Cobalt-Catalyzed CâH Activation - ACS Catalysis (ACS Publications)

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Cobalt-catalyzed C-H activation Marc Moselage, Jie Li, and Lutz Ackermann ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.5b02344 • Publication Date (Web): 24 Nov 2015 Downloaded from http://pubs.acs.org on November 25, 2015

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ACS Catalysis

Cobalt-Catalyzed C–H Activation Marc Moselage,¶ Jie Li,¶ and Lutz Ackermann* Institut für Organische und Biomolekulare Chemie, Georg-August-Universität, Tammannstraße 2, 37077 Göttingen, Germany. ¶

Both authors contributed equally.

ABSTRACT: Catalytic C–H activation has emerged as a powerful tool for sustainable syntheses. In the recent years, notable success was achieved with the development of cobalt-catalyzed C–H functionalizations with either in-situ generated or singlecomponent cobalt-complexes under mild reaction conditions. Herein, recent progress in the field of organometallic cobalt-catalyzed C–H activation is reviewed until November 2015. KEYWORDS: C–H activation, cobalt, C–C formation, C–Het formation, homogenous catalysis

1. Introduction In the recent years, considerable advances have been achieved in transition-metal-catalyzed C–H functionalization, thereby characterizing this research area as an increasingly viable toolbox for selective C–C and C–X bond forming reactions.1 Thus, C–H functionalization processes can significantly simplify the synthesis of pharmaceuticals, natural products, agrochemicals, polymers and feedstock commodity chemicals.2 Until recently, the majority of catalyzed C−H functionalization was achieved employing precious second- and third-row transition metals.3 The development of catalysts based on the naturally more abundant and, hence, cost efficient 3d transition metal complexes, represents an attractive alternative.4 As a result, the use of inexpensive first row transition metal catalysts for C–C transformations has gained considerable recent momentum. In this context, rather environmentally-benign cobalt complexes bear great potential for applications in homogenous catalysis. Thus, already in 1941 Karash and Fields disclosed the cobalt-catalyzed homo-coupling of Grignard reagents.5 Based on these pioneering findings 70 years of research have turned cobalt into one of the most promising metals for future use in homogenous catalysis, with important applications among others in the hydroformylation,6 or the

Phausen-Khand reaction.7 Given the success of precious 4d and 5d transition metals with d8 or d10 electron configuration, numerous researches have recently been attracted by exploring easily accessible cobalt complexes for C–H activation chemistry. Yet, a notable challenge is constituted by the fact that the electronic properties of the 3d transition metal cobalt significantly differ from those of 4d or 5d homologues in terms of electronegativity (Figure 1) and spin orbit couplings, among others.8

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Figure 1. Electronegativities of Group 8, 9 and 10 elements according to the Pauling scale. The reduced electronegativity of cobalt as compared to the homologous group 9 elements translates into more nucleophilic organometallic cobalt intermediates which allow for unprecedented reaction pathways in transition-metal catalyzed C–H activations as well as significantly improved positional and chemo-selectivities. Herein, we summarize the progress in stoichiometric and catalytic organometallic C–H activation9 with cost-effective cobalt complexes until autumn 2015. C–H functionalizations by outer-sphere radical-type reaction manifolds are not covered herein.10 2. Stoichiometric C–H Activation As to the elementary step of C–H cobaltation, Klein and coworkers isolated the cyclometalated cobalt complex 2 by treating azobenzene (1) with [Co(CH3)(PMe3)4] (3) (Scheme 1).11 The cyclometalation process was proposed to proceed via coordination of the Lewis basic directing group with loss of

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one PMe3 ligand, along with oxidative addition of the cobalt(I) species into the C–H bond and reductive elimination of methane to give the cyclometalated species 2. In contrast, replacing the cobalt(I) complex by [Co(C2H4)(PMe3)3] did not lead to the desired cyclometalation. In subsequent studies, Klein and coworkers showed that various arenes 1–16, containing phosphorus,12,13 nitrogen,14 oxygen15 or sulfur16 donor groups also form cyclocobaltated complexes 2–17. The cyclometalation was not restricted to the formation of five-membered cobaltacycles, but the formation of six-membered complex 13 and even less favorable four-membered cobaltacycle 15 could be realized as well. When [Co(CH3)(PMe3)4] (3) was reacted with pentafluorobenzophenone (16), the site-selective cyclometallation was observed at the electron-deficient fluorinated arene, thus indicating the ortho-C–F cleavage being favored over the ortho C–H metalation.15 The formation of stoichiometrically metalated complexes was thereby well established. Despite these undisputed advances, further C–C, C–N or C–X forming functionalizations remained rare in the following years. N

N

Ph

Co(PMe3 )3 Ph F

X

O Co(PMe 3 )3

F F

R

2

Ph O

F

F

N

Ph N

Co(PMe3 )3 5,7

H

17

R F4 16

R

1

PPh 2 Ph2 P Co(PMe 3 )3

R

X = O, S

X H

R

4,6 14 H

[Co(CH3)(PMe 3)4]

H

R

15 8

Ph2 P

12

PPh2 Co(PMe3 ) 3

N Co (PMe 3) 3

9

N H

H Ph2 P 10 P(Ph) 2 Co(PMe3 )3 11

13

Scheme 1. Cyclocobaltated compounds by stochiometric C–H or C–F cleavage using [Co(CH3)(PMe3)4] (3). A notable exception was constituted by the transformation of the strained 4-membered cyclocobaltated complex 15 (Scheme 2).12 Under an atmosphere of ambient CO, insertion of CO into the C–Co bond yielded the acyl complex 18, albeit in rather low yield.

When complex 18 was further exposed to CO a cobalt carbonyl complex was formed, while the C–Co bond of the 5membered metallacycle remained intact.11 Several other manipulations of the cyclometalated complexes with, for instance, alkyl iodides or ethylene led to a variety of cobalt complexes, while the C–Co was not cleaved here.

Scheme 2. Insertion of CO into a C–Co bond.


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ACS Catalysis

3. Catalytic C–H Activation 3.1 Early Examples Murahashi elegantly unraveled a cobalt-catalyzed carbonylative cyclizations of azobenzene (1) or aldimines to indazolones 19 (Scheme 3),17,18 which in more general terms represent early examples of chelation-assisted C–H functionalization reactions. Though this cobalt-catalyzed process indicated the potential of cobalt complexes for C–H functionalizations, further applications were largely limited by the rather forcing reaction conditions, that is a reaction temperature of 190 °C at a pressure of 150 atm.

devised a ternary catalytic system consisting of CoBr2, a phosphine ligand (PMePh2) and a stoichiometric reductant (MeMgCl), which efficiently catalyzed the hydroarylation of alkynes 20 with 2-aryl pyridines 22 to yield the desired products 23 at lower catalyst loadings (Scheme 5a).20 Based on the work of Ackermann on C-2-selective C–H functionalizations on heteroarenes using a removable pyrimidyl directing group,21 the hydroarylation of alkynes 20 with indoles 24 and benzimidazoles 25 was realized by low-valent cobalt catalysis at ambient reaction temperature in a site-selective manner (Scheme 5b).22

Scheme 3. Cobalt-catalyzed carbonylative cyclization of azobenzene 1.

3.2 Addition Reactions 3.2.1 Hydroarylation Reactions The development of modern cobalt-catalyzed C–H functionalization remained somewhat dormant, until Kisch and coworkers reported, in 1994, the first cobalt-catalyzed hydroarylation of alkynes 20 using a cobalt(I) complex featuring a labile N2 ligand (Scheme 4).19 Here, the active catalyst was generated via substitution of the N2 ligand by the Lewisbasic azobenzene substrate 1. Alternatively, [CoH(H2)(PMe3)3] was also successfully employed as the pre-catalyst.

Scheme 4. Cobalt-catalyzed hydroarylation of tolane (20a). Scheme 5. Cobalt-catalyzed hydroarylation of alkynes 20. Based on Kisch’s work, the development of cobalt-catalyzed hydroarylations of alkynes and olefins gained a significant momentum during the last five years, especially through the elegant work of Yoshikai. Thus, Yoshikai and coworkers


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Imines also turned out to be powerful directing groups. The additions of aryl ketimines 28 or aldimines 29 to internal alkynes were achieved by a catalytic system comprising of CoBr2, a phosphine ligand, a Grignard reagent and pyridine.23 After acidic hydrolysis, diarylacetylenes 20 afforded the corresponding aromatic ketones 30a-d (Scheme 6a) and aldehydes 31 (Scheme 6b), while the hydrolysis of alkenylated imines 32 with alkyl substituents on the alkene led to a cyclization, furnishing benzofulvene derivatives 33 and 33’ (Scheme 6c).23,24 It is noteworthy that the hydroarylation of unsymmetrical dialkyl-substituted alkynes proceeded with synthetically useful levels of regio control.

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less hindered acetylenic site. This regioselectivity can be rationalized in terms of significant steric interactions exerted by the cobalt center within the elementary step of migratory insertion. The reason as to why stoichiometric amounts of Grignard regents are required beyond the reduction of the cobalt precursor is as of yet not fully understood.

Scheme 7. Plausible catalytic cycle for the cobaltcatalyzed hydroarylation of internal alkynes 20.

Exploiting the differences in the inherent kinetic acidities is another viable approach to perform site-selective C−H functionalizations of heteroaromatic compounds. Thus, Yoshikai and coworkers developed a cobalt-catalyzed syn-addition of (benz)oxazoles 37 and thiazoles 38 onto internal alkynes 20 via C−H functionalization with high chemo-, site- and stereo-selectivities (Scheme 8).26,27

Scheme 6. Cobalt-catalyzed hydroarylation with aryl ketimines 28 and aldimines 29.

