Progress in classical chemistry of metal-carbenoids from α -diazocarbonyls

 - Diazocarbonyls are well known precursors of reactive intermediate carbenes that coordinate with metal salts and complexes to react as metal-carbenoids. Insertion into carbon-hydrogen and heteroatom-hydrogen bonds, and addition across various multiple bonds are the classical reactions of metal-carbenoids. These reactions have been widely employed as a key reaction in the synthesis of diverse classes of biologically relevant natural and synthetic scaffolds. Recent years have seen design and development of novel  -diazocarbonyl molecules, metal complexes and cooperative catalysis concept to achieve construction of complex molecular structures from insertion, addition, and cascade reactions. The reactions of ylides, generated from the reaction of metal-carbenoids with carbon-heteroatom (C-N, C-O, C-S) have also led to the synthesis of several novel heterocyclic motifs. The present review article discusses the recent progress in study of such reactions of metal-carbenoids from  -diazocarbonyls.


Introduction
2][3][4] Many of them are commercially available while others are easily accessible in the laboratory by simple synthetic procedures.-Diazocarbonyls undergo thermal, photochemical, and microwave-assisted decomposition generating carbonylcarbenes.6][7] However, several metal salts and complexes are known to coordinate with carbenes preventing the Wolff-rearrangement and generating metal-carbenoids with enhanced electrophilicity making it more reactive towards nucleophiles.Although copper and rhodium catalysts have been more popular traditionally, other metals such as cobalt, nickel, silver, gold, iron, and ruthenium, etc. have been employed in recent years.Also, several new and novel chiral metal complexes have been developed for stereoselective synthetic protocols employing diverse types of -diazocarbonyl compounds (Figure 1). 8,9ommon synthetic methods involve benchmark reactions of metal-carbenoids such as insertion into C-H and X-H (X = O, N, S, and Si, etc.) bonds, cyclopropanation, and ylide generation followed by cyclization and cycloaddition reaction (Scheme 1). 10 These reactions have led to the synthesis of diverse classes of biologically relevant natural products (Figure 2) and synthetic molecules of complex architecture. 11The chemistry of different types of diazo compounds focusing on different aspects have been reviewed from time to time.Gurmessa and Singh published a review on the insertion and cyclopropanation reactions employing -diazocarbonyls in the presence of metal salts and complexes in 2017, covering literature till 2016. 8he application of microwave irradiation in the reactions of -diazocarbonyl compounds has also been reviewed by me recently. 12Two brief accounts on different aspects of metal-carbenoids chemistry from diazo compounds have been published by Harada and coworkers. 13,14The synthesis and chemistry of diazoketones was reviewed in 2019 by Arora et.al. 15The chemistry of silver carbenoids from diazo compounds has been reviewed by Zhang and coworkers. 6Recently, Soam and coworkers have published their review on Rh-catalyzed cascade reactions using diazo compounds as carbene precursor to construct diverse heterocycles. 16Xiang and coworkers have reviewed the application of diazo compounds in synthesis of nitrogen heterocycles via transition metalcatalyzed cascade C-H activation/carbene insertion/annulation reactions. 17he bulk of literature appearing in this research area in recent years necessitates a more frequent review.The aim of the present article is to update the chemistry of metal-carbenoids generated from -diazocarbonyl compounds and present an overview of the development since 2016 till date.

Synthesis of α-Diazocarbonyl Compounds
Although the objective of this article is not to review the synthetic methods for getting access to -diazocarbonyl compounds it is pertinent to mention about some methods of preparation of these reagents whose reactivity is being discussed.Acylation of diazomethane with acyl chloride in the presence of bases (The Arndt-Eistert method) and the diazo-transfer reactions of carbonyl compounds 1 (Scheme 2) are the two long-known classical methods for the preparation of α-diazocarbonyls 2. 18 A range of sulfonyl azides are commercially available as diazo-transfer reagents that transfer diazo group to methylene carbon  to carbonyl groups.Yi and coworkers have used microwave irradiation for the preparation of -diazoesters 4 from the reaction of 2-phenyl acetates 3 by diazo-transfer reaction (Scheme 3). 19Another common method that our group has been using is the metalcatalyzed dehydrogenation of -carbonyl hydrazones. 20,21More recently, Tanbouza and coworkers have developed a new bismuth(V) catalytic system for oxidation of hydrazones 5 to diazo compounds 6 including -© AUTHOR(S) diazocarbonyls (Scheme 4). 22Use of low catalytic amounts of triphenylbismuth and acetic acid with sodium borate hydrate as a terminal oxidant leads to in situ generation of Ph3Bi(OAc)2 that is capable to oxidize hydrazones in excellent yields.Sharma and coworkers have developed a metal-free method for a quick oxidation of alkynyl hydrazones 7 to alkynyl diazoesters 8 using phenyliodine(III) diacetate (PIDA) (Scheme 5). 23

Insertion Reactions
Insertion reactions are powerful tools for construction of C-C and C-heteroatom (N, O, S, and Si) bonds.The reactions of metal-carbenoids, generated in situ from the decomposition of -diazocarbonyls at C-H, N-H, O-H, S-H, and Si-H bonds alkylating them are very common and well-established synthetic protocols.However, insertion is not limited only to these listed bonds.Metal-catalyzed carbene insertions are also reported in P-H, B-H, C-C, Sn-H, Ge-H, F-H and metal-metal bonds, but they are yet referred as "uncommon". 24,25The electronic demand of the substituent attached to the carbene carbon atom affects the selectivity of insertion reactions.Highly electrophilic carbenoid intermediates display little regioselectivity and stereoselectivity, favoring the occurrence of side reactions.A less electrophilic carbenoid intermediate, on the other hand, has a lower reactivity, but its regioselectivity and stereoselectivity are better. 26espite the importance of electronic factors to the reactivity and selectivity of carbenoid intermediates, steric and conformational effects are also determining factors in carbenoid chemistry.Steric as well as electronic factors and the chemical properties of the ligands around the metal center also significantly determine the type of insertion by the carbenoid intermediate.The complexes used for the formation of carbenoids in enantioselective insertion reactions must present a balance between steric and electronic factors, to promote the formation of a specific enantiomer. 27The succeeding paragraphs discuss selected examples of common insertion reactions useful to organic chemists.

