Metal-free C–H arylation of imidazoheterocycles with aryl hydrazines

A simple and efficient metal-free arylation of imidazo[1,2-a]pyridines at the C-3 position with arylhydrazine has been achieved at room temperature under ambient air conditions. Various 2,3-disubstituted imidazopyridines and imidazothiazoles were synthesized with high yields. The present methodology demonstrates the usefulness of commercially available aryl hydrazine as an arylating agent.

Metal-free C–H arylation of imidazo[1,2-a]pyridines at C-3 position with arylhydrazines in presence of DBU has been developed at room temperature under ambient air.     

Cobalt(iii)-catalyzed site-selective C–H amidation of pyridones and isoquinolones

In this study, Cp*Co(iii)-catalyzed site-selective amidation of pyridones and isoquinolones using oxazolones as the amidation reagent is reported. This approach features mild conditions, high efficiency and good functional tolerance. Furthermore, gram-scale preparation and preliminary mechanism experiments were carried out. It provides a straightforward approach for the direct modification of pyridone derivatives.

In this study, Cp*Co(iii)-catalyzed site-selective amidation of pyridones and isoquinolones using oxazolones as the amidation reagent is reported.     

Ruthenium-catalyzed,site-selective C–H activation: access to C5-substituted azaflavanone

A site-selective ruthenium-catalyzed keto group assisted C–H bond activation of 2-aryl tetrahydroquinoline (azaflavanone) derivatives has been achieved with a variety of alkenes for the first time. A wide range of substrates was utilized for the synthesis of a wide variety of alkenylated azaflavanones. This simple and efficient protocol provides the C5-substituted azaflavanone derivatives in high yields with a broad range of functional group tolerance. Further, the C5-alkenylated products were converted into substituted 2-aryl quinoline derivatives in good yields.

A site-selective ruthenium-catalyzed keto group assisted C–H bond activation of 2-aryl tetrahydroquinoline (azaflavanone) derivatives has been achieved with a variety of alkenes for the first time.     

Visible light-induced photoredox catalyzed C–N coupling of amides with alcohols

A visible-light-mediated method for the construction of N-monoalkylated products from easily available benzamides and benzyl alcohol in the presence of eosin Y has been developed. The reaction proceeded smoothly, for a wide range of derivatives of benzamides and benzyl alcohols, to give the desired products in good to excellent yields. Biological studies, such as those on drug-likeness and molecular docking, are carried out on the molecules.

A visible-light-mediated method for the construction of N-monoalkylated products from easily available benzamides and benzyl alcohol in the presence of eosin Y has been developed.     

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

Transition-metal-catalyzed remote C–H functionalization of thioethers

In the last decade, transition-metal-catalyzed direct C–H bond functionalization has been recognized as one of most efficient approaches for the derivatization of thioethers. Within this category, both mono- and bidentate-directing group strategies achieved the remote C(sp²)–H and C(sp³)–H functionalization of thioethers, respectively. This review systematically introduces the major advances and their mechanisms in the field of transition-metal-catalyzed remote C–H functionalization of thioethers from 2010 to 2021.

This minireview systematically introduces the major advances and their mechanisms in the field of transition-metal-catalyzed remote C–H functionalization of thioethers.     

Progress and prospects in copper-catalyzed C–H functionalization

Copper-catalyzed C–H functionalization is becoming a significant area in organic chemistry. Copper is now widely used as a catalyst in organic synthesis as it is inexpensive and not very toxic. Functionalization of C–H bonds to construct wide varieties of organic compounds has received much attention in recent times. This review focuses on the recent advances in Cu-catalyzed C–H functionalization and covers literature from 2018–2020.

Copper-catalyzed C–H functionalization has gone through some major progress in recent times. These efficient, selective and cost-effective reactions offer new avenues towards the synthesis of complex organic compounds.     

Ligand-free iridium-catalyzed regioselective C–H borylation of indoles

We herein report a ligand-free Ir-catalyzed C–H borylation of N-acyl protected indoles. This simple protocol could tolerate a variety of functional groups, affording C3 borylated indoles in good yields with excellent regioselectivities. We also demonstrated that the current method is amenable to gram-scale borylation and the C–B bonds could be easily converted to C–C and C-heteroatom bonds.

