N-Heterocyclic carbenes: Advances in transition metal and organic catalysis

N-Heterocyclic carbenes: advances in transitionmetal-mediated transformations andorganocatalysis

Herve Clavier and Steven P. Nolan*DOI: 10.1039/b614412h

This report provides a critical overview of recent developments in the use ofN-heterocyclic carbenes (NHCs) with transition metals. For these NHCligand-containing complexes, an analysis is focused on their performanceand scope in catalysis. There is also an increasing interest in the role ofnucleophilic carbenes as organocatalysts; the latest advances in applicationsof NHCs in organocatalysis are also reviewed.

1. Introduction

Since the first report of N-heterocyclic carbenes (NHCs) by Wanzlick1 in the earlysixties, and later the seminal discoveries of the first (NHC)–transition metalcomplexes,2,3 the development and applications of NHCs has increased tremen-dously, to reach now a status of ‘‘privileged’’ ligands in both organometallicchemistry and organic catalysis.4 This evolution was marked by several majorcontributions, such as the first application of NHC-containing metal-complexes byLappert5 and the isolation of free carbenes from imidazolium salts prepared in asingle step-procedure by Arduengo.6

Considered for a while as simple phosphine ligand mimics in organometallicchemistry,7 NHCs have also been utilized as organocatalysts.8 Recent studieshighlight the nucleophilic carbenes as a very versatile class of ligands due to theirinteresting and tunable steric and electronic properties.9 These ligands have severaladvantages over the commonly used phosphines such as stabilizing e!ect, highthermal stability, and good resistance to dissociation from the metallic center. As aresult, increasing experimental data now showcases the NHC systems as surpassingtheir phosphine-containing analogues in both activity and scope.10 These versatileligands have been widely used in organic chemistry and have allowed for majorimprovements in Ru-mediated olefin metathesis transformations11 and Pd-catalysedC–C bond formations,12 for example.In this report, attention is focused on the latest uses of N-heterocyclic carbenes in

catalysis including asymmetric reactions and organocatalysis. For the Reader’sconvenience, the structures of the most frequently encountered NHC ligands areshown in Fig. 1.

2. NHC synthesis

The most widely used NHCs possess a symmetrical imidazolylidene or imidazoli-nylidene skeleton, but other categories of nucleophilic carbenes such as the

Institute of Chemical Research of Catalonia (ICIQ), Av. Paısos Catalans, 16, 43007Tarragona, Spain. E-mail: [email protected]; Fax: (+34) 977-920-224

Annu. Rep. Prog. Chem., Sect. B, 2007, 103, 193–222 | 193

This journal is !c The Royal Society of Chemistry 2007

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triazolylidene or the benzimidazolylidene have also attracted attention. Recently, thedisymmetrical imidazolinylidene moiety has attracted much attention because of itspotential for bidendate and chiral ligands. Preparation of such NHCs could beachieved following the straightforward synthetic pathway shown in Scheme 1.13

Starting from ethyl chlorooxoacetate 2, condensation with an aniline and subsequentamidation with an amine, which could contain functional groups such as alcohols orester, a!ords the corresponding oxalamide. Reduction and cyclization of theobtained diamine with triethylorthoformate under acidic conditions led in excellentoverall yield to the salt 1, the precursor to the NHC. A similar procedure wasreported by Kotschy,14 who used chloroacetyl chloride 3 as a starting material(Scheme 2).

In spite of satisfactory yields, the main problem with the imidazolinylidenesynthesis is related to the prolonged heating required at reflux conditions to performthe condensation-cyclization of the diamide with triethylorthoformate. Delaude andco-workers have examined the possibility to carry out this key step under microwaveirradiation.15 The microwave assistance allowed for complete conversion on multi-gram scale with only 5 min of irradiation.The free carbenes can be synthesized following several procedures, the most

widely utilized being the deprotonation of the corresponding imidazolinium salt by astrong base (typically, sodium hydride, potassium hydride, potassium tert-butoxide,sodium tert-butoxide, DBU (1,8-diazabicyclo[5.4.0undec-7-ene]), etc.). Recently,Astruc presented an interesting alternative using an electron-reservoir complex[FeICp-(Z6-C6Me6)] 4 (Scheme 3).16 E"cient formation of IPr and IMes from thecorresponding imidazolium salts proceeded under ambient conditions using theeasily available green—black complex 4 and in the presence of O2. In a few secondsof reaction, yellow salt 5 precipitated in the reaction mixture and could be easily

Fig. 1 The most frequently encountered NHCs.

Scheme 1

Scheme 2

194 | Annu. Rep. Prog. Chem., Sect. B, 2007, 103, 193–222


removed by filtration. This alternative system for generation of free carbenes isparticularly useful when the deprotonation involves base-sensitive species.

3. Palladium–NHC complexes

Palladium-catalysed transformations have become increasingly important in thefield of organic synthesis and are widely used in industrial arenas.17 NHC-containingpalladium species were found to be extremely e"cient to performed many reactions,such as the numerous cross-coupling reactions, telomerization or oxidations, andrepresent currently a field of extensive and productive research.4 A large variety ofPd–NHC complexes have been developed and are used in catalysis each year. Thisreview will mentions the most significant advances.

3.1 Palladium–NHC complexes

A straightforward catalyst synthesis with high yield should be considered as animportant requirement to their ultimate use in catalysis. Nolan and Navarroreported recently a new one-pot synthetic procedure of [(IPr)Pd(allyl)Cl] 6 and[(SIMes)Pd(allyl)Cl] 7 starting from the imidazolium salts and using technical gradesolvents (Scheme 4).18 The deprotonation of the imidazolium salt was carried out intechnical grade isopropanol, followed by the addition of the palladium dimer. Whenthe reaction was complete, addition of water led to the precipitation of the complex,which was then filtered a!ording 6 and 7 in high yields and on a large scale (up to10 g). Since the air and moisture-stable 6 was found to possess excellent activity aspre-catalyst in a variety of cross-coupling reactions19 (Suzuki-Miyaura, Buchwald-Hartwig and a-ketone arylation), its facile preparation is of great benefit.

