direct conversion of carbon–hydrogen into carbon–carbon ...€¦ · transition-metal catalysis...

REVIEW 4087

Direct Conversion of Carbon–Hydrogen into Carbon–Carbon Bonds by First-Row Transition-Metal CatalysisConversion of C–H Bonds into C–C Bonds Amol A. Kulkarni, Olafs Daugulis*Department of Chemistry, University of Houston, Houston, TX 77204-5003, USAFax +1(713)7432701; E-mail: [email protected] 4 August 2009; revised 21 September 2009

SYNTHESIS 2009, No. 24, pp 4087–4109xx.xx.2009Advanced online publication: 20.11.2009DOI: 10.1055/s-0029-1217131; Art ID: E25109SS© Georg Thieme Verlag Stuttgart · New York

Abstract: This review summarizes first-row transition-metal catal-ysis for the conversion of carbon–hydrogen into carbon–carbonbonds. In particular, catalysis by manganese, iron, cobalt, copper,and nickel is covered. These metals are abundant in the Earth’s crustbut so far they have been comparatively underutilized in carbon–hydrogen bond-functionalization reactions.

1 Introduction2 Manganese-Mediated C–H Bond Functionalization3 Iron-Mediated C–H Bond Functionalization 4 Cobalt-Mediated C–H Bond Functionalization4.1 Directed C–H Bond Functionalization4.2 Functionalization of the Aldehyde C–H Bond4.3 Tandem C–H Activation/Enyne-Cyclization Reactions4.4 Functionalization of sp3 C–H Bonds5 Copper-Mediated C–H Bond Functionalization6 Nickel in C–H Bond Functionalization7 Concluding Remarks

Key words: iron, cobalt, copper, manganese, nickel, C–H activa-tion

1 Introduction

Transition-metal catalysis in organic synthesis has experi-enced an exponential growth in the past few decades. Thesynthesis of new metal complexes has led to their use in adiverse array of reaction manifolds, such as cycloaddition,metathesis, and carbon–hydrogen bond-functionalizationreactions. New routes for carbon–carbon bond formationhave been provided. The interest in these classes of reac-tions has also led to mechanistic studies that have resultedin the improvement of catalyst efficiency. In some cases,novel reaction protocols have been developed based onthe fundamental understanding of the reaction mecha-nism.

The most attractive feature of the C–H activation protocolis its ability to utilize a carbon–hydrogen bond as a func-tional group. In the presence of certain directing groups,these carbon–hydrogen bonds undergo functionalizationand yield the desired cross-coupled product. This offers adirect, efficient route for the creation of carbon–carbonand carbon–heteroatom bonds (Scheme 1).

Scheme 1

This review describes the direct conversion of carbon–hydrogen bonds into carbon–carbon bonds using non-noble transition metals, in particular, manganese, iron, co-balt, copper, and nickel. Compared to their 4d and 5d an-alogues, these elements are abundantly available in theEarth’s crust. Despite the low cost associated with thesemetals coupled with their unique reactivity profiles, theyhave been comparatively underutilized. The reactions de-veloped in the last twenty or so years using these metalsare highlighted in this review with an emphasis on the pro-tocols that employ the metal complexes in catalyticamounts. The carbon–hydrogen bond functionalizationvia the intermediacy of radicals1a or carbenoid species1i,2c,e

is not included. Many aspects of carbon–hydrogen bond-activation reactions have been reviewed previously.1,2

2 Manganese-Mediated C–H Bond Functional-ization

Manganese is the twelfth most readily available elementand is present at a concentration of 950 g/ton in the Earth’scrust.3a Its 4d homologue, technetium, is not found natu-rally, and its 5d homologue, rhenium, is present at a con-centration of only 4 g/ton in the Earth’s crust.3a

Manganese catalysts have been used extensively in organ-ic synthesis.3b–d

One of the first applications of manganese in carbon–hydrogen bond activation was reported by Bruce and co-workers. The authors employed Mn(CO)5Me (2) for thedirected arene metalation reaction.4 When equimolarquantities of imine 1 and complex 2 were refluxed in lightpetroleum oil, ortho-metalated species 3 was formed(Scheme 2). An analogous ortho-metalation reaction waspreviously established by employing an azobenzene sub-strate.5 The products were found to be air-stable and couldbe purified either by recrystallization from light petro-leum or by flash column chromatography.

conventional cross-coupling reactions

R1–FG1 + R2–FG2 MLn

C–H bond-functionalization reactions

R1–FG1 +MLn

R1–R2

R2–H R1–R2

4088 A. A. Kulkarni, O. Daugulis REVIEW

Synthesis 2009, No. 24, 4087–4109 © Thieme Stuttgart · New York

Nicholson’s research group utilized the directed ortho-metalation reaction for the synthesis of ortho-deuteroace-tophenones in good yields (Scheme 3).6 The authors wereable to convert the ortho-manganated arenes into ortho-deutero compounds by treatment of 5 with ceric ammoni-um nitrate (CAN) in acetic acid-d4.

Interestingly, 5 also reacted with a variety of electro-philes, giving access to the ortho-halogenated acetophe-none derivatives, 7.6 It is noteworthy that the reactionproceeds in good yield in spite of the steric constraints im-posed by the methoxy groups (Scheme 4).

Upon reaction of ortho-deutero substrate 8 withMn(CO)5Bn, two regioisomeric products 9 and 10 wereobtained. The kinetic hydrogen isotope effect (kH/kD) wasdetermined to be 3.0. The corresponding value for the un-substituted acetophenone was found to be 3.2(Scheme 5).6

Scheme 2

NRMnNR

Mn(CO)5Me

(CO)4

+light petroleum

1 32

reflux

R = Ph 37% (2 h)R = Me 70% (5.5 h)

Scheme 3

O

MeO

MeO

OMe

O

MeO

MeO

OMe

Mn(CO)4

O

MeO

MeO

OMe

D

4 5

6

RMn(CO)5

heptane, reflux90%

CANCD3CO2D

50%

Amol A. Kulkarni ob-tained his Ph.D. from theState University of NewYork–Buffalo under thesupervision of ProfessorSteven T. Diver. During his

graduate research, he devel-oped a methylene-freeenyne metathesis protocolfor the synthesis of carbocy-clic dienes. In 2008, hejoined the Daugulis group as

a postdoctoral researchassociate. Currently, he isworking on the develop-ment of C–H bond-func-tionalization reactions.

Olafs Daugulis was born inRiga, Latvia in 1968. He ob-tained his B.S. degree inchemical engineering fromRiga Technical Universityin 1991. His Ph.D. research

was performed at theUniversity of Wisconsin–Madison in the group ofProfessor E. Vedejs. In1999, he joined the group ofProfessor M. Brookhart at

the University of NorthCarolina–Chapel Hill as apostdoctoral associate. He iscurrently an Associate Pro-fessor of Chemistry at theUniversity of Houston.

Biographical Sketches

Scheme 4

O

Mn(CO)4

OMe

OMeMeO

O

Br

OMe

OMeMeO

5 7

Br2, CCl4

quant.

Scheme 5

O

R

R

R

8

D

O

R

R

R

9

D Mn(CO)4

O

R

R

R

10

H Mn(CO)4

+BnMn(CO)5

9/10 = 3.0:1 (R = OMe)9/10 = 3.2:1 (R = H)

REVIEW Conversion of C–H Bonds into C–C Bonds 4089


Liebeskind et al. studied the regiochemistry of the ortho-manganation reaction with meta-substituted acetophe-nones (Table 1).7 For arenes possessing small electroneg-ative substituents, the chemoselective manganationafforded 12 as the major product. As the steric bulk of themeta-substituent increased, the chemoselectivity re-versed, ultimately resulting in the exclusive formation of13. Thus, steric effects are important in determining theregioselectivity of the manganation.

The authors demonstrated a powerful application of theortho-manganated arenes in the synthesis of substitutedindenol derivatives. Treatment of 14 with anhydrous tri-methylamine N-oxide (TMANO) in acetonitrile led to thedecarbonylative coupling with various alkynes, resultingin the production of the substituted indenols 15 in good toexcellent yields (Table 2). A variety of terminal, internal,electron-rich, and electron-deficient alkynes could be em-ployed in this reaction manifold, affording a general pro-tocol for indenol synthesis.

Kuninobu, Takai and co-workers have investigated the in-sertion of aldehydes into aromatic carbon–hydrogenbonds.8 Initial studies using a stoichiometric amount ofcomplex 17 led to the isolation of the desired product 18in 52% yield (Scheme 6).

