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Synthesis 2024; 56(01): 29-46
DOI: 10.1055/a-2134-0352
short review

Recent Progress on Copper-Catalyzed C–C Bond Formation via C(sp2)–H Insertions Using Diazo and Related Compounds

Satabdi Bera
,
Subhenira Jana
,
Rajarshi Samanta∗

We thank the Science and Engineering Research Board (SERB), India for financial support (CRG/2022/000398). S.B. and S.J. acknowledge the Indian Institute of Technology Kharagpur for their fellowships.
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Abstract

The site-selective insertion of metal carbenes via C(sp2)–H bond functionalization is an interesting topic within the synthetic chemistry community. In recent years, studies on the formation and applications of copper carbene intermediates have increased significantly due to their cost-effectiveness and versatile reactivities. Furthermore, copper-catalyzed transformations involving C(sp2)–H insertions using diazo and related compounds, along with asymmetric versions, have emerged as new tools for C–C bond formation. This short review summarizes selected recent advances in this field.

1 Introduction

2 Insertion of Copper Carbenes into Aryl C(sp2)–H Bonds of Arenes

3 Copper Carbene Insertion into Aryl C(sp2)–H Bonds of Azaheteroarenes

4 Copper Carbene Insertion into C(sp2)–H Bonds of Alkenes

5 Conclusions and Perspectives


#

Key words

copper catalysis - metal carbenes - C(sp2)–H insertion - C–C bond - diazo compounds
1

Introduction

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Rajarshi Samanta completed his bachelor’s (2002) and master’s degrees (2004) in chemistry at Jadavpur University, Kolkata, India. He carried out his doctoral work (2010) under the supervision of Prof. Tushar Kanti Chakraborty at the Indian Institute of Chemical Technology, Hyderabad, India. After postdoctoral studies with Dr. Andrey P Antonchick at the Max Planck Institute of Molecular Physiology (Dortmund, Germany), he joined the Department of Chemistry at the Indian Institute of Technology Kharagpur as an assistant professor in September 2013. Currently he is an associate professor at the same institute. His research interests include transition-metal catalyzed transformations using metallocarbenes/nitrenes, the step-economic construction of extended π-conjugated systems, and atroposelective synthesis.

Diazo compounds have proven to be valuable synthons in organic synthesis due to their ability to undergo thermolytic or photolytic decomposition, and accelerate the formation of highly reactive free carbene intermediates through nitrogen extrusion. However, the inherent high reactivity and poor selectivity of free carbene species limit their synthetic applications in most chemical transformations. Contrarily, the weak complexation of carbenes to transition-metal atoms provides an elegant approach to control their reactivity and stereoselectivity, opening new avenues for their use in synthetic chemistry. Indeed, transition-metal-catalyzed reactions of diazo compounds, leading to the generation of metal carbene species, are recognized as versatile for the formation of reactive intermediates. These metal carbene species can undergo a wide range of conversions, including insertions into various X–H bonds (where X = C, Si, N, O, etc.), ylide formation, cyclopropanation and 1,2-migration. These transformations offer diverse synthetic possibilities and have found widespread utility in organic synthesis. Among different reactions, C(sp2)–H insertion reactions are often considered challenging due to site-selectivity issues. For several decades, a wide range of transition metals have been employed for the generation of metal carbene species.[1`] [b] [c] [d] [e] Nevertheless, copper catalysts are selected for the generation of metal carbene intermediates since they are less expensive, less toxic, and abundant in nature.

The discovery of copper carbene species by Roy et al. in 1906 was a significant milestone.[2] Initially, these species were generated through the decomposition of ethyl diazoacetate in the presence of copper dust under high-temperature conditions (above 80 °C). However, progress in this field remained slow over the course of the last century. Nevertheless, the easy availability of various copper salts has contributed to the remarkable expansion of copper carbene chemistry.[3`] [b] [c] The effectiveness of these copper salts as catalysts has been well established, driving notable progress in diverse copper carbene reactions and contributing significantly to advancements in this field. Furthermore, significant progress in ligand design during the modern era has further accelerated advancements in copper carbene chemistry,[4a–j] particularly in the context of catalytic asymmetric reactions. The development of innovative ligands has played a crucial role in achieving high degrees of enantioselectivity in copper-catalyzed carbene transformations. These developments have opened new opportunities for the synthesis of chiral molecules and have greatly expanded the scope and applicability of copper carbene chemistry in asymmetric catalysis. By utilizing copper carbene intermediates, several stereoselective reactions have been accomplished, including X–H insertion,[5] cyclopropanation,[6] cycloaddition,[7] ylide formation,[8] and others.[9]

Notable advances in the field of copper carbene chemistry have been summarized and documented by several groups. These include the comprehensive studies of Doyle,[10] Zhou,[11] Wang,[12] Pérez,[13] and Davies.[14] Their contributions have provided valuable insights, methodologies, and strategies that have significantly advanced our understanding and applications of copper carbene chemistry. Further, Wang’s group has explored copper-catalyzed reactions of diazo compounds[15] and Kirmse’s group has reported new insights on copper carbene complexes involving advanced catalysts.[16] In 2022, Xu’s group discussed the recent developments made utilizing copper carbene intermediates in the field of catalytic alkyne transformation.[17] Despite tremendous progress having been realized in the field of C–C bond formation via C(sp2)–H functionalizations based on the insertion of copper carbene intermediates, to date, there are no reviews summarizing these important advancements. Herein, we highlight recent developments in the area of copper-catalyzed C–C bond formation via C(sp2)–H insertions of copper carbene species.


# 2

Insertion of Copper Carbenes into Aryl C(sp2)–H Bonds of Arenes

Transition-metal-catalyzed direct transformations of C(sp2)–H bonds of arenes into C–C bonds has emerged as an effective method for simplifying the synthesis of complicated molecular scaffolds.[18] Among the various types of synthetic strategies for C–C bond-forming reactions, transition-metal-catalyzed cross-couplings using diazo compounds, which proceed through carbene migratory insertion, are regarded as potent and atom-economic methods for expanding molecular complexity. Over the last decade, there has been considerable growth in transition-metal-catalyzed carbene-insertion processes utilizing unactivated C(sp2)–H bonds of various arene/heteroarene scaffolds.[15] [19] [20] Notably, the copper-catalyzed direct C(sp2)–H bond alkylation of functionalized aniline derivatives and other electron-rich(hetero)arenes with diazo compounds or diazo precursors (N-tosylhydrazones) is considered to be one of the most effective methods.