Subsequently to the [(NHC)Pd(allyl)Cl] complexes, the same group reported aseries of a modified version of the previous catalysts.20 These new complexes werevery straightforwardly synthesized, involving the simple cleavage of the correspond-ing dimeric palladium complex by IPr or SIPr carbene in dry THF (Scheme 5). It is

Scheme 3

Scheme 4



noteworthy that these complexes are air- and moisture-stable and can be prepared inmultigram quantities in high yields. In the Buchwald-Hartwig amination, the bestcatalytic performances were obtained with 11, and led Nolan et al. to broaden itsreaction scope (Table 1). This catalyst permitted the cross coupling reaction with awide range of amines with functionalized aryl chlorides at room temperature inminutes. The reactions were heated at 80 1C and allowed the catalyst to be reducedto 10 ppm, providing the highest turnover number reported to date.The Suzuki–Miyaura reaction involving the coupling of organoboron reagents

with organic halides serves as one of the most useful cross-coupling tools in synthetic

Scheme 5

Table 1 Representative N-aryl amination reactions using modified [(NHC)Pd(allyl)Cl]complexes

Entry Amine Ar–X Product

Time

(h)

Yield

(%)

1 1.5 97

2 0.1 90

3 1 92

4 0.3 89

5 1 92



chemistry.21 The activity of complexes 8–11 in the Suzuki–Miyaura cross-couplinghas showed that [(IPr)Pd(cin)Cl] 10 (cin = cinnamyl) to be the most e"cient.Complex 10 catalysed at room temperature in short reaction time the coupling of aryltriflates, bromides and chlorides with boronic acids using a very low catalyst loading(0.05 mol%) and technical solvent grade. As shown in Table 2, this catalytic systemallowed for a wide reaction scope involving reagents such as unactivated arylchloride, heteroaromatic chloride and bromide, or alkenyl boronic acids. Accordingto the authors, the high activity of these catalysts is attributed to an easier activationstep leading to e"cient generation of catalytically active palladium(0) species insolution.Following their work on [(NHC)Pd(OAc)2],

22 Nolan reported the synthesis of anew class of palladium-based catalysts for cross coupling reactions.23 The synthesisof [(IPr)Pd(acac)Cl] 12 (acac = acetylacetonate) is an extremely simple syntheticprocedure, as shown in Scheme 6. Direct reaction of Pd(acac)2 with an excess of

Table 2 Representative Suzuki–Miyaura reactions using modified [(NHC)Pd(allyl)Cl]complexes

Entry R1–B(OH)2 Ar–X Product

Catalyst

loading

(mol%)

Time

(h)

Yield

(%)

1 0.05 15 97

2 0.05 15 90

3 0.05 15 92

4 0.05 15 89

5 1 1 92



IPr "HCl in refluxing 1,4-dioxane for 24 h yielded 12 quantitatively. Of note, no basewas employed to generate the new complexes. Complex 12 has shown excellentcatalytic activity in the Suzuki–Miyaura and Buchwald–Hartwig reactions, and alsoin the a-ketone arylation cross coupling using aryl chloride under mild conditions(Table 3). In spite of the required heating to 60 1C, the couplings occurred in a fewhours using only 1 mol% of 12 and with a good tolerance to functional groups andsteric hindrance.In order to accelerate the formation of the active species, Organ and co-workers

synthesized a new series of labile ligand-containing pre-catalysts [(NHC)Pd-(3-ClPy)Cl2] (3-ClPy = 3-chloropyridine).24 Heating of IPr "HCl with PdCl2 andK2CO3 as a base in neat 3-chloropyridine, in air, yielded quantitatively thecorresponding complex 13 (Scheme 7). Surprisingly, the authors described theirsynthesis as direct C–H insertion on the metal center, whereas NHCs are well knownto be easily generated in the presence of metal and weak base such as carbonate orpyridine. The evaluation of 13 in the Suzuki–Miyaura reaction showed a goodactivity for di!erent substrates, however thermal activation or/and higher catalystloading were generally required compared to [(IPr)Pd(cin)Cl] 10. In 2005, Organreported that a combination of IPr "HCl and Pd2(dba)3(dba = dibenzylideneacetone), in THF/NMP (NMP = N-methyl-2-pyrrolidone) or THF/NMI (NMI =N-methylimidazole) catalysed the cross coupling of unactivated alkyl bromides withalkyl organozinc reagents at room temperature.25 The use of well-defined complex13 in the Negishi reaction allowed for reducing the reaction time but also broadenedthe scope of the reaction (Table 4).Andrus investigated the relation between the steric hindrance of NHC ligands and

their performances in cross coupling reactions using bulky phenanthryl N-substi-tuents (Fig. 2).26 A dramatic dependence on the steric bulk of the nitrogen-substituent was observed; the rate of the reductive elimination step may be enhancedwhen congested NHC ligands are used. Catalyst generated in situ using imidazoliumsalt 16 led to the best activity for Suzuki–Miyaura and Kumada reactions, but theactivity remained lower than that displayed with well-defined complexes 10–13.Sigman demonstrated the advantages of using NHC ligands in Pd-catalysed

oxidation reactions, particularly using a new class of NHC–Pd complexes,[(NHC)Pd(O2CR)2(OH2)], that are highly e!ective catalysts for aerobic alcoholoxidation.27 Recently, Stahl reported that these complexes were also competent tocatalyse aerobic intramolecular oxidative amination of alkenes.28 Starting fromcrotyl tosylanilides, dihydroindoles were isolated in good yields using IMes-contain-ing complex 17 and air or pure oxygen as source of molecular oxygen, as shown inScheme 8. The use of carboxylic acid co-catalysts (acetic acid and benzoic acid) ledto significant improvement in catalyst stability and product yield. As anotherexample of the beneficial e!ect of additives, Fagnou used a combination of[(IPr)Pd(OAc)2(OH2)] and imidazolium salt IPr "HCl to perform intramoleculararylation reactions with aryl chlorides (Scheme 9).29 Whereas the bis-NHC

Scheme 6



palladium catalysts are recognized to display poor activity,30 this addition of carbeneprecursor led to higher turnover numbers in the coupling. As an explanation, theauthors proposed the in situ formation of unusual bis-NHC palladium complexes inwhich one of the NHCs binds at the C5 position.31 An alternative possibility is that