Addition of triethylsilane (2.0 equiv) to the reaction mix-ture rendered the reaction catalytic in complex 17. The re-action did not proceed using the carbonyl complexes ofother metals, such as [{ReBr(CO)3(thf)}2], [Ru3(CO)12],or [Ir4(CO)12]. The reaction worked well with variouselectron-rich as well as electron-poor benzaldehyde deriv-atives, heteroaromatic and aliphatic aldehydes, furnishingthe corresponding silyl ethers in good yields (Scheme 7).

To gain insight into the mechanism, the authors per-formed a sequential transformation wherein arene deriva-

tive 16 was treated with a stoichiometric amount of 17before the addition of benzaldehyde (Scheme 8). This ledto the formation of intermediate 20. Addition of triethyl-silane at the end of the reaction resulted in the formationof the silyl ether 19.

The above reaction was also employed for the diastereo-selective synthesis of silyl ethers. When chiral imidazo-line 21 reacted with benzaldehyde under the standardreaction conditions, silyl ether 22 was obtained in goodyield and 95% de (Scheme 9). However, the use of nona-nal as the coupling partner led to a diastereomeric excessof 38%.

Table 1 Regiochemistry in the ortho-Manganation Reaction of Acetophenones

Entry X Ratio 12/13 Yield (%)

1 F 4.54:1 85

2 Cl 1.05:1 86

3 Br 1:1.44 65

4 Me 13 only 77

5 OMe 2.07:1 94

6 CF3 13 only 85

7 CN 13 only 11

O

X

O

X

Mn(CO)4

+O

Mn(CO)4

X

11 12 13

BnMn(CO)5

Table 2 Synthesis of Substituted Indenol Derivatives

Entry R1 R2 Yield (%)

1 Et Et 77

2 H c-Hex 71

3 H SiMe3 69

4 Me CO2Et 75

5 c-Hex CO2Et 55

6 OEt Et 82

7 OEt SiMe3 70

O

Mn(CO)42. R1 R2

HO

R2

R1

14 15

1. TMANO, MeCN

Scheme 6

N

NMe

+

1. toluene, 100 °C, 5 min2. PhCHO toluene, 115 C, 10 h N

NMe

OH

Ph1617

18

[MnBr(CO)5]3. TBAF, r.t., 4 h

52%

Scheme 7

N

NMe

+ Et3SiH (2.0 equiv)

16

R H

ON

NMe

19

OSiEt3

R

R = 4-MeOC6H4 87%

R = 4-F3CC6H4 87%

R = 2-MeC6H4 59%

R = n-C8H17 75%

R = c-Hex 56%

R = 2-furyl 66%

[MnBr(CO)5] (5 mol%)toluene, 115 °C, 24 h



The authors proposed that the reaction takes place via ox-idative addition of the arene carbon–hydrogen bond to themanganese(I) catalyst, leading to the manganese(III) spe-cies 24. The regiochemistry of the insertion is governedby the directing imidazole group. Insertion is followed byreaction of the aldehyde with the carbon–manganese bondleading to the formation of intermediate 25. Reaction ofthe latter with the triethylsilane results in the formation ofthe desired product along with the regeneration of the cat-alytically active manganese(I) species (Scheme 10).

The ability of manganese(I) compounds to insert into spcarbon–hydrogen bonds was explored for the synthesis ofhydantoin derivatives.9 Terminal alkynes were treatedwith two equivalents of phenyl isocyanate in the presenceof a catalytic amount of Mn(CO)5Br to give 27(Scheme 11). The research groups of Kuninobu and Takailater demonstrated a reaction involving the Mn(CO)5Br-catalyzed insertion of terminal acetylenes into b-keto es-ters affording 2-pyranone derivatives 28 (Scheme 11).10

3 Iron-Mediated C–H Bond Functionalization

Iron is the fourth most abundant element and is present ata concentration of 56300 g/ton in the Earth’s crust.3a Its 4d

homologue, ruthenium, is present at a concentration of0.001 g/ton. Osmium can be found at a concentration of0.0015 g/ton in the Earth’s crust.3a Iron plays a critical rolein various biological redox reactions and is thus necessaryfor life processes.11a–c It is nontoxic and hence is consid-ered to be environmentally benign. In spite of these attrac-tive features, only a few examples of iron-catalyzedreactions had been described in the literature until recent-ly. However, the past decade has witnessed a growing in-terest in the use of iron catalysts for a variety of organictransformations, including cross-coupling reactions, cy-cloaddition reactions, skeletal rearrangements, carbon–hydrogen bond functionalization, and alkene polymeriza-tion.11d–g Indeed, in many cases, the iron-based catalystsystems offer distinct advantages with respect to the com-plimentary reactivity profile of the late transition metalssuch as nickel and palladium. With the advent of robust,well-defined catalysts, the research in this field seems tobe progressing exponentially.

In 1978, Tolman and colleagues reported the activation ofa vinylic carbon–hydrogen bond using the coordinativelyunsaturated iron species 29 (Np = 2-naphthyl anddmpe = Me2PCH2CH2PMe2).

12 The Fe(dmpe)2 generatedin situ undergoes oxidative insertion into a variety of ole-

Scheme 8

N

NMe

+

16 1. toluene, 100 °C, 5 min2. PhCHO

O

Ph

N

NMe

[Mn]-H

HSiEt3 (1.0 equiv)toluene, 115 °C, 4 h

OSiEt3

Ph

N

NMe

19 58%

20[MnBr(CO)5]

17

toluene, 115 °C, 10 h

Scheme 9

N

NMe

+

Ph H

O

HSiEt3 (2.0 equiv) N

NMe

OSiEt3

Ph

21

22

[MnBr(CO)5] (5 mol%)toluene, 115 °C, 24 h

80%, 95% de

Scheme 10

LnMn+1

N

NMe

23

H

N

NMe

Mn+3

H

R H

O

N

NMe

O

R

Mn+3

H

N

NMe

OSiEt3

R26

2425

HSiEt3

H2

Scheme 11

R H + Ph N C OMnBr(CO)5 (5 mol%)

N

NR

O

O Ph

Ph

27

Ph HOEt

O O

+MnBr(CO)5 (5 mol%) O

O

Ph

28

dioxane, 150 °C, 24 h

neat, 80 °C, 24 h



finic carbon–hydrogen bonds to result in the formation ofiron(II) species 30 (Scheme 12).

Scheme 12

An example of carbon–hydrogen bond functionalizationusing catalytic iron was reported by Jones and co-work-ers, who employed complex 31.13 The latter was synthe-sized by the reaction of Fe(PMe3)4 with isonitriles(Scheme 13).

Scheme 13

Under the optimized reaction conditions, the insertion ofthe isonitrile into an aromatic carbon–hydrogen bond af-forded aldimine 32 with 97% conversion, albeit with only4.9 turnovers for the iron catalyst (Scheme 14). Based ontheir mechanistic studies, the authors proposed the reac-tion mechanism shown in Scheme 15.13 The reaction be-gins with the formation of the coordinatively unsaturatediron(0) species 33 via light-induced dissociation of theisonitrile ligand. Oxidative addition of 33 to the aromaticcarbon–hydrogen bond leads to the formation of iron(II)intermediate 34. Migratory insertion and subsequent re-ductive elimination results in the release of aldimine prod-uct 32 and regeneration of the catalytically active ironspecies 33.

Scheme 14

In 2005, Klein and co-workers demonstrated that when anequimolar mixture of tetrakis(trimethylphosphinyl)ironand imine 37 was warmed from –70 °C to 20 °C, the ini-tially orange mixture turned dark red, indicating forma-tion of the aryliron species 38 (Scheme 16).14

Wang and colleagues reported a coupling reaction of ter-minal alkynes, aldehydes and secondary amines.15 Theauthors proposed the intermediacy of an alkynyliron spe-cies which adds nucleophilically into the iminium iongenerated in situ via the reaction of aldehydes and second-ary amines. The transformation afforded propargylicamines 39 via a ligand-free three-component coupling re-action (Scheme 17).

Methylpropargylamines could also be synthesized fromthe reaction of dimethylanilines and terminal alkynes.16

The authors proposed the initial oxidation of the tertiaryamines with the peroxide to take place, leading to the for-

mation of an iminium ion. The latter is subsequentlyquenched by the alkynyliron species formed in situ by thereaction of terminal alkyne with iron(II) chloride(Scheme 18).