In 2012, Eiji Tayama’s group delineated the copper(II)-catalyzed alkylation of N,N-disubstituted anilines 1 with aryl diazoesters 2 in the presence of Cu(OTf)2 as the catalyst in CH2Cl2 at room temperature (Scheme [1]).[21] Other Lewis acids were also screened to accelerate the aromatic substitution reaction, but the results did not show any further improvement. The reactions of α-phenyl-α-diazoacetates with N-alkyl-N-methylanilines under standard reaction conditions furnished the alkylated products 3a–d in good yields.

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Scheme 1 Cu(II) triflate catalyzed intermolecular aromatic substitution of N,N-disubstituted anilines with diazoesters

Unfortunately, the phenyl ketone derivative 1g was unable to deliver the desired product 3g due to the acidic α-proton which inhibited the reaction. Also, simpler substrates such as N-benzyl-N-methylaniline (1e) and N,N-dimethylaniline (1f) delivered the desired products in lower yields along with recovery of the starting material 2. This finding indicated that substrate 1 might act as a ligand for the Cu(OTf)2 catalyst and that the structure of the complex determined the catalytic activity. Therefore, to improve the yield of the product further, para-methyl N-alkyl-N-methylanilines L1, L2 and L3 were employed as ligands for the Cu(OTf)2 catalyst, with a significant increase in the yield (71%) being observed for the reaction of N-benzyl-N-methylaniline (1e) with the corresponding diazoester 2 (Scheme [2]). In a continuation of this strategy, in 2012, Tayama established a method for the copper(II)-catalyzed intermolecular substitution of electron-rich aromatic compounds 1 with diazoesters in the presence of a Lewis or Brønsted acid (Scheme [3]).[22]

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Scheme 2 Cu(II) triflate catalyzed intermolecular aromatic substitution of N,N-disubstituted anilines with diazoesters in the presence of ligands
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Scheme 3 Cu(II)–acid co-catalyzed intermolecular substitution of electron-rich aromatics with diazoesters

The use of the copper salt Cu(acac)2 (0.5 mol%) along with the Lewis acid BF3·OEt2 (0.5 mol%) in CH2Cl2 as the solvent offered the best yield of the alkylated product 3. During exploration of the substrate scope using various types of N,N-dialkylanilines and diazoesters, the yields of the products were found to be comparable with those of the previous method, whilst an improvement in the yield was observed for the formation of phenyl ketone derivative 3g (76%). Unfortunately, N,N-dimethylaniline again failed to generate the alkylated product. Additionally, the scope of this reaction was expanded to include the poor electron-donor alkoxybenzene 3m using Cu(phen)Cl2 (1 mol%) as the catalyst and BF3·OEt2 as the Lewis acid.

Very recently, Shi’s group described a similar type of reaction involving N-protected tetrahydroquinoline 4 and α-aryl-α-diazoesters 2 in the presence of CuCl2 as the catalyst without any additive or ligand (Scheme [4]).[23] Gratifyingly, a wide range of α-aryl-α-diazoesters having electron-donating or electron-withdrawing groups were compatible, providing the desired para-C(sp2)–H alkylated products 5a–c in good to excellent yields. Impressively, an unprotected tetrahydroquinoline also reacted to afford the corresponding N-alkylated and C(sp2)–H alkylated product 5f in a good yield.

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Scheme 4 Ligand- and additive-free Cu(II)-catalyzed para-C(sp2)–H alkylation of electron-rich arenes

Moreover, this classical approach was expanded using different N-substituted compounds, including cyclic and acyclic anilines, a dihydrobenzooxazine and a tetrahydrobenzoazepine, which were all competent substrates and gave the desired alkylated products 6a–d under slightly modified conditions (Scheme [5]). A carbazole derivative provided exclusively the mono-alkylated product 6e. However, N-methylindole gave selectively the C-3 alkylated product 6f. The probable catalytic cycle for this copper(II)-catalyzed alkylation of arenes is depicted in Scheme [6]. Initially, the α-aryl-α-diazoester reacted with the copper catalyst to generate copper carbene intermediate 7 by releasing N2. Subsequently, the aniline 1 underwent nucleophilic addition to intermediate 7 to furnish the zwitterionic intermediate 8. Finally, deprotonation and re-aromatization of intermediate 8 followed by protonation of the Cu-based enolate provided the desired alkylated product 5 or 6.

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Scheme 5 Ligand- and additive-free Cu(II)-catalyzed para-C(sp2)–H alkylation of electron-rich heteroarenes
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Scheme 6 Probable mechanism

Inspired by these strategies, an elegant protocol was reported by Koenigs for the Cu(I)-catalyzed one-step difluoro-olefination of electron-rich arenes 1 using trifluorodiazoethanes 9 as the coupling partners, which proceeded via direct C(sp2)–H bond functionalization (Scheme [7]).[24] Among organofluorine compounds, gem-difluoro olefins play a significant role as electronic and geometric isomers of carbonyl groups.[25] Further, the pharmacological profile can be improved and the in vivo metabolism can be decreased by replacing a carbonyl group with a gem-difluoro olefin. However, the developed method for the gem-difluoro-olefination reaction via direct C(sp2)–H bond functionalization requires either harsh reaction conditions or the involvement of highly reactive intermediates. In contrast, the transition-metal-catalyzed one-step difluoro-olefination of electron-rich arenes using trifluorodiazoethane will be a highly demanding strategy. During investigations of the reaction parameters, it was observed that the reactions of N,N-dialkylanilines using 1-phenyl-2,2,2-trifluorodiazoethane as the coupling partner provided the best yields in the presence of CuI (5 mol%) in chloroform at 60 °C.

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Scheme 7 Cu(I)-catalyzed one-step difluoro-olefination of electron-rich arenes using trifluorodiazoethanes

Surprisingly, the addition of ligands such as a phosphine ligand or 1,10-phenanthroline completely inhibited the reaction, while the addition of a base to facilitate the elimination of hydrogen fluoride reduced the yield of the product. Notably, differently substituted N,N-dimethylanilines, as well as anilines containing allyl or propargyl groups on the nitrogen center, reacted efficiently to provide the desired gem-difluoro-olefins, with the difluoro substituent at the para-position of the aniline moiety (10a, 10h). However, an ortho-substituted aniline generated only a mixture of isomers due to the lack of selectivity of the C(sp2)–H bond functionalization reaction. The introduction of a differently substituted fluorinated diazo compound was fruitful in achieving high yields of the corresponding products 10b–e. Different N-alkylated indoline and tetrahydroquinoline substrates were also compatible under the standard reaction conditions, furnishing the expected products 10f and 10g.

DFT calculations indicated that initiation of the gem-difluoro-olefination reaction occurs through nucleophilic attack of the aniline derivative on an electrophilic copper carbene complex. Subsequently, elimination of HF takes place, facilitated by the presence of a second aniline molecule that acts as a basic promoter.