First example of ligand-free Iridium-catalyzed Regioselective C–H borylation of indoles under mild reaction conditions.

Indoles are not only widespread subunits but also useful building blocks in drug discovery and synthetic chemistry.¹ Thus, their functionalization and transformation have gained attention. In particular, borylated indoles are of significant importance because they can serve as useful synthons by converting C–B bonds into many other functionalities.² As a result, a number of regioselective C–H borylation methods have been developed. In this context, regioselective transition-metal-catalyzed C–H borylation has emerged as a powerful tool for preparing borylated indoles in an atom- and step-economic way under mild reaction condition.^3,4 Because the C–H borylation at the C2 positions of indoles are electronically more favorable,^4f–i the reactions at the other positions are more challenging. In general, directing groups are usually required to realize regioselective C–H borylation reactions. For example, bulky directing groups at nitrogen atoms such as Boc and Si(i-Pr)₃ could result in C3-selective C–H borylation enabled by dtbpy/Ir catalysis (dtbpy = 4,4′-di-tert-butyl-2,2′-bipyridine).⁵ The N-Bpin moiety could serve as a traceless directing group for the dtbpy/Ir- and Ni(IMes)₂-catalyzed C–H borylation at C3 positions.⁶ The use of C2 substituted indoles enables nitrogen-directed dtbpy/Ir-catalyzed C7-selective C–H borylation.⁷ Hartwig and co-workers used N–SiEt₂H as the directing group to achieve relay directed dtbpy/Ir-catalyzed C7-selective C–H borylation.⁸ Another attractive and simple approach is the metal-free C–H borylation, which can regioselectively provide borylated indoles at C2, C3, C4, and C7 positions under mild reaction conditions.⁹ Despite the fact, the compatibility of functional groups is still narrow and usually limited to halogens, alkyl, and alkoxy substituted indoles. Thus, it is still appealing to develop complementary methods in this area.Ligand-free Ir-catalyzed regioselective C–H borylation of arenes have received growing interest. In this context, a judicious choice of directing group (DG) is crucial to promote the reaction. Usually, strong coordinating DGs are required. In this context, dithioacetal,¹⁰ pyrazorylaniline-modified boronic acid,¹¹ phosphine,¹² pyridine¹³ are commonly used for these transformations. It should be noted that all of the above-mentioned methods result in ortho-borylated products (Scheme 1A). In this work, we disclose the first example of ligand-free Ir-catalyzed C3-selective C–H borylation of N-acyl protected indoles. The current simple method could tolerate a variety of functionalities, including ester, ketone, nitro, and cyanide.Open in a separate windowScheme 1Ligand-free Ir-catalyzed C–H borylation of arenes.Our research commenced with the optimization of the reaction conditions. We chose N-isobutyryl indole 1a as our pilot substrate.¹⁴ The reaction 1a (0.20 mmol) with 1.5 equivalents of HBpin (pinacolborane) in the presence of a catalytic amount of [IrCl(cod)]₂ (5.0 mol%) (cod: 1,5-cyclooctadiene) in n-hexane (1.0 mL) at 80 °C for 12 h affords C–H borylated product 2a in 79% yield with 97% C3 selectivity (15 Replacement of [IrCl(cod)]₂ to either [Ir(OMe)(cod)]₂ or [IrCl(coe)₂]₂ (coe: cyclooctene) results in significantly decreased yields (16 The solvent effect showed that the reaction in THF yield and regioselectivity (17Optimization of reaction conditions for the Ir-catalyzed distal hydroboration of 1a^a

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

C–H activation-annulation on the N-heterocyclic carbene platform

Ring-fused cationic N-heterocycles are an important class of organic compounds recognized to be of significant interest in diverse research areas including bioactivity, materials chemistry, supramolecular chemistry, etc. Toward the synthesis of such molecules, recently unique chemistry has been explored utilizing a novel conjugative action of NHC ligands as a functionalizable directing group in rhodium(iii)-catalyzed aromatic/heteroaromatic/non-aromatic C–H activation and subsequent annulation of various imidazolium salts with internal alkynes. This review highlights the initial development and underscores the potential of this chemistry.