Scheme 7

Table 3 Representative a-ketone arylation reactions using [(IPr)Pd(acac)Cl] 12

Entry Ketone Ar–X Product

Time

(h)

Yield

(%)

1 3.5 89

2 0.75 93

3 2.5 91

4 3 96

5 1 95



the excess of free IPr in the reaction mixture stabilizes the bare palladium(0) species,thereby hindering the formation of inactive palladium black.Moreover, Pd–NHC complexes were found e"cient to catalyse three component

cross-coupling of pyridine halides, carbon monoxide, and boronic acid, the so-calledcarbonylative Suzuki reaction, leading to useful building blocks for the syntheses ofvarious natural products and drugs (Scheme 10).32 Even if catalytic systems based on

Table 4 Representative Negishi cross coupling reactions using catalyst 13

Entry R1–X Cl/BrZn–R2 Product

Yield

(%)

1 87

2 89

3 83

4 96

5 90

Fig. 2



tertiary phosphines do not react, use of in situ generated NHC ligands, such as IMes,allowed for the isolation, in moderate to good yields and with excellent selectivity, ofthe carbonyl product. The bisdiene cyclization-trapping reaction represents anotherattractive transformation carried out by Pd–NHC complexes a!ording functiona-lized rings (Scheme 11).33 First explored with phosphine-containing catalysts,palladium-catalysed carbocyclization reactions of bisdiene were improved using[(NHC)Pd(allyl)Cl] complexes, reaching very high TONs (7.6 # 103).Palladacycles are ortho-metalated Pd(II) complexes, in which an aromatic carbon

atom adjacent to a functional group binds to the metal center.34 The high activity ofthese complexes has been improved by introducing NHC ligands.19b Since then,several other interesting NHC-containing complexes have been synthesized andcharacterized such as phospha-palladacycles 20 35 and triarylphophite-palladacycles

Scheme 8

Scheme 9

Scheme 10

Scheme 11



21 (Fig. 3).36 Complexes 20 and 21 have been evaluated, respectively in Mizoroki–Heck reaction and Suzuki–Miyaura cross-coupling. Despite good catalytic perfor-mances, high reaction temperatures were required to perform these cross-couplings.Complexes bearing bidentate or pincer-type ligands with a combination of

di!erent donor moieties have found widespread use in catalysis. Indeed, newfunctional groups-containing NHCs have been developed and used to generatewell-defined palladium-based complexes (Fig. 3). Palladium-catalysed couplingreactions of aryl halides and styrene using catalysts 22 37 bearing a phosphine-functionalized benzimidazolin-2-ylidene ligand, occurred e"ciently, although thereactions necessitated thermal activation. Of note, significantly higher activity wasobserved for complex 23 compared to 24 during assays in Mizoroki–Heck reac-tions.38 The authors explained this di!erence by the thermal stability of thepalladium complex 24 bearing a rigid pincer-type ligand, in which a short Pd–Cbond distance was found. One could also propose that the lability of pyridine favorsthe generation of the mono-ligated Pd(0) active species.

3.2 Palladium–chiral NHC complexes

As a logical extension, the development of chiral versions of these valuable ligandsfor palladium-catalysed enantioselective catalysis occurred about a decade ago andstill continues to attract attention.39 Kondo and Aoyama reported the synthesis ofnew chiral imidazolium salts 25, possessing stereogenic centers on the imidazolebackbone, and their use in enantioselective intramolecular a-arylation of amides.40

These C2-symmetrical NHCs were found to display, for this reaction, both moderatecatalytic performance and chiral induction (up to 67% ee), whereas the parent NHCligands a!orded good results for other asymmetric reactions.39 It illustrates perfectlythe di"culty in anticipating or predicting the activity and enantioselectivity inducedby a specific ligand for metal-catalyzed reactions. The developmental trend in chiralNHCs is moving to ever more structural complexity, as illustrated by the imidazo-lium salt 26 41 and complexes 27 42 and 28.43 Unfortunately, their evaluation inasymmetric allylic alkylation, enantioselective transfer hydrogenation, or asym-metric hydroamination did not lead to excellent chiral inductions. Nonetheless,reaction and substrate screening with these NHC ligands could allow for interestingresults or, at worst, better understanding (Fig. 4).

Fig. 3

Fig. 4



3.3 Palladium-supported NHC complexes

Development of immobilized catalysts has attracted a great deal of attention inorganic chemistry due to the possibilities of recycling as well as avoidance of thereaction product contamination with metal-containing waste. Several supported-palladium complexes have been developed and tested, mainly for cross-couplingreactions (Fig. 5). Lee and co-workers have shown that polymer-supported NHC-palladium complex 29 can perform up to 6 consecutive runs of the Mirozoki–Heckreaction with quantitative yields and without loss of activity.44 Independently, Luoreported a similar immobilized catalyst allowing for Suzuki–Miyaura cross coupling,but, regrettably, the exact structure of the complex is not indicated.45 Karimi andEnders described a new concept of simultaneous covalent anchoring of a NHCpalladium/ionic liquid matrix on a silica surface, complex 30.46 This reusable systemwas found to be very active in Heck reaction as only 0.01 mol% of palladium wasused. Of note, to determine the reusability of 30, the reaction mixture was heated to140 1C over one day, without major alteration of the catalyst activity, showing thegood thermal stability of the system. The comparable [(NHC)2PdCl2] complex 31was immobilized on an amorphous silica.47 This high thermally stable catalystshowed interesting activity for Mizoroki–Heck reactions and has been reused up to10 times. The authors highlighted the presence of ligand-free palladium in thereaction, meaning that 31 acts more as a reservoir of active species than a truerecyclable catalyst. A palladium-based catalyst has been grafted to an amphiphilicpolymer (containing a Merrifield resin part and a polyethylene glycol (PEG) spacer)to yield complex 32, in order to perform Suzuki–Miyaura cross-coupling reactions inwater.48 Complex 32 exhibited an interesting activity, because only a moderatetemperature (50 1C) was required to perform the reaction. In addition, the longerPEG chain led to the best activity, due a better water compatibility. Catalyticreactions were repeated up to 5 times, showing a slight decrease in activity from onerun to another.Besides a loss of activity compared to homogeneous catalysts, the major drawback

of these reusable catalytic systems remains the characterization of the active or pre-catalyst complexes. Basically, the only analysis performed on such systems to date isinductively coupled plasma-atomic emission spectroscopy (ICP-AES) to calculatethe loading of immobilized palladium. Therefore, the exact structure of the complexcannot, at this point, be confirmed.