HFeNp(dmpe)2 [Fe(dmpe)2] HFe(dmpe)2R

29 30

– HNp R–H

(not isolated)

+ 3 RNC Fe(PMe3)2(CNR)3 + 2 Me3P

31

Fe(PMe3)4

RNC + N

R

Ph

H

31

32

hνPhH

Scheme 15

Fe

Fe

PMe3

PMe3RNC

RNC

H

Fe

PMe3

PMe3H

RNC NR

Fe

PMe3

PMe3RNC

RNC NR

H

H

NR

Fe

PMe3

PMe3

CNRRNC

RNC

hν– RNC

Me3P PMe3

CNR

RNC

31

33

34

35

36

32Ph-H

RNC

Scheme 16

NH NHFeHMe3P

PMe3PMe3

37

38

Fe(PMe3)4

pentane

Scheme 17

H

+ + R22NH

R1

NR22

39

FeCl3, PhMeR1CHO

4 Å MS, 120 °C

Scheme 18

R1

N

Me

Me

+

H SiEt3

FeCl2 (10 mol%)(t-BuO)2 (2 equiv)

R1

N

Me

SiEt3100 °C, 30 h, air



Simple, commercially available iron salts such as iron(III)sulfate were found to be highly effective for the direct ary-lation of unactivated arenes. Under the optimized condi-tions, Yu and co-workers observed that functionalizedarylboronic acids 40 can be coupled with benzene deriva-tives to afford biphenyls 41 in good yields.17 The scope ofthis transformation is depicted in Scheme 19.

However, with more sterically demanding arene deriva-tives, the desired products were obtained only in traceamounts. Also, the unprotected carboxylic acid (–CO2H)group was found to be incompatible with this procedure.

The ability of iron to functionalize arene carbon–hydro-gen bonds was further extended by Nakamura and col-leagues for the synthesis of carbon–carbon bonds viadirect arylation. When benzoquinoline 48 was allowed toreact with the in situ generated phenylzinc reagent in thepresence of catalytic Fe(acac)3 and phenanthroline, thearylation product was obtained in near quantitative yield(Scheme 20).18

As shown in Table 3, the combination of Fe(acac)3 (10mol%) and 1,10-phenanthroline (10 mol%) affordedquantitative conversion of the substrates into a mixture ofmono- and di-arylated compounds (entries 1–4). In gener-al, the reaction proceeded more efficiently when the phe-nyl ring undergoing arylation was electron-rich (entry 2).Other directing-group-containing arenes such as phe-nylpyrimidine (entry 7) and phenylpyrazole (entry 8) alsoyielded the arylated products. Scheme 19

+

B(OH)2

R Fe2(SO4)3⋅7 H2O (1.0 equiv)cyclen (1.0 equiv)

R

40

41

Cl

42 (73%) 43 (82%)

Br

44 (62%) 45 (62%)

MeO

O2N

46 (51%) 47 (31%)

MeO2C

K3PO4 (4.0 equiv), pyrazole (2.0 equiv)benzene, 80 °C, 48 h

Scheme 20

N

PhMgBr (6.0 equiv)ZnCl2⋅TMEDA (3 equiv)Fe(acac)3 (10 mol%)

ClCl (2 equiv)

N

Ph

4948 THF, 0 °C, r.t., 16 h

1,10-phenanthroline (10 mol%)

99%

Table 3 Iron-Catalyzed Direct Arylation

Entry Substrate Product(s)a R Time (h) Yield (%)mono + di

1234

HOMeFCO2Et

1564848

82 + 1265 + 2180 + 2077 + 13

56

PhMe

4848

6017

7 48 81 + 9

8 48 59 + 10

a R1 = H (mono), R1 = Ph (di).

substrate

PhMgBr, ZnCl2, TMEDAFe(acac)3, 1,10-phenanthroline

product

ClCl THF, 0 °C, r.t.

N

R

N

RPh

R1

N

R

N

R

Ph

N

N

N

N

Ph

R1

N

N

N

N

Ph

R1



Iron catalysts are capable of effecting chemoselective di-rect ortho-arylation of aryl imines. Similar to the aboveconditions, in situ generated phenylzinc species were usedas the arylating agents. During the ligand optimizationstudies, it was observed that di-tert-butylbipyridine(dtbpy) exhibited promising activity as compared to thepreviously established phenanthroline ligand.19 It wasnecessary to carry out the reaction at 0 °C because highertemperatures led to a loss of catalytic activity. A variety ofaromatic imines could be arylated under mild reactionconditions by employing this protocol and the couplingproducts were obtained in good yields (Scheme 21). Theimines underwent hydrolysis during the isolation and thecorresponding ketones were obtained as the final prod-ucts. Electron-poor aromatic imines afforded the productsin good yield (54 and 56). It is noteworthy that an aromat-ic triflate was tolerated in this reaction (53). Aromatic het-erocycles such as thiophene were also reactive (55), andthe reaction was well-suited for the arylation of 1-tetra-lone (57). Aromatic chlorides and bromides were well tol-erated, though the iodide functionality was reduced to thecorresponding deiodinated product.

Barton has developed conditions for the direct andchemoselective oxidation of aliphatic carbon–hydrogenbonds using iron catalysts and an oxidant.1a Related reac-tions have been studied extensively and the applicationsfor the generation of carbon–carbon bonds have been de-scribed.20–23

4 Cobalt-Mediated C–H Bond Functionaliza-tion

Cobalt is the thirtieth most abundant element and ispresent at a concentration of 25 g/ton in the Earth’scrust.3a Its 4d and 5d homologues, rhodium and iridium,are present at a concentration of 0.001 g/ton in the Earth’scrust.3a Some of the noteworthy transformations catalyzed

by cobalt include cross-couplings, multi-component cy-cloadditions, alkene polymerizations, and oxidation reac-tions.24

4.1 Directed C–H Bond Functionalization

One of the first examples of directed carbon–hydrogenbond-functionalization reactions was reported byMurahashi in 1955. The treatment of a benzene solution ofSchiff base 58 with catalytic dicobalt octacarbonyl at hightemperature and pressure led to the isolation of phthalim-idine 59 in good yield (Scheme 22).25 The reaction did notwork with nickel catalysts or in the presence of protic sol-vents such as water or alcohol.

Scheme 22

It was later shown that azobenzene (60) could undergo asimilar cyclization to furnish indazolinone 61 (Scheme23).26 In 1993, Klein et al. demonstrated the formation ofarylcobalt species 63 in the reaction of azobenzene with62 (Scheme 23). Compound 63 was isolated in good yieldas red crystals.27 Pyridine can also serve as a directinggroup for the metalation reaction. In the case of 2-vinylpy-ridine (64), the activation of the vinylic carbon–hydrogenbond was achieved using 62 to furnish the metalabicycle65 (Scheme 23).28

Analogous ortho-metalation has also been reported for anaryl phosphine directing group. In this case, the reactionof the dioxolane-containing phosphine 66 with 62 fur-nished the aryl C–H activation product 67 (Scheme 24).29

Cobalt-mediated cyclometalation of various other sub-strates has been reported.30

Scheme 21

R2

NR1

R3

+ZnCl2⋅TMEDA (3.0 equiv)

+PhMgBr (6.0 equiv)

Fe(acac)3 (10 mol%)ligand (10 mol%)

THF, 0 °C, 20 h

ClCl R2

NR1

R3

Ph

Et

O

Ph

50 (99%)

Me

O

Ph

51 (92%)

ClMe

O

Ph

52 (88%)Br

Me

O

Ph

53 (89%)

TfO

Me

O

Ph

54 (90%)

F3CS

Ph

O

55 (96%)

Me

O

Ph

56 (57%)

NC

OPh

57 (93%)

N

Co2(CO)8CO (100–200 atm)

N

O

58 59

220–230 °C, 5–6 h80%



4.2 Functionalization of the Aldehyde C–H Bond

In 1997, Lenges and Brookhart reported the hydroacyla-tion of vinylsilane 68 using cobalt catalyst 69, which bearsbulky and highly labile vinyltrimethylsilane ligands(Scheme 25).31a The reaction led to the synthesis of aro-matic ketones 70 in good yield. This was the first exampleof the use of cobalt catalysis for intermolecular hydroacy-lation via the activation of an aldehyde carbon–hydrogenbond. Previously, more expensive rhodium catalysis wasutilized for such reactions.31b The catalyst showed goodturnover frequency and the transformation could be per-formed under relatively mild reaction conditions.

Subsequent studies showed that aliphatic aldehydes bear-ing various substitution patterns could be employed as thecoupling partners and the products were obtained in highyields using 69 as the catalyst (2.5 mol%) (Figure 1).32

The unbranched (71), b-branched (72, 73 and 76), and a-branched aldehydes (74, 75) were all reactive. The proto-col was also tolerant of aldehydes with a trisubstitutedalkene moiety (76).