The proposed catalytic cycle of the cobalt-catalyzed hydroarylations is initiated by an ill-defined low-valent cobalt complex, generated from the cobalt(II) precatalyst and an excess t-BuCH2MgBr (Scheme 7). Precoordination of the alkyne 20 to the active cobalt species is followed by oxidative addition of the ortho C−H bond in intermediate 34 to give the cobalt complex 35. Intramolecular hydrocobaltation of complex 35 and subsequent reductive elimination of the intermediate 36 furnish the desired product and regenerate the cobalt catalyst.23,25 In the case of unsymmertrical alkynes 20, the C–C bond formation takes predominantly place at the

Scheme 8. Additions of (a) azoles 37 or (b) thiazoles 38 to alkynes 20.


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ACS Catalysis

Notably, the hydroarylation proceeded not only with arenes, but also with olefins via vinylic C−H activation.28 Thus, dihydropyridine derivatives 41 were prepared by annulations of α,β-unsaturated imines 42 (Scheme 9). Related to similar reactions of this type by rhodium(I) catalysis,29,30 the mechanism was proposed to proceed by oxidative C–H activation/alkenylation followed by 6 -electrocyclization of the key azatriene intermediate.28

Figure 2. NHC Preligands utilized for cobalt-catalyzed C–H funtionalizations. Thus, a catalytic system consisting of CoBr2, IMesHCl (46a) as a NHC precursor and neo-pentylmagnesium bromide afforded the linear alkylated products 47 with moderate to good selectivities, as depicted in Scheme 11a.32

Scheme 9. Cobalt-catalyzed unsaturated imines 42.

annulations

with

α,β-

Based on the remarkably high efficacy of the alkyne hydroarylations, Nakamura and Yoshikai succeeded in developing analogous hydroarylations of generally more challenging alkenes 43, again using a low-valent cobalt-catalyst.31 Hence, Nakamura and coworkers reported on the hydroarylation of alkenes 43 with benzamides 44 (Scheme 10).

The selectivity also depended on the electronic features of the substrate. For example, when 4-trifluoromethylphenyl pyridine (22a) was employed, both catalytic systems delivered the branched adduct as the major product 47aa’. Also the use of 2-vinylnaphtalene (43b) significantly decreased the selectivity for the linear addition. Besides styrene derivatives 43, vinylsilanes 43c as well as alkyl-substituted alkenes 43d proved applicable for hydroarylations with linear selectivity. In the case of vinylsilanes 43c, 1,10-phenantroline turned out to be the ligand of choice for the reaction with ketimine 28e (Scheme 11b).33 The addition of N-pyrimidylindole to vinylsilane was achieved in a similar fashion (not shown). When an aliphatic olefin, such as 43d, was used, the best yield was obtained with neocuproine (2,9-dimethyl-1,10-phenantroline) as the ligand and Me3SiCH2MgCl as the stoichiometric reductant which gave the alkylated product 48ed in 68% yield (Scheme 11c).33

Scheme 10. Cobalt-catalyzed alkene hydroarylation with benzamides 44. Meanwhile, the Yoshikai group established hydroarylations of styrenes 43 giving selectively linear or branched adducts largely by the judicious choice of either a phosphine or a Nheterocyclic carbene (NHC) ligand (Figure 2), respectively.32


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(c) unactivated alkyl alkenes Cy H

N

PMP Cy +

28e

CoBr2 (5 mol %) neocuproine (10 mol %)

O H+

Me3SiCH2MgCl THF, 23 °C, 24 h 43d

48ed, 68%

Scheme 11. Hydroarylation of alkenes with linear selectivity.

In contrast to the linear-selective hydroarylation, a protocol for the preparation of branched products would arguably be more valuable in terms of stereo-selectivity. A catalytic system based on CoBr2, a phosphine ligand and Me3SiCH2MgCl allowed for the branched-selective addition of aryl pyridines as well as PMP-protected imines to styrenes 43 (Scheme 12a and 12b).25,32 The catalytic system showed a broad substrate scope with good to excellent selectivities. When exploring aldimines 29 as the substrates, a substituent at the ortho position was necessary to prevent twofold hydroarylation (Scheme 12b).25,34 Interestingly, the double functionalization did not occur with ketimines 28 displaying increased steric bulk (Scheme 12c).25,35

Scheme 12. Branched-selective hydroarylation of alkenes 43. Experiments with pentadeuterophenyl pyridine revealed a H/D exchange between the ortho-positions of the arene and the olefinic C–H bonds to take place prior to the C–C formation. A mechanism addressing these findings was proposed (Scheme 13),25 in which a reversible oxidative addition of the in situ generated cobalt catalyst into the ortho-C– H bond provides intermediate 50. Thereafter, migratory insertion of the styrene into the Co–H bond leads to either the linear 51 or the branched intermediate 51’. Finally, irreversible reductive elimination governs the regioselectivity and furnishes either the linear or branched alkylated arene.


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ACS Catalysis

Scheme 13. Proposed catalytic cycles for the branchedand linear-selective hydroarylations of styrenes 43a.

The first example of an intramolecular cobalt-catalyzed hydroarylation of alkenes via C–H activation at the C-2 position of indoles, was reported by Yoshikai and coworkers (Scheme 14).36a The reaction allowed for the direct transformation of indole derivatives 52 and 53 into dihydropyrroloindoles 54 or tetrahydropyridoindoles 55 under mild reaction conditions. Interestingly, the ring size of the formed product did not only depend on the length of the tether, but was also controlled by the steric properties of the NHC ligand. Thus, the cobalt catalyst derived from the NHC IPr promoted the regioselective cyclizations to afford tetrahydropyridoindoles 55, whereas the SIMes analog inverted the regioselectivity towards the formation of dihydropyrroloindole 54.

Scheme 14. Cyclization of indoles bearing olefin tethers (rr: regioisomeric ratio). Addition reactions with low-valent cobalt catalysts were not restricted to alkynes and alkenes.37 Indeed, aziridines 56 proved likewise applicable, yielding β-aryl amines 57 (Scheme 15a).37a The reaction displayed a broad substrate scope with excellent site- and regioselectivities in moderate to good yields. Moreover, reaction conditions were devised for powerful hydroarylations of aromatic aldimines 29 (Scheme 15b).37b

While the scope with homoallyl and bis(homoallyl) indoles was rather moderate, the study represented a proof of concept for a regiodivergent cobalt catalysis. When a methylene cyclohexenyl indole was submitted to the reaction conditions, the product 55a bearing a bicyclic [3.3.1]-moiety was isolated in 43% yield. The cyclization with homoallyl indoles delivered the six-membered ring compound as the major product 55b with just minor amounts of the seven-membered product. This observation illustrated that the regioselectivity was strongly influenced by the steric properties of the NHC ligand, while a dependence on the tether length was also of relevance. Based on the ketamine-assisted hydroarylations of alkenes, a tandem isomerization/hydroarylation sequence proved viable as well.36b

Scheme 15. Alkyation of aryl pyridines with aziridines 56 (a) and aldimines (b).


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In this context it is noteworthy that Matsunaga/Kanai and coworkers developed unusual cobalt-catalyzed remote C-4alkylations38 of pyridines with styrenes, occurring in a branched-selective fashion (Scheme 16).39

Scheme 16. Cobalt-catalyzed C-4-selective alkylation of pyridine (58). Very recently, the first enantioselective hydroaralytion of styrenes 43 with indoles 60 was disclosed by Yoshikai.40 A chiral phophoramidate ligand 61 delivered the branched alkylated products in moderate to good yields with remarkable levels of enantioselectivity (Scheme 17). Among various mono- and diphosphine ligands, the phosphoramidate 61 gave best results. Furthermore, yields and enantioselectivities strongly depended on the substitution pattern on the Nposition of the indole. While methyl, tosyl and acetyl groups gave unsatisfactory yields and low enantioselectivities (not shown), the N-Boc protected indoles 60a-c delivered optimal results. The substrate scope included a range of styrene derivatives 43 that gave the branched alkylated indoles 62 with good enantioselectivities.

Scheme 17. Enantioselective hydroarylation of alkenes 43.

3.2.2 Hydroacylation Reactions The first cobalt-catalyzed hydroacylations were developed by Vinogradov41 (Scheme 18a) and later Brookhart.42-43 The latter protocol utilized the cobalt(I) complex 63 for the intermolecular hydroacylation of vinyl silane 43e with aromatic and aliphatic aldehydes 64 (Scheme 18b).42-43 The reaction proceeded under mild reaction conditions in excellent yields with low catalyst loading.

Scheme 18. Intramolecular and intermolecular Hydroacylations. Despite the enormous potential of this catalytic system at this time, the hydroacylation was limited to vinyl silanes. Attemps to perform hydroacylations with ethylene using [Cp*Co(C2H2)2] as the catalyst did not deliver the desired ketone. In contrast, recent progress in the field of cobaltcatalyted hydroacylation was achieved recently by Dong and Yoshikai.44-46 Hence, Dong and coworkers developed hydroacylations of aromatic and aliphatic aldehyds 64 with 1,3dienes 66 (Scheme 19).44 This transformation turned out to be challenging with respect to regio- and diastereoselectivity. First, depending on the regioselectivity the hydroacylation could occur at the C-3 position of the diene, as shown by Krische47 and Ryu48 for ruthenium catalysis, as well as at the C-1 position. Second, the position of the second double bond could lead to β,γ or γ,δ unsaturated ketones. Third, in case of β,γ unsaturated systems, the configuration of the double had to be controlled. After optimizing the reactions conditions, a catalytic system consisting of the cobalt(II) complex 67 bearing a modified dppp ligand 68 and catalytic amounts of In and InBr3 to generate the catalytically active Co(I) species enabled the C-1-selective hydroacylation of aromatic aldehyds with 1,3-dienes in a highly selective 1,4-addition manner and very good Z-selectivity.44 The broad scope with different aryl aldehydes 64 and dienes 66 highlighted the synthetic utility of this catalyst. When using aliphatic aldehydes, the selectivity between β,γ, and γ,δ, unsaturated ketones significantly dropped. However, when the bis-aryl diphosphane ligand 68 was replaced by a more electrondonating bis-cyclohexyl diphosphane ligand, γ,δ unsaturated ketone 69aa’ was obtained in very good yields and high selectivity.