In contrast to electron-rich arene systems, direct functionalizations of the C(sp2)–H bond of electron-deficient polyfluoroarenes are limited due to the poor ability of electron-deficient polyfluoroarenes to coordinate with catalysts. Additionally, the strong σ-bonding interaction between transition metals and polyfluoroaryl groups poses limitations for subsequent transformations. This strong bond hinders the direct functionalization of polyfluoroarenes, making it challenging to carry out direct C(sp2)–H alkylation reactions. Traditional methods such as the Friedel–Crafts alkylation are not feasible due to the electron-deficient nature of polyfluoroarenes, further complicating the development of methodologies for their direct functionalization. As a result, the direct C(sp2)–H alkylation of polyfluoroarenes remains a rare and challenging transformation in synthetic chemistry. In this regard, the groups of Nakamura[26] and Zhang[27] independently reported direct C(sp2)–H bond alkylation using a polyfluoroaryl zinc reagent and a palladium catalyst, respectively. However, these methods are limited to primary benzylation as β-hydride elimination takes place when using secondary halides.

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Scheme 8 Cu(I)-catalyzed C(sp2)–H bond benzylation of polyfluoroarenes using N-tosylhydrazones
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Scheme 9 Cu(I)-catalyzed alkylation of polyfluoroarenes using diazoesters or diazo precursors

In 2015, Wang’s group developed an elegant methodology for the copper(I)-catalyzed C(sp2)–H bond functionalization of polyfluoroarenes 11 using N-tosylhydrazones 12 as the coupling partners (Scheme [8]).[28] In the presence of CuI (20 mol%) as the catalyst, 1,10-phenanthroline (20 mol%) as the ligand, and LiO t Bu (3.0 equiv) as the base in 1,4-dioxane/MeCN (1:1) as the solvent, the reaction between polyfluoroarenes 11 and N-tosylhydrazones 12 provided the desired alkylated products 13 in moderate to good yields. Surprisingly, the presence of the base and ligand were found to be crucial for this transformation. Various substituents on the aromatic ring of the N-tosylhydrazone delivered the desired alkylated products 13a–d in acceptable yields. N-Tosylhydrazones having electron-donating groups on the aromatic ring performed better, yielding the desired products 13b and 13c. Furthermore, the reaction between polyfluoroarenes 11 and diaryldiazomethanes 14 was equally applicable to this transformation (Scheme [9]). Unfortunately, diazoesters afforded the corresponding alkylated products in trace amounts under the standard reaction conditions. However, switching the catalyst from CuI to [Cu(MeCN)4]BF4 improved the yields of the products 13a′′–c′′. It is worth highlighting that the reactions involving diazoesters exhibited remarkable sensitivity towards the substituents present on the aromatic ring of the diazo substrates. Diazoesters having electron-withdrawing or electron-deficient groups on the aromatic ring delivered the desired products in unsatisfactory yields.

Based on previous literature, a plausible mechanism has been proposed. Initially, the relatively acidic C(sp2)–H bond of the polyfluoroarene substrate underwent deprotonation and formed a bond with the copper(I) catalyst, resulting in the formation of a polyfluoroaryl copper species 15 (Scheme [10]). In the next step, intermediate 15 reacted with the diazo compound, leading to the generation of copper carbene species 16. Subsequent migratory insertion of intermediate 16 followed by protonation delivered the desired alkylated product 13.

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Scheme 10 Possible mechanism

In general, in both Schemes 8 and 9, the copper carbene insertion took place on the electron-deficient fluorinated arene to provide fluoroalkylated arenes. Recently, Liu’s group developed an elegant protocol for the copper-catalyzed ortho-selective C(sp2)–H bond alkylation of phenols or naphthols 18 using α-aryl-α-diazoesters 2 as alkylating agents (Scheme [11]).[29] Among various types of copper salts, CuCl2 was found to be the best for this transformation and afforded the desired alkylated products 19. The α-aryl-α-diazoacetates 2, having various substituents at different positions of the phenyl ring, were well tolerated and furnished the desired alkylated products 19a and 19b in good to excellent yields. It was observed that an α-aryl-α-diazoacetate having a strong electron-donating group (OMe) on the aryl ring facilitated the reaction to provide compound 19b. On the other hand, the presence of a strong electron-withdrawing group (CF3) on the aryl ring afforded product 19a in a lower yield. Furthermore, differently substituted 1- and 2-naphthols were easily consumed under the standard reaction conditions to afford the desired products. Of note, only an alkoxy-substituted phenol moiety was able to give the corresponding product 19d. The reaction of 1-methoxynaphthol (20) with phenyl-diazoester 2a in the presence of CuCl2 delivered only a trace amount of the alkylated product 21 (Scheme [11]).

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Scheme 11 Cu(II)-catalyzed ortho-selective C(sp2)–H bond alkylation of phenols and naphthols using α-aryl-α-diazoesters

This finding concluded that the hydroxy group was essential for both site-selectivity and reactivity, and its interaction with the copper catalyst might result in the ortho selectivity. Based on experimental results, two possible catalytic cycles accounting for this transformation are shown in Schemes 12 and 13. The first involves copper carbene insertion into the ortho C(sp2)–H bond of naphthol (Scheme [12]) and the second proceeds via a Lewis acid (CuCl2) assisted transformation (Scheme [13]). According to the copper carbene insertion process, α-aryl-α-diazoacetates 2 reacted with CuCl2 to generate the Cu(II)-carbene intermediate 22, which then underwent coordination with the phenol to form intermediate 23. In the subsequent step of the mechanism, the copper carbene species underwent electrophilic addition at the ortho position of the phenol substrate, resulting in the formation of intermediate 24. Finally, aromatization and protonation of the copper-enolate intermediate 24 occurred, resulting in formation of the desired alkylated product 19.

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Scheme 12 Plausible mechanism: carbene process
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Scheme 13 Plausible mechanism: Lewis acid process

According to the second procedure, CuCl2 acted as a Lewis acid and coordinated with the nitrogen atom of the α-aryl-α-diazoacetate to produce intermediate 25, which further coordinated with the oxygen of the phenol to generate intermediate 26. Next, the copper carbocation intermediate 26 underwent electrophilic addition at the ortho position of the phenol followed by aromatization, denitrogenation, and protonation to generate the ortho-alkylated phenol 19 and regenerate the copper catalyst.

Cycloalkynes are a class of distinct and intriguing compounds that belong to bioactive molecules,[30] natural products[31] and organic materials.[32] Two primary methods for the construction of cycloalkynes are ring-closing alkyne metathesis (RCAM) and coupling reactions. To achieve high reactivity and selectivity in these procedures, prefunctionalization of the starting materials is required. Even though metal carbene reactions have been thoroughly investigated in numerous transformations, there are no reports where this strategy has been explored for the synthesis of macrocyclic alkynes.