Depending on the nature of the cobalt(I) species and otherreaction conditions such as temperature and solvent, theinsertion into an aldehydic carbon–hydrogen bond couldsubsequently lead to the decarbonylation of the aldehyde.Thus, the reaction of cobalt(I) catalyst 62 with substitutedaromatic aldehydes 77 led to the formation of arylcobaltspecies 78 as a result of decarbonylation (Scheme 26).33

4.3 Tandem C–H Activation/Enyne Cyclization Reactions

Tandem reactions are particularly attractive in catalysisbecause structural complexity can be attained rapidly.During their studies involving the cyclization of 1,7-enyne 79, Malacria and co-workers observed that thetreatment of 79 with a stoichiometric amount of dicarbo-nylcyclopentadienyl cobalt(I) [CpCo(CO)2, 80] resultedin the formation of three products, 81–83 (Scheme 27).34

The authors proposed the intermediacy of cobalt hydridespecies 84 formed as a result of the allylic carbon–hydro-

Scheme 23

NN

Co2(CO)8CO (100–200 atm)

NH

N

O

60 61

NN

MeCo(PMe3)4 62

pentane

60 63

NN

Co(PMe3)3

N+

pentane, r.t.

– CH4, – PMe3

NCo

64 6562

MeCo(PMe3)4

(PMe3)3

220–230 °C, 5–6 h55%

91%

45%

Scheme 24

PPh

Ph

O

O

PPh

Ph

O

O

Co

66 67

62

(PMe3)3

Scheme 25

SiMe3

catalyst 69

r.t. to 55 °C

H

O

X

O

SiMe3

Co

Me5

Me3Si

SiMe3

catalyst 69

70

68

+

X

Figure 1 Hydroacylation of aliphatic aldehydes with vinyltri-methylsilane using cobalt catalyst 69 (% conversion by 1H NMR)

Me3Si

O

71 (92%)

Me3Si

O

72 (99%)

Me3Si

O

73 (97%)

Me3Si

O

75 (94%)

Me3Si

O

76 (98%)

Me3Si

O

74 (99%)

Scheme 26

R1

R2

H

O

62

THF, –70 °C+

R1

R2

Co

Me3PPMe3

PMe3

CO

77 78

MeCo(PMe3)4– CH4, – PMe3



gen bond activation. Intramolecular cyclization leads tothe formation of the cobalt hydride intermediate 85. Re-ductive elimination affords diene product 81 and cobaltcomplex 82, and allylic isomerization of the intermediate85 leads to the formation of cyclopentadiene-containingproduct 83 via the cobalt hydride intermediate 87.

To test the possibility of synthesizing six-membered-ringsystems using this protocol, the authors employed 1,8-enyne 88 for the cascade cyclization. However, the reac-tion furnished a mixture of the three diene products 89–91, each bearing a five-membered ring (Scheme 28).Mechanistically, this reaction proceeds via an isomeriza-tion/cyclization pathway similar to that outlined inScheme 27.34

Dolaine and Gleason reported the thermolysis of 1,6-enyne 92 using stoichiometric dicobalt octacarbonyl un-der an atmosphere of argon, that led to the formation ofcyclopentene 93 and the isomerized enyne 94 (Scheme29).35 Bubbling of argon through the reaction mixture ledto the isolation of only 93. The formal 5-endo-dig cycliza-

tion leading to 93 was postulated to proceed via an allylicC–H oxidative addition (Scheme 30).

The complexation of dicobalt octacarbonyl with thealkyne moiety in 92 leads to the formation of 95. Loss ofcarbon monoxide followed by complexation of the pen-dant alkene produces intermediate 96. Allylic C–H activa-tion then affords cobalt hydride species 97. The latterundergoes an intramolecular cyclization and forms cobal-tabicycle 99. Decomplexation affords the product 93. Al-ternatively, cobalt hydride 97 could undergo allylicisomerization leading to intermediate 100. Decomplex-ation of the metal from 100 leads to the formation of theisomerized product 94.

Later, Ajamian and Gleason expanded the substrate scopeof this reaction by using allyl propargyl ethers. Under op-timized conditions, ether 101, derived from cyclohexanecarboxaldehyde, yielded the desired 2,5-dihydrofuranproduct as the only diastereomer (Scheme 31).36 The reac-tion gave modest yields in the absence of an additive, butpremixing of the cobalt catalyst with tert-butyl hydroper-oxide (TBHP) as oxidant led to a substantial increase inthe yield of product 102. The reaction could be performedin an iterative fashion, thus producing bis-THF units ofgeneral structure 103 with excellent diastereoselectivity.36

Because of the excellent diastereoselectivity and func-tional-group tolerance observed in these reactions, theabove two protocols are particularly attractive for the syn-

Scheme 27

E

E

SiMe3

CpCo(CO)2 80

allylic C–H activation

H

MeO2C

MeO2C

SiMe3

Co HCp

Me3Si

cyclization

C–H activationCo

Cp

H

E

E

CpCo(CO)2

Me3Si

E

E+

Me3Si

E

ECoCp

reductiveelimination

81 82

85

79

84

+

Me3Si

CpCo

H

E

E

86

Et

E

E

87

SiMe3CoH

Cp

Et

E

E

SiMe3

83

CoCphν

Scheme 28

MeO2C

MeO2C

SiMe3CpCo(CO)2

E

E

SiMe3

CoCp

E

E

SiMe3

CoCp+ +E

E

SiMe3

88

89 90 91

Scheme 29

TBSO

TMSCo2(CO)8

heat, Ar

TMS

OTBS TBSO

TMS+

9293 94



thesis of cyclopentene and dihydrofuran units. However,the requirement of stoichiometric cobalt limits the practi-

cality of this procedure. The transformation could be ren-dered catalytic in metal by the addition of trimethylphosphite to the reaction mixture (Scheme 32).37 Underthese conditions, the protected propargylic alcohol 104 aswell as the propargyl allyl ether 101 furnished the corre-sponding products in good yield.

An interesting process was employed by Li and Jones to-wards the synthesis of quinolines from diallylanilines106.38 Here, the treatment of diallylanilines with catalyticdicobalt octacarbonyl under one atmosphere of carbonmonoxide led to the isolation of quinoline derivatives 107in good yield (Scheme 33).

The reaction tolerated electron-donating substituents onthe aromatic ring, but the presence of electron-withdraw-ing substituents led to poor or no conversion. Based ontheir isotope labeling studies, the authors proposed the in-termediacy of species 108 (Figure 2) formed as a result ofC–H activation.

Figure 2

Scheme 30

TBSO

TMSTBSO

CoCo(CO)3

TMSTBSO

CoCo(CO)3

TMS

– COH

H

– CO

TBSO

CoCo(CO)3

HCO

TMSTMS

Co

TBSO

CoLnLn

OTBS

CoLn

CoLn

H

TMS

TBSO

CoCo(CO)3

TMS

H

OTBS

H

TMS

92 95 96

979899

93100

94Ln

Co2(CO)8

(CO)3 (CO)2

Scheme 31

O

TMS

1,2-DME, 85 °CO

H H

TMS

101 102

O OH

TMS

HH H

103

Co2(CO)8 (1.1 equiv)TBHP (3.3 equiv)

65%

Scheme 32

TMS

OTBSCo2(CO)8 (10 mol%)

(MeO)3P (10 mol%)

PhMe, reflux

OTBS

TMS104

105

Co2(CO)8 (10 mol%)

(MeO)3P (10 mol%)

PhMe, reflux O

TMS

101 102

O

TMS

HH

61%

52%

Scheme 33

NCo2(CO)8 (10 mol%)

CO (1 atm), THF, 95 °C

N

RR

106 107

N

Co(CO)3

Co(CO)3

Et

108



4.4 Functionalization of sp3 C–H Bonds

An example of cobalt-catalyzed functionalization of sp3

carbon–hydrogen bonds was reported by Bolig andBrookhart.39 Using cobalt catalyst 69(VTMS = vinyltrimethylsilane), the authors were able toachieve transfer dehydrogenation of the heterocyclic sub-strates 109, resulting in the formation of unsaturated prod-ucts 110 (Table 4). The reaction proved to be general fora variety of cyclic substrates and afforded the products inhigh conversion.

The cobalt-based catalyst system efficiently convertedsaturated nitrogen heterocycles into the corresponding cy-clic enamines in excellent yield. The ring size had no im-pact on the overall yield of the transformation (entry 1).Substituted piperidines gave the products bearing the di-substituted alkenes as the only detectable products (entries2 and 3). Under the reaction conditions, no isomerizationto the more highly substituted alkene was observed. Vi-nyldimethylsilyl-protected piperazine and morpholinealso underwent this transformation (entries 4 and 5) in ex-cellent yield. The authors postulated that poisoning of thecatalyst by the sulfur atom could account for the low yieldobserved in entry 6. Lastly, when there were two sitesavailable for the dehydrogenation, the reaction yielded the

exocyclic enamine as the only detectable product (entry7).