4. Ruthenium–NHC complexes

NHC-containing ruthenium chemistry has culminated with the development ofsecond-generation metathesis catalysts allowing for higher complex stability andconsequently broadening the olefin metathesis reaction scope.49 As a result,

Fig. 5



ruthenium–NHC complexes have gained attention in other catalytic reactions, suchas hydrogenation and isomerisation.Independently, Ledoux and Blechert reported the synthesis of new ruthenium

alkylidene-containing unsymmetrical NHC ligands (Fig. 6, 33, 34, 38 and 39,Blechert;50 33, 35–37, Ledoux).51 The activity displayed by these pre-catalysts indi!erent metathesis reactions was found to be lower than or similar to those of theirsymmetrical counterparts. Of particular interest, complexes 33 and 38 gave sig-nificantly di!erent E:Z ratios in cross metathesis reactions. Inexplicably, investiga-tion of the activity of 33 by both groups for ring-closing metathesis (RCM) led todivergent results: whereas Blechert observed a similar activity to that of Grubbs’second-generation catalyst, Ledoux reported a significant reactivity enhancement.Four-membered NHC ligands are considered a laboratory curiosity, but never-

theless Grubbs has reported the synthesis of a ruthenium olefin metathesis catalystbearing a four-membered NHC 40.52 Catalytic studies on the ring-opening poly-merization (ROMP) of cycloota-1,5-diene showed that high temperatures arerequired to promote polymerization catalyzed by 40.The tuning of the NHC skeleton provides a promising opportunity to obtain even

more active 14-electron methylidene species. Grubbs recently introduced onto theruthenium center a fluorinated NHC.53 Starting form the imidazolium salt 41,reaction with silver oxide and then transmetalation furnished complex 42. Thephosphine-free analogue 43 was prepared by carbene exchange with o-isopropoxy-b-methylstyrene (Scheme 12). Whereas 42 possesses a distorted square pyramidalgeometry, traditional for ruthenium metathesis complexes, the structure of 43 showsa rotation of one aromatic ring and a coordination of a fluorine atom to theruthenium center. The structural di!erence between these complexes has an influenceon their catalytic activity. Contrary to complex 43, 42 e"ciently catalysed RCMreactions, due probably to the fluorine–ruthenium interaction, which might inhibitintramolecular C–H bond activation, which is a potential decomposition pathway.

Fig. 6

Scheme 12



Subsequent to the first reported enantioselective ruthenium-catalysed ring-closingmetathesis,54 Grubbs et al. investigated several new structures of chiral NHCs.55 Thestrategy for the chiral induction is based on a transfer of stereochemistry from thechirality of the backbone to the N-substituents of the NHC. Complexes 44 and 45,possessing an isopropyl group in the ortho position were found to be extremelycompetent for the desymmetrization of trienes to form dihydrofurans (Scheme 13).Moreover, the halide ligands of the ruthenium complexes and NaI addition to thereaction mixture were both found to possess a crucial role in both activity andenantioselectivity. According to the authors, the bulkier iodide may decrease thereaction rate and as a result lead to higher enantiomeric excesses. Of note, complex45 containing sterically hindered N-substitutents did not required additives to reachhigh chiral inductions.

Recently, Arisawa and Nishida presented a convenient derivatization of thesecond generation Grubbs catalyst yielding a ruthenium hydride complex.56 Thereaction at 50 1C of a second generation Grubbs catalyst with vinyloxytrimethyl-silane led cleanly and quantitatively to the generation of ruthenium hydride 46,which was fully characterized (Scheme 14). Complex 46 showed high catalyticactivity for isomerisation or cycloisomerisation as a function of the reactionconditions. Protected N-allyl-o-vinilaniline 47 was isomerised at moderate tempera-ture to form the disubstituted olefin 48, but when the reaction was carried out at hightemperature, cycloisomerisation yielding the 2,3-dihydroindole 49 was observed with

Scheme 13

Scheme 14



a good selectivity in favor of the exocyclic double bond. These reactions were foundto have good tolerance toward the protecting groups used and aniline substitution.Ruthenium complexes are also well known for their ability to add or remove

hydrogen from organic substrates by either direct or transfer hydrogenationprocesses, and this is a valuable synthetic tool. Nevertheless only a few NHC–Rucomplexes have been shown to be excellent catalysts for hydrogen transfer reactionsfrom alcohols to ketones. Recently, new catalytic systems have been developed, forexample the in situ generated catalyst from [Ru(cod)(methylallyl)2], imidazolium saltand iPrONa,57 complex 50,58 and the arene–rutheniun complexes 51–53.59 Interest-ing performances in catalysis have been observed, in particular with 50, whichrequired only 0.05 mol% of catalyst to complete the reaction. However, thermalactivation (80–100 1C) was necessary. Williams investigated the activity of ruthe-nium hydride complex 54 at a lower temperature (50 1C) and, remarkably, expandedthe scope to transfer hydrogenation between alcohols and ketenes, and alcohols andimines60 (Fig. 7).