C-H bond insertion reactions
For decades, the stereoselective carbon-carbon bond formation by activation of a C-H bond in the synthesis of pharmaceuticals, natural products, and other industrially relevant target molecules has been a challenging aspect in organic chemistry.A powerful approach to achieve such useful C-H functionalization is via C-H insertion of metal carbenoids. 28The activation of the C-H bond needs an appropriate interaction between the carbenoid intermediate and the carbon atom of the C-H bond.The mechanistic details of this reaction have been discussed previously. 8Recent literature shows some excellent reports on the application of C(sp3)-H and C(sp2)-H insertion/activation/annulation reactions in synthesis of complex molecules that are discussed below.The literature is arranged mostly according to the metal catalyst used beginning with less common metal catalysts for the reactions of -diazocarbonyls.
Liu and coworkers have investigated the reactions of -diazocarbonyl compounds 9 with 1,3-dicarbonyl compounds 10 in the presence of silver and scandium catalysts. 29The formal C-H insertion led to the formation of 2-alkylated 1,3-dicarbonyl compounds 11 in the presence of Sc(III) triflate (Scheme 6).In the presence of silver(I) triflate, however, the reaction switched to insertion into the C(=O)-C bond of the 1,3-dicarbonyl substrate forming a 1,4-dicarbonyl product (in up to 96% yield).This was the first example of a C-C bond insertion of metal-carbenoid from diazo compound in acyclic C-C bonds.

Scheme 6
Page 7 of 39 © AUTHOR(S) Yan and coworkers have reported an efficient Cp*Co(III)-catalyzed reaction of -diazocarbonyls 13 with 8methylquinoline 12 resulting into insertion at the methyl group forming quinoline derivatives 14. 30 The protocol tolerates a variety of functional groups (Scheme 7) and can be scaled up easily.The alkylated products can be used to synthesize important intermediates of azatricyclic antibiotic compounds.According to the proposed mechanism, the reaction proceeds through a quinolyl-directed C(sp3)-H activation by cobalt, cobalt-carbenoid formation, migratory insertion, and subsequent protonation.The active catalyst [Cp*Co(III)OAc + ] was generated by the ligand abstraction with AgSbF6/Mn(OAc)2.

Scheme 7
A ligand-dependent enantioselectivity has been demonstrated in copper-bisoxazoline systems in studies reported by the Ford group. 31The -diazo--sulfonyl ketone substrate 15 is just one example in a recent report on copper-catalyzed 1,5-C-H insertion product 17 formation that was investigated with three different commercially available bisoxazoline ligands 16.A wide variation in enantioselectivity was observed with the different ligands employed; the highest asymmetric induction (87%) was achieved with the indane-derived bisoxazoline ligand 16c (Scheme 8).

Scheme 8
Kui and coworkers have studied the metal-catalyzed reactions of -diazo--hydroxyamino esters 18.An intramolecular 1,5-C-H insertion forming fused cyclic product 20 was the principal reaction in copper-catalyzed reaction of piperidine-based substrate (Scheme 9) while a selective 1,2-hydride shift forming ketonitrones 19 was observed in pyrrolidine-based substrates. 32© AUTHOR(S) Scheme 9 Bhat and coworkers have developed a copper-catalyzed arene C(sp2)-H insertion/Michael-type annulation reaction involving α-diazocarbonyl compounds. 33The reactions of α-diazocarbonyl compounds 22 with suitably substituted indoles 21 containing alkynyl ester electrophiles yield a variety of fused indole 23 scaffolds in a stereoselective manner by varying the location of the electrophile on the indole derivatives (Scheme 10).The method features low catalyst loadings, reasonable yields, and excellent regio-and stereoselectivity.Further, a one-pot copper carbene coupling/base promoted annulation sequence, which extended the electrophile scope past alkynyl-ester, was developed to synthesize a series of interesting, cyclized products.The electron-deficient internal alkynes appeared central to the success of the copper cascade conditions.Switching the ester group at the terminal end of the alkyne acceptor for an alkyl group resulted in formation of C-H insertion product only.The copper catalyst has been proposed to play dual role in the mechanistic pathway.First, it activated the diazocarbonyl to generate the copper-carbenoid 24 for C-H functionalization 25 and then double activated the enolate and alkyne electrophile in 26 invoking 5-exo-dig syn addition furnishing cyclized intermediate 27 which underwent protodemetalation to give cyclized Z-alkene isomer and regenerate the catalyst.

Scheme 13
Merey and coworkers have studied the rhodium and copper-catalyzed reactions of -diazoesters bearing a tertiary amide group in which the nitrogen atom was substituted with an alkoxy group having a carbon-carbon double bond together with another group. 37In the presence of Rh2(OAc)4, intramolecular 1,5-C-H insertion product isooxazolidinone was obtained predominantly while cyclopropanation was the main course of reaction in the presence of CuCl/AgSbF6.A Rh2(OAc)4-catalyzed intermolecular cyclization of pyrazol-5-amine and cyclic 2-diazo-1,3-diketones in N,N-dimethylformamide (DMF) has been developed. 38Various pyrazolo [3,4-b]pyridine derivatives were obtained in this reaction under mild conditions.Interestingly, the metal-carbenoid underwent C-H insertion with methyl group of DMF.Thus, DMF provided a carbon atom in the construction of pyridine ring.
In a recent communication, Sihag and coworkers have reported insertion of rhodium-carbenoids from diazocarbonyls into an allylic C-H bond of unactivated alkenes. 39In this protocol acceptor-acceptor diazo compounds bypassed cyclopropanation.Further, the method was compatible with diverse unactivated alkenes functionalized with different sensitive functional groups.A rhodacycle -allyl intermediate has been proved to be an active intermediate in the mechanistic pathway.
A copper-catalyzed C(sp2)-H insertion has been described previously. 32Several other reports have appeared on Csp 2 -H insertion reactions of -diazocarbonyl compounds using rhodium, gold, iron, and iridium catalysts.Vinogradov and coworkers have reported consecutive alkylation of 9-isopropyl-6-phenyl-9H-purine 40 on treatment with diethyl diazomalonate 22 and then with methyl 2-diazo-3,3,3-trifluoropropionate 41 at the ortho-positions of the phenyl substituent furnishing product 43 via the first insertion product 42. 40This reaction proceeded under chelation assistance of the purine core that led to high regioselectivity at the ortho-position of phenyl substituent.The dimeric rhodium(III) complex [Cp*RhCl2]2 was discovered as the most efficient catalyst.However, when the sequence of diazocarbonyls was reversed then an unusual triple alkylation product 44 was obtained because of the third alkylation due to simple electrophilic metal carbenoid insertion to the C−H bond of the malonate moiety (Scheme 14). 41