5 Copper-Mediated C–H Bond Functionaliza-tion

Copper has been known since prehistoric times and is thetwenty-sixth most abundant element. It is present at a con-centration of 60 g/ton in the Earth’s crust.3a Its 4d homo-logue, silver, is present at a concentration of 0.075 g/ton,whereas gold is present at a concentration of 0.004 g/tonin the Earth’s crust.3a Copper catalysts have been used ex-tensively for a variety of cycloaddition reactions.40a Theyhave also been employed as catalysts in other organictransformations such as nucleophilic additions and redoxreactions.40b–g

In 1941, Steinkopf et al. reported that heating a solution of2-bromothiophene with copper-bronze resulted in the iso-lation of a mixture of dithienyl (111, n = 0), trithienyl(111, n = 1), and quaterthienyl (111, n = 2) (Scheme34).41 Sease and Zechmeister reported the chromato-graphic separation of these polythienyl compounds onalumina.42

Scheme 34

Forrest observed that the use of m-dinitrobenzene as anadditive in the coupling reaction of iodobenzene resultedin formation of small amounts of 2,6-dinitrobiphenyl(112) (Scheme 35).43 Björklund and Nilsson demonstrat-ed that 2,6-dinitrophenylated arenes were formed in goodyield when m-dinitrobenzene and copper(I) oxide wereheated in quinoline with aryl iodides.44a The authors alsodocumented the arylation of 1,3,5-trinitrobenzene.44b,c

Scheme 35

Akin to the iron acetylides reported by Li et al.,15 copperacetylides can be generated in situ by the reaction of cop-per(I) salts with terminal alkynes. The latter underwentnucleophilic addition to the iminium ions and provided di-rect access to the substituted propargylic amines.45,46

Gaunt and co-workers reported a copper(II)-catalyzed ox-idative C–H bond-functionalization strategy for the selec-tive arylation of indoles at the 3-position under mildconditions (Scheme 36).47 To this end, the treatment of N-

Table 4 Cobalt-Catalyzed Transfer Dehydrogenationa

Entry Substrate Product Yield (%)b

1> 90 (n = 1)> 90 (n = 2)> 95 (n = 3)

2 > 99

3 > 95

4 > 95

5 > 99

6 13

7 > 95

a VDMS = vinyldimethylsilyl, EDMS = ethyldimethylsilyl.b By 1H NMR spectroscopy.

N

X

VDMS

(Cp*)Co(VTMS)2 69

C6H6, 80 °C, 6 h N

X

EDMS

n n

109 110

N VDMSn

N EDMSn

N VDMS N EDMS

N VDMS N EDMS

NN VDMSMe NN EDMSMe

NO VDMS NO EDMS

NS VDMS NS EDMS

NO

N

VDMS

EDMSNO

N(EDMS)2

S Br + Cu-bronze

200–210 °C15 min

S S Sn

111

NO2

NO2

+ I

NO2

NO2

112 (minor product)

Cu



methylindole with diphenyliodonium triflate using a cop-per(II) triflate catalyst resulted in the formation of thephenylated product 113 in good yield.

Scheme 36

The authors designed an unsymmetrical diaryl iodine(III)reagent containing a bulky ‘spectator’ aryl group thatwould not transfer under the reaction conditions. Use ofreagent 114 in the reaction with N-methylindole led to theformation of the desired product 113 in good yield and se-lectivity (Scheme 37).47

Scheme 37

A variety of indole derivatives can be employed as sub-strates for this arylation protocol (Table 5). It was ob-served that both N-H and N-alkyl indoles were convertedinto the corresponding products at room temperature (en-tries 1 and 2). Electron-rich (entries 3 and 4) as well aselectron-poor (entries 5–7) indole systems were arylated,although the latter required elevated temperature. Theabove results are consistent with an electrophilic metala-tion mechanism for the arylation process.

Interestingly, when N-acetylindoles were employed as thereactants, the authors observed a switch in the regioselec-tivity. The reaction afforded 116, the arylation product atthe indole 2-position (Scheme 38).

Scheme 38

Phipps and Gaunt developed conditions for the arylationof anilide derivatives leading to the formation of meta-arylation products. The treatment of anilide 117 with cat-alytic copper triflate and an iodonium salt led to the isola-tion of 118 as the only product (Scheme 39).48

Scheme 39

To rationalize the unusual chemoselectivity of the meta-arylation process, the authors proposed an anti-oxycupra-tion of substrate 117 to yield intermediate 119 (Scheme40). This dearomatizing transformation places the cop-per(III) species at the meta-position of the aryl ring. Re-aromatization via the loss of the meta proton leads to theformation of the intermediate 120. Reductive eliminationthen produces 118.

Scheme 40

Table 5 Copper-Catalyzed Arylation of Indoles

Entry R1 R2 X Temp (°C) Yield (%)a

1 Me H OTf r.t. 72

2 H H OTf r.t. 74

3 H 5-OMe BF4 r.t. 64

4 H 2-Me BF4 60 63

5 H 6-CO2Me OTf 60 85

6 H 5-CHO BF4 60 70

7 H 5-NO2 OTf 60 73

8 H 5-Br OTf 35 75

a Isolated yield.

N

Me

Cu(OTf)2 (10 mol%)dtbpy (1 equiv)

+ [Ph-I+-Ph] OTf–N

Me

Ph

(1.1 equiv)

113

CH2Cl2, r.t., 24 h

72%

N

Me

+ i-Pr

i-Pr

i-Pr

I Ph

OTfN

Me

Ph

114 113

73% (C3/C2 >20:1)

+

Cu(OTf)2 (10 mol%)

dtbpy, CH2Cl2, 35 °C

N

R1

+Cu(OTf)2 (10 mol%)

R2

N

R1

R2Ph

[Ph-I-Ph]Xdtbpy

N

R

Ac

+

Cu(OTf)2 (10 mol%)

N

R

Ac

Ph

116

115

[Ph-I-Ph]OTf

dtbpy, DCE, 60–70 °C37–83% (selectivity >6:1)

N O

t-Bu

HN O

t-Bu

H

Ph

Cu(OTf)2 (10 mol%)

117 118

Ph2IOTf (2 equiv)DCE, 70 °C

79%

N O

R

H

Cu(OTf)2

Ph2IOTf

N O

R

H

H

HCu(III)

Ph

OTf

NH

O

R

Cu(III)

OTf

Ph

NH

O

R

Ph

117

119

120

118

TfO–



A variety of ortho-substituted pivanilides underwent thistransformation affording the meta-phenylation productsexclusively (Figure 3). For the anilides that possess elec-tron-donating substituents, the reaction gave couplingproducts (121, 132) in good yield. Even in the presence ofa strong meta-directing group (–SO2Me), the reaction af-forded the phenylation product meta to the anilide func-tionality (127), albeit in low yield. A variety of electron-donating and electron-withdrawing groups were toleratedin the meta-position of the anilide. Interestingly, a hexa-substituted benzene derivative (131) could be synthesizedusing this protocol.

Figure 3 Substrate scope of meta-arylation reaction

A variety of aryl groups could be transferred regioselec-tively to the meta-position of the anilides leading to thesynthesis of functionalized biaryl compounds (Scheme41).48 This protocol is useful for the transfer of both elec-tron-rich and electron-poor aryl groups.

The selectivity can be overridden by the placement of astrong electron-donating group meta to the anilide func-tionality. In the case of 133, arylation occurred exclusive-ly at the ortho-position (Scheme 42).