This review highlights the initial development of a new C–H activation–annulation chemistry accessible on the metal–N-heterocyclic carbene platform.     

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

Step-saving synthesis of star-shaped hole-transporting materials with carbazole or phenothiazine cores via optimized C–H/C–Br coupling reactions

In most research papers, synthesis of organic hole-transporting materials relies on a key-reaction: Stille cross-couplings. This requires tedious prefunctionalizations including the preparation and treatment of unstable organolithium and toxicity-concern organotin reagents. In contrast to traditional multistep synthesis, this work describes that a series of star-shaped small molecules with a carbazole or phenothiazine core can be efficiently synthesized through a shortcut using optimized direct C–H/C–Br cross-couplings as the key step, thus avoiding dealing with the highly reactive organolithium or the toxic organotin species. Device fabrication of perovskite solar cells employing these molecules (6–13) as hole-transporting layers exhibit promising power conversion efficiencies of up to 17.57%.

Carbazole or phenothiazine core-based hole-transport materials are facilely accessed by an optimized synthesis-shortcut. Perovskite solar cell devices with 6–13 demonstrate PCEs of up to 17.57%.     

Palladium-catalyzed intramolecular C–H arylation of 2-halo-N-Boc-N-arylbenzamides for the synthesis of N–H phenanthridinones

A palladium catalyzed synthesis of N–H phenanthridinones was developed via C–H arylation. The protocol gives phenanthridinones regioselectively by one-pot reaction without deprotection. It exhibits broad substrate scope and affords targets in up to 95% yields. Importantly, it could be applied for the less reactive o-chlorobenzamides.

Pd(t-Bu₃P)₂/KOAc proved to be a good combination for one-pot synthesis of N–H phenanthridinones with up to 95% yield.     

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.     

Metal catalyzed C–H functionalization on triazole rings

The present review covers advancement in the area of C–H functionalization on triazole rings, by utilizing various substrates with palladium or copper as catalysts, and resulting in the development of various substituted 1,2,3- and 1,2,4-triazoles. Synthesis of these substituted compounds is necessary from the perspective of pharmaceutical, medicinal, and materials chemistry.

The present review covers advancement in the area of C–H functionalization on triazole rings, by utilizing various substrates with palladium or copper as catalysts, and resulting in the development of various substituted 1,2,3- and 1,2,4-triazoles.     

Direct phosphorylation of benzylic C–H bonds under transition metal-free conditions forming sp3C–P bonds

Direct phosphorylation of benzylic C–H bonds was achieved in a biphasic system under transition metal-free conditions. A selective radical/radical sp³C–H/P(O)–H cross coupling was proposed, and various substituted toluenes were applicable. The transformation provided a promising method for constructing sp³C–P bonds.

Direct phosphorylation of benzylic C–H bonds with secondary phosphine oxides was first realized. The reaction was performed in organo/aqueous biphasic system and under transition metal-free conditions, proceeding via the cross dehydrogenative coupling.