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ACS Catalysis

Scheme 20. Proposed catalytic cycles for the cobaltcatalyzed hydroacylation of dienes.

Scheme 19. Hydroacylation of aldehydes with 1,3-dienes. Z/E selectivity >20:1, unless otherwise noted. [a] [Co(dcpe)I2] (5.0 mol %), In (20 mol %), InBr3 (5.0 mol %), DCE/EtOAc (3:1), 50 °C, 20-24 h; dcpe = 1,2bis(dicyclohexylphosphino)ethane. As mechanistic experiments disfavor a more traditional C–H activation pathway, as earlier proposed by Kisch19 and Brookhart,41-43 it was suggested that this reaction proceeds via an oxidative cyclization of cobalt(I) species 70, yielding a -allyl complex 71, which then isomerizes either by 1,2- or 1,4-addition the five- or seven-membered cobaltacycle 72 or 72’, respectively. β-H elimination to 73 and 73’, followed by reductive elimination delivered either β,γ- or γ,δ- unsaturated ketones 69 and 69’ (Scheme 20). The proposed mechanism also provides a rationale for the observed Z-selectivity in case of a 1,4-addition, as the formation of the cobaltacycle 72 requires a cis-olefin geometry.

A recent report by Yoshikai and coworkers documented the hydroacylation of simple unactivated alkenes.46 In this work, terminal alkenes 43 were hydroacylated with benzaldimines 74 bearing a picolyl-directing49 group (Scheme 21).46 Optimization of the cobalt source, ligand, catalytic reductant and solvent revealed a system consisting of CoBr2, the ferrocenyl bisphosphine ligand dippf 75 and Zn in acetonitrile to give the optimal results. The catalytic system proved suitable for aryl and alkyl alkenes 43 and allowed for the use of a large range of substituted benzaldimines 74 with very good yields and good linear selectivity under mild reaction conditions. Limitations occurred when using aryl benzaldimines 74 bearing an ortho substituent on the arene. Likewise, further substitution on the pyridine ring led to a significant decrease in efficacy, whereas the hydroacylation with aliphatic aldehydes could not be realized.


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replacing indium by zinc or manganese, the enantioselectivities remained constant, but the yields dropped significantly. The scope was shown to include a variety of differently substituted 2-acetyl benzaldehydes (Scheme 23). A broad range of substituents on the arene 81 gave good yields of the desired products 83 with high enantio-selectivities. Furthermore, different acyl groups were well tolerated by the catalyst. Limitations were found when a substituent in the ortho position on one of the carbonyl groups was present, which shut down the reaction completely.

Scheme 21. Hydroacylation of alkenes. Linear to branched (l/b) ratio > 20:1, unless otherwise noted. The catalytic cycle of this reaction was proposed to commence by oxidative addition of the catalytically active cobalt(I) species 77 into the C–H bond of the aldimine 74 leading to intermediate 78 (Scheme 22). Migratory insertion of the olefin into the Co–H bond then occurs and leads to intermediates 79. Reductive elimination finally delivers the product 80 and regenerates the active catalyst 77. N(pic) R

1

R2 80

oxidative addition

Me N

For the enantioselective hydroacylation of 2-alkenylated benzaldehydes 82, slight changes in the catalytic system afforded enantioenriched 3-substituted indanones 84 (Scheme 24).45 Hence, CoBr2 was replaced by CoCl2, (R,R)BDPP proved to be the best chiral ligand and zinc was the reductant of choice allowing for the enantioselective hydroacylation of olefins.

74

[Co]I 77

reductive elimination

R1

Scheme 23. Enantioselective intramolecular hydroacylation of ketones 81.

Me N

N

[Co]III

R

H 79

R2

migratory insertion

1

N [Co]III H 78

43

Scheme 22. Plausible catalytic cycle for hydroacylation of olefins 43. Beyond the intermolecular hydroacylation, Yoshikai and coworkers discovered an enantio-selective intramolecular hydroacylation with a chiral diphosphine ligand which was successfully applied to 2-acetoxybenzaldehydes 81 as well as 2-vinyl benzaldehydes 82.45 Related to the work of Dong for the enantioselective intramolecular hydroacylation using a chrial rhodium diphosphine complex,50 Yoshikai’s protocol for the cobalt-catalyzed intramolecular hydroacylation included CoCl2 as the cobalt source, (R,R)-Ph-DPE as the best chiral ligand and indium as the reductant of choice.45 When

Scheme 24. Enantio-selective intramolecular hydroacylation. The alkene hydroacylation reaction proved to be rather sensitive and allowed only for a limited number of substituents on the vinyl group. The substitution pattern on the aromatic ring only tolerated the 4-fluoro group in compound 84a. Based on a kinetic isotope effect of 1.1 for the ketone hydroacylation the authors suggested the C–H activation to be facile, while the reductive elimination was proposed to be the rate determining step.


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ACS Catalysis (b) aryl sulfamates

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3.3 C–H Arylations

R

N

Until 2012, low-valent cobalt catalysis was restricted to addition reactions, namely hydroarylations and hydroacylations (vide supra). The first arylation reactions with organic electrophiles via C–H/C–O51 bond cleavage were reported by Ackermann and Song in 2012.52 The catalytic system consisting of Co(acac)2, IMesHCl as a NHC precursor and cyclohexylmagnesium chloride allowed for the arylation of aryl pyridines 22 as well as 2-pyridyl and 2-pyrimidyl indoles 24 with phenol derived aryl carbamates 85 and sulfamates 86 at rather low reaction temperatures, as compared to related arylation methods (Scheme 25).53,54 In continuation of these studies, the Ackermann group extended the scope of electrophiles to include readily accessible aryl chlorides 87.55 The catalytic system displayed a broad substrate scope to include electron-rich and electron-deficient aryl and indolyl pyridines. Double arylation was negligible and was only oberserved in trace amounts for a few substrates at elevated reaction temperatures. A remarkable feature of this reaction was the regioselectivity of the arylation with metasubstituted phenyl pyridines. For most arylation reactions, the C–H functionalization took place at the sterically less hindered position, which hence was observed for products 88da-dd, with the exception of meta-fluorophenyl56 pyridines, as shown for product 88eb.52,55 For the cobaltcatalyzed C–H arylation, challenging aryl carbamates and sulfamates were also amenable substrates. Aryl chlorides led to the substitution at the sterically more hindered position when bearing a methoxy group (88fa, 88fc, 88fe, and 88ff in Scheme 25c). This secondary directing effect overcompensated even the high steric repulsion of 2-methyl and 2’methoxy groups on the biaryl moiety of product 88ff with a relatively high yield of 76%.

N

R

Me

N

OMe

Me

R=H R = Me

(88da): 70% (88dc): 80%

Me

R = OMe: 95% R = Me: 88% R = F: 84%

88dd: 83%

(c) aryl chlorides

R

N

N

R

N

R

OMe R R = CF3: 73% R = OMe: 66%

N

R = OMe: 94% R = Me: 95% R = F: 88% N

N

R = H (88fa): 79% R = Me (88fc): 88% R = F (88fe): 77% R OMe N 2-py

Me OMe 88ff: 76%

R = OMe: 85% R = Me: 76% R = F: 66%

75%

Scheme 25. C–H arylation with aryl carbamates 85, sulfamates 86 and chlorides 87. Related to the concept of cobalt-catalyzed C–H arylation with organic electrophiles, Yoshikai and coworkers concurrently unravelled the use of synthetically useful ketimines 28 as directing groups (Scheme 26).57 Hydrolysis of the ketimines yielded the corresponding ortho-arylated ketones 90. The reaction showed ample substrate scope with moderate to good yields.

Scheme 26. Imine-directed arylation with aryl chlorides 87.


ACS Catalysis

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Further progress in this field was achieved by the Ackermann group by establishing synthetically useful amides 44 as well as tetrazoles 91 as suitable directing groups.58 The ideal system for the arylation of benzamides 44 turned out to be Co(acac)2 as the cobalt source, a slightly modified NHC precursor ICyHCl (46d) and cyclohexylmagnesium chloride (Scheme 27). This reaction displayed a broad substrate scope for benzamides 44 and aryl chlorides 87. For further product diversification these benzamides 92 could be treated with PCl5 and sodium azide to give biaryl tetrazoles 93 which are highly important motifs in drug design, such as in angiotensin-IIreceptor blockers (ARBs) Valsartan, Losartan or Candesartan.59

Scheme 28. C–H arylation of aryl tetrazoles 91 by C– H/C–O bond cleavage. Despite considerable progress, the full mechanistic details of these arylation reactions have not been elucidated. A proposed catalytic cycle starts by cylocobaltation and features a SET-type mechanism (Scheme 29), as was suggested for the cobalt-catalyzed alkylation (vide infra, see chapter 3.5). Experiments with radical scavengers provided support for this hypothesis.55

Scheme 27. (a) C–H arylation of benzamides 44, (b) synthesis of biaryl tetrazoles 93.

While the most common access to ARBs was until recently represented by palladium-catalyzed cross-coupling reactions,60 considerable progress has been made with the aid of ruthenium-catalyzed C–H bond arylation of aryl tetrazoles.59,61 The low-valent cobalt catalyst also proved to be suitable for the direct arylation of aryltetrazoles 91 with aryl carbamates 85, albeit as of yet with somewhat reduced efficiency (Scheme 28).