Direct arylation of the aromatic heterocycles has attracteda lot of attention lately.49a Do and Daugulis reported the

arylation of acidic heterocycles such as benzoxazole. Us-ing catalytic copper(I) iodide and various aromatic io-dides, benzoxazole was efficiently arylated at the 2-position (Scheme 43).49b

Both electron-donating (136–138) as well as electron-withdrawing (135) aryl iodides could be employed as thecoupling partners. The reaction was tolerant of substantialsteric hindrance (137 and 138). Heteroaryl iodides werealso shown to be good coupling partners (140). An aryla-

HN t-Bu

O

Ph

MeO

121 (93%)

HN t-Bu

O

Ph

F

122 (55%)

HN t-Bu

O

Ph

123 (67%)

HN t-Bu

O

Ph

124 (65%)

Br

HN t-Bu

O

Ph

125 (62%)

HN t-Bu

O

Ph

126 (31%)

HN t-Bu

O

Ph

MeO2S

127 (11%)

HN t-Bu

O

Ph

128 (66%)

HN t-Bu

O

Ph

129 (83%)

HN t-Bu

O

Ph

130 (81%)

HN t-Bu

O

Ph

131 (44%)

Ph

132 (77%)

F EtO2C

Ph Ph

Ph

N

t-Bu

O

Scheme 41

NH

O

t-Bu

Cu(OTf)2 (10 mol%)DCE, 70 °C, 24–48 h

Mes I Ar OTf

NH

O

t-Bu

R

R = 4-Me 82%R = 4-I 49%R = 4-CO2Et 82%R = 4-NO2 60%R = 3-CF3 70%R = 3-Br 72%R = 2-Me 44%

+ –

Scheme 42

NH

O

t-Bu

MeODCE, 50 °C, 22 h

NH

O

t-Bu

MeO

Ph

133 134

Cu(OTf)2 (10 mol%)Ph2IOTf (1.5 equiv)

76%

Scheme 43

O

N CuI (10 mol%)

O

NAr

O

N

135 (91%)

CF3

O

N

136 (80%)

OMe

O

N

137 (91%)

O

N

138 (55%)

O

N

139 (90%)

O

N

140 (89%)

N

ArI, DMF, LiOt-Bu140 °C, 10 min



tion of benzoxazoles using aryl iodides and a copper(I) io-dide/triphenylphosphine-based system has been reportedby Miura and colleagues.49c

Other acidic heterocycles were also reactive (Table 6).49b

Phenylation of oxazole (entry 1) produced the monoary-lated product in 59% yield along with 7% of the diarylatedproduct. Thiazole was diarylated in good yield (entry 2).4,5-Dimethylthiazole, benzimidazole and caffeine under-went monoarylation in good yield (entries 3–5). Interest-ingly, electron-deficient 2-phenylpyridine oxide wasarylated in the 6-position in 66% yield. In most of theseexamples, the use of lithium tert-butoxide as base afford-ed the best yields.

In order to gain an insight into the possible mechanism forthis transformation, the authors performed the arylation of4,5-dimethylthiazole using potassium tert-butoxide asbase and iodobenzene-d5. Tetradeutero compound 142was isolated with a single hydrogen introduced at theortho-position of the phenyl group (Scheme 44).

The formation of product 142 strongly indicates that thereaction proceeds via a copper-assisted benzyne-typemechanism when potassium tert-butoxide base is em-ployed. When lithium tert-butoxide was used as a base in-stead, the hydrogen incorporation was not observed(Scheme 45). The involvement of the benzyne intermedi-ate is unlikely in this case. Also, no H–D exchange wasobserved when 143 was subjected to the reaction condi-tions.

Scheme 45

Piguel and co-workers reported that stereoselective directalkenylation of 5-aryloxazoles could be achieved usingcatalytic copper(I) iodide and trans-N,N¢-dimethylcyclo-hexane-1,2-diamine (145) as ligand (Scheme 46).49d Doand Daugulis demonstrated that polyfluorobenzenes canbe arylated when the proper combination of base, solvent,and copper catalyst is used. Upon optimization of the re-action conditions, the authors observed that pentafluo-robenzene underwent arylation in good yields when a 1:1mixture of N,N-dimethylformamide and xylene was usedas a solvent along with phenanthroline as ligand and po-tassium phosphate as base. In this protocol, aryl bromidescould be used as coupling partners. The substrate scope ofthis reaction with respect to aryl bromides is depicted inScheme 47.50a

Scheme 46

Both electron-rich (147–149) as well as electron-poor(151–153) bromobenzene derivatives were effective ascoupling partners. Steric constraints posed by the methylsubstituent in 148 did not affect the yield of this transfor-mation. Other aryl halides such as naphthyl (150), pyridyl(154, 155), and thienyl (156) could be employed. Bro-mostyrene (157) and benzyl bromide (158) were alsocompetent coupling partners. Other polyfluorobenzenessuch as tetrafluorobenzenes, 1,3,5-trifluorobenzene, and1,3-difluorobenzene were also reactive.

Table 6 Copper-Catalyzed Arylation of Heterocycles

Entry Heterocycle Product Yield (%)

1 59

2 59

3 84

4 89

5 78

6 66

heterocycleCuI (10 mol%)

phenylatedproductPhI, DMF

LiOt-Bu or KOt-Bu140 °C, 10–20 min

N

O

N

O Ph

N

S

N

S PhPh

N

S

N

S Ph

N

N

Me

N

N

Me

Ph

N

N

N

N

Me

MeMe

O

O

N

N

N

N

Me

MeMe

O

O

Ph

N

O

Ph N

O

PhPh

Scheme 44

N

S

N

S

H D

D

DD

141142

DMF

KOt-Bu, CuIC6D5Br or C6D5I

N

S LiOt-Bu, CuI

C6D5I, DMF N

S

D D

D

DD

141143

O

N

R CuI (10 mol%)ligand 145 (20 mol%)

MeHN

MeHN

BrR

+ O

N

R

R

ligand 145

144

146

LiOt-Bu (2.1 equiv)dioxane, 100 °C, 4 h

33–83%



The Daugulis research group further optimized conditionsfor the arylation of electron-rich heterocycles. It is note-worthy that previous attempts to arylate these compounds

relied upon expensive palladium catalysts. The scope ofthe arylation reaction of the electron-rich heterocycles isdepicted in Table 7.51 For the most acidic heterocyclessuch as benzothiazole, it was possible to employ potassi-um phosphate as base (entry 1). Less acidic substratessuch as N-methyl-1,2,4-triazole were arylated when lithi-um tert-butoxide was employed (entry 2). For the leastacidic substrates, sterically hindered Et3COLi base wasrequired (entries 3–5). When 2-iodotoluene was used as acoupling partner, ortho-tolylated thiophene was formedexclusively (entry 6). The lack of formation of an isomericmixture strongly suggests that a benzyne mechanism isnot operative under the reaction conditions.

Gratifyingly, these conditions were also successful in thearylation of electron-poor heterocycles (Table 8). Thus,pyridine N-oxide was arylated at the 2-position using 2-io-dopyridine (entry 1). A para-substituted iodide and 1-io-donaphthalene were excellent coupling partners (entries 2and 3). Other heterocycles such as pyridazine (entry 4)and pyrimidine afforded the cross-coupled products inreasonable yields.

Copper catalysis has also been successfully employed forthe arylation of electron-poor arenes. The cross-coupledproducts were obtained in good to excellent yield(Table 9). For example, pentafluorobenzene reacted withvinyl bromide (entry 1) and activated aryl chloride (entry3). Tetrafluorobenzene derivatives (entries 2, 4) and tetra-chlorobenzene underwent functionalization smoothly(entry 5). Other arenes bearing relatively acidic protons(entry 6) were also arylated.

Scheme 47

F

FF

F F

H

CuI (10 mol%)phenanthroline

F

FF

F F

R

C6F5

147 (91%)

C6F5

148 (87%)

C6F5

149 (88%)

OMe

C6F5

150 (68%)

C6F5 CF3

151 (88%)

C6F5 CO2Et

153 (90%)

N

155 (86%)

C6F5

SC6F5

156 (92%)

C6F5Ph

157 (89%)E/Z = 6.4:1

C6F5 Ph

158 (31%)

C6F5 F

152 (92%)

N

154 (90%)

C6F5

RBr, DMF–xyleneK3PO4, 120–140 °C

Table 7 Copper-Catalyzed Arylation of Electron-Rich Heterocycles

Entry Heterocycle Aryl halide Base Product Yield (%)

1 K3PO4 89

2 PhI t-BuOLi 88

3 PhI Et3COLi 87

4 PhI Et3COLi 52

5 PhI Et3COLi 86

6 t-BuOLi 89

heterocycleCuI (10 mol%), phenanthroline

Ar–X, solvent, base, 100–125 °C, 5–12 hproduct

N

S

N Br N

S

N

N

N

N

Me

N

N

N

Me

Ph

S

Cl

S

Cl

Ph Ph

NN

Ph

NN

Ph

Ph

S SPh

SClI

SCl



Table 8 Copper-Catalyzed Arylation of Electron-Poor Heterocycles

Entry Heterocycle Aryl halide Base Product Yield (%)