Thus, in 2019, Xu’s group envisioned that transition-metal-catalyzed direct intramolecular carbene insertion into aryl C(sp2)–H bonds in alkynyl-functionalized diazoacetates 28 would lead to the construction of macrocyclic scaffolds 29 (Scheme [14]).[9a] In general, the alkyne motif has a greater tendency to undergo carbene/alkyne metathesis (CAM) via the formation of a 5- or 6-membered cyclic transition state.[33] However, it was hypothesized that electron-rich aromatic rings, due to their high nucleophilic character, would undergo selective C(sp2)–H bond insertion keeping the alkyne motif intact. According to their hypothesis, they initiated their reaction by employing an ortho-disubstituted benzene unit. The rationale behind this choice was twofold. First, the presence of the ortho substituents would introduce a bending effect on the linear architecture of the molecule. This distortion of the molecular geometry increases the proximity and spatial arrangement of the reactive sites, enhancing the likelihood of a reaction between the two reactive species. The reaction conditions employed for the transformation involved the use of 5 mol% of Cu(hfacac)2 as the catalyst. In addition, 4 Å molecular sieves were used as an additive in dichloromethane at 40 °C to deliver macrocyclic alkynes (13- to 17-membered rings) in good to excellent yields. Various N-alkyl- and N-phenyl-substituted substrates furnished the desired macrocycles 29a–c in high yields. Of note, the nature of the substituent on the ortho-disubstituted benzene unit had a slight impact on the reactivity and led to the formation of the corresponding macrocyclic products 29d and 29e in excellent yields. During the formation of 16- and 17-membered macrocycles, small amounts of C(sp3)–H inserted products were formed.

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Scheme 14 Cu(II)-catalyzed construction of macrocyclic alkynes via catalytic metal carbene C(sp2)–H insertion

In 2018, Pérez’s group demonstrated a method for the copper-catalyzed C(sp2)–H functionalization of azulene systems (Scheme [15]).[34] Among various types of aromatic compounds, azulenes, an isomeric form of naphthalene, exhibit interesting characteristics due to the presence of asymmetric π-polarization between the 5- and 7-membered rings. They display a characteristic deep blue color and a large dipole moment of 1.08 D. Due to this interesting characteristic and their applications in medicinal chemistry, modification of the azulene skeleton has become important in organic synthesis. Thus, transition-metal-catalyzed carbene transfer would be one of the most valuable reactions for alkylation of the azulene moiety. It was shown that the reaction of azulene (30) with ethyl diazoester (EDA) 31a in a 1:2 ratio in the presence of CuTp(CF3)2,BrCu(NCCH3) delivered the monoalkylated product 32 exclusively, while a 2.4:1 ratio of azulene and EDA provided only an 11% yield of the C1-monoalkylated product 32 along with 39% of the C1/C3-dialkylated product 33. However, when ethyl diazo(phenyl)acetate (Ph-EDA) was used as the coupling partner in the presence of Rh2(OOCCF3)4 as the catalyst, the dialkylated product was formed in 46% yield (Scheme [15]).

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Scheme 15 Cu-catalyzed alkylation of azulene. a Ethyl diazo(phenyl)acetate (Ph-EDA) was used instead of EDA.

Pérez also achieved sequential dialkylation using different diazo compounds. Treatment of tert-butyl diazoacetate (31b) with azulene (30) in the presence of Tp(CF3)2,BrCu(NCCH3) as the catalyst furnished mono-alkylated product 32a in 47% yield. A second alkylation using Ph-EDA in the presence of Rh2(OOCCF3)4 then afforded the unsymmetrical bis-alkylated azulene 33a in 45% yield (Scheme [16]).

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Scheme 16 Synthesis of asymmetrically disubstituted azulenes

# 3

Copper Carbene Insertion into Aryl C(sp2)–H Bonds of Azaheteroarenes

Azaheterocycles are recognized as a crucial structural element in medicinal chemistry. They are also frequently present in biomolecules, including vitamins, enzymes, natural products, and biologically active compounds demonstrating antibacterial,[35`] [b] [c] anticonvulsant,[36] antifungal,[37a–c] anti-allergic,[38`] [b] herbicidal,[39a] [b] and anticancer[40`] [b] [c] properties. Therefore, the functionalization of nitrogen-containing heterocyclic compounds is very important. Strategically, one of the more straightforward methodologies for the functionalization of heteroarenes is transition-metal-catalyzed direct C(sp2)–H bond formation via metal carbene insertion. Among various type of N-heterocyclic compounds, pyridine and its congeners (quinoline, isoquinoline, etc.) are considered as important scaffolds due to their common occurrence in natural products, pharmaceuticals, and organic materials. Pyridine N-oxides are regarded as important intermediates as they can act as a directing groups for transition-metal-catalyzed regioselective functional group introduction.

In 2016, Jain’s group reported a copper-catalyzed, microwave-assisted ortho-alkylation of azine N-oxides 34 with N-tosylhydrazones 35 as alkylating agents (Scheme [17]).[41] The reaction of pyridine N-oxide with the N-tosylhydrazone of acetophenone in the presence of CuI (10 mol%) and LiO t Bu as the base at 120 °C under N2 in toluene furnished the desired alkylated product in 52% yield. However, irradiation of the reaction mixture at 100 °C under microwave conditions provided the alkylated product in 77% yield after only one hour. It was noteworthy that halogen substituents (F, Br) on the phenyl ring of the hydrazone did not hamper the reaction and delivered the alkylated products 36a and 36b. Further, electron-withdrawing and electron-donating groups on the phenyl ring of the N-tosylhydrazones were well tolerated to furnish the desired products (e.g., 36c). However, N-tosylhydrazones derived from benzophenones gave moderate yields due to steric issues (e.g., 36d). Furthermore, aliphatic ketone-derived hydrazones also provided alkylated products (e.g., 36e) in excellent yields. Again, differently, substituted pyridine N-oxides were found to be compatible under the standard reaction conditions. Quinoline N-oxide and isoquinoline N-oxide were also used as substrates to further investigate the generality of the reaction, leading to the formation of products 34f and 34g (Scheme [17]). A control experiment hinted that C(sp2)–H bond cleavage was not involved in the rate-determining step.