Scheme 14
The reactions of dialkyl diazomalonates (dimethyl diazomalonate 46) with O-aryl N,Ndimethylthiocarbamates 45 using [Cp*RhCl2]2 in acetic acid as a catalytic system is reported. 42The reaction was directed by thiocarbamate group leading to alkylation of aromatic C-H ortho to thiocarbamate group in moderate to good amounts (Scheme 15).The plausible mechanism involved the ligand exchange of enolate form of thiocarbamate group with [Cp*RhCl2]2 inducing a reversible ortho C−H activation via electrophilic metalation to form a six-membered cyclorhodium species 48.This species reacted with diazomalonate to afford the key Rh-carbenoid intermediate 49 accompanied with the nitrogen release.Next migratory insertion and protonation by acetic acid furnished the alkylation product 47 and the catalyst is generated by attack of chloride ion on the rhodium center in the complex 50 (Scheme 16).

Scheme 15 Scheme 16
Phenols are important motifs in natural products and pharmaceutical products.The C-H functionalization of phenols employing metal-carbenoids is a challenging endeavor due to competing insertion into the O-H bond.Toward this end, Yang and coworkers have developed a novel multicomponent reaction of free phenols 51, methyl 2-diazo-2-phenylacetate 52, and allylic carbonate 53 in the presence of Rh(II) and a Xantphos ligand as the catalyst, furnishing a wide range of phenol derivatives 54, bearing an all-carbon quaternary center and a synthetically useful allylic unit (Scheme 17). 43Probably, the reaction proceeds via a tandem process of carbeneinduced para-selective C−H functionalization, followed by Rh(II)/Xantphos-catalyzed allylation.

Scheme 17
An example of Csp 2 -H bond insertion of metal-carbenoids involves the reaction of aryl diazoacetates 6 with anisole 55 in the presence of an achiral gold complex and chiral phosphoric acid 56 as a cooperative catalytic system (Scheme 18). 44This reaction offers a protocol for an enantioselective synthesis of -diary acetates 57.The reactivity and enantioselectivity of this reaction have been explained by DFT calculations.More recently, a Csp 2 -H activation on 2-aryl group of 2-arylbenzimidazoles with α-trifluoromethyl-α-diazoketones followed by Page 13 of 39 © AUTHOR(S) defluorinative annulation is reported. 45The reaction sequence leads to easy access to 6-fluorobenzimidazo[2,1a]isoquinolines in high yields and excellent functional group compatibility.

Scheme 18
Yang and coworkers reported the application of FeCl3 for a chemo-and regioselective arylation of -aryl diazoacetates 58 using N,N,dimethylaniline 59. 46 The group has used iron(III) chloride in combination with 1,10phenanthrolene and NaBArF as the catalytic system.The reaction led to exclusive formation of 4-substituted N,N,dimethylanilines 60 in very good yields (Scheme 19).No 2-substitution or insertion into C-H bond of methyl group was observed.The diazo compounds with fused ring or heteroaromatic ring also worked efficiently.

Scheme 19
Balhara and Jindal published their density functional theory (DFT) study of indole alkylation with diazoacetates catalyzed by Fe(ClO4)TMEDA/spirobisoxazoline and myoglobin catalytic system.This study was conducted to get a clue of low stereoselectivity in C-H functionalization of indoles with Fe-carbenoids.Three mechanistic pathways: nucleophilic, radical, and oxocarbenium routes were explored.The nucleophilic pathway is the most feasible involving an enol species that furnishes the alkylated indole on tautomerization.The present study showed that the conventionally proposed enol pathway was not responsible for the low enantiomeric excess.The enol intermediate can stay coordinated to the catalyst via different binding sites placing the enol in proximity to the chiral environment and affecting the stereoselective proton transfer.Both the binding strength and the chiral environment were crucial for obtaining high selectivity.This study might be helpful in finding an efficient catalytic system for efficient enantioselective C-H insertion. 47atel and Borah have reported Ir(III)-catalyzed reactions of -diazocarbonyl compounds 62 with readily available acetanilides 61. 48The reaction resulted into C-H insertion at ortho to anilide group forming 63 and annulation under mild conditions allowing direct access to indoles 64 (Scheme 20).Diverse types of Nsubstituted indoles, including N-acetyl, N-pivolyl, and N-benzoyl indoles, were obtained in good yields.

N-H bond insertion reactions
One of the most efficient methods for the construction of the carbon-nitrogen bond is through N-H bond insertion reactions of metal-carbenoids, generated from metal-catalyzed reactions of diazo compounds. 8Recent literature shows notable development in this area of research.Chemoselective and in some cases enantioselective N-H bond insertion reactions have been reported with primary and secondary amines, heterocyclic amines, imines, and ammonia as well.Copper, rhodium, iron, and silver catalysts have been employed to achieve the reaction.The N-H bond insertion of the metal-carbene from diazocarbonyls has been reviewed by Jiajun et al. in Chinese language. 49The products obtained from the N-H insertion reaction are useful building blocks in organic synthesis.The N-H insertion reaction provides an attractive access for the synthesis of α-amino esters, dipeptides, nitrogen-containing heterocycles, and other amino acid derivatives.
Arredondo and coworkers reported that Pd(II)-chiral biosoxazoline 67 catalyzed highly enatioselective N-H bond insertion of the metal-carbenoids from -diazoesters 66 into N-H bonds of aromatic heterocycles such as C-3 substituted indoles and carbazoles 65 (Scheme 21). 50The products 68 were obtained in good yields and ee up to 99%.The method was applied to the synthesis of the core of a bioactive carbazole derivative.