Scheme 29. Plausible catalytic cycle for the cobaltcatalyzed C–H arylation. 3.4 C–H Alkenylations Until very recently, alkenylated arenes were solely accessed through hydroarylation reactions of alkynes by cobalt catalysis (vide supra).19,22,23,26,27 However, this strategy inherently showed two major limitations. First, cycloalkenylated derivatives could not be prepared by this method. Second, the regioselectivity of the transformations was purely sterically controlled. Thus, internal alkynes with substituents having close steric parameters resulted in a difficult to separate mixture of regioisomeric products. To circumvent these limitations a general protocol for the direct alkenylation of alkenyl derivatives was desirable. In a


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ACS Catalysis

recent contribution, Ackermann and coworkers presented the first direct alkenylation of (hetero-)arenes with easily accessible enol esters (Scheme 30).62 CoI2, IPrHCl (46b) as a NHC precursor and the base CyMgCl gave the best results for C–H alkenylations of indoles with cyclohexenyl acetate 94a. This method could be applied to numerous indoles 24 as well as enol acetates 94. Pleasantly, 2-pyridylferrocene was successfully alkenylated as well, giving the alkenyl ferrocene 95. While the yield was rather moderate in this case, it represented the first example of cobalt-catalyzed C– H functionalization on ferrocenes.

Scheme 30. Cobalt-catalyzed alkenylation with cyclic alkenyl acetates 94 by C–H/C–O cleavage. [a] 46d (10 mol %) used at 60 °C. The behavior of acyclic enol acetates 94 was found to be equally interesting. Hence, mixtures of diastereomers exclusively yielded the alkene with E configuration in a diastereoconvergent fashion as the sole product (Scheme 31).

Scheme 32. Cobalt-catalyzed alkenylation with enol (a) phosphates 96, (b) carbamates 97, and (c) carbonates 98. A series of competition experiments between enol acetates, carbamates and phosphates illustrated that acetates and carbamates displayed close reactivities, while phosphates were inherently less reactive. This order of reactivity was unexpected, since it was not in line with the corresponding bond dissociation energies. Mechanistic investigations suggested that an isomerization process took place and that the thus formed E isomer reacted preferentially. Reactions in the presence of radical scavengers, such as TEMPO, could not exclude a radical-type mechanism. However, it was suggested that the catalytic cycle initiates with the formation of cyclocobaltated complex 99 (vide supra), followed by coordination of the enol derivative to intermediate 100 and subsequent migratory insertion. β-Elimination delivers the product and reductive elimination regenerates the active catalyst (Scheme 33).

Scheme 31. Stereo-convergent alkenylation with acyclic enol acetates 94. It should be noted that this reaction was not restricted to enol acetates, but proved also applicable to enol phosphates 96, carbamates 97 and carbonates 98 (Scheme 32). Furthermore, it is noteworthy that direct C–H alkenylations of arenes 22 with enol acetates have as of yet only be achieved by ruthenium catalysis under more drastic reaction conditions.63,64


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CoI2, IPrHCl

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N

CyMgCl

H

MgCl(OY) reductive elimination, transmetalation

[Co] Cy

C H metalation

CyMgCl

CyH

[Co] OY N

R2

N [Co]

R1 99 insertion & -elimination

N

YO

R1

OY

[Co] R2

R

1

R2

coordination

100

E/Z isomerization

Y = Ac (94), P(O)(OEt) 2(96), C(O)(NMe) 2 (97), CO2Et (98)

OY R1

R2

Scheme 33. Proposed catalytic cycle for the cobaltcatalyzed C–H alkenylation with enol esters.

3.5 C–H Alkylations Protocols for the synthesis of alkylated arenes by cobalt catalysis were until recently only viable through hydroarylations of alkenes (vide supra). However, the hydroarylation was mostly restricted to styrenes 43 and examples for branched-selective hydroarylations continue to be rare. Therefore, a general protocol for direct alkylations with organic electrophiles, such as alkyl halides, was in high demand.65 A cobalt-catalyzed ortho-alkylation using alkyl chlorides 101 was reported by the group of Nakamura.66 Here, the alkylation of benzamides 44 was accomplished with various alkyl chlorides 101 (Scheme 34). The lowvalent cobalt catalyst was generated in-situ from Co(acac)2 and cyclohexylmagnesium chloride. Interestingly, the use of a σ-donating NHC or phosphine ligand was not required. When using substrates 44a with a substituent in the metaposition, the alkylation proceeded exclusively at the sterically less hindered position (45aa–45ad in Scheme 34). Moreover, meta- or ortho-substitution was essential to avoid double alkylation (45ba). Replacing alkyl chlorides 101 by alkyl bromides led to a significant decrease in the yield. The N–H proton on the benzamide was identified as being crucial, because a reaction with a tertiary benzamide did not deliver any product. Furthermore, replacing Co(acac)2 by Co(acac)3 or CoCl2 did not significantly affect the outcome of the catalytic reaction, which suggests that these cobalt precursors were converted into a comparable catalytically active species. Interestingly, t-BuCl 101d furnished the iso-butyl alkylated benzamide 45ad. This finding can be explained by an initial β-eliminative.

Scheme 34. Direct alkylation of benzamides 44. The synthetic utility of cobalt-catalyzed C–H alkylation by ligand acceleration was independently unraveled by Ackermann and Yoshikai. The Ackermann group established a general protocol for the site- and chemoselective alkylation of aryl pyridines as well as N-pyridyl and pyrimidyl indoles with alkyl chlorides.55 Notably, the reaction did not proceed in the absence of a ligand. Among various ligands and preligands, the use of IPrHCl (46b), along with Co(acac)2 and CyMgCl, provided best results (Scheme 35). The substrate scope included several decorated aryl pyridines 22 as well as different alkyl chlorides 101. Moreover, indoles 24 with pyridiyl or pyrimidyl directing groups were site-selectively converted at the C-2 position. Alkylation at the inherently more reactive C-3 position of the indole was not observed. Note, that sterically more congested derivatives with substituents at the C-3 or C-7 position were smoothly converted to products 102b and 102ce as well. Beside primary alkyl chlorides, this method was also successfully applied to secondary alkyl chlorides, yielding 47af and 102df. Competition experiments between aryl pyridines and pyrimidyl indoles clearly showed indoles to react preferentially, likely due to the increased C–H acidity. Moreover, electron-deficient arenes, such as substrate 22a, turned out to feature a higher reactivity in this reaction compared to electron-rich derivatives, rendering a simple electrophilic C–H activation manifold less likely to be operative. Instead, the kinetic C–H acidity appears to be of key importance.


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ACS Catalysis tertiary alkyl halides were not viable. The catalytic system was not restricted to aromatic imines 28, but was also subsequently adopted to aryl pyridines.68 However, substituents on the aryl or pyridyl ring turned out to be mandatory to prevent double alkylation.

Scheme 35. C–H alkylation with alkyl chlorides 101. Beyond C–H alkylations, the Ackermann group also developed the unprecedented cobalt-catalyzed benzylation in 2012 (Scheme 36).52 Thus, indoles were selectively benzylated with phosphates 103 at ambient reaction temperature.

Scheme 36. Benzylation of indole 24d with phosphate 103a.

In addition, the Yoshikai group established direct alkylations of ketimines with primary and secondary alkyl halides 101 and 105 in independent studies.67 Here, NHC preligands 46e and 46f gave best results. The substrate scope involved primary and secondary alkyl chlorides 101 as well as alkyl bromides 105 (Scheme 37). Primary alkyl halides delivered significantly higher yields and even the steric hindrance of the neo-pentyl substituent did not interfere with the catalytic reaction, as illustrated for compound 48gg. Secondary alkyl halides were converted in moderate to good yields. Acyclic secondary alkyl halides, such as electrophile 103i, gave small amounts of isomerization products. In contrast, cycloalkyl halides furnished the desired products more efficiently. In addition to five-, six- and seven-membered electrophiles 101l, 101f and 101m, strained four-membered analog 101k could successfully be employed. However, alkylations with

Scheme 37. Direct C–H alkylation of ketimines 28 with (a) primary and (b) secondary alkyl halides. Mechanistic studies by the groups of Ackermann52,55 and Yoshikai67,69 have been performed to gain insights into the catalysts mode of action. A simple electrophilic-type C–H activation mode could be ruled out, as electron-deficient arenes reacted preferentially, which is in good agreement with a deprotonative-type C–H metalation pathway. A potential reaction mode via β-elimination and hydroarylation was also ruled out. In the presence of the radical scavenger TEMPO a significant decrease of catalytic activity was observed.55 When enantiomerically pure secondary alkyl halides were employed, a significant racemization was observed.67 Moreover, experiments with typical radical clocks provided strong support for SET-type processes. These findings strongly suggested a radical-based reaction mechanism to be operative. Based on these findings, a plausible catalytic cycle55,67 was proposed to initiate by cyclometalation of the arene yielding complex 106 (Scheme 38). The C–X bond activation is then suggested to proceed by a SET-type process to give cobalt-halide species 107 and the alkyl radical. Subsequent radical rebound generates intermediate 108, while reductive elimination and transmetalation delivers the product and regenerates the active cobalt species.


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Scheme 40. Cobalt(III)-catalyzed addition reactions with aldimines 117.

Scheme 38. Proposed catalytic cycle for the cobaltcatalyzed C–H alkylation with organic electrophiles. 3.6 Catalysis with Cp*Co(III) Complexes Until recently, cobalt-catalyzed C–H functionalization chemistry was dominated by low-valent cobalt complexes. These transformations somewhat suffered from the use of a Grignard reagent which limited the functional group tolerance. However, Brookhart’s studies on Cp*Co(I) complexes for hydroacylations indicated the unique potential of the Cp* ligand motif for cobalt-catalyzed C–H functionalizations. The development of well-defined cobalt(III) complexes70 as candidates for C–H activation reactions represented an advance in cobalt catalysis, being reminiscent of related rhodium(III) catalyses. Thus, a series of analogues Cp*Co(III) has been prepared (Scheme 39),70,71 and recently been evaluated for catalytic C–H functionalizations.