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Scheme 17 The microwave-assisted, Cu(I)-catalyzed ortho-alkylation of azine N-oxides with N-tosylhydrazones

Subsequently, our group disclosed a method for the construction of heteroarene-containing conjugated systems 39 via copper-catalyzed cascade regioselective C2-alkylation, followed by cyclization of quinoline N-oxides 37 with diazoesters 38 (Scheme [18]).[42] During the course of the reaction, CuI was found to be the superior catalyst and toluene was the optimum solvent, allowing the generation of the desired heteroarenes 39a–j in good to excellent yields. However, using ethyl 2-diazo-2-(phenylsulfonyl)acetate as the coupling partner only furnished alkylated product 39k in 72% yield. Control experiments suggested that sterically less congested diazo compounds had a greater tendency to undergo nucleophilic attack of quinoline N-oxide to deliver cyclized products. In this transformation, CuI played a dual role in C(sp2)–H bond functionalization and Lewis acid promoted cyclization.

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Scheme 18 Cu(I)-catalyzed synthesis of conjugated π-systems via cascade alkylation and cyclocondensation of quinoline N-oxides

Mechanistic studies revealed that atmospheric oxygen acted as an oxidant and the C(sp2)–H metalation step occurred much faster than the formation of the metal carbene intermediate. A possible catalytic cycle is shown in Scheme [19]. Initially, oxidation of the Cu(I) salt in the presence of atmospheric oxygen led to the formation of a Cu(II) salt. Subsequently, concerted deprotonation–metalation of the C(sp2)–H bond at the C2 position of the quinoline N-oxide resulted in the generation of intermediate 40. In the next step, the diazo compound reacted with intermediate 40 to generate copper carbene intermediate 41, which underwent migratory insertion to deliver intermediate 42. Subsequent protodemetalation of intermediate 42 provided intermediate 43. Finally, Lewis acid assisted nucleophilic attack of the oxygen of the quinoline N-oxide followed by elimination of an alcohol delivered the desired product 39.

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Scheme 19 Probable mechanism

Very recently, the Pla-Quintana group demonstrated a method for the Cu(I)-catalyzed (5+1) annulation of pyridinium 1,4-thiolates 45 and diazo compounds 46 to afford dihydropyrido[2,1-c][1,4]thiazine derivatives. Subsequent oxidation with DDQ and sulfur extrusion provided the desired indolizine moiety 47 (Scheme [20]).[43] Initially, they performed extensive density functional theory (DFT) calculations to evaluate the feasibility of this transformation and found that slight heating of the reaction was required to overcome the activation energies. DFT calculations also predicted that Cu(I) salts were the more appropriate choice for achieving the desired products at a comparatively low temperature, with CuBr demonstrating the highest yield at 40 °C. During exploration of the substrate scope, an intriguing observation was made (Scheme [20]). It was found that increasing the bulkiness of the carbonyl groups on the pyridinium 1,4-thiolates led to higher yields of the products 47a–c. This phenomenon was attributed to the suppression of side reactions. The desired indolizine 47e was obtained in moderate yield when a quinolinium 1,4-thiolate derivative was used. However, the presence of an electron-donating dimethylamino group at the para position of the pyridinium ring was found to be ineffective in providing the product 47i. In contrast, the utilization of different diazo compounds, such as benzyl diazoacetate, 2-methylpropyl diazoacetate, and a diazoketone, led to lower yields of the corresponding products (e.g., 47j and 47k). This decrease in yield can be attributed to their high reactivities, lower stabilities, and greater tendency to undergo dimerization reactions.

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Scheme 20 CuBr-catalyzed synthesis of indolizines via (5+1) annulation of pyridinium 1,4-thiolates

In 2010, Kerr’s group developed a methodology for the selective C2-alkylation of 3-substituted indoles 48 in the presence of 1 mol% of Cu(acac)2 as the catalyst in refluxing benzene using diazomalonate 38 as the alkylating agent (Scheme [21]).[44] However, indole moieties without C3 substitution provided exclusively C3 alkylated products 49c–h. It was observed that the protecting group on the indole nitrogen played a crucial role in this transformation. When the nitrogen was protected with benzyl (48b) or methyl (48a) groups, the efficiency of the reaction was facilitated, while Boc (48d) and Ts groups (48c) diminished the reaction efficiency. Interestingly, an NH-free indole was also able to deliver the desired C3-alkylated product 49h. Significantly, the N-protected indoles exhibited successful carbene insertion reactions, leading to the formation of the desired products in relatively high yields when microwave irradiation was employed.

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Scheme 21 Cu(II)-catalyzed alkylation of indoles using diazoacetates

In addition, Pérez’s group reported a copper-catalyzed selective C(sp2)–H bond functionalization of N-methylindoles 50 via two consecutive pathways, i.e., cyclopropanation followed by ring opening in the presence of SiO2 to furnish C3-alkylated indoles 51 exclusively (Scheme [22]).[45] Initially, cyclopropane derivatives were synthesized from differently substituted N-methylindoles and ethyl diazoacetate. Next, these products were quantitatively transformed into the respective C3-substituted indole derivatives 51a–c after being exposed to silica gel. On the other hand, a C3-substituted N-methylindole delivered the C2-alkylated indole 51d exclusively. Not only differently substituted N-methylindoles, but other diazo compounds like ethyl α-diazo-phenylacetate and ethyl α-diazomethyl acetate were also equally competent substrates that delivered the desired products 51e and 51f. However, the less reactive ethyl diazomalonate required an increased catalyst loading (2 mol%) and a longer reaction time. Unfortunately, when unprotected indoles were subjected to reactions with ethyl diazoacetate, a mixture of products was observed along with N–H insertion products 51a′–c′. The reaction was initiated via copper-catalyzed cyclopropane ring formation from the indole substrates (Scheme [23]). Subsequently, the cyclopropane ring of intermediate I underwent ring opening in the presence of an acid catalyst [Ac] (silica gel), followed by proton transfer to provide the desired products 51.

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Scheme 22 Copper (I)-catalyzed functionalization of N-methylindole substrates with aryl diazoesters
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Scheme 23 Possible mechanism

In 2016, Zhou’s group reported the Cu(I)-catalyzed enantioselective C–H functionalization of indoles 52 using axially chiral bipyridine ligands Cn-ACBP.[19d] During fine-tuning of the reaction conditions, it was observed that CuCl as the catalyst in the presence of L1 as the ligand was superior in delivering the desired products with good yields and enantioselectivities (Scheme [24]).

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Scheme 24 Ligand screening

The temperature also played a crucial role in improving the yield as well the ee, with 60 °C being the optimum temperature for this transformation. Differently substituted N-protected 2-methyl indoles reacted efficiently to furnish the alkylated products 53a–c in excellent yields (Scheme [25]). Notably, a nitrogen-protected 2-unsubstituted indole provided the exclusive C3-alkylated product 53d, albeit with moderate enantioselectivity.