Scheme 21
Knoll and coworkers in 2019 reported a new class of planar chiral [2.2]paracyclophane-based bisoxazoline (BOX) ligand 70 for the Cu(MeCN)4PF6 complex showing good selectivity in N-H insertion reactions of methyl 2diazo-2-benzyl/phenyl esters 66 into the N-H bond of aniline 69. 51Lowering the temperature to room temperature increased the selectivity to an excellent ratio of 93:5 with Cu(MeCN)4PF6.When β-hydrogen lacking 66 (R = Ph) was used, product 72 was detected from the dimerization of the α-diazocarbonyl compound.Dropwise addition of 66 (R = Ph) to the reaction mixture alleviated this issue for the most part.With these optimized reaction conditions, the same copper catalyst Cu(MeCN)4PF6 led to excellent yields of 98% for the desired insertion products (Scheme 22).Notably, in both cases the product was formed even in the absence of the ligand in 13% and 40% yields, respectively.

Scheme 22
Earlier in 2017, Ramakrishna and Sivasankar had reported an efficient green method for acceptor/acceptor type carbene insertion into the N-H bonds of various anilines in water.The study revealed that the [(COD)IrCl]2 catalyzed the N-H insertion furnishing product in up to 98% yields. 52liphatic amines strongly coordinate, and therefore easily inhibit the activity of transition-metal catalysts, posing a marked challenge to N-H insertion reactions.Toward this challenge Li et al. used two catalysts in tandem: an achiral copper complex and a chiral amino-thiourea and developed highly enantioselective carbene insertion into N-H bonds of aliphatic amines. 53Coordination by a homoscorpionate ligand protects the copper center that activates the carbene precursor.The chiral amino-thiourea catalyst then promotes enantioselective proton transfer to generate the stereocenter of the insertion product.This reaction couples a wide variety of diazo esters and amines to produce chiral α-alkyl α-amino acid derivatives.
Tanbouza et al. in their study on N-H bond insertion of Fe-carbenoids, generated from the Fe(OTf)2catalyzed decomposition of methyl 2-diazo-2-phenyl acetate, observed that the reactions were strongly dependent on the type of amine used.Secondary amines afforded moderate yields of (57-68%) of tert-amine, with prolonged reaction time (72 h) and increased temperatures (80 °C) to reach completion.Primary aromatic amines offered improved yields of the insertion products, sec-amines (74-84%).It is noteworthy that in case of primary amines, the reaction was selective toward a single-insertion with no sign of a double insertion product. 54andit and coworkers have used iron(III) catalyst, Fe(OTf)3 in the reaction of -diazocarbonyls 73 and ophenylenediamines 74 in water. 55The reaction proceeds by a domino N−H insertion, cyclization, and oxidation reactions resulting in construction of polyfunctionalized quinoxalines 75 in high yields (Scheme 23).A total of 41 compounds were synthesized using monocyclic and bicyclic diamines.This methodology also allows the synthesis of biologically relevant pyrazines and benzoquinoxalines.

Scheme 23
The reaction of -diazoesters 4 with benzophenone imines 76 using Rh2(esp)2 and chiral guanidine 77 cooperative catalysis results into an efficient enantioselective N-H bond insertion. 56Both aliphatic and aromatic substituted -amino esters 78 were obtained in high yields (up to 99%) and good enantioselectivities (up to 95.5: 4.5 er) under mild reaction conditions (Scheme 24).

Scheme 24
Insertion of metal-carbenoids into the N−H bond of ammonia persists as a longstanding challenge in carbene chemistry because of the tendency of Lewis basic ammonia (NH3) to bind with metal and inhibit metal catalysis.To address this challenge, Liu and coworkers investigated the reactions of diverse diazo compounds 6 with ammonia using a Tp Br3 Ag-catalyzed two-phase system (Scheme 25). 57These reactions resulted in a chemoselective carbene N−H bond insertion of NH3•H2O.Coordination of silver to a homoscorpionate Tp Br3 ligand renders silver compatible with NH3 and H2O and enables the generation of electrophilic silver-carbenoid.Water promotes subsequent [1,2]-proton shift to generate N−H insertion products 79 with high chemoselectivity.

Scheme 25
Li and coworkers have reported an enantioselective N-H bond insertion to construct C-N bond by reaction of a wide variety of diazoesters with ammonia under the cooperative action of copper complexes and chiral hydrogen-bond donors. 58The reaction resulted into formation of natural and nonnatural chiral -amino acids in excellent yields and enantioselectivity.

O-H bond insertion reactions
Carbenes can insert into O-H bond forming ethers.The mechanism involves usual addition of the oxygen lone pair into an empty p-orbital on the carbene, followed by proton transfer to generate a neutral molecule from the first formed ylide.
Tanbouza and coworkers have reported O-H bond insertion of iron-carbenoids, generated in situ from Fe(OTf)2-catalyzed decomposition of methyl 2-diazo-2-phenyl acetate 52, into the O-H bonds of water, alcohols and acetic acid 80. 54 The products 81 were obtained in good yields in an emerging green solvent dimethyl carbonate (DMC) (Scheme 26).The catalyst and solvent were also good for N-H, Si-H, and S-H insertion reactions.

Scheme 26
In recent years cooperative catalysis by Rh(II)-chiral phosphoric acids has been employed in some enantioselective O-H insertion reactions.Li and coworkers reported the first asymmetric O-H insertion of metal-carbenes from α-diazoketones with alcohols co-catalyzed by achiral dirhodium complexes and chiral spiro phosphoric acids. 59The products were obtained in high yields and high enantioselectivity (up to 95% ee) (Scheme 27).This reaction offers an efficient approach to the synthesis of very useful chiral α-alkoxy ketones, which are easily transformed to corresponding 1,2-diol derivatives with excellent diastereoselectivity.The DFT calculation revealed that the chiral spiro phosphoric acid can promote the proton transfer process of enol intermediates generated from rhodium carbene and alcohol like chiral proton-transfer shuttle and realize enantioselectivity control accordingly.Water is likely to participate in this proton transfer step and has a remarkable effect on the enantiocontrol of the reaction.