1 K3PO4 41

2 t-BuOLi 80

3 t-BuOLi 91

4 PhI Et3COLi 60

5 PhI Et3COLi 31

heterocycleCuI (10 mol%), phenanthroline

Ar–X, solvent, base, 120–125 °C, 1–12 hproduct

N

ON I

N

O N

N

O

Ph

I

CF3

N

O

Ph

CF3

N

O

PhI

N

O

Ph

NN

NN

Ph

N

N

N

N

Ph

Table 9 Copper-Catalyzed Cross-Coupling of Electron-Poor Arenes

Entry Arene Aryl halide Base Product Yield (%)

1 C6F5H K3PO4 81

2 K3PO4 52

3 C6F5H K3PO4 85

4 K3PO4 95

5 t-BuOLi 74

arene + R–I or R–BrCuI (10 mol%)

productphenanthroline (10 mol%)

base, 120–150 °C, 12–24 h

Br C6F5

F

F

F

F

Br

Ph

O Ph

O

F

F

F

F

N Cl N C6F5

F

F

F

FBr

F

F

F

F

Cl

Cl

Cl

Cl I

Cl

Cl

Cl

Cl



Yoshida and co-workers synthesized meso-disubstitutedanthracenes bearing pentafluorobenzene moieties(Scheme 48).50b Arylboronic acids can also be used ascoupling partners for direct arylation reactions. Itami re-ported the cross-coupling of an electron-rich arene 161with various arylboronic acids using stoichiometric cop-per(II) salts affording arylated product 162 (Scheme 48).52

Scheme 48

A stoichiometric amount of copper(II) acetate promotedthe oxidative dimerization of 2-phenylpyridine deriva-tives, affording the homodimers 164 regardless of theelectronic nature of the substituents on the phenyl ring(Scheme 49).53 Ackermann et al. reported direct arylationof triazoles using copper(I) iodide (Scheme 49).54a Theproducts were obtained in good to excellent yields regard-less of the electronic nature of the aryl iodide. The authorsfurther expanded this protocol for the synthesis of fullysubstituted triazoles via a one-pot click-chemistry/copper-catalyzed-arylation procedure.54a Bergman and Ellmanhave reported a method for the direct arylation of benzo-triazepines by employing an aryl iodide coupling partner,copper iodide catalyst, and lithium tert-butoxide base.54b

6 Nickel in C–H Bond Functionalization

Nickel is the twenty-third most abundant element and ispresent at a concentration of 84 g/ton in the Earth’scrust.3a Its 4d homologue, palladium, is present at a con-centration of 0.015 g/ton. Platinum is present at a concen-tration of 0.005 g/ton in the Earth’s crust.3a In organic

synthesis, nickel catalysts have been employed extensive-ly in a wide array of reactions such as cycloaddition andcycloisomerization, carbonylation/decarbonylation andalkene polymerization.55

In 1964, Kleinman and Dubeck reported a nickel-mediat-ed aromatic C–H activation.56 The authors observed thatheating a mixture of dicyclopentadienylnickel with excessazobenzene at high temperature resulted in the formationof the purple-blue organonickel species 167 (Scheme 50).

Scheme 50

Hiyama and colleagues reported the addition of pyridineN-oxides across various alkynes using nickel catalysis.57a

The reaction was not successful with pyridines, even at el-evated temperatures. The addition was highly chemose-lective and occurred exclusively at the 2-position of thepyridine oxides. The scope of this transformation is de-picted in Table 10.

The addition of mono- and disubstituted pyridine-N-ox-ides to symmetrical alkynes afforded the products in goodyield and excellent E/Z selectivity (entries 1–3). The esterfunctionality was well tolerated in this reaction (entry 3),

6 K3PO4 51

Table 9 Copper-Catalyzed Cross-Coupling of Electron-Poor Arenes (continued)

Entry Arene Aryl halide Base Product Yield (%)

arene + R–I or R–BrCuI (10 mol%)

productphenanthroline (10 mol%)

base, 120–150 °C, 12–24 h

NO2

CN

N

I

NO2

CN

N

Br

Br

140 °C, 24 h

C6F5

C6F5

159 160

+H

OMe

MeO

OMe

Cu(OCOCF3)2CF3CO2H, (CH2Cl)2

Ar

OMe

MeO

OMe161 162

ArBH(OH)2

C6F5H, phenanthrolineCuI, Ag2O, DMF–xylene

80 °C, 13 h, air45–68%

47%

Scheme 49

N

R

N

R N

R

Cu(OAc)2 (1.0 equiv)I2 (1.0 equiv)

MeCN, air, 130 °C, 24 h

NN

N

R2

R1

+

I

R3

Cul (10 mol%)

LiOt-Bu, DMF140 °C, 24 h

71–98%

NN

N

R2

R1

R3

163 164

165 166

N

N+Cp2Ni

N135 °C, 4 h

Ni

Cp

167

N

60

– CpH



and isoquinoline N-oxide afforded the addition product ingood yield (entry 4). The use of unsymmetrical alkynesdemonstrated remarkable regioselectivity and the prod-ucts were obtained in good yields (entry 5).

The Hiyama research group studied the alkenylation ofpentafluorobenzene using nickel catalysis (Table 11).57b

They found that, for symmetrical alkynes, the reactionproceeded smoothly and afforded the coupling products ingood yields (entries 1 and 2). For sterically biased internalalkynes, the reaction displayed excellent regiocontrol andthe products were obtained in moderate to good yields(entries 3 and 4). The chemoselectivity of the insertion(C–H over C–F bond) is particularly noteworthy.

Other polyfluoroarenes also underwent this addition. Se-lected examples are depicted in Table 12. Tetrafluoroben-zenes were shown to be good substrates for thistransformation (entries 1–5). With more equivalents of thealkyne and longer reaction times, the dialkenylated prod-ucts 169 could be obtained in good yields (entries 2–5).Substrates with smaller numbers of fluorine atoms gavelower conversion, presumably because of decreased acid-ity of the aromatic protons. The reaction was highlychemoselective for the activation of the carbon–hydrogenbonds ortho to the fluorines. The reaction was tolerant ofelectron-withdrawing and electron-donating groups onthe aromatic ring (entries 7 and 8) and was even per-formed on a difluoropyridine (entry 9). Hiyama andcolleagues later reported a similar C2-alkenylation of py-

ridines by nickel–Lewis acid cooperative catalysis. Thereaction afforded a wide array of 2-alkenylated pyridineswith high regiocontrol.57c

Recently, Itami and co-workers demonstrated the biarylcoupling of heteroarenes with aryl halides and triflates.58

The use of nickel(II) acetate as the nickel source and 2,2¢-

Table 10 Nickel-Catalyzed Addition of Pyridine N-Oxides to Alkynes

Entry Pyridine Alkyne Product Yield (E/Z)

1 67 (93:7)

2 66 (> 99:1)

3 81 (> 99:1)

4 60 (> 99:1)

5 63 (> 99:1)

N

O–

R3R2

N

O– R2

R3

R1 +

(1.5 equiv)

[Ni(cod)2] (10 mol%)

PCyp3 (10 mol%)PhMe, 35 °C, 15–40 h

++

N

O–

PrPrN

O– Pr

Pr

N

O–

PrPrN

O– Pr

Pr

N

O–

CO2Me

PrPrN

O– Pr

Pr

CO2Me

N

O–

PrPr

N

O– Pr

Pr

N

O–

t-BuN

O–

t-Bu

Table 11 Nickel-Catalyzed Alkenylation of Pentafluorobenzene

Entry R1, R2 Time (h)

Product Yield (%)

1 Pr 3 99

2 CH2SiMe3 6 75

3 Me, t-Bu 3 89

4 Me, SiMe3 13 47

FF

F

F

F

H

+ R2R1

PhMe, 80 °C

FF

F

F

F

R1 R2

H(1.5–3.0 equiv)

(Pcyp3 = tricyclopentylphosphine)

[Ni(cod)2] (10 mol%)PCyp3 (10 mol%)

Pr Pr

C6F5

C6F5

SiMe3Me3Si

t-Bu

C6F5

SiMe3

C6F5



bipyridyl (bipy) as the ligand gave the best yield. Initially,the authors employed aryl iodides and bromides for thearylations. The scope of the arylation reaction is depictedin Table 13, where it can be seen that both electron-rich aswell as electron-poor aryl iodides could be used as thecoupling partners (entries 1 and 2). The use of an aryl bro-mide instead of aryl iodide resulted in a comparable yieldof product formation (entry 1).

A variety of aryl chlorides were also shown to be goodcoupling partners (Table 14).58 The use of chlorobenzene(entry 1) as well as its electron-rich (entry 2) and electron-poor (entry 3) derivatives led to product formation in goodyield. Replacement of chlorobenzene with the corre-sponding triflate led to only a modest yield. The hetero-aryl chloride shown in entry 4 was also a good couplingpartner for this reaction.