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Scheme 25 Cu(I)-catalyzed enantioselective C–H alkylation of indoles using an axially chiral bipyridine ligand

Next, the scope of diazoacetates bearing different ester groups or having aryl groups with various substituents was examined. Products 53e and 53f, with slightly marginal enantioselectivity, were observed upon increasing the steric hindrance of the starting diazoacetates. However, α-alkyl-α-diazoacetates delivered the corresponding alkylated products (e.g., 53g) with moderate yields and poor selectivity.

A plausible mechanism based on experimental results and previous literature consists of the following steps: (i) generation of copper carbene intermediate 55, (ii) coordination of intermediate 55 with indole 52 to form the zwitterionic intermediate 56, and (iii) migration of the proton from the C3 position of indole to the α-position of the ester led to the desired product 53 (Scheme [26]).

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Scheme 26 Plausible mechanism

Among the numerous types of organic transformations facilitated by diazo compounds, the transition-metal-catalyzed [n+1] cycloaddition of metal carbene species (also known as the 1C-synthon) holds significant importance in organic synthesis. This transformation provides a direct and efficient method for constructing cyclic frameworks with diverse ring sizes.[14a] [46] The advantages of this transformation lie in its direct and efficient nature, as it enables the rapid construction of cyclic frameworks without the need for complex and time-consuming synthetic steps. The versatility of the reaction also allows for the synthesis of diverse cyclic structures with different ring sizes, providing access to a wide range of target molecules with potential applications in various areas of organic synthesis.

In 2019, Xu’s group introduced a methodology for the synthesis of multi-substituted dihydrocyclopenta[b]indoles 58 through a copper-catalyzed [4+1] annulation reaction between 2-vinylindoles 57 and α-aryl diazoacetates 2 (Scheme [27]).[7b] They selected 2-alkenylindoles 57 having an electron-deficient alkenyl group at the C2 position as a 4-C synthon to avoid the stepwise cyclopropanation/ring-expansion reaction occurring for electron-rich dienes.[47] Reaction of the 2-alkenylindole and methyl phenyldiazoacetate in the presence of Cu(CH3CN)4PF6 as the catalyst in dichloromethane at 35 °C provided the best yield of cyclized product 58. A variety of diazo compounds with aryl groups containing electron-neutral, electron-rich, or electron-deficient substituents successfully interacted with 57 to produce the desired products 58a–d in high yields. However, under the standard reaction conditions, α-styryl and α-benzyl diazoacetates did not undergo the reaction to yield the annulated products. The incorporation of various substituents at different positions of the indole moiety resulted in the formation of the desired annulated products with good to excellent yields.

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Scheme 27 Cu(I)-catalyzed [4+1]-annulation of 2-alkenylindoles with diazoacetates

Moreover, N-allyl- and N-benzyl-protected 2-alkenylindoles provided the corresponding annulated products 58f and 58g in good yields, avoiding the formation of C–H insertion and/or cyclopropane products. When an aryl diazoketone was used instead of the aryl diazoester, only C(sp2)–H insertion product 58h was formed. Similarly, 2-alkenylindoles having mono electron-withdrawing substituents, such as ester and cyano, imparted C(sp2)–H insertion products 58i and 58j.

When C–H insertion product 59 was treated under the standard reaction conditions, no [4+1]-annulation product 58a was observed. Next, N-Boc-protected 2-alkenylindole 60 was subjected to the standard reaction conditions but no cyclopropanated product was obtained. Additionally, when the reaction was performed using compounds 61 and 62, both reactions yielded the corresponding products 58l and 58m as single diastereoisomers (Scheme [28]). Based on these control experiments, it was suggested that the reaction followed a concerted annulation process rather than a stepwise process. Specifically, it involves C(sp2)–H insertion followed by a [4+1] annulation. The catalytic cycle began with the formation of intermediate 22 in the presence of the aryl diazoester and the Cu(I) catalyst (Scheme [29]). In the next step, electrophilic addition between intermediate 22 and the 2-alkenylindole 57 via TS led to the formation of zwitterionic intermediate 63. In this step, the less hindered carbonyl group preferably coordinated with the Cu catalyst to afford the syn geometry of the aryl and the other carbonyl (COR2) groups. Finally, zwitterionic intermediate 63 underwent a concerted and asynchronous annulation to offer intermediate 65, which after aromatization generated the desired annulated product 58. However, the C(sp2)–H insertion product was formed from intermediate 63 via a direct 1,2-H shift.

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Scheme 28 Control experiments
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Scheme 29 Plausible mechanism

Very recently, Grover’s group demonstrated an elegant approach for the Cu(II)-catalyzed C(sp2)–H bond functionalization and cascade annulation of heteroaromatic compounds (Scheme [30]).[48] They commenced their investigation by utilizing functionalized indoles containing alkynyl-ester electrophiles 66 and α-diazocarbonyl compounds 38 as starting materials in the presence of a catalytic amount of Cu(tfacac)2. Differently substituted ester moieties on the indole substrates delivered the desired annulated products 67a–d in good to moderate yields.

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Scheme 30 Cu(II)-catalyzed C–H functionalization/Michael-type annulation of indole-containing alkynyl-esters

An interesting observation was made when an indole nitrogen with a one-carbon extended electrophile tether was utilized. In this case, the reaction resulted in the formation of pyrido-indole 67e, indicating a successful transformation. However, no annulated product was obtained when the chain length of the electrophile was increased further. This observation indicated that the distance between the functionalized C(sp2)–H bond and the electrophile was a crucial factor in this particular transformation. Furthermore, when an alkyl group was present at the terminal end of the alkyne instead of an ester group, only the alkylated product 67f was obtained. This result implies that the presence of the alkynyl-ester moiety is important for the annulation reaction to take place.

These findings highlight the significance of the specific structural features and distances in the reactants for a successful annulation process. The presence of an extended electrophile tether and appropriate functional groups are essential for achieving the desired annulated products. Indoles with alkynyl-ester electrophiles at the C2 or C3 positions were also reactive, affording the corresponding tetrahydrocarbazoles 67h and 67i. However, when a donor–acceptor-substituted diazo compound was employed, only a small amount of the annulated product 67a′, consisting of a mixture of olefin isomers, was formed along with the alkylated product 68 (Scheme [31]). Fortunately, treatment of the mixture of olefin isomers 67a′ and alkylated product 68 in the presence of Cs2CO3 (1.2 equiv) led exclusively to the double-bond-isomerized annulated product 69.

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Scheme 31 Cu(II)-catalyzed C–H functionalization/Michael-type annulation of an indole-containing alkynyl-ester and base-promoted isomerization

Upon subjecting other indole-containing electrophiles, such as alkenyl-esters 70, to the standard reaction conditions in the presence of a base, the desired annulated products 71a–c were formed, albeit in modest yields (Scheme [32]).