Scheme 27
Recently, Li and coworkers have reported the first highly enantioselective O-H bond insertion reaction of metal-carbenoids from -alkyl-and -alkenyl--diazoesters 6 into the O-H bond of water using a combination of achiral dirhodium complexes and chiral phosphoric acids or chiral phosphoramides 84 as a catalytic system (Scheme 28). 60The use of phosphoric acid or phosphoramide in the reaction was observed to suppress the side reactions such as carbene dimerization, olefin isomerization, and -hydrogen shift.The products chiral -alkyland -alkenyl hydroxyl esters 85, obtained in excellent yields readily undergo various transformations to give biologically relevant molecules.
Massaro and coworkers have reported a convergent cascade approach for the stereoselective synthesis of diverse lactones. 62The Rh2(TFA)4-catalyzed cascade reaction proceeds via a carboxylic acid O-H insertion furnishing 87 and aldol cyclization of insertion products 87 with high chemo-, regio-, and diastereoselectivity leading to a quick entry into highly functionalized γ-butyro-and δ-valerolactones 88 from readily accessible ketoacid 86 and diazo synthons 2 (Scheme 29).The reaction has wide scope as a range of ketoacids with electron-donating and electron-withdrawing groups, and diazocarbonyls react to provide functionalized lactones of varying ring sizes.

Scheme 29
Dias and coworkers have investigated the reaction of stable 2-diazo-1,3-diketones 89 with phenols 90. 63The optimization studies with different rhodium and copper catalysts established Cu(hfac)2 as the most efficient catalyst.Anisole at 120 o C using microwave irradiation was discovered as the most efficient solvent.The coppercatalyzed insertion products 91 were obtained with substrates bearing diverse groups on the phenyl ring of phenol.The insertion products were reduced to obtain -O-4-lignin models 92, a sustainable source of aromatic compounds (Scheme 30).

S-H and Si-H bonds insertion reactions
Insertion reactions of metal-carbenoids into the Si-H bond are known since 1988.However, they did not receive much attention compared to their N-H and O-H bonds counterparts.Recently, there have been a few notable © AUTHOR(S) developments, particularly in the field of asymmetric reactions of diazo compounds with substrates containing Si-H bond.Chiral copper, rhodium, iridium, ruthenium, and iron catalysts have shown to be very promising for the purpose. 19Keipour and Ollivier reviewed the insertion reactions of metal-carbenoid from diazo compounds into the Si-H bond in 2017. 64eipour and coworkers have reported iron-and copper-catalyzed carbenoid insertion reaction of α-diazo carbonyl compounds 93 into Si-H and S-H bonds of silanes 94 and thiols 96, respectively. 65-67Several αsilyllesters 95 (Scheme 31) and α-thioesters 97 (Scheme 32) were obtained in high yields from α-diazoesters 93 using a simple iron(II) salt as a catalyst.Substrates with electron-donating and electron-withdrawing groups were used in these studies.A 4-chloro group on the diazoester gave low yield of the corresponding α-thiolester in reaction with thiophenol (35%).A wide range of α-silylesters and α-thioesters was also obtained in high yields (up to 98%) from α-diazoesters using 5 mol% of a simple copper(I) salt as catalyst.Using 0.05 mol% of the same catalyst, α-diazoketones led to the formation of α-silylketones in low to good yields (up to 70%).

Scheme 31 Scheme 32
Tanbouza and coworkers observed that the Fe(OTf)2-catalyzed insertion using a wide range of diazo compounds into Si-H bond of silanes occurred in an emerging green solvent, dimethyl carbonate (MeO)2C=O. 54he α-silylated products were obtained in good to excellent yields.Kinetic studies of the reaction revealed that the extrusion of N2 leading to the generation of iron-carbenoid was rate-limiting step.
Komarova and coworkers have reported the cyclopentadienyl rhodium(III) complexes [CpRhI2]2 (Cp = cyclopentadienyl ring bearing five methyl groups) as catalysts for the insertion of rhodium carbenoids from phenyl diazoacetate into Si-H and N-H bonds. 68Iodide complex was observed more efficient than common chloride complex.However, the C-H bond insertion with substrates 1,4-cyclohexadiene and with cycloheptatriene was not possible even on employing the most efficient catalyst of the series.Also, the catalysts of this class were less effective than Rh(II) carboxylates despite the higher oxidation state of the metal.The authors attributed the low electrophilicity of such carbenoids to electron donation from the anionic cyclopentadienyl and iodide ligands.

Scheme 33
Chen and coworkers reported the first rhodium(I)-catalyzed enantioselective insertion of carbenoids from -diazoesters into Si-H bond. 69This group used a C1-symmetric chiral bicyclo[2.2.2]octadiene ligand 101 that enabled the reaction to proceed under extremely mild conditions to furnish diverse -silyl esters 102 with excellent enantioselectivities.A wide range of substrates including both aryl-and alkyldiazoacetates 4 reacted with several trialkyl-and dialkylaryl silanes 100 to afford products 102 in moderate to good yields (Scheme 34).

Cyclopropanation and other reactions across carbon-carbon multiple bonds
Along with insertion reactions, cycloprppanation is the oldest known classical reaction of carbenes.The cyclopropanation reactions of metal-carbenoids and its mechanistic aspects were discussed in detail in a review article by Gurmessa and Singh. 8Several transition-metal-catalyzed asymmetric cyclopropanation of olefins with diazocarbonyls furnishing optically active cyclopropane derivatives were described.1][72] Even though unstable and highly reactive, cyclopropane rings are prevalent structural unit in natural products and bioactive compounds. 73Enantioselective cyclopropanation of a wide variety of olefins catalyzed by Ru(II)-Pheox complexes was accounted by Chanthamath and Iwasa in 2016. 74Roy and coworkers have discussed the role of ligand types used in catalytic metal complexes in selectivity in asymmetric cyclopropanation reactions using diazo compounds. 75 Chanthamath group reported the first highly stereoselective cyclopropanation of diazo Weinreb amides 103 with olefins 104 using chiral Ru(II)-Amm-Pheox complex 105 to give the corresponding chiral cyclopropyl Weinreb amides 106 in high yields (up to 99%) with excellent diastereoselectivities (up to 99: 1 dr) and enantioselectivities (up to 96% ee) (Scheme 35). 77The use of acetoxy-functionalized diazoacetamide as a carbene precursor was observed to be crucial for the high trans-selectivity of the cyclopropanation reaction.In another paper, this group has reported intramolecular cyclopropanation in trans-allylic diazo Weinreb amides using chiral ruthenium(II)-Amm-Pheox catalyst to give the corresponding chiral cyclopropyl Weinreb amides in excellent yield (up to 99%) with excellent enantioselectivity (up to 99% ee). 78Using a catalyst (p-nitro-Ru(II)diphenyl-Pheox) of same class, intermolecular cyclopropanations of diazo acetoxy acetone with various olefins were accomplished. 79Optically active cyclopropane derivatives were obtained in good yields (up to 95%) with excellent diastereoselectivities (up to 99:1) and enantioselectivities (up to 98% ee).