It is noteworthy that further additives, such as silver salts or σ-donating ligands were not required. Moreover, the simple cobalt salt CoCl2 did not allow for a catalytic reaction to occur (Table 1, entries 1, and 2). Probing different welldefined cobalt(III) complexes suggested the substitution pattern on the Cp-ring to be of key importance. Thus, sterically more congested complexes 109–111 also led to a decrease of catalytic efficacy (entries 3–5). Further, tetramethylcyclopentadienyl-cobalt complex 112 gave rather poor yields (entry 6). The direct comparison of the sandwich complex 113 with the cationic complex in-situ generated from neutral complex 116 and a silver salt revealed the single-component sandwich complex to be more reactive (entries 7, and 8). The substrate scope of the optimized catalyst 113 included differently decorated imines. However, a decrease in performance was noted when using electron-rich imines. Table 1. Catalytic activity of cobalt complexes.

[Co] (mol %)

t [h]

Yield [%][a]

1

CoCl2 (10)

12

0

2

CoCl2 (10) + AgPF6 (20)

12

0

3

109 (10)

20

39

4

110 (10)

20

11

5

111 (10)

20

traces

6

112 (10)

20

22

7

113 (10)

20

80[b]

8

116[c] (10) + AgPF6 (20)

20

48

Entry

[a]

Scheme 39. High-valent cobalt(III) complexes.

3.6.1 Hydroarylations The direct addition of 2-aryl pyridines to imines, and α,βunsaturated enones using the cobalt(III) complex 113 was described by Matsunaga/Kanai.72 For the addition to imines 117, best yields were obtained with complex 113 in 1,2dichloroethane as the solvent (Scheme 40).

Yield was determined by 1H-NMR spectroscopy, [b] Yield of isolated product. [c] The tetra-chloro complex was used.

In addition to aryl pyridines, biologically more attractive indoles 24 proved to be suitable starting materials, with the C–H functionalization occurring solely at the C-2 position of the heterocycle by chelation assistance (Scheme 41).73 It was also found that the addition of catalytic amounts of KOAc improved the catalysts’ performance.


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ACS Catalysis A plausible mechanism was elaborated based on related rhodium(III)-catalyzed transformations,75,76 and is depicted in Scheme 43.72 Initially, the precatalyst 113 upon heating dissociates benzene and two aryl pyridines 22 coordinate to complex 122. Afterwards, the C–H activation takes place likely via concerted metalation-deprotonation-type (CMD) mechanism74,77 or an electrophilic-type metalation to form the cyclometalated intermediate 123. Thereafter, coordination of the imine 117 occurs to generate intermediate 124. Subsequently, insertion of the imine into the Co–C bond takes place, thereby forming the seven-membered cobaltacycle 125. Coordination of another aryl pyridine 22 delivers 126 and finally proto-demetalation furnishes the product and regenerates the catalytically active species 123.

Scheme 41. Additions with 2-pyrimidyl indoles 24. The versatile cobalt(III) catalyst proved applicable to a range of imines 117 as well as differently decorated 2-pyrimidyl indoles 24. The increased reactivity of the KOAc modified catalyst could be explained by a carboxylate-assisted C–H activation mechanism74 via the in-situ formation of the cobalt acetate complex [Cp*Co(OAc)2]. The addition reaction was not restricted to imines 117 as the electrophiles. Indeed, similar observations were made for Michael acceptors including α,β-unsaturated enones and Nacylpyrroles 120, as depicted in Scheme 42.72 The catalyst featured an excellent functional group tolerance with ample substrate scope, enabling the conversion of arenes displaying bromo (22g), dimethylamino (22i) or even free hydroxyl substituents (22h). Scheme 43. Proposed catalytic cycle for the cobalt(III)catalyzed addition (L = 2-Phpy). While these studies focused on the addition onto double bonds, Matsunaga/Kanai and coworkers also devised related additions onto triple bonds. Based on rhodium-catalyzed transformations reported by the late Fagnou,78 a cobalt(III) catalyst emerged for the hydroarylation of alkynes with Ncarbamoylindoles 127, using the versatile cobalt-catalyst 113 and catalytic amounts of KOAc (Scheme 44).79 Here, both electron-donating and electron-withdrawing groups on the indole (127b and 127c) were well tolerated. As to the alkynes 20, both alkyl as well as aryl substitution patterns proved suitable, including challenging terminal alkynes 20d. Limitations were found in the case of sterically demanding alkynes and low regioselectivities were observed when using sterically close substituents on the alkyne (128af). These limitations were reminiscent of the ones observed for the low-valent cobalt catalysts (see chapter 3.2.1).22

Scheme 42. C–H functionalization by conjugate addition to Michael acceptors 120.


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Scheme 44. Cobalt(III)-catalyzed hydroarylation of alkynes. Since the electronegativity of cobalt is lower than the one reported for rhodium, the organometallic Cp*Co(III) intermediates generated by C–H activation should be more nucleophilic.79 Matsunaga/Kanai and coworkers envisioned that thereby a more electrophilic carbomyl moity would lead to nucleophilic attack and, thus, directly furnish pyrroloindolones 129 in a one pot fashion. This hypothesis was put into practice with a better leaving group, namely the morpholino carbamoyl moiety (Scheme 45). Both electrondonating and electron-withdrawing substituents on the indole were tolerated (129eg and 129fg), and most reactions delivered a single regioisomer when using unsymmetrical alkynes 20.79 While viable alkynes included bisaryl and aryl/alkyl substitution patterns, bisalkyl and terminal alkynes gave the alkenylated products 128 instead. Furthermore, the attempted synthesis of pyrroloindolone 129 from alkenylated indole 128 under otherwise identical reaction conditions failed, indicating the proto-demetalation to be irreversible in nature.

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this H/D scrambling was due to the action of a Lewis-acid. In contrast, complex 113 modified with KOAc resulted in a selective H/D scrambling at the C-2 position which provided strong evidence for a carboxylate-assisted C–H activation to be operative.74 Based on the mechanistic findings a possible catalytic cycle for the carboxylate-assisted hydroarylation/annulation sequence was put forward (Scheme 46).79 Dissociation of the benzene ligand from complex 113 as well as ligand exchange with acetate generates the neutral complex [Cp*Co(OAc)2] (130). Dissociation of an acetate anion delivers the catalytically active cationic complex [Cp*Co(OAc)]+ (131). This complex is coordinated by the carbamoyl group of the indole 127 and acetate-assisted C–H activation delivers the cyclometalated complex 132. This is followed by insertion of the alkyne into the Co–C bond which gives the sevenmembered cobaltacycle 133. Depending on the directing group, two reaction pathways are a priori possible. In case of the N,N-dimethylaminocarbamoyl group, protodemetalation delivers the alkenylated indole 128 and regenerates the active species 131. If the carbamoyl group bears a better leaving group, annulation takes place by intramolecular nucleophilic attack to provide product 134 with release of the morpholinide, giving the desired pyrroloindolone 129 and the catalytically active species 131.

Scheme 46. Cobalt(III)-catalyzed hydroarylation/annulation reaction.

Scheme 45. Pyrroloindolones 129 via C–H alkenylation/annulation. As to the reaction mechanism, experiments with isotopicallylabeled substrates showed that complex 113 catalyzed a H/Dexchange at the C-3 position of the indole. The same result was observed, when Sc(OTf)3 was used, demonstrating that

As discussed in chapter 3.6.1, Cp*Co(III)-catalyzed reactions proceeded via cyclocobaltation and addition onto the multiple bonds. These additions were until recently restricted to alkynes and conjugated double bonds. Additions to aldehydes, yielding either alcohols or further annulation products were in contrast as of yet largely achieved by rhodium80 or rhenium81 catalysis. However, in a recent report the Ellman


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ACS Catalysis

group disclosed a cobalt-catalyzed addition of C–H bonds to carbonyl compounds.82 The step-economical method involved the C–H functionalization of azobenzenes 1 as well as α,β-unsaturated oximes 135 (Scheme 47). Insertion of aromatic aldehydes and trapping of the thus formed alcohols by nucleophilic attack delivered indazoles 136 or furans 137, respectively. Best yields were achieved with the dimeric complex 116, AgB(C6F5)4 and AgOAc. On the downside, this catalytic system required two relatively costly silver salts as additives. To circumvent this problem, the Ellman group synthesized the novel cobalt complex [Cp*Co(PhH)][B(C6F5)4]2 (114) by salt metathesis from the sandwich complex 113 and KB(C6F5)4. With this precatalyst in hand, only catalytic amounts of acetic acid were required to perform the C–H cascade reaction, leading to indazoles 136 and furans 137.

It is noteworthy that the products were usually obtained in higher yields as compared to those under the rhodium(III) catalysis regime.82 To confirm the postulated cascade reaction, the independently prepared addition product 138a was submitted to the optimized reaction conditions in the presence of aldehyde 64a.82 In addition to the annulated product 136a, the cross addition product 136aa was observed, indicating the reversible nature of the C–H functionalization process (Scheme 48). N N Ph N

O Ph N + H p-Tol OH

Ph 138a

64a

114 (10 mol %) AcOH (10 mol %) 1,4-dioxane 100 °C, 24 h

Ph 136a: 45% + N N Ph p-Tol 136aa: 23%

Scheme 48. Experimental evidence for the reversibility of the C–H functionalization.

Based on these findings, a plausible catalytic cycle was put forward (Scheme 49). Dissociation of the benzene ligand delivers the active catalyst 139. Then, C–H metalation of the arene takes place by chelation assistance (140). Coordination (141) and migratory insertion form the seven-membered metallacycle 142, while protodemetalation yields the alkylated intermediate 138. Thereafter, intramolecular nucleophilic substitution and deprotonation furnish the indazole 136.