5. Nickel–NHC complexes

Due to their ability to promote reactions generally di"cult with other group 10 metals,Ni chemistry plays an important role in the field of catalysis. Since the introduction ofNHC ligands, the number of Ni-catalysed reactions has increased considerably. Thereplacement of traditional phosphine or amine ligands with electron-rich NHCs hassignificantly enhanced the catalytic activity of these complexes.The Ni–NHC complexes are usually generated in situ from a source of nickel,

typically Ni(cod)2 or Ni(acac)2, and the free carbene or the imidazolium salt in thepresence of base. Recently, Jamison reported the enantioselective and regioselectivecoupling of allenes, aldehydes, and silanes (Scheme 15).61 This three-componentreaction is e"ciently promoted by Ni complexes for a wide range of allenes andaldehydes. Interestingly, the nature of the ligand (NHC or phosphine) on the metal

Fig. 7

Scheme 15



center was found to be crucial in defining the catalytic activity. Whereas tricyclo-pentylphosphine was found to be the optimal ligand for aliphatic aldehydes, IPr gaveexcellent results with aromatic aldehydes. In spite of the fact that a large amount ofnickel is used to perform these reactions, for this study, a few di!erent hinderedphosphines were investigated and only IPr as NHC ligand was examined. Similarreaction was reported by Montgomery and co-workers using alkynes instead ofallenes as starting material.62 The reaction scope was expanded to a-silyloxyalde-hydes leading after deprotection to allyl-anti-1,2-diols with excellent yield anddiastereoselectivity.In addition of C–C bond formation, Ni–NHC complexes were found to be

competent in cycloaddition reactions of alkynes and isocyanates63 or diynes andnitriles.64 For the cycloaddition of alkynes and isocyanates, when untethered alkynespossessing a large substituent were employed, coupling of two isocyanates and analkyne a!orded pyrimidine-diones (Scheme 16). The in situ Ni-catalysed cycloaddi-tion of diynes and nitriles was found to be a convenient method for preparingfunctionalized pyridines. The catalyst system is generated from commercially avail-able precursors, Ni(acac)2, imidazolium salts, and n-BuLi, and exhibited a goodtolerance towards steric hindrance and functional groups.

These catalytic applications have led to the development of well-defined NHC-containing Ni-based catalysts. The straightforward reaction of NHC "HCl withnickelocene allowed for the clean formation of [CpNi(NHC)Cl] 55.65 The activity ofthese complexes have been investigated in the dehalogenation of aryl halide and thearyl amination reactions. Whereas the dehalogenation of p-bromotoluene gavemoderate results, low to good conversions depending upon the substrates used wereobtained for C–N bond formation between aryl bromide or bromide and morpho-line. Complexes of type 55 have been also used to perform the selective transfer of asingle arylthio group in the catalytic hydrothiolation of alkynes.66 The addition ofthiophenol to 1-heptyne was carried out with a high regioselectivity and goodisolated yield (Fig. 8).

Scheme 16

Fig. 8



The catalytic activity of 56–58 has been studied for cross-coupling reactions, andwas poorer than for bis-NHC complexes. To isolate acceptable yields of product fora nickel-catalysed Suzuki–Miyaura reaction, complex 56 was cooked to 150 1C forseveral days.67 Furthermore, the comparison of the activity between 57 and 58 in theKumada-Tamao-Corriu cross-coupling reaction demonstrated unambiguously thesuperiority in catalysis of mono-NHC species.68

6. Iridium– and rhodium–NHC complexes

Since iridium and rhodium are known to promote e"ciently numerous catalyticreactions (hydrogenation, hydrosilylation, hydroformylation, hydroamination, C–Hactivation, 1,2-addition, cycloaddition), Ir– and Rh–NHC complexes have beenextensively investigated. A simple way to evaluate the basicity of NHC ligands is tocompare the IR stretching frequency of carbon monoxide ligands in the correspond-ing [(NHC)M(CO)n] complexes (M = Ir or Rh).69 The frequency of the CO-stretchis representative of the back donation from the metal center. A very basic NHCligand should result in a relatively low wavenumber value induced by a strongs-donation of the NHC to the metal and little p-back donation from the metal centerto the NHC ligand.Interesting investigations have been carried out on the development of chiral

NHC ligands for asymmetric hydrogenation and hydrosilylation reactions, princi-pally focused on bidentate NHCs (Fig. 9). Complex 59 bearing a thiazole archi-tecture has displayed a chiral induction of up to 90% ee for the hydrogenation oftri-substituted alkenes.70 Compared to other NHC–Ir or –Rh complexes, a highpressure of hydrogen (50 bar) was found optimal for the reaction, which seems incontradiction with activity enhancement due to the NHCs. Chiral NHC-oxazolineligands possessing a remarkable potential particularly for hydrogenation andhydrosilylation,71 has led Pfalz to examine several structures of iridium-basedcomplexes containing these ligands.72 The modular syntheses of the oxazoline-imidazolium salts developed allowed for the construction of two libraries of chiralNHC precursors. The series of complexes was tested in the asymmetric hydrogena-tion of unfunctionalized and functionalized olefins. Of note, complexes 60 and 61showed a comparable activity and exhibited similar enantioselectivity (up to 90%).This study has pointed out once again the crucial aspect for chiral induction of therequired steric hindrance of the NHC N-subtituents.The chiral induction strategy employed by Faller is based on the di!erent concept

of a monodentate NHC in which the chiral centers are situated on the backbone ofthe imidazole ring.73 This type of chiral NHC was proven e"cient for thedesymmetrization of trienes, however, the evaluation of the performances incatalysis of 62 in hydrosilylation of acetophenone showed poor to moderate resultsin both activity and enantioselectivity (up to 58%). This report highlights thedi"culty in transposing e"cient chiral ligands from one metal-catalysed reactionto another.

Fig. 9



As an alternative to Ru-based catalysis, the Oppenauer-type oxidation can beperformed with iridium complexes such as 63.74 Conveniently, this NHC complexbearing an amine-functionalized Cp* ligand did not required additional base in thereaction mixture for selective oxidation of alcohols. Moreover, for the catalyticsystem 63/AgOTf, the reaction scope has been expanded to acid-sensitive alcohols.Despite the myriad of transformations utilizing NHC–metal complexes, there are