Scheme 36
Page 22 of 39 © AUTHOR(S) Thanh and coworkers have reported the development of an intramolecular cyclopropanation followed by ring-expansion (Buchner reaction) of a variety of N-benzyl diazoamide derivatives 111 in the presence of a chiral Ru(II)-Pheox catalyst 112. 82The aromatic rings are transformed into the corresponding -lactam-fused cycloheptatriene ring system 113 with high regio-and stereoselectivity (Scheme 37).The C-H insertion products, 2-azetidinones 114 were obtained as side-products in most cases.A substrate bearing a methyl group and a benzyl group on the amide nitrogen yielded insertion product and Buchner product in 55:45 ratio.The corresponding Buchner reaction products were obtained in excellent yields (up to 99%) and enantioselectivity (up to 99% ee) in case of substrates with electron-donating groups.In the case of substrates bearing an electronwithdrawing group, the rate of the Buchner reaction slightly decreased and formation of the C-H insertion product 2-azetidinones was observed.An asymmetric intramolecular Buchner ring expansion of -alky-diazoesters has also been developed using rhodium(II) catalysts. 83

Scheme 37
Besides ruthenium, complexes of iron and copper with spirobisoxazolines have also shown good enantioselectivity in cyclopropanation reactions.Xu and coworkers reported the first intramolecular enantioselective cyclopropanation at C2-C3 double bond of indoles, which was achieved in good to high yields (up to 94%) with excellent enantioselectivity (ee: up to >99.9%) by using copper or iron complexes of chiral spiro bisoxazolines as catalysts. 84This reaction offered a straightforward, efficient method for constructing polycyclic compounds with an all-carbon quaternary stereogenic center at the 3-position of the indole skeleton.Inoue and coworkers reported the copper(I)-catalyzed asymmetric intramolecular cyclopropanation using bis-oxazoline ligands. 85The products 3-oxabicyclo[3.1.0]hexan-2-oneswere obtained in 48-83% yields and up to 91% ee.In another communication, this group has reported intramolecular cyclopropanation of α-diazo-α-silyl acetate 115 using the same catalytic system 116 yielding cyclopropane-fused -lactone 117 (Scheme 38). 86Cu(I) catalyst was found to play a crucial role in determining the yields and enantioselectivities. Anionic counteranions improved both yields and enantioselectivities.
The latest example of cyclopropanation reported involved the reaction of copper-carbenoid, obtained from the [Cu(MeCN)4]PF6-catalyzed decomposition of alkynyl diazoacetates 8, with alkenes 118 furnishing alkynyl cyclopropane carboxylic esters 119 in good to excellent yields and with excellent diastereoselectivity (Scheme 39). 23The steric effect on ester alkyl group led to reduced yield but the diastereselectivity was unaffected.The substrates alkenes and styrenes with wide variety of substituents reacted excellently.The authors attributed the observed high diastereoselectivity to the presence of the ester acceptor and alkynyl donor.The donor group could stabilize the electrophilic copper-carbenoid that attenuated the reactivity and enhanced the diastereoselectivity.

Scheme 40
Page 24 of 39 © AUTHOR(S) Ventura and Lincourt reported on the use of metallophthalocyanines (MPc's) with different transition metal cores to investigate the ratio of intermolecular cyclopropanation and C-H insertion products upon reaction of cyclohexene 127 and the donor-acceptor methyl 2-diazo-2-phenyl acetate, 52 (Scheme 41). 88The reactions displayed similar chemoselectivity furnishing cyclopropanation and allylic C-H insertion products 128, and 129, respectively, at a nearly 1:1 ratio except in case of CuPc where cyclopropanation was favored (6.4:1).

Scheme 41
Rhodium carboxylates and complexes are among the oldest known catalysts for cyclopropanation of metalcarbenoids.Davies group developed a tandem reaction for the preparation of donor/acceptor-substituted diazocarbonyls in continuous flow coupled with dirhodium-catalyzed cyclopropanation of styrenes. 89ydrazones were oxidized in flow by solid-supported N-iodo-p-toluenesulfonamide potassium salt (PS-SO2NIK) to furnish the -diazocarbonyls, which were then purified by passing through a column of molecular sieves/sodium thiosulfate.A rhodium(II)-mediated cascade cyclopropanation/ rearrangement/isomerization of diazo 2,3,5-trisubstituted furans 130 yielding penta-substituted aromatic compounds is reported. 90The reactions occurring under mild conditions show excellent chemoselectivity.No C(sp 2 )-H insertion products were detected.In most cases, the reaction yielded either nonisomerization products 131 or pentasubstituted aromatic compounds 132 (Scheme 42).The former products could be isomerized using Lewis acid.The cyclopropanation of furan C=C bond by Rh-carbenoid followed by rearrangement and isomerization led to the formation of final product.

Scheme 42
Dutta and coworkers have reported the first manganese catalyzed cyclopropanation of N-acylindoles 133 with several methyl 2-diazo-2-arylaceates 66 (Scheme 43). 91Acetyl group has directing influence in this strategy.© AUTHOR(S) In the absence of stereodirecting group the desired products 134 were obtained as a mixture of diastereomers (7:3 to 8:2).The reaction of unprotected indole yielded the desired product in trace amount.Also, N-benzoyland N-t Boc-protected indoles were not found appropriate in this strategy.

Scheme 43
Zhou and coworkers considered the development of the novel and practical [4 + 2] annulation via selective C−H bond functionalization of alkene as the key step for a possible strategy for the regiospecific synthesis of polyfunctionalized benzene rings in a one-step manner. 92To explore this strategy, this group investigated the possibility of site-selective carbon insertion into the β-C−H bond of dialkenyl ketones with diazo compounds assisted by weak coordination of ketone to control the substitution patterns though it was challenging due to the different Csp2−H bonds and possible competition with the cyclopropanation of alkenes.The study resulted into development of a novel method for direct access to highly functionalized benzene rings 137 by regioselective formal [4 + 2] cycloaddition of enaminones 135 with diazocarbonyls 136 via C-H functionalization product 138 in the presence of a Rh(III) catalyst (Scheme 44).Deuterium labeling experiments supported the involvement of weakly directed site-selective alkenyl C−H bond functionalization as the key step.A broad range of substrates were tolerated under mild conditions, affording the desired products in good to excellent yields.