Scheme 49. Proposed mechanism of cobalt(III)-catalyzed indazole synthesis.

Scheme 47. Cobalt-catalyzed C–H activation/annulation cascade.

3.6.2 C–H Amidations The synthetic utility of the cobalt(III) catalysis was extended to amidations of arenes.83-86 In 2014, Matsunaga/Kanai reported the cobalt(III)-catalyzed amidation pyrimidyl-


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substituted indoles 24 with sulfonyl azides 143 (Scheme 50a).84 As the previously established sandwich complex 113 hardly gave any conversion, the catalytic activity of the neutral complex 115 was particularly noteworthy. The generation of the active cationic complex by the addition of a silver salt proved to be essential. With complex 115, AgSbF6 and KOAc as the optimal catalytic system, a wide range of indoles 24 and sulfonyl azides 143 could be directly functionalized with a high functional group tolerance. In a more recent contribution, Matsunaga/Kanai extended this strategy to include phosphoryl azides 144 for phosporamidation of indoles (Scheme 50b).86 Optimization studies revealed the sandwich complex 113 to be unreactive. Instead, the dimeric complex [Cp*CoI2]2 (116), modified with AgSbF6, proved to be ideal here, and furnished the products selectively. Cobalt(III)-catalyzed amidation reactions were not restricted to azides as the nitrogen source. Thus, Chang and coworkers discovered the cobalt-catalyzed amidation of aryl pyridines with most user-friendly carbamates (Scheme 50c).85 Best results were obtained with N-Boc-protected carbamate 145 using the catalytic system derived complex 115 and AgSbF6. Using their optimized reaction conditions, a variety of aryl pyridines with electron-donating or electronwithdrawing groups was successfully converted. It is noteworthy that the amidation of arenes bearing biologically valuable purine directing groups87,88 was also accomplished.

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Scheme 50. C–H Amidation of (hetero)arenes. A plausible catalytic cycle for these transformations is suggested to commence by the action of a cationic Cp*Co(III) species (Scheme 51). C–H cobaltation delivers the cyclometalated complex 149 and is proposed to proceed via a CMDtype74 mechanism or electrophilic-type metalation. After coordination of the azide or carbamate, migratory insertion takes place and the leaving group is released to form species 150. Finally, protodemetalation releases the products and regenerates the active catalyst.

Scheme 51. Proposed catalytic cycle for Cp*Co(III)catalyzed amidation.

3.6.3 C–H Cyanations Benzonitriles are key structural motifs in natural products, pharmaceuticals and agrochemicals.89 C–H cyanations were as of yet only achieved with 4d transition-metal complexes of ruthenium90 or rhodium.91 The Ackermann group reported the first Cp*Co(III)-catalyzed cyanation of (hetero-)arenes using N-cyano-N-phenyl-p-toluenesulfonamid (151) as an


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ACS Catalysis

easy to handle cyanating reagent (Scheme 52a).92 Optimization studies on the nature of the cobalt catalyst and additives revealed [Cp*Co(CO)I2] (115), AgSbF6 and KOAc to be ideal. The system proofed to be highly chemo- and regioselective. In case of meta-substituted arenes 22, the cyanation was observed to selectively take place at the sterically less hindered position, except for 3,4-difluororphenyl pyridine 22j where a secondary directing group effect was noted. The method was not limited to aryl-substituted pyridines, but also proceeded well by chelation assistance with indoles, pyrazoles and pyrroles. With the Cp*Co(III) catalyst, C-2selective cyanations of indoles 24 were achieved with excellent functional group tolerance and ample scope. Moreover, sterically congested C-3 substituted indoles 24b did not intervene with the catalytic transformation. It should be noted that the facile removal of the pyrimidyl group succeeded in a traceless fashion (Scheme 52b).

Scheme 53. C–H Cyanation of 2-pyridylpropene (155). The group of Chang established N-cyanosuccinimide (157) as an easily accessible and bench-stable electrophilic cyanating reagent.94 Optimization studies illustrated its improved performance as compared to N-cyanophthalimides. Studies directed towards the scope of aryl pyridines 22 and indoles 24 revealed substrate 157 as being slightly less active. It is particularly noteworthy that the protocol proved applicable to the cyanation of 6-arylpurines 15887,88 (Scheme 54).

Scheme 54. C–H Cyanation of 6-arylpurines 158 with Ncyanosuccinimide (157).

Scheme 52. C–H Cyanation of arenes and heteroarenes. In an independent study, the group of Glorius thereafter reported on an efficient system in which KOAc was replaced by NaOAc.93 The selectivities and yields were comparable to the Ackermann system. However, the scope was significantly expanded to include the chelation-assisted cyanation of alkenes 155 as well (Scheme 53).

To gain insights into the reaction mechanism, inter- and intramolecular competition experiments were performed and gave a KIE of 1.0-1.2,92,94 which indicated that the C–H cleavage was likely not involved in the rate-determining step. Furthermore, a Hammett-plot correlation indicated a change in the rate-determining step depending on the substitution on the arene, as reported by Ackermann and Li.92 Based on these findings a catalytic cycle (Scheme 55) involves initial reversible C–H metalation to deliver complex 149. Reversible coordination of the cyanating reagent forms intermediate 160 and migratory insertion furnishes complex 161. Finally, β-elimination and protodemetalation delivers the cyanated arene and regenerates the active catalyst.


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(b) aminocarbonylation with acyl azides

Scheme 55. Plausible catalytic cycle for the cobalt(III)catalyzed C–H cyanation. N

N

115 (5 mol %) AgNTf2 (10 mol %) AgOPiv (10 mol %)

O H

+

162

Ar

N3

165

N

N

DCE, 80 °C, 16 h

O N H

Ar

164 Ar = 4-BrC6H4: 63% Ar = 3-MeC6H4: 63% Ar = 2-FC6H4: 78%

3.6.4 C–H Aminocarbonylations Recently, the Ackermann group developed the cobalt(III)catalyzed aminocarbonylation of aryl pyrazoles 162.95 The aminocarbonylation with isocyanates 163 as the electrophiles gave optimal results with [Cp*Co(CO)I2] (115) as the precatalyst, along with AgSbF6 and AgOPiv as the additives (Scheme 56a). The reaction showed a high functional group tolerance and remarkable site-selectivity with metasubstituted arenes 162. Furthermore, isocyanates bearing electron-donating as well as electron-withdrawing groups were smoothly converted. As isocyanates are frequently generated in-situ from acyl azides by a Curtius rearrangement,96 the Ackermann group also devised a protocol for the aminocarbonylation using a broad range of acyl azides 165 (Scheme 56b).95

Scheme 56. Aminocarbonylation of aryl pyrazoles 162 with (a) isocyanates 163, and (b) acyl azides 165. For this C–H transformation, a kinetic isotopic effect (KIE) of 1.4 within inter- and intramolecular reaction was determined, indicating the C–H metalation likely not to be ratedetermining. Furthermore, competition experiments showed that electron-rich arenes 162 and electron-deficient electrophiles 163 reacted preferentially, which again provides strong support for a rate-determining nucleophilic attack. In a concurrent study the Ellman group reported the aminocarbonylation of aryl pyrazoles 162 with isocyanates 163.97 Among different cobalt complexes, the sandwich complex 113 in combination with KOAc was identified as being optimal here.

3.6.5 C–H Halogenations As cyanides can be regarded as pseudo-halides, cobalt(III) catalysts were also explored for C–H halogenations. Thus, Glorius and coworkers disclosed versatile cobalt(III)catalyzed brominations and iodinations with easily accessible N-iodosuccinimide (NIS) or N-bromophthalimide (NBP) 166, respectively, under reaction conditions being otherwise identical to those for the C–H cyanation (Scheme 57).93 Replacing the acetate base by pivalic acid furnished best results in most cases, which can be rationalized in terms of


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ACS Catalysis

an activation of the halogenation reagent by generation of a more reactive cobalt catalyst with a vacant coordination side. The method proved applicable to aryl pyridines 22, acryl amides 167, as well as N-alkylbenzamides 44a–c, giving the desired products in moderate to good yields.

O

DG H

N

+

X

O 166 X = I, Br

22, 44, 167

O

N

DG

115 (10 mol %) AgSbF 6 (20 mol %)

X

PivOH (25-50 mol %) DCE, 60-100 °C 20-48 h

H N

Br

salts AgOTf and AgOAc were mandatory. The reaction tolerated a broad range of indoles with substitution at various positions. Furthermore, allylic alcohols 175 with substitution at the 1- and 3-position turned out to be suitable substrates for C–H allylations with notable selectivities.

168, 169, 170

O R I

N(i-Pr) 2 I

R R = H: 45% R = Me: 48%

R = Me 169aa : 55% R = n-Bu 169ba : 67% R = i-Pr 169ca : 61%

170aa : 54%

Scheme 57. C–H Halogenation.

3.6.6 C–H Allylations An allyl group can easily be transferred into a plethora of useful functionalities. Therefore, C–H allylations have been intensively studied in recent years, being dominated by 4d transition-metal catalysis.98 Efforts towards cobalt-catalyzed C–H allylation have been devoted by the groups of Glorius, Ackermann and Matsunaga/Kanai.93,99-101 In a contribution by Glorius a catalytic system consisting of the complex [Cp*Co(CO)I2] (115), AgSbF6 and pivalic acid enabled the allylation of 2-pyrimidyl indoles 24 with allyl methyl carbonate (171) in a formal SN-type reaction (Scheme 58a).93 The substrate scope showed high functional group tolerance, delivering C-2-selective allylated indoles 172 in excellent yields. A remarkable feature of this catalytic system was represented by a low catalyst loading of 0.5 mol % of the cobalt complex and 1.25 mol % of the silver(I) salt additive. Furthermore, the versatility of the approach was highlighted by the allylation to benzamides 44 and acrylamides 167.99 Moreover, the allylation with 1- or 3-substituted allyl carbonates could be realized. However, 3-substituted allyl carbonates were converted in only moderate yields, as shown for 172ac. In independent studies, the Ackermann group showed that Cp*Co(III)-catalyzed C–H allylation was achieved with readily available allyl acetates (173) (Scheme 58b).100 The robustness of the user-friendly catalyst allowed for the use of a broad range of indole derivatives, being selectively allylated at the C-2 position with excellent functional group tolerance, such as amides 172fd and nitro 172gd groups. The catalytic system was not restricted to 2-pyrimidyl indoles, but enabled reactions with pyrroles 174a,b and aryl pyri(mi)dines. Very recent progress was achieved by Matsunaga/Kanai using allyl alcohols 175 (Scheme 58c).101 Minor changes in the catalytic system had to be adjusted, in that the two silver


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Scheme 59. Proposed catalytic cycle for the cobaltcatalyzed allylation.