relatively few examples of their use in carbocyclization reactions. Evans reported thediastereoselectively rhodium catalysed [4 + 2 + 2] carbocyclization of 1,6-enynesleading to bicyclic cycloocta-1,4-dienes.75 Besides the high diastereoselectivity of thereaction, the simplicity of the catalytic system is remarkable, the air- and moisture-stable [(IMes)RhCl(cod)] in the presence of silver triflate and 1,3-butadiene allowingfor good isolated yields. Similar systems with di!erent phosphines (mono- andbidentates) were also examined but led to more modest success. A similar catalyticsystem using [(IPr)RhCl(cod)] was applied successfully to intramolecular andintermolecular [4 + 2] and [5 + 2] cycloaddition reactions of, respectively, dienynesand diene and dienophile.76 Having a broad scope and good reactivity, thesereactions represent a viable access route to various middle and large carbocycles(Fig. 10).Murakami reported a remarkable and intriguing example of preferential activa-

tion of a cyclobutanone C–C bond over an aldehyde C–H bond catalysed byRh-complexes.77 As shown in Scheme 17, the decarbonylation reaction of keto-aldehydes occurred selectively on the ketone or aldehyde depending upon thecatalyst used. NHC-containing complex 64 led to the extrusion of CO from thecyclobutanone moiety, but the employment of a stoichiometric amount of Wilkinsoncatalyst led cleanly to the decarbonylation of the aldehyde. These results indicatethat, with a NHC-containing catalyst, C–C bond insertion is favored, whereas C–Hbond activation is known to be preferential for phosphine systems.

Since C–H activation is gaining a renewed interest in organometallic chemistry,rhodium and iridium have been widely investigated to this end. The bis-NHC

Fig. 10

Scheme 17



iridium(I) complex 65, showed significant catalytic performance in the directborylation of arenes.78 This is in accordance with previous observations thatcomplexes with strong donor ligands provide good catalytic activities in thisreaction.79 Due to its high selectivity, this first example for the application ofNHC complexes in the catalytic activation and functionalization of aromatic C–Hbonds is promising.Peris et al. have obtained catalysts such as 66 that have been tested in the

deuteriation of a wide range of organic molecules, using CD3OD as deuteriumsource, providing high activities under relatively mild conditions.80 The performanceof 66 has been compared to the phosphine analogue [IrCp*Cl2(PMe3)], showing thatIr–NHC complexes displayed significantly better performance in terms of conver-sion, range of applicability, and catalyst stability.

7. Copper–NHC complexes

The first report of a NHC–copper complex was the synthesis of bis-cationic complexprepared from a triflate salt and two equivalents of free carbene.81 Later, mono-NHC copper(I) complexes were synthesized by alkylation of thiazoyl or imidazolyl-cuprates.82 For a long time, NHC-containing copper complexes were mainly usedfor the hydrosilylation of carbonyl compounds83 and for the conjugate addition ofdialkylzinc reagents,84 including the asymmetric version.85 Recently, these copper-based complexes were employed to catalyse numerous reactions such as [3 + 2]cycloaddition, tandem reductive aldol reaction, cyclopropanation, or olefination.The reaction of azides and alkynes yielding 1,2,3-triazoles is the most common

Huisgen 1,3-dipolar cycloaddition.86 With the recent progress in the use of copper(I)as an e"cient and regiospecific catalyst,87 it has become the best ‘‘click’’ reaction,88

with a wide scope of applications. Nolan and co-workers reported that[(NHC)CuBr] complexes are extremely competent to perform this cycloadditionfrom previously isolated or in situ generated azides (Scheme 18).89 The best catalystsystem, using SIMes as the NHC ligand, has shown good tolerance towards variousfunctional groups and conveniently the reactions were carried out in water orwithout solvent in neat substrate. Furthermore, an internal alkyne was successfullyused for the first time in this copper-catalysed [3 + 2] cycloaddition. DFTcalculations have shown that the mechanistic pathway of the reaction depends uponthe alkyne substitution.

A version of the [(NHC)CuX] (X = halide) system was developed for thereductive aldol reaction in order to avoid basic activation and generate thecatalytically active copper hydride species. Complex 67 bearing an IMes anddibenzoylmethanoate ligand was evaluated for the three-component tandem reduc-tive aldol reaction (Scheme 19).90 Use of 67 has allowed a control of the directreduction of the electrophile and has broadened the reaction scope to include

Scheme 18



aldehydes or ketones as electrophiles. A moderate syn/anti ratio is observed for thiscatalytic system.Diazocompounds are well known to be a carbene source for carbene transfer

reactions such as cyclopropanation or methylenation.91 Phosphorus-containingligands could not be employed for this chemistry due to their ability to form ylidederivatives, and particular attention was therefore focused on the use of NHCs.Gawley reported that [(IPr)CuCl] catalysed the diastereoselective cyclopropanationof stannyldiazoacetate esters with styrene or vinyl ethers (Scheme 20).92 In spite ofthe drastic reaction conditions in terms of stability of the carbene, moderate to goodyields were obtained with an excellent control of the diastereoselectivity. Also,[(IPr)CuCl] has displayed good activity for the methylenation of various ketonesusing trimethylsilyldiazomethane as a carbene source.93 The catalyst loading of5 mol% has been decreased to 0.5 mol% for large scale reaction and some alkeneshave been obtained in good yields from unactivated ketones.

The proposal that an NHC ligand could provide an accelerating e!ect due tostrong s-donation led Woodward and co-workers to use these ligands instead ofphosphorus-based donor.84 This work employed SIMes, generated in situ, for theconjugate addition of diethylzinc to various enones with the observation of a strongligand accelerating e!ect. Since then, studies have been carried out to developenantioselective catalytic systems and more recently using the higher reactivity ofCu–NHC complexes to generate all-carbon quaternary chiral centers, which wasfound impossible with classical chiral ligands. Hoveyda reported the asymmetricconjugate addition of alkyl- and arylzinc reagents to unactivated b-substituted cyclicenones using silver complex 68.94 The corresponding Cu(II)–NHC complexes havedisplayed both lower activity and lower enantiomeric excesses. The authors haveproposed that the slow reduction of Cu(II) to the active species Cu(I) was responsiblefor this di!erence. Chiral inductions of up to 97% ee have been reached and thecatalytic system was tolerant to various zinc reagents. It is noteworthy that, for thesame reaction, Mauduit and Alexakis have employed other alkylating reagentsnamely Grignard reagents.95 Whereas the imidazolium salts of type 69 yielded

