the substrates in combination with N-aminoethyl pyrrole 2a, affording chiral products 3′,4′-dihydro-2′H-spiro[indoline-3,1′-pyrrolo[1,2-a]pyrazin]-2-ones in moderate to excellent yields ( Open in a separate window^aReaction conditions: 1a (0.2 mmol), 2a (1.2 equiv.), (R)-PA 5a (10 mol%), 4 Å MS (50 mg), 2.0 mL of solvent, overnight.^bIsolated yield.^cee was determined by chiral HPLC.Next, the substrate scope of N-aminoalkylpyrroles was also investigated. As shown in Open in a separate window^aReaction conditions: 1a (0.2 mmol), 2a (1.2 equiv.), (R)-PA 5a (10 mol%), 4 Å MS (50 mg), 2.0 mL of solvent, overnight.^bIsolated yield.^cee was determined by chiral HPLC.Furthermore, a scale up reaction of 1a and 2a was performed, generating product 3aa in 89% yield and 82% ee (Fig. 2).Open in a separate windowFig. 2Scale-up reaction.Finally, based on the experimental results, together with related studies on CPA-catalyzed reactions,^5f–5i we proposed a possible reaction pathway to explain the stereochemistry of the formation of spirooxindoles 3 (Scheme 2). Isatins 1 initially participated in a Mannich reaction with N-aminoethylpyrroles 2, affording transient intermediates 6 under the catalysis of Brønsted acid. Through the dual-hydrogen-bond, (R)-CPA 5a interacted with intermediates 6 to realize their catalysis and stereocontrol. The enantioenriched spirooxindoles 3 were subsequently yielded via the intramolecular Friedel–Crafts reaction of intermediates 6.Open in a separate windowScheme 2Proposed reaction pathway and activation mode.     

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

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

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

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