To construct C–P bonds is of great significance in modern organic synthesis,¹ because organophosphorus compounds play varied roles in medical,^2,3 materials,⁴ and synthetic chemistry fields.⁵ Traditionally, the C–P bonds were formed from P–Cl species via nucleophilic substitutions with organometallic reagents,⁶ P–OR species via Michaelis–Arbusov reactions,⁷ or P–H species via the alkylation in the present of a base or a transition metal.⁸Over the past decades, cross dehydrogenative coupling reactions (CDC reactions) have become a powerful and atom-economic methodology for constructing chemical bonds.⁹ By using this strategy, C–H bonds can couple with Z–H bonds without prefunctionalization and thus short-cut the synthetic procedures (Scheme 1a).Open in a separate windowScheme 1Cross dehydrogenative coupling reactions and direct phosphorylation of benzylic C–H bonds.A similar construction of C–P bonds via CDC was also realized.^10,11 Among these methods, the phosphorylation of sp³C–H having an adjacent N or O atom, or the carbonyl group was well-developed.¹¹ Relatively, the formation of benzylic sp³C–P bond was less reported,^11w which was mainly limited to the sp³C–H of xanthene or 8-methylquinoline (Scheme 1b).¹² In these reported processes, transition metal catalysts or photo-, electro-catalysts were usually involved,^11v and an excess of P(O)–H compounds was usually employed.^11,13 To the best of our knowledge, the phosphorylation of non-active benzylic C–H bonds has scarcely been reported.Considering both benzylic and phosphorus radicals could be generated by oxidation,¹⁴ which might subsequently couple, the phosphorylation of benzylic sp³C–H bonds would be achieved (Scheme 1c). Herein, we disclosed the construction of benzylic C–P bonds from toluene and P–H species. The reaction was carried out under transition metal-free reaction conditions,¹⁵ and exhibited high regio-selectivity. The aromatic C–H remained intact during the reaction.We began our investigation by exploring the reaction of toluene 1a and diphenylphosphine oxide 2a in the presence of an oxidant (16 Other persulfates could also be used as an oxidant albeit with decreasing yields ( EntryOxidantToluene/water (v/v)Additive3a yield^b (%)3a/4^c1K₂S₂O₈1 : 0—Trace—2K₂S₂O₈1 : 1—1216 : 843K₂S₂O₈1 : 1SDS3726 : 744Na₂S₂O₈1 : 1SDS3127 : 735(NH₄)₂S₂O₈1 : 1SDS2723 : 776Oxone1 : 1SDSNone—7—1 : 1SDSNone—8—1 : 1—None—9K₂S₂O₈1 : 1SDBS4136 : 6410K₂S₂O₈1 : 2SDBS4628 : 7211K₂S₂O₈1 : 3SDBS3524 : 7612^dK₂S₂O₈1 : 2SDBS4632 : 6813^eK₂S₂O₈1 : 2SDBS2621 : 7914^fK₂S₂O₈1 : 2SDBS2926 : 7415^gK₂S₂O₈1 : 2SDBS4838 : 6216^g,hK₂S₂O₈1 : 2SDBS0—Open in a separate window^aReaction condition: 1a (1 mL), 2a (0.2 mmol), oxidant (2 equiv.), additive (1 equiv.) and H₂O, 120 °C, 3 h. under N₂.^bGC yields using n-dodecane as an internal standard.^cThe ratio of 3a/4 was determined by GC analysis.^d50 mol% SDBS was used.^e20 mol% SDBS was used.^fAt 100 °C.^g1 (0.8 mL) and H₂O (1.6 mL), 3 equiv. K₂S₂O₈ was used, 120 °C for 15 min.^h3 equiv. TEMPO was added.Based on the above results, we can easily find that a serious amount of 1,2-diphenylethane 4 was formed. These results suggest that the homocoupling rate of 1a was very quick. Thus, the choice of the phase transfer reagent and oxidant is the key to cross-coupling of toluene and diphenylphosphine oxide in this biphasic solvent system.Excessive P–H species were usually employed in reported CDC reactions to form C–P bonds, because of their facile oxidation.¹³ In our procedure, toluene was excessive, thus the yields were calculated based on 2a. The yields looked like low, which did not indicate the poorer conversion rate of P–H species. With the optimized conditions in hand, the substrate scope of the CDC reactions was explored ( Open in a separate window^aReaction conditions: 1 (0.8 mL), 2 (0.2 mmol), K₂S₂O₈ (3 equiv.), SDBS (50%) and H₂O (1.6 mL), 120 °C, under N₂, the reactions were monitored by TLC and/or GC until 2 work out.^b1 mmol scale, 30 min.^c130 °C.^d100 °C.In addition to toluene, o-xylene, m-xylene, p-xylene, mesitylene, and 1,2,4,5-tetramethylbenzene all coupled with 2a to give the expected 3b–f in moderate yields. Methoxy substituted toluene gave relatively lower yields of 3g and 3h. para-Halo substituted toluene exhibited good reactivity, furnishing the coupling products 3i and 3j in moderate yields. Comparing to toluene, a decreasing order of reactivity was observed for ethyl benzene (3l, 30% yield), isobutyl benzene (3m, 27% yield), isopropyl benzene (3n, <10% yield), and diphenyl methane (3o, trace). The order was probably controlled by the steric hindrance around the benzylic carbon. 1-Methylnaphthalene and 2-methylnaphthalene also gave low yields (3p and 3q). However, 2-methylquinoline served well and coupled with 2a, affording the product 3r in 49% yield, which could be ascribed to the activation of the nitrogen atom. Besides of 2a, diaryl phosphine oxides having methyl, F, and Cl substituents could also be employed as the substrate, producing 3s–3u in moderate yields under similar reaction conditions.Although the mechanism of the direct phosphorylation of benzyl C–H bond in aqueous solution is not quite clear, some aspects could be grasped based on experimental results. Firstly, the desired product 3a was not detected when the 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was added, implying that a radical pathway might be possible in this reaction (entry 16). Secondly, the reaction only occurred in aqueous phase, and relied on the presence of PTC (phase transfer catalyst), as seen in that 3a was difficultly formed in entries 1 and 2 of 17We supposed 1 is converted to benzyl radical 5 by SO₄⁻ radical that is generated via hemolytic cleavage of potassium persulfates.¹⁸ Meanwhile, phosphorus radical 6 is similarly formed from 2. Because potassium persulfate was water soluble, both 1 and 2 had to be transferred into aqueous solution to react with potassium persulfates.¹⁹ This proposal is also in accord with the experimental results that no products of sp²C–H phosphorylation are detected, which are the main products in the previous radical systems.²⁰ Finally, cross couplings between 5 and 6 produce 3 (Scheme 2).Open in a separate windowScheme 2Proposed mechanism for the direct phosphorylation of benzylic C–H bonds under transition metal-free reaction conditions.     