Scheme 19

Scheme 20



moderate enantioselectivity, the use of alkoxy-containing imidazolium salts 70 asNHC precursors allowed for ee’s of 96%. Due to the easy accessibility of Grignardreagents, this catalytic system is very promising. It is of note that, 68 has also beenapplied to the copper-free catalytic asymmetric allylic alkylation of g-chloro-a,b-unsaturated esters with alkyl-based Grignard reagents.96 This direct activation ofalkylmagnesium halides with chiral NHCs was promoted by 68 and, more e"ciently,the corresponding imidazolinium salt, leading to b,g-unsaturated esters with up to97% ee and excellent selectivity in the case of the salt. The catalytic enantioselectiveaddition may be initiated by a NHC–Mg species, for which the formation of O–Mgbond would be responsible for the selectivity. Moreover, the energetically unfavor-able carbene transfer for Ag to Mg could explain the better performances observedwith the imidazolinium salt.As an alternative to formation of a C–C bonds, Cu–NHC-catalysed conjugate

addition has been studied for the formation of C–N and C–O bonds.97 Complexes[(IPr)CuZ] (Z = NHPh, OEt or OPh) were found to be highly active for N–H andN–O addition to electron-deficient olefins (Fig. 11).

8. Silver– and gold–NHC complexes

Regardless of their ease of synthesis and the numerous examples of NHC-containingsilver complexes, they have been scarcely investigated in catalysis.98 Their applica-tions are mainly related to the NHC ligand transmetalation reaction from silver toother late-transition metals. Nonetheless, a combination of IPr and AgOTf has beenapplied with success to the hydrosilylation of aldehydes.99 A good chemoselectivityin reduction was observed for both aromatic and aliphatic aldehydes. Ag–NHCcomplexes have also been tested for the ring-opening polymerization of L-lactides.Both cationic 71100 and neutral 72101 complexes were found to be active at elevatedtemperatures under solvent-free conditions to give polylactide of low to moderatemolecular weight distribution. The gold-based complex 73 also catalyses the bulkyring-polymerization of L-lactides with comparable performance to 72 (Fig. 12).Homogenous gold catalysis is currently undergoing impressive advances, gener-

ally using well-defined or non-phosphine-containing complexes. The synthesis ofNHC–Au catalysts by numerous routes is straightforward.102 However, the use ofsuch complexes in catalysis remains scarce. Comparative theoretical studies havebeen carried out showing that the NHC ligands bind AuCl significantly morestrongly than phosphine congeners, and their use may therefore lead to improved

Fig. 11



or di!erent reaction profiles in catalysis.103 Platinum- or gold-catalyzed cycloisome-risation of the 1,5-enyne bearing a propargylic acetate 74 led until recentlyexclusively to the formation of bicyclo compounds 75 and 76 in various ratiosdepending of the catalyst and reaction conditions (Scheme 21). When this reactionwas performed with well-defined cationic complex [(IPr)Au(NCMe)PF6], formationof 75 and 76, was observed but also the unprecedented bicyclo[3.1.0]hexene 77 as amajor product.104 When re-examination of the gold-catalyzed cycloisomerisation of1,5-enynes with phosphines as ligand was performed, only 12% of 77 was isolated.Moreover, a parent catalytic system made of [(NHC)AuCl] and AgBF4 e"cientlycatalysed tamdem [3,3]-rearrangement-intramolecular hydroarylation of aryl pro-pargyl acetates to yield cleanly and quantitatively substituted indenes.105 In additionto the apparent superiority of the NHC–Au complexes over the phosphine con-geners, the reaction scope for this transformation was found to be tolerant to diversesubstitutions of the aromatic ring.

In gold catalysis, attention is mainly focused on the activation of C–C triple bondsand allenes, but Widenhoefer reported the hydroamination of unactivated alkenes inpresence of [(IPr)AuCl] and AgOTf to form the corresponding nitrogen heterocyclesin excellent yield (Scheme 22).106 Of note, the catalyst was highly active for theselective exo-hydroamination of ureas, and, when the substrate led the formation ofdiastereoisomers, a moderate to good selectivity was observed.

9. Platinum–NHC complexes

Hydrosilylation of alkenes and alkynes is a highly atom-economical and e"cientprocess allowing for the formation of silicon derivatives that are gaining importance

Scheme 21

Fig. 12

Scheme 22



in synthesis as surrogates for their boron and tin counterparts. Whereas this reactioncan be performed in numerous ways,107 the use of transition metal complexes andspecifically platinum was found to be most e"cient.108 Subsequent to a firstcommunication on a new class of NHC–platinum(0) complexes which e"cientlycatalysed the hydrosilylation of alkenes,109 Marko and co-workers reported thestraightforward synthesis of benzimidazolylidene-containing platinum(0) complexes(Scheme 23).110 The in situ deprotonation of the corresponding benzimidazoliumsalts using tBuOK in the presence of Karstedt’s catalyst 78 yielded 79.

The activity of these carbene–platinum complexes was investigated for the modelreaction of hydrosilylation of 1-octene by silane using a low catalyst loading (5 #10$3 mol%) (Scheme 24). The N-substituents of the benzimidazole ring influencedsignificantly the rate of the reaction, the n-butyl group allowing for the highestactivity. Notably, the catalytic activity displayed by 79 was superior to the parentimidazolylidene NHC-containing complexes.111

Using the parent imidazolylidene complexes, the hydrosilylation of alkynes hasalso been examined.112 The di"culty in hydrosilylating alkynes is inherent in theregioselectivity of the addition: three regioisomers could be formed, the a, the b-(E)and the b-(Z). Their distribution is always related to the metal, the ligand, and thealkynes, as well as the silane used. In spite of extensive studies only a few catalyticsystems produce e"ciently one single regioisomer. For the hydrosilylation of1-octyne by bis(trimethylsilyloxy)methylsilane (Scheme 25), several NHC–Pt(dvtms)complexes (dvtms = divinyltetramethyldisiloxane) were evaluated and the sterichindrance of the NHC was found to be critical to both activity and regioselectivity.As an example, SIPr-containing complex 80 catalysed the addition in 3 h with a ratioa/b-(E) of 10, whereas the IAd equivalent led to a ratio of 2.3 after 55 h of reaction.