Scheme 44
Wu and coworkers have reported the cycloaddition reactions of -daizocarbonyls with 1,5-enynes 139 in the presence of dual metal catalysts, rhodium, and copper. 93

Scheme 45 Scheme 46
It is well known that the reactions of carbenoids depend on electronic factors as seen in the preceding example.However, they are also very sensitive to catalysts and reaction conditions.James and coworkers have reported synthesis of five different scaffolds 147-151 from a single indolyl -diazocarbonyl precursor 146 using different catalysts and reaction conditions (Scheme 47). 94A range of catalysts including complexes of Rh(II), Pd(II), and Cu(II), as well as SiO2, were used under argon or air to promote diazo decomposition and subsequent Page 27 of 39 © AUTHOR(S) cyclization/ rearrangement of the diazocarbonyl precursor through different mechanistic pathways resulting into C-3 functionalization and C-2 annulation of indole ring.The product 148 could be further transformed to isomeric spirooxindoles by simple acidic and basic treatment.More recently, a catalyst dependent visible light-induced reaction of -diazocarbonyls with different types of alkenes is reported. 95The reaction in the presence of an Ir(III) catalyst yielded cyclopropanation products (up to 99% yield).A simple addition of Rh2(OAc)4 co-catalyst in the Ir(III)-catalyzed process yielded cyclobutanes by [2+2]-cycloaddition.However, both these processes have been explained through energy transfer in the presence of metal catalysts and not via metal-carbenoids.

Scheme 48
Zhang and coworkers reported the synthesis of multi-substituted/fused pyrroles via copper-catalyzed carbene cascade reaction of propargyl α-iminodiazoacetates 160. 97The products 161 were obtained in high yields with broad substrate scope.Among the products were tetrasubstituted N-H 3-formylpyrroles (Scheme 49) as well, known to be synthesized with difficulty by alternate approaches.Mechanistic studies indicated that these transformations were initiated by a Cu-catalyzed carbene/alkyne metathesis furnishing 162 and followed by two disparate cascade transformations via products 163-165.

Scheme 49
Petzold and coworkers have employed cooperative Rh(II), Lewis and Brønsted acid catalysis in the decomposition of readily available O-diazoacyl-substituted arene carboxylate 166 to obtain scaffolds 167 and 168 with the 5,9-epoxycyclohepta[b]pyran-2(3H)-one core (Scheme 50). 10 This regio-and diastereoselective protocol led to the formation of four new bonds, three functional groups (lactone, ketal, and alcohol) and four contiguous stereocenters in a single synthetic step.The reaction is proposed to proceed via carbonyl ylide 169 and transient species 171-172 of the ketocarbene 170 equilibrium that undergo a cascade of cycloaddition and skeletal rearrangements giving the desired products.

Scheme 50
Cheng and coworkers have reported a wonderful example of dirhodium(II)-catalyzed reaction between two diazocarbonyl compounds, an enoldiazoacetamide and a 2-diazoketone, resulting into annulation of enoldiazoacetamides 173 with 2-diazoketones 174. 98This annulation reaction allows the efficient construction of donor-acceptor cyclopropane-fused benzoxa-[3.2.1]octane 175 scaffold with excellent chemo-, regio-, and diastereoselectivity under mild conditions.The study of substrate scope of this reaction revealed that enoldiazoacetamides 173 bearing dialkylamino, and cyclic amino moieties were all ideal reagents for this reaction.For 2-diazoketones 174, changing the ester group or introducing substituents onto the phenyl ring didn't affect the efficiency of this process.Mechanistically, enoldiazoacetamides 173 generate donor-acceptor cyclopropenes 176 in the presence of Rh2(pfb) that undergo [3+2]-cycloaddition with carbonyl ylides 178, generated from intramolecular reaction of rhodium-carbenoid 177 with carbonyl group in -diazoketones 174 (Scheme 51) The use of Rh2(pfb)4 and enoldiazoacetamides was crucial for achieving compatible reactivity and controllable selectivity in this reaction.

Scheme 51
Page 30 of 39 © AUTHOR(S) The copper-catalyzed reaction of -diazocarbonyl compounds 180 with α-(N-aryl)imino-β-oxodithioesters 179 results into [4+1]-heterocyclization furnishing 2,3-dihydrothiazoles 181 in good yields (Scheme 52). 99When nitrogen atom was bearing a hydroxyl group instead of an aryl group, the reaction afforded functionalized thiazoles.A wide variety of substituents are tolerated in the reaction.Mechanistically, the copper-carbenoid reacts with C=S bond in preference to C=O and C=N bonds generating the thiocarbonyl ylide 182.After losing the catalyst, the ylide is converted into a zwitterion 183 that cyclizes to give the 2,3-dihydrothiazole products.In the case of N-OH substrates, dehydration led to aromatization forming thiazoles.

Reactions via Ylides from C-N, C-O, and C-S Bonds
The reactions of metal-carbenoids with heteroatoms generating yildes and subsequent transformations have wide applications in organic synthesis. 2Recently, some interesting applications of this protocol have been reported by metal-catalyzed reactions of -diazocarbonyls with small-ring heterocyclic motifs such as oxiranes, azetidines, and thiiranes.A microwave-assisted ring expansion reaction of oxirane 184 with −diazo-−ketoester 185 using copper hexafluoroacetylacetonate as a catalyst giving rise to 2-acyl-5,6-dihydro-1,4dioxines 186 has been developed (Scheme 53). 100 1,2-Disubstituted cis-oxiranes afforded cis-3-acyl-5,6-dihydro-1,4-dioxines as stereospecific products.The yields of the products in all cases were below 50%.The stereochemical outcome in case of oxiranes was explained by formation of the final product via an intimate ionpair 188, generated after the elimination of copper-complex from the ylide 187.Similar reactions of aziridines with these -diazocarbonyl compounds to synthesize 3-acyl-5,6-dihydro-1,4-oxazines were investigated in different solvents under catalysis of different transition metal catalysts used in the reactions of oxiranes and thiiranes, but the reactions did not yield the desired products.