Evaluation and comparison of antioxidant abilities of five bioactive molecules with C–H and O–H bonds in thermodynamics and kinetics

In this work, the antioxidant abilities of NADH coenzyme analogue BNAH, F420 reduction prototype analogue F420H, vitamin C analogue iAscH⁻, caffeic acid, and (+)-catechin in acetonitrile in chemical reactions were studied and discussed. Three physical parameters of the antioxidant XH, homolytic bond dissociation free energy ΔG^°(XH), self-exchange HAT reaction activation free energy ΔG^≠_XH/X, and thermo-kinetic parameter ΔG^≠°(XH), were used to evaluate the antioxidant ability of XH in thermodynamics, kinetics, and thermo-kinetics. By comparing ΔG^°(XH), ΔG^≠_XH/X and ΔG^≠°(XH) of these five bioactive antioxidants to release hydrogen atoms, it is easy to find that iAscH⁻ is the best hydrogen atom donor both thermodynamically and kinetically among these antioxidants. Caffeic acid is the worst hydrogen atom donor thermodynamically, and F420H is the worst hydrogen atom donor kinetically. In addition, the thermodynamic hydride donating abilities of BNAH, F420H, and iAscH⁻ were also discussed, and the order of thermodynamic hydride donating abilities was BNAH > F420H > iAscH⁻. Four HAT reactions BNAH/DPPH^˙, (+)-catechin/DPPH^˙, F420H/DPPH^˙, and caffeic acid/DPPH^˙ in acetonitrile at 298 K were studied by the stopped-flow method. The actual order of H-donating abilities of these four antioxidants in the HAT reactions is consistent with the order predicted by thermo-kinetic parameters. It is feasible to predict accurately the antioxidant abilities of antioxidants using thermo-kinetic parameters.

In this work, the antioxidant abilities of NADH coenzyme analogue BNAH, F420 reduction prototype analogue F420H, vitamin C analogue iAscH⁻, caffeic acid, and (+)-catechin in acetonitrile in chemical reactions were studied and discussed.     