3.6.7 C–H Alkynylations

Scheme 58. Cobalt-catalyzed allylation with (a) allyl carbonates 171, (b) allyl acetates 173 and (c) allyl alcohols 175. [a] 5 mol % of 115, 40 mol % of AgSbF6, 20 mol % of PivOH, 80 °C, 16 h. [b] 110 °C. [c] 175 (10 equiv).

Until very recently, C–H alkynylations were not viable with cobalt catalysts, but mostly required more costly 4d transition metal complexes of palladium102 or rhodium.103 In independent studies, the groups of Shi and Ackermann devised two protocols for the cobalt(III)-catalyzed C2-selective C–H alkynylation of indoles (Scheme 60).104 The reaction discovered by Shi and coworkers comprised a hypervalent iodine reagent 181, Mg(OMe)2 and a catalytic system consisting of complex 115 and AgF (Scheme 60a).104a In contrast, Ackermann and coworkers devised the C–H alkynylation with synthetically useful silylbromoalkynes employing complex 116, along with KOAc (Scheme 60b).104b It is noteworthy that the later protocol was characterized by a considerable tolerance of functional groups, such as iodo or ketone substituents, under mild reaction conditions.

Based on the previous reports on cobalt(III) catalysis, a plausible catalytic cycle is based on initial C–H cobaltation of the cationic cobalt species 131 (Scheme 59). This results in the formation of complex 149, which then undergoes coordination by the allyl alcohol derivative. Thereafter, migratory insertion of the allylic double bond into the Co-C bond yields key intermediate 180. An alternative concerted SN2’ mechanism is unlikely according to very recent DFT calculations.101 Finally, the product is released via β-oxygen elimination which is about 2.4 kcal/mol more favorable than a β-hydride elimination.


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ACS Catalysis Scheme 61. Isoquinoline synthesis from oximes 184 under cobalt(III) catalysis. [a] 15 min. [b] In HFIP.

With respect to redox-neutral C–H/N–O cleavages, cobalt(III)-catalyzed amidations were also recently accomplished with 1,4,2-dioxazol-5-ones 185 as robust amidating reagents.108,109 While the previously described amidation methods (Chapter 3.6.2) were restricted to the synthesis of phosporyl- and sulfonamides as well as carbamates,84-86 the use of heterocycles 185 allowed for the preparation of a variety of aryl as well as alkyl amides.109 The transformation exploited the power of complex [Cp*Co(MeCN)3][SbF6] (186), transforming aryl pyridines 22, alkenyl pyridines 155, as well as 6-aryl purines 158 (Scheme 62).

Scheme 60. C−H alkynylation of indoles 24. performed at 80 °C.

[a]

Reaction Scheme 62. Cobalt(III)-catalyzed amidation with dioxazolone 185a. [a] 186 (2.5 mol %).

3.6.8 Isohypsic C–H/N–O Functionalizations Very recently the cobalt-catalyzed synthesis of isoquinolines 183 from oximes 184 was independently discovered by Ackermann,105 Sundaraju,106 and Matsunaga/Kanai107 (Scheme 61). These catalytic systems are based on related cobalt(III) precatalyst 115, NaOAc and AbSbF6.105 The isohypsic, i.e. redox-neutral, reaction provided access to a wide range of isoquinolines 183 with high regio-selectivities.105

3.7 Oxidative C–H Functionalizations & Annulations Since Daugulis initially devised directing groups based on 8aminoquinoline (Q) for the palladium-catalyzed functionalization of C−H bonds,110 the monoanionic, bidentate directing group has been extensively exploited for palladium-, ruthenium-, iron-, nickel- or copper-catalyzed C–H functionalizations, among others.111,112 As discussed above, cobalt(III) complexes participated in C–H activation, followed by alkyne or alkene insertion. Based on these findings, Daugulis and coworkers reported on the cobalt-catalyzed oxidative alkyne annulation with the bidentate Q-auxiliary.113 The alkyne annulation with amide 187 led to best results when inexpensive Co(OAc)2.4H2O, sodium pivalate and Mn(OAc)2 were utilized (Scheme 63a). A broad range of benzamides 187 as well as internal and even terminal alkynes 20 were efficiently converted. Alkyne annulations with a picolinaminde directing group 188 gave rather moderate yields with stoichiometric amounts of Co(OAc)2.4H2O (Scheme 63b), while the cleavage of the picolinamide occurred efficiently (Scheme 63c).


ACS Catalysis

to a variety of dihydroisoquinolinones 194 (Scheme 65a). Furthermore, the 4-methoxy-substituted Q-directing group was cleaved in a traceless fashion with ceric(IV) ammonium nitrate (CAN), thereby furnishing the desired NH-free dihydroisoquinolinones 195 (Scheme 65b).

(a) Q-assisted anulation

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

N

O

R2 +

N H

R1 H

R3

187

Co(OAc)2.4H2O (10 mol %)

O

NaOPiv (2 equiv) Mn(OAc) 2 (1 equiv) air, TFE, 80 °C, 6 h

R3 R2 189

20 O

O

O N

R1

Q

X

N

Ph

Q Ph

Ph

N Ph

R1 = H: 78% R1 = CF3: 70% R1 = Br: 73%

X = O: 81% X = S: 86%

O

O N

Q Me

Me

Ph

Q

N N

R1

Page 26 of 32

75%

O N

Q

N

Q

Ph

Ph Me 95%

95% (rr: 14:1)

84% (rr: 13:1)

(b) picolinamide-directed anulation O Me

O

2-py N

Co(OAc)2.4H2O (1 equiv) NaOPiv (2 equiv) Mn(OAc) 2 (2 equiv) TFE, 100 °C, 36 h

Me H H

+ Me

188a

Me

2-py N

Me Me

20h

190ah: 44%

(c) cleavage of the directing group O 2-py Me

N

Me 190ah

Me

Me NaOH/MeOH 80 °C, 12 h

N

Me Me

191ah: 93%

Scheme 63. Cobalt-catalyzed oxidative alkyne annulations. Since it is well established that the bidentate Q-directing group stabilizes transition metals in high oxidation states, it was proposed that cyclometalation and oxidation furnish cobalt(III) intermediate 192. This species undergoes migratory insertion with the alkyne 20 to furnish intermediate 193 (Scheme 64). Reductive elimination finally delivers the product 189 by elimination of Co(I). Alternative pathways via protodemetalation of 193 and oxidative cyclization are less likely to be operative.

Scheme 65. Aminoquinoline-directed alkene annulations. While the system developed by Daugulis furnished sixmembered hetreocycles, ring-closure to yield five-membered isoindolin-1-ones 196 could not be accomplished until recently. Thus, Ackermann and Ma discovered a procedure for the cobalt-catalyzed oxidative alkenylation with electrondeficient alkenes that selectively delivered isoindolin-1-ones 196 (Scheme 66).115 Best results were obtained when Co(OAc)2 and AgOPiv were employed in a 4:1 mixture of PEG400 and TFE as the reaction medium. The use of PEG400 had previously been exploited for ruthenium- and palladium-catalyzed C–H arylations.116 Differently substituted N-quinolinyl benzamides 187 and acrylates 197 furnished a broad range of isoindolin-1-ones 196.115

Scheme 64. Mechanistic considerations for aminiquinoline-directed alkyne anuulation. Subsequently, Daugulis developed the alkene annulation by benzamides 187 with the Q-directing group.114 Slight changes in the reaction conditions had to be adjusted to get access


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ACS Catalysis halogen, nitrile, ester and cyano substituents, was well tolerated under the optimized reaction conditions. Intramolecular competition experiments with meta-substituted arene exhibited high levels of site-selectivity control. The directing group was easily removed by treatment with methanolic ammonia, delivering the parent phthalimide in high yield.

Scheme 66. Cobalt-catalyzed isoindolinone synthesis. Scheme 68. C–H Carbonylation of benzamides 187. Mechanistic studies with deuterium labeled arenes unraveled the C–H cobaltation as an irreversible elementary step and a KIE of 1.4 and 1.6 for the intermolecular and intramolecular competition experiment suggested that the C–H metalation is likely kinetically relevant. Based on these mechanistic studies a plausible catalytic cycle was proposed to proceed by a carboxylate-assisted C–H cobaltation to furnish complex 198 (Scheme 67). Subsequent migratory insertion and β-hydride elimination furnished the alkenylated species 199. Finally, isoindolinones 196 was generated after intramolecular alkene hydroamidation.

Recently Song and coworkers developed the cobaltcatalyzed C−H alkoxylation of benzamindes 201 bearing a 2aminopyridine-1-oxide moiety with simple alcohols 202.118 The reaction proceeded under mild reaction conditions using Co(OAc)2·4H2O as the catalyst and Ag2O as the oxidant of choice (Scheme 69a). With the optimized conditions in hand, various benzamides 201 as well as different alcohols 202 were efficiently transformed. Furthermore, this strategy enabled selective alkoxylation of acrylamides, while the 2aminopyridine-1-oxide directing group was easily removed to afford the benzoic acid 204 (Scheme 69b).