Scheme 53
Egger and coworkers have reported the reaction -diazo--ketoesters 190 with -aryloxitanes 189 in the presence of [CpRu(CH3CN)3][BArF] and 1,10-phenanthroline. 101 The products dioxepines 191 are obtained in moderated yields (Scheme 54) but with a good enantiospecificity by regioselective [4+3]-insertion that follows SN1-like transformation, as determined by vibrational circular dichroism and X-ray diffraction analyses.The preferential formation of dioxepines 4 vs. furan 5 was explained by applying the Baldwin's rules for the ring closure.Furans, products of [4+1] insertions, were only observed as traces in this protocol.

Scheme 54
A simple method for the synthesis of 3-acyl-5,6-dihydro-1,4-oxathiienes 194 has been developed by employing the chemistry of -dizaocarbonyl compounds in microwave. 102The reaction between −diazo-−1,3dicarbonyl compounds 193 and thiiranes 192 under microwave and copper sulfate assistance, yields 3-acyl-5,6dihydro-1,4-oxathiines.The cis-1,2-disubstituted thiiranes yielded trans-3-acyl-5,6-dihydro-1,4-oxathiines (opposite stereochemistry to that of oxiranes) in moderate yields (Scheme 55).The study on scope of the method indicated that the yields with monosubstituted thiiranes were generally lower than those with disubstituted thiiranes, and the longer the alkyl chain, the lower was the yield.The reaction is also sensitive to steric factors.The proposed mechanism in this case involves nucleophilic reaction of thiirane 192 with coppercarbenoid 195, formed from the reaction of copper salt with keto-carbene generated in situ by decomposition of diazocarbonyl compound 193.This reaction generates a metal-sulfonium ylide 196 that isomerizes to an enolate with elimination of copper moiety.The enolate attacks the thiiranium ring from back side to yield the 1,4-oxathiienes.
Page 32 of 39 © AUTHOR(S) Scheme 55 Sun and coworkers have reported a novel copper(II)-catalyzed domino reaction between the alkyl diazoacetates 198 and acyclic ketene-(S,S)-acetals 197. 103This reaction offered a simple and convenient approach to a range of poly-substituted thiophenes 199 and 200.A diverse range of acyclic ketene-(S,S)-acetals are tolerated in the protocol (Scheme 56).The reaction proceeds via a copper-catalyzed tandem process involving the generation of sulfur ylides 201 followed by the nucleophilic attack of carbanion in the ylide on the carbonyl carbon forming a five-membered ring 202 and leading to a cleavage sequence furnishing product 199.The product 200 was obtained together with 199 when R 1 was CO2Me, CO2Et, and 4-MeOC6H4 by the reaction of second mol of the metal-carbenoid at SR 2 of product 199.Regarding the scope of -diazocarbonyls, if H was replaced with Ph, COPh, Ac, CO2Et, the reaction did not proceed probably due to steric factors.Scheme 56

Concluding Remarks
The insertion and addition reactions of metal-carbenoids, generated from -diazocarbonyl compounds, constitute easy and straight forward methods for construction of carbon-carbon, and carbon-heteroatom © AUTHOR(S) bonds.The last decade has witnessed enormous growth in application of these reactions in the construction of complex molecular structures.The present review paper reveals the design and development of several novel -diazocarbonyl compounds, and their applications in organic synthesis.Among C-H insertion reactions, several novel intramolecular S(sp3)-H insertion and C(sp2)-H insertion reactions are notable developments.The C-H activation and annulation has furnished some biologically relevant scaffolds.The catalytic system has been diversified too.Besides copper and rhodium, iron, silver, cobalt, gold, and scandium have been employed for the purpose.Among heteroatom-H insertion, insertion into N-H and O-H bonds of ammonia and water, respectively, are significant developments as well.Interestingly, most of these protocols report insertion reactions in a highly chemoselective manner.In a few reactions, cooperative catalysis has also been employed.A three-component reaction of vinyl diazoacetate, alcohols, and amines has been reported resulting into a 1,3difunctionalization of the vinyl carbene in highly regio, diastereo-and enantioselective manner.Although copper, and rhodium complexes have been employed for cyclopropanation ruthenium complexes appear the catalysts of choice for the purpose.The dependence of reactions on steric and electronic factors on substrates, catalytic systems, and conditions, have been excellently demonstrated by preparation of five different scaffolds from a single indole-tethered diazocarbonyl compound.A novel reaction between two diazocarbonyl compounds, both reacting selectively in different manner -one generating a cyclopropene and other generating carbonyl ylide, and then [3+2]-cycloaddition between the cyclopropene and carbonyl ylide, has been reported.The reactions of metal-carbenoids with compounds containing carbon-heteroatom double bonds have been published furnishing 1,2-dihydropyrimidine-2-carboxylates, multifunctional pyrroles, 5,9epoxycyclohepta[b]pyran-2(3H)-ones, and 2,3-dihydrothiazoles, etc.The ylides, generated from the reaction of metal-carbenoids with oxygen atom of oxiranes and oxetanes, and with sulfur atom of thiirane have resulted into cleavage and annulation forming 1,4-dioxines, dioxepines, and 1,4-oxathiienes, respectively.Thus, there has been highly encouraging progress in this area of organic chemistry during last couple of years and many more interesting developments are anticipated.

Figure 1 . 1 Figure 2 .
Figure 1.Some metal complexes and ligands used in carbene chemistry.

Page
A short review on cyclopropanation of semi-stabilized and non-stabilized diazo compounds was published by Allouche et al.76 The reaction was guided by the substituents on the -diazocarbonyls.Ethyl diazoacetate and 2-diazo-1-(p-tolyl)ethan-1-one 140 yielded 2-naphthalenylmethanones 141 while ethyl diazoacetates 142, bearing aryl groups on C-2, afforded a series of substituted benzo[b]fluorenes 143 (Scheme 45).Furthermore, the ethyl diazoacetate offered very good to excellent yields.The formation of products has been explained via an allene intermediate 145, obtained from the reaction of rhodium-carbenoids 144 with enynes involving -ligand-exchange of Rh-carbenoids, migration insertion, enolization and H-abstraction.An intramolecular [4+2]-cycloaddition (route A) in allene followed by Page 26 of 39 © AUTHOR(S) dehydrogenation affords the benzo[b]fluorenes 143 while a pericyclic reaction of allene furnishes naphthalene derivatives 141 (Scheme 46).