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Scheme 32 Cu-catalyzed C–H functionalization/Michael-type annulation of indole-containing alkenyl-esters

Based on mechanistic findings, Grover suggested that the copper catalyst played a dual role in this transformation.[48] The diazocarbonyl compound 38a was initially activated by the copper salt to produce the reactive carbenoid intermediate 72, which then produced the copper intermediate 73 via C(sp2)–H functionalization of substrate 66. The enolate (derived from a carbonyl compound) and the alkyne electrophile 74 were both activated by the copper catalyst and underwent a 5-exo-dig syn addition, resulting in the formation of cyclized intermediate 75. Finally, the cyclized Z-alkene isomer 67 was produced by protodemetalation with regeneration of the active copper catalytic species (Scheme [33]).

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Scheme 33 Possible mechanism

Next, in 2011, Wang’s group demonstrated an elegant method for the Cu(I)-catalyzed C(sp2)–H bond alkylation of 1,3-azoles 76 using N-tosylhydrazones 35 as alkylating agents (Scheme [34]).[49] This protocol featured a wide substrate scope, including N-tosylhydrazones with differently substituted aryl rings, and proceeded smoothly under standard reaction conditions. Other aromatic heterocycles, such as 5-phenyloxazole, reacted efficiently under similar reaction conditions to afford the desired alkylated products (e.g., 77g). Delightfully, thiazoles were able to form the desired products 77e and 77f when the catalyst loading was increased and dioxane was used as the solvent. Moreover, direct allylation of benzo[d]oxazoles was also achieved (e.g., 77h) under this protocol by employing the corresponding N-tosylhydrazones derived from 3-methylcyclohex-2-enone and 20 mol% of CuI.

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Scheme 34 Cu(I)-catalyzed benzylation of oxazoles with N-tosylhydrazones

Zou’s group described a method for the copper-carbene-mediated C(sp2)–H bond functionalization of biologically relevant triazolopyridines (Scheme [35]).[50] The reaction of [1,2,4]triazolo[4,3-a]pyridine (78) and N-tosylhydrazones 35 in the presence of CuI (10 mol%) as the catalyst and Li t OBu as the base in toluene furnished the best yields of benzylated products 79. Electronically and sterically different N-tosylhydrazones provided the desired benzylated products 79a–c in good to excellent yields. Additionally, heterocycle-containing hydrazones were also found to be competent substrates, leading to the desired products 79d and 79e. While 8-chloro and 6-bromo[1,2,4]triazolo[4,3-a]pyridines gave the desired benzylated products 79f and 79g, the 5-chloro variant failed to react due to the instability of the starting materials.

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Scheme 35 Copper(I)-catalyzed benzylation of triazolopyridines

Axially chiral biaryl motifs are widely present in natural products and pharmaceuticals.[51] Among the various types of axially chiral biaryl scaffolds, the use of heterobiaryls (QUINOL, QUINOX, QUINAP, PINAP, PHENAP, 8-azaBINOL) as ligands with non-equivalent donor atoms is regarded as a suitable alternative in transition-metal-catalyzed transformations. Additionally, they are also widely used in a variety of enantioselective reactions due to their ability to bind with metal ions through their inherent nitrogens and other donor atoms.[52] Traditionally, the synthesis of atropoisomeric heterobiaryl scaffolds has primarily focused on chirality resolution methods applied to racemic axial heterobiaryl backbones. However, an alternative, simple, direct, and economically efficient approach for constructing these heterobiaryls could proceed via transition-metal-catalyzed site-selective C(sp2)–H bond functionalizations.

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Scheme 36 Cu(II)-catalyzed arylation of quinoline N-oxides

Recently, our research group made a significant contribution to this field by introducing a naphthol moiety at the C1 position of isoquinoline N-oxide 80 (Scheme [36]).[53] Under the standard reaction conditions, we observed that quinoline N-oxides with different electronic and steric properties exhibited excellent tolerance. Additionally, alkene- and alkyne-functionalized isoquinolines, which are sensitive to diazo compounds, were able to maintain their integrity during the reaction, providing the desired heterobiaryl products (e.g., 82d). Moreover, differently substituted phthalazine N-oxides also gave excellent yields and site selectivities for the synthesis of heterobiaryls (e.g., 82e). Building upon this methodology, we have successfully prepared various types of chiral heterobiaryl ligands or their precursors. These ligands, including QUINOL (83), QUINOX (84), QUINAP (85), IAN (86), and PHENAP (87), were synthesized using our approach and have shown promising potential in various applications (Schemes 37 and 38).

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Scheme 37 Synthesis of QUINOL and QUINOX
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Scheme 38 Synthesis of QUINAP, IAN and PHENAP

A plausible catalytic cycle is shown in Scheme [39]. The catalytic cycle begins with the exchange of ligands between 2,2′-bipyridine and Cu(OTf)2. Next, the C1 position of the isoquinoline N-oxide undergoes deprotonation, leading to the formation of intermediate 89. Subsequent binding of 1-diazonaphthalen-2(1H)-one with intermediate 89 formed the copper species 90, which underwent migratory insertion at the C1 position of the isoquinoline N-oxide to deliver intermediate 91. Finally, the desired heterobiaryl product 82 was formed via protodemetalation of intermediate 91 with renewal of the active Cu catalyst (Scheme [39]).

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Scheme 39 Plausible mechanism

# 4

Copper Carbene Insertion into C(sp2)–H Bonds of Alkenes

Besides copper-carbene-catalyzed insertion into aromatic C(sp2)–H bonds, direct insertion of carbenes into vinylic C(sp2)–H bonds is particularly challenging. In general, it competes with cyclopropanation of the alkene. Nevertheless, this obstacle can be overcome by utilizing intramolecular reactions, thereby preventing the undesired side reaction.

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Scheme 40 Cu(I)-catalyzed intramolecular carbene insertion into vinylic C(sp2)–H bonds

In 2017, Wang’s group presented a method demonstrating rhodium(II)- or copper(I)-catalyzed carbene insertion into vinylic C(sp2)–H bonds, providing direct access to substituted 1H-indenes (Scheme [40]).[54] A variety of substituted N-tosylhydrazone substrates resulted in the formation of the corresponding indene products 93a–d with high yields under the developed reaction conditions. In contrast, when a substrate containing an alkyl substituent at C2 of the vinylic double bond was subjected to the reaction, the desired product 93e was obtained in a relatively low yield of 18%. An N-tosylhydrazone containing an unsubstituted vinylic double bond provided a mixture of the corresponding isomeric indene products 93f and 93f′.