The scope of the arylation was further expanded to usingother heterocycles (Scheme 51).58 Under the reaction con-

ditions, thiazole, oxazole, benzoxazole and N-methyl-benzimidazole could be phenylated using iodobenzene togive products 170–173 in moderate to good yield.

The synthetic utility of this transformation was highlight-ed by the use of this protocol towards a rapid synthesis ofFebuxostat, a selective, non-purine inhibitor of the en-

Table 12 Nickel-Catalyzed Alkenylation of Fluoroarenes

Entry Fluoroarene X Y Yield (%) of 168 Yield (%) of 169

1 1.0 1.5 71 < 5

23

1.02.0

4.01.0

<548

877

45

1.02.0

4.01.0

<553

997

6 2.0 1.0 35 2

7 1.0 1.5 71 <5

8 1.0 1.5 87 –

9 2.0 1.0 99 <5

fluoroarene

(x mmol)

+ Pr PrNi(cod)2 (10 mol%) X

Pr Pr

H

+X

Pr Pr

H

Pr

Pr

H(y mmol)

Fn Fn

168 169

PCyp3 (10 mol%)PhMe, 80 °C

F

FF

F

F

F

F F

F

F F

F

F

F

F

F F

CO2Me

F F

OMe

F F

N

F F

Scheme 51

Z

NH +

Ni(OAc)2 (10 mol%)bipy (10 mol%)

Z

NPh

S

NPh

170 (61%)

O

NPh

172 (53%)

O

NPh

171 (47%)

NMe

NPh

173 (41%)

Ph-ILiOt-Bu (1.5 equiv)




zyme xanthine oxidase. The nickel(II) acetate mediatedcoupling of thiazole derivative 174 and iodobenzene de-rivative 175, followed by deprotection of the tert-butylester with trifluoroacetic acid, afforded Febuxostat in 51%isolated yield (Scheme 52).

A similar direct arylation protocol via deprotonative C–Hactivation was reported by Miura and co-workers.59 Theauthors employed nickel(II) bromide–diglyme as catalystand 1,10-phenanthroline as ligand. Under the optimizedconditions, the authors were able to arylate benzothiazoleat the 2-position using various aryl bromides. The scopeof this reaction is depicted in Scheme 53.

The reaction worked well with electron-rich (177, 178 and180) as well as with electron-poor (181 and 182) bro-mobenzene derivatives. 1-Bromonaphthalene also afford-ed product 179 in good yield.

Upon application of these reaction conditions to the aryla-tion of benzoxazole, the authors observed product forma-tion in only 8% yield. The reaction conditions were re-optimized and the coupling product was obtained in goodyield using various aryl bromides (Scheme 54). The opti-mized conditions proved to be general for aryl derivativesregardless of the electronics of the aryl bromide.

Yamakawa and co-workers developed a dicyclopenta-dienylnickel–potassium tert-butoxide–triethylborane (or–triphenylphosphine) system for the direct arylation of ar-omatic nuclei of benzene, naphthalene, and pyridine.60 Inall of the cases, the arene coupling partner was used as thesolvent. The scope of the coupling reaction between ben-zene and aryl halides is shown in Table 15. Electron-rich

Table 13 Nickel-Catalyzed Arylation of 1,3-Benzothiazole with Aryl Iodides and Bromides

Entry Ar–X Yield (%)

1X = I; 90X = Br; 82

23-CF3; 754-CF3; 68

3 91

4 57

5 58

S

NH +

Ni(OAc)2 (10 mol%)bipy (10 mol%)

S

NAr

(X = I, Br)

Ar–XLiOt-Bu (1.5 equiv)


X

ICF3

I

N

I

SBr

Table 14 Nickel-Catalyzed Arylation of 1,3-Benzothiazole with Aryl Chlorides and Triflates

Entry Ar–X Yield (%)

1X = Cl; 74X = OTf; 48

2 85

3 65

4 58

S

NH +

Ni(OAc)2 (10 mol%)dppf (10 mol%)

S

NAr

(X = Cl, OTf)

Ar–XLiOt-Bu (1.5 equiv)


X

Cl

Cl F

S

Cl

Scheme 52

S

N

t-BuO

O

+

I

CN

O

174 (1.5 equiv)

175 (1.0 equiv)

S

N

HO2C

CN

O

176

2. CF3CO2H, CH2Cl251%

1. Ni(OAc)2 (10 mol%) bipy (10 mol%) LiOt-Bu (1.5 equiv) dioxane, 100 °C

Scheme 53

S

N

+

NiBr2 (10 mol%)1,10-phenanthroline (12 mol%)

S

NAr

S

N

S

N

S

N

S

NOMe

S

NF

S

NCF3

177 (67%) 178 (61%)

179 (76%) 180 (56%)

181 (60%) 182 (70%)

Ar–BrLiOt-Bu (4.0 equiv)diglyme, 150 °C, 4 h



phenyl bromides (entries 1–3) gave good yields of prod-uct. The lower yield obtained for 2-bromotoluene couldbe attributed to the steric hindrance offered by the ortho-methyl group (entry 3). An electron-deficient aryl bro-mide (entry 4) afforded the product in poor yield. Bro-mopyridines were effective coupling partners for thisreaction (entry 5). When aryl chlorides were used as cou-pling partners, however, a significant decrease in theproduct yield was observed.

Naphthalene was arylated under these reaction conditions,yielding a mixture of 1- and 2-substituted derivatives(Table 16). The ratio of isomers ranged from 2.3:1 to3.8:1.

A modified nickel catalyst system was also employed forthe direct C–H arylation of pyridine and led to the forma-tion of a mixture of 2-, 3- and 4-substituted arylated deriv-atives (Table 17).60 The formation of 3- and 4-arylpyridine suggests that the arylation does not proceedthrough ortho-metalation.

Nickel(0) has also been used for the addition of terminalalkyne carbon–hydrogen bonds to conjugated dienes andstyrenes.61 The reaction works well for a wide array of cy-clic and acyclic dienes. Recently, a nickel-based catalystsystem (NiCl2·6H2O, CuI) along with TMEDA was ap-

Scheme 54

O

N

+

NiBr2 (10 mol%)1,10-phenanthroline (12 mol%)

O

NAr

O

N

O

NOMe

O

N

183 (66%) 184 (50%)

185 (62%)

O

N

Ph

186 (60%)

O

N

187 (83%)

O

N

188 (68%)

Ar–BrLiOt-Bu (4.0 equiv)

Zn powder (0.5 equiv)o-xylene, 150 °C, 4 h

Table 15 Nickel-Catalyzed Arylation of Benzene

Entry Ar–Br Yield (%)

1 72

2 70

3 33

4 31

5 51

+

Cp2Ni (5.0 mol%)KOt-Bu (3.0 equiv)

ArAr–Br

(solvent)

Et3B (5.0 mol%)80 °C, 12 h

Br OMe

Br

Br

Br CO2Et

N

Br

Table 16 Nickel-Catalyzed Arylation of Naphthalene

Entry Ar–Br Yield (%) 189/190

1 73 2.5:1

2 44 2.3:1

3 68 3.8:1

+


Ar

+

Ar

189

190

Ar–Br

(solvent)

Et3B (5.0 mol%)80 °C, 12 h

Br OMe

Br

N

Br

Table 17 Nickel-Catalyzed Arylation of Pyridine

Entry Ar–Br Yield (%) Isomer ratio(2-/3-/4-)

1 53 48:36:16

2 70 46:43:11

3 73 48:41:11

N N

ArAr–Br+


(solvent)

Et3B (5.0 mol%)100 °C, 12 h

Br OMe

Br

Br Ph



plied for the coupling of two different terminal alkynes.62

The reaction displayed excellent cross-selectivity and wastolerant of functionalities such as free hydroxy and sec-ondary amino groups.

7 Concluding Remarks

Because of their availability, the non-noble transitionmetals are well suited for the development of catalysts forcarbon–hydrogen bond-functionalization reactions. Thesemetals have demonstrated outstanding reactivity and se-lectivity in a vast array of organic transformations. Thishas enabled the chemists to utilize the carbon–hydrogenbond as a functional group in organic synthesis. These cat-alysts are capable of activating densely functionalizedsubstrates and furnish products of high molecular com-plexity. It is likely that future investigations will result inthe discovery of many new catalytic reaction manifoldsfor the non-noble transition metals.

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direct conversion of carbon–hydrogen into carbon–carbon ...€¦ · transition-metal catalysis...

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