Scheme 23

Scheme 24

Scheme 25



Other NHC–Platinum complexes reported by Chung et al. were employed for thereductive cyclization of diynes and enynes.113 Following the synthetic approach of[Pd(Z3-allyl(NHC)Cl] developed by Nolan19a,f involving the simple cleavage of adimeric metal complex such as [Pt(Z3-allylCl]2, a small number of NHC–platinumcomplexes were synthesized in moderate to good yields (Scheme 26). Compound 82,the precursor to a cationic species, was prepared from 81 using SnCl2 in dichloro-methane. 81 was employed for the reductive cyclization of diyne leading to theformation in moderate to good yields of 2,5-dihydrofuran, 2,5-dihydropyrrole, orcyclopentene derivatives (Scheme 27). For this rare four-hydrogen addition to diyneand cyclization, the presence of SnCl2 is crucial; use of a silver salt such as AgPF6

yielded only a small amount of final product.

10. Organocatalysis

Generally known as excellent ligands for metal-based catalysis, there is also anincreasing interest in the role of nucleophilic carbenes as promoters in organocata-lysis. These transformations include the benzoin condensation, Stetter reaction,transformations involving homoenolate, transesterification reactions, 1,2-additions,and ring-opening polymerization. For those reactions, triazolydidenes, thiazolydi-denes and even imidazolylidene are e"cient, and a wide array of NHCs includingchiral versions is now available. An excellent review highlighting the recent progressof NHC in organocatalysis has appeared in the literature,8d and therefore we reporthere only the latest and major advances.The discovery that the cyanosilylation of carbonyl compounds leading to silylated

cyanohydrin could be catalysed by nucleophilic carbenes114 led Kondo and Aoyamato explore the cyanation of ketimines (Scheme 28).115 This Strecker reaction wase"ciently catalysed by IMes "HCl in presence of sub-stoichiometric amounts oftBuOK, and furthermore the scope was expanded to aliphatic substituents of

Scheme 26

Scheme 27

Scheme 28



ketimines and showed higher reactivity. As for the reaction mechanism, the authorssuggest a pathway involving activation of the carbon–silicon bond in TMSCN by thenucleophilic NHC catalyst by binding the silicon center. The resulting species(hypervalent silicate or imidazolium cyanate) allows for transfer of the cyano group.This noteworthy reaction is very promising and the development of the asymmetricversion cannot be far away.Immediately following a report dealing with the ring-opening reactions of

aziridines with aldehydes under aerobic conditions,116 the same reaction wasperformed with acid anhydride in lieu of oxidized aldehydes.117 The scope of thisregioselective reaction yielding alkylated trans-1,2-amino alcohols was investigated,and it proved compatible with a wide range of aziridine substitution; moreovervarious acid anhydrides could be used.Scheidt reported a convenient method of hydroacylation of activated ketones

catalysed by NHC generated in situ from triazolium salt 82 (Scheme 29).118 Thereducing agent was obtained by the interaction of a nucleophilic NHC species and anaromatic aldehyde. The subsequent alcohol underwent acylation with the resultingheteroazolium intermediate formed between the NHC and aldehyde. This multiplebond-forming reaction accommodated aromatic aldehydes and various electron-deficient ketones.

The extension of the benzoin condensation to Michael acceptors, namely theStetter reaction, has been extensively examined with chiral triazolydidenes orthiazolydidenes as catalysts with excellent results. Tomioka reported that C2

symmetrical chiral NHCs 83 are equally competent in the cyclization of o-formyla,b-unsaturated compounds.119 A significant e!ect of the counter anion probablydue to the salt solubility was observed and could be compensated for by anappropriate choice of base. Moderate to good enantioselectivity was obtained,remarkably at 100 1C (up to 80%), and could be improved by using dissymmetricalN-substituents analogous to complexes 44 and 45 (Fig. 13).According to the well-established mechanism of benzoin condensation proposed

by Breslow,120 nucleophilic carbenes react with carbonyl units of aldehydes which

Scheme 29

Fig. 13



are converted into nucleophilic species of the hydroxy-enamine-type. A range ofelectrophilic reagents could react with the key intermediates in an intermolecular orintramolecular fashion. As shown in the Scheme 30, the nucleophilic substitutionreaction of a suitable leaving group allowed for the construction of benzopyronesand benzofuranones.121 This reaction, catalysed by the thiazolium iodide 84 in thepresence of DBU and occurring at high temperature, was found to be dependentupon the steric hindrance of the substrate. When R1 was a phenyl group, thecyclization process was accompanied by isomerisation, leading to the formation ofbenzofuran.

An emerging aspect of NHC-catalysed reactions is their use to generate homo-enolates from a,b-unsaturated aldehydes which are utilized as key intermediates innew reactions. Recently, Nair reported the [8 + 3] annelation of tropone via theenolate generated from cinnamaldehyde in presence of IMesHCl and tBuOK(Scheme 31).122 This reaction, leading to a bicyclic d-lactone moiety present in avariety of natural products, tolerates di!erent substitution in the cinnamaldehyde.Unfortunately, no asymmetric version has been reported to date. Remarkably, Bodeand co-workers presented a new procedure to obtain chiral homoenolates and theirapplications in Diels-Alder reactions (Scheme 32).123 The NHC resulting from 85

Scheme 30

Scheme 31

Scheme 32



catalysed redox reactions of racemic a-chloroaldehydes, leading to the generation ofchiral enolates that were found suitable for highly enantioselective 1-oxodiene Diels-Alder reactions. It is of note that these reactions proceeded under mild conditions(ethyl acetate as solvent, rt and 2–8 h) using a low loading of 85. Due to the widereaction scope, numerous functionalized dihydropyranones bearing either aliphaticor aromatic substituents have been isolated in excellent yields and outstandingenantioselectivities. The use of easily available racemic a-chloroaldehydes as homo-enolate precursors will certainly lead to expansion of this chemistry into newarchitectures.

Acknowledgements

We gratefully thank the ICIQ Foundation for financial support. SPN is an ICREAResearch Professor.

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N-Heterocyclic carbenes: Advances in transition metal and organic catalysis

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