# 5

Conclusions and Perspectives

Copper catalysts are widely accepted as cheap, earth-abundant catalysts for the decomposition of diazo compounds, yielding copper carbenoid intermediates that thereafter undergo numerous transformations. In recent years, remarkable advances in the chemistry of copper-salt-catalyzed C–C bond formation using diazo compounds have been observed, which have opened up new avenues for the development of efficient and sustainable synthetic methodologies. The remarkable progress made on catalytic polar X–H bond insertions has expanded the scope and applications of copper carbene intermediates, offering exciting opportunities for the synthesis of complex molecules and functional materials. Another important advancement in this field is the copper-catalyzed cross-coupling of diazo compounds or their precursor N-tosylhydrazones with suitable coupling partners. However, copper-catalyzed direct C(sp2)–H bond functionalizations of aromatic and heteroaromatic compounds using diazo compounds are still at the initial stage of development. In this short review, we have summarized recent progress on copper-catalyzed direct C–C bond formations from C(sp2)–H bonds via insertion of copper carbene intermediates, and have briefly discussed the substrate scope, limitations and mechanistic insights of these protocols. Importantly, the copper-catalyzed arylation of heteroaromatic compounds via migratory insertion is rare. Significant research is still underway in the following areas: (i) the exploration of additional substrates toward copper-catalyzed arylation using quinone diazides, (ii) asymmetric transformations to furnish chiral naphthyl ligands using copper-based quinoid carbenes, (iii) the development of mild copper catalyzed C–C bond-forming reactions using diazo compounds, and (iv) the application of copper carbenes for the total synthesis of natural products.


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Conflict of Interest

The authors declare no conflict of interest.


Corresponding Author

Rajarshi Samanta
Department of Chemistry, Indian Institute of Technology Kharagpur
Kharagpur-721302, West Bengal
India   

Publication History

Received: 31 May 2023

Accepted after revision: 20 July 2023

Accepted Manuscript online:
20 July 2023

Article published online:
08 September 2023

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Rajarshi Samanta completed his bachelor’s (2002) and master’s degrees (2004) in chemistry at Jadavpur University, Kolkata, India. He carried out his doctoral work (2010) under the supervision of Prof. Tushar Kanti Chakraborty at the Indian Institute of Chemical Technology, Hyderabad, India. After postdoctoral studies with Dr. Andrey P Antonchick at the Max Planck Institute of Molecular Physiology (Dortmund, Germany), he joined the Department of Chemistry at the Indian Institute of Technology Kharagpur as an assistant professor in September 2013. Currently he is an associate professor at the same institute. His research interests include transition-metal catalyzed transformations using metallocarbenes/nitrenes, the step-economic construction of extended π-conjugated systems, and atroposelective synthesis.
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Scheme 1 Cu(II) triflate catalyzed intermolecular aromatic substitution of N,N-disubstituted anilines with diazoesters
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Scheme 2 Cu(II) triflate catalyzed intermolecular aromatic substitution of N,N-disubstituted anilines with diazoesters in the presence of ligands
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Scheme 3 Cu(II)–acid co-catalyzed intermolecular substitution of electron-rich aromatics with diazoesters
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Scheme 4 Ligand- and additive-free Cu(II)-catalyzed para-C(sp2)–H alkylation of electron-rich arenes
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Scheme 5 Ligand- and additive-free Cu(II)-catalyzed para-C(sp2)–H alkylation of electron-rich heteroarenes
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Scheme 6 Probable mechanism
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Scheme 7 Cu(I)-catalyzed one-step difluoro-olefination of electron-rich arenes using trifluorodiazoethanes
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Scheme 8 Cu(I)-catalyzed C(sp2)–H bond benzylation of polyfluoroarenes using N-tosylhydrazones
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Scheme 9 Cu(I)-catalyzed alkylation of polyfluoroarenes using diazoesters or diazo precursors
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Scheme 10 Possible mechanism
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Scheme 11 Cu(II)-catalyzed ortho-selective C(sp2)–H bond alkylation of phenols and naphthols using α-aryl-α-diazoesters
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Scheme 12 Plausible mechanism: carbene process
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Scheme 13 Plausible mechanism: Lewis acid process
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Scheme 14 Cu(II)-catalyzed construction of macrocyclic alkynes via catalytic metal carbene C(sp2)–H insertion
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Scheme 15 Cu-catalyzed alkylation of azulene. a Ethyl diazo(phenyl)acetate (Ph-EDA) was used instead of EDA.
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Scheme 16 Synthesis of asymmetrically disubstituted azulenes
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Scheme 17 The microwave-assisted, Cu(I)-catalyzed ortho-alkylation of azine N-oxides with N-tosylhydrazones
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Scheme 18 Cu(I)-catalyzed synthesis of conjugated π-systems via cascade alkylation and cyclocondensation of quinoline N-oxides
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Scheme 19 Probable mechanism
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Scheme 20 CuBr-catalyzed synthesis of indolizines via (5+1) annulation of pyridinium 1,4-thiolates
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Scheme 21 Cu(II)-catalyzed alkylation of indoles using diazoacetates
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Scheme 22 Copper (I)-catalyzed functionalization of N-methylindole substrates with aryl diazoesters
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Scheme 23 Possible mechanism
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Scheme 24 Ligand screening
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Scheme 25 Cu(I)-catalyzed enantioselective C–H alkylation of indoles using an axially chiral bipyridine ligand
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Scheme 26 Plausible mechanism
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Scheme 27 Cu(I)-catalyzed [4+1]-annulation of 2-alkenylindoles with diazoacetates
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Scheme 28 Control experiments
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Scheme 29 Plausible mechanism
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Scheme 30 Cu(II)-catalyzed C–H functionalization/Michael-type annulation of indole-containing alkynyl-esters
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Scheme 31 Cu(II)-catalyzed C–H functionalization/Michael-type annulation of an indole-containing alkynyl-ester and base-promoted isomerization
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Scheme 32 Cu-catalyzed C–H functionalization/Michael-type annulation of indole-containing alkenyl-esters
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Scheme 33 Possible mechanism
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Scheme 34 Cu(I)-catalyzed benzylation of oxazoles with N-tosylhydrazones
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Scheme 35 Copper(I)-catalyzed benzylation of triazolopyridines
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Scheme 36 Cu(II)-catalyzed arylation of quinoline N-oxides
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Scheme 37 Synthesis of QUINOL and QUINOX
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Scheme 38 Synthesis of QUINAP, IAN and PHENAP
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Scheme 39 Plausible mechanism
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Scheme 40 Cu(I)-catalyzed intramolecular carbene insertion into vinylic C(sp2)–H bonds