Reactions of triosmium and triruthenium clusters with 2-ethynylpyridine: new modes for alkyne C–C bond coupling and C–H bond activation

The reaction of the trimetallic clusters [H₂Os₃(CO)₁₀] and [Ru₃(CO)₁₀L₂] (L = CO, MeCN) with 2-ethynylpyridine has been investigated. Treatment of [H₂Os₃(CO)₁₀] with excess 2-ethynylpyridine affords [HOs₃(CO)₁₀(μ-C₅H₄NCH=CH)] (1), [HOs₃(CO)₉(μ₃-C₅H₄NC CH₂)] (2), [HOs₃(CO)₉(μ₃-C₅H₄NC CCO₂)] (3), and [HOs₃(CO)₁₀(μ-CH CHC₅H₄N)] (4) formed through either the direct addition of the Os–H bond across the C C bond or acetylenic C–H bond activation of the 2-ethynylpyridine substrate. In contrast, the dominant pathway for the reaction between [Ru₃(CO)₁₂] and 2-ethynylpyridine is C–C bond coupling of the alkyne moiety to furnish the triruthenium clusters [Ru₃(CO)₇(μ-CO){μ₃-C₅H₄NC CHC(C₅H₄N) CH}] (5) and [Ru₃(CO)₇(μ-CO){μ₃-C₅H₄NCCHC(C₅H₄N)CHCHC(C₅H₄N)}] (6). Cluster 5 contains a metalated 2-pyridyl-substituted diene while 6 exhibits a metalated 2-pyridyl-substituted triene moiety. The functionalized pyridyl ligands in 5 and 6 derive via the formal C–C bond coupling of two and three 2-ethynylpyridine molecules, respectively, and 5 and 6 provide evidence for facile alkyne insertion at ruthenium clusters. The solid-state structures of 1–3, 5, and 6 have been determined by single-crystal X-ray diffraction analyses, and the bonding in the product clusters has been investigated by DFT. In the case of 1, the computational results reveal a rare thermodynamic preference for a terminal hydride ligand as opposed to a hydride-bridged Os–Os bond (3c,2e Os–Os–H bond).

The reactivity of 2-ethynylpyridine at low-valent triosmium and triruthenium centers has been investigated.     

An efficient nickel/silver co-catalyzed remote C–H amination of 8-aminoquinolines with azodicarboxylates at room temperature

A highly efficient nickel/silver co-catalyzed C–H amination at the C5 position of 8-aminoquinolines with azodicarboxylates at room temperature is reported. The reaction undergoes a self-redox process without the necessity of external oxidant. It proceeded under simple and mild conditions without any additional ligand, base or oxidant and provided the desired products in good to excellent yields. This method also possessed the merits of good functional group compatibility and air and moisture tolerance. It provides an efficient strategy for the synthesis of useful quinoline derivatives.

C–H amination at the C5 position of 8-aminoquinolines with azodicarboxylates proceeded efficiently using a nickel/silver co-catalyst at room temperature without any additional ligand, base or oxidant.     

Direct C–H photoarylation of diazines using aryldiazonium salts and visible-light

In this study, direct C–H photoarylation of pyrazine with aryldiazonium salts under visible-light irradiation (blue-LEDs) is described, and additional examples including photoarylations of pyrimidine and pyridazine are also covered. The corresponding aryl-diazines were prepared in yields up to 84% only by mixing and irradiating the reaction with no need for an additional photocatalyst. We demonstrate the efficacy of this protocol by the scope with electron-donor, -neutral, and -withdrawing groups attached at the ortho, meta, and para positions of the aryldiazonium salts; the results are better than those reported for ruthenium-complex mediated photoarylations. Additionally, we demonstrate the robustness of this methodology with a 5 mmol scaled-up experiment. Mechanistic studies were carried out giving support to the proposal of a photocatalyzed approach by an electron donor–acceptor (EDA) complex, also highlighting the crucial role that solvents play in the formation of the EDA complex.

An electron donor–acceptor (EDA) approach for the direct C–H photoarylation of diazines using aryldiazonium salts and visible-light is described.