Scheme 67. Proposed catalytic cycle for the oxidative C– H alkenylation. Based on the high catalytic efficacy of the cobalt catalyst in oxidative annulations of alkynes 20 and alkenes 197, Daugulis and coworkers disclosed the cobalt-catalyzed direct carbonylation of benzamdies 187 through bidentate-chelation assistance (Scheme 68).117 The C–H transformation occurred at ambient reaction temperature and afforded the desired phthalimides 200. A wide range of functional groups, such as

Scheme 69. (a) Cobalt-catalyzed alkoxylation of benzamides 201, (b) directing group removal.

EPR spectroscopy studies and control experiments with TEMPO as radical scavenger suggested a radical-based reaction pathway likely to be operative.118 DFT calculations


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by Wei and Niu provided further strong support for an intermolecular SET-type mechanism, and set the stage for a novel catalyst design.119

3.8 Organometallic C–H activation by cobalt carbenoids Very recently, Glorius and Wang independently described the effective C–H functionalization with α-diazo esters 205 as carbene precursors under cobalt(III) catalysis.120 When using aryl pyridines and benzo[h]quinolone 22 an interesting class of diverse conjugated polycyclic hetereocarbons 206 could be accessed (Scheme 70).

Scheme 71. Proposed reaction mechanism for the Cp*Co(III)-catalyzed C–H activation/annulation reaction.

This approach draws inspiration from the previous use of carbene precursors for cobalt-catalyzed C–H functionalization. Thus, Miura and coworkers exploited tosylhydrazons 210 as valuable reagents for the C–H alkylation of azoles 37/38.121 Best catalytic performance was achieved here when using CoBr2 as the cobalt source, phenantroline (phen) as the ligand, and LiOtBu as the base (Scheme 72).

Scheme 70. Cobalt(III)-catalyzed annulation with diazocompounds 205. Interestingly, when the Cp*Co(III) complex was replaced by the analogous Cp*Rh(III) complex, the corresponding alkylated arenes were obtained, highlighting the unique features of cobalt(III) catalysis. The difference in chemo-selectivity can be rationalized by the lower electronegativity of cobalt as compared to rhodium. Hence, in both cases the orthoalkylation is supposed to occur first. However, the cobalt(III) catalyst is also acting as Lewis-acid, therefore, enabling the nucleophilic addition. Based on this rationale, a catalytic cycle was proposed to commence with C–H metalation (Scheme 71), followed by metal-carbene formation with the diazo compound. Migratory insertion to intermediate 208 and protodemetalation delivers the alkylated arene 209. Lewis-acid activation of the carbonyl group by the cobalt(III) species sets the stage for the nucleophilic attack of the pyridine nitrogen to give the polycyclic compound 206.

Scheme 72: C–H Alkylations with tosylhydrazons 210. [a] With NaOtBu and DMF instead of LiOtBu and 1,4dioxane.

4 Conclusion During the past few years, organometallic cobalt-catalyzed C–H activation has emerged as an increasingly viable tool for the step-economical functionalization and assembly of organic molecules. Thus, the development of low-valent


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ACS Catalysis

cobalt-catalysis set the stage for C–H arylations, alkenylations, benzylations and alkylations of arenes as well as alkenes under rather mild reaction conditions. In addition to hydroarylations and hydroacylations, C–H functionalizations with organic electrophiles have proven particularly instrumental for the development of step-economical syntheses. Hence, these inexpensive catalysts proved generally applicable and enabled applications to the synthesis of block-buster drug scaffolds, among others. Here, a significant ligand rate acceleration was achieved, most notably with mono-dentate N-heterocyclic carbene or phosphine ligands that provide kinetic stabilization through a bulky substitution pattern. The vast majority of low-valent cobalt-catalyzed C–H activations thus far called for stoichiometric amounts of Grignard reagents, partly because of the reductive in-situ generation of the catalytically active cobalt catalysts. In contrast, the discovery of high-valent cobalt(II) and cobalt(III) catalysis recently set the stage for versatile C–H functionalization processes. A significant impetus was gained by the identification of a Cp*-derived ligand design for cobalt(I) and cobalt(III) catalysts by Brookhart and Matsunaga/Kanai that – to some extent – mimic the previously used, more expensive122 rhodium and iridium catalysts. However, based on inter alia the different electronic properties between iridium and rhodium versus cobalt, this strategy enabled improved selectivities and entirely novel chemical transformations, which were largely based on the higher nucleophilicity of organometallic cobalt(III) species, along with their Lewisacidic properties. For instance, the positional and chemo selectivities in direct allylations,101 and annulations120 were found considerably improved, while the catalytic efficacy in C–H amidations108 or annulations od aldehydes82 proceeded best with cobalt(III) catalysts. Generally, the high-valent cobalt catalyst precursors are air-stable and offer an excellent functional group tolerance at rather low catalyst loading. While in cobalt(III)-catalyzed C–H functionalizations silver(I) salts are often used as stoichiometric oxidants or cocatalytic additives, strategies for their replacement by less expensive reagents have emerged. The cobalt(III)-catalyzed C–H activation mostly occurs by facile carboxylate-assisted C–H metalation, and proved amenable to removable directing group strategies. The outstanding potential of cobalt catalysis for and beyond C–H functionalizations is further reflected by the very recent application to the transformation of C(sp3)–H bonds,123 as well as to the catalytic activation of C–C bonds.124 Thus far, the majority of cobalt-catalyzed C– H activations utilized relatively high catalyst loadings. Thus, future efforts should inter alia be directed towards the design of more effective and robust catalysts. In addition, in lowvalent cobalt-catalyzed C–H functionalization chemistry it is desirable to establish a replacement for the omnipresent Grignard reagents. Considering the sustainable nature of C– H functionalization technologies, along with the costeffective nature of cobalt catalysis, further exciting developments are expected in this rapidly evolving research area.

2013)/ ERC Grant agreement no. 307535, the DFG (priority program SPP 1807) and the CSC (fellowship to JL) is gratefully acknowledged.

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Corresponding Author *E-mail: [email protected]. (+49)551-39-6777. Tel: (+49)551-39-3202

Fax:

Funding Sources Generous support by the European Research Council under the European Community’s Seventh Framework Program (FP 2007-

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Representative recent reviews on C–H activation: (a) Li, J.; De Sarkar, S.; Ackermann, L. Top. Organomet. Chem. 2015, DOI:10.1007/3418_2015_130. (b) Kuhl, N.; Schroeder, N.; Glorius, F. Adv. Synth. Catal. 2014, 356, 1443-1460. (c) Tani, S.; Uehara, T. N.; Yamaguchi, J.; Itami, K. Chem. Sci. 2014, 5, 123-135. (d) Girard, S. A.; Knauber, T.; Li, C.-J. Angew. Chem., Int. Ed. 2014, 53, 74-80. (e) Thirunavukkarasu, V. S.; Kozhushkov, S. I.; Ackermann, L. Chem. Commun. 2014, 50, 29-39. (f) Rouquet, G.; Chatani, N. Angew. Chem., Int. Ed. 2013, 52, 11726-11743. (g) Satoh, T.; Miura, M. Chem. Eur. J. 2010, 16, 11212-11222. (h) Daugulis, O. Top. Curr. Chem. 2010, 292, 57-84. (i) Giri, R.; Shi, B.-F.; Engle, K. M.; Maugel, N.; Yu, J.-Q. Chem. Soc. Rev. 2009, 38, 3242-3272. (j) Ackermann, L.; Vicente, R.; Kapdi, A. Angew. Chem., Int. Ed. 2009, 48, 9792-9826. (k) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094-5115. (a) Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369-375. (b) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960-9009. (c) Schipper, D. J.; Fagnou, K. Chem Mater. 2011, 23, 1594-1600. For selected reviews and accounts, see (a) Ye, B.; Cramer, N. Acc. Chem. Res. 2015, 48, 1308-1318. (b) Li, J.; Ackermann, L. Nat. Chem. 2015, 7, 686-687. (c) Zhang, X.-S.; Chen, K.; Shi, Z.-J. Chem. Sci. 2014, 5, 2146-2159. (d) Girard, S. A.; Knauber, T.; Li, C.-J. Angew. Chem., Int. Ed. 2014, 53, 74-100. (e) Ackermann, L. Acc. Chem. Res. 2014, 47, 281-295. (f) Kuhl, N.; Hopkinson, M. N.; Wencel- Delord, J.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 1023610254. (g) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879-5918. (h) Neufeldt, S. R.; Sanford, M. S. Acc. Chem. Res. 2012, 45, 936-946. (i) Brückl, T.; Baxter, R. D.; Ishihara, Y.; Baran, P. S. Acc. Chem. Res. 2012, 45, 826-839. (j) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788-802. (k) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068-5083. (l) Zhao, D.; You, J.; Hu, C. Chem. Eur. J. 2011, 17, 5466-5492. (m) Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780-1824. (n) Satoh, T.; Miura, M. Chem. Eur. J. 2010, 16, 11212-11222. (o) Ackermann, L.; Vicente, R. Top. Curr. Chem. 2010, 292, 211-229. (p) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624-655. For selected reviews, see: (a) Su, B.; Cao, Z.-C.; Shi, Z.J. Acc. Chem Res. 2015, 48, 886-896. (b) Ackermann, L. J. Org. Chem. 2014, 79, 8948-8954. (c) Yamaguchi, J.; Muto, K.; Itami, K. Eur. J. Org. Chem. 2013, 19-30. (d) Yoshikai, N. Synlett, 2011, 1047-1051. (e) Nakao, Y. Chem Rec. 2011, 11, 242-251. (f) Nakamura, E.; Yoshikai, N. J. Org. Chem. 2010, 75, 6061-6067. (g) Kulkarni, A. A.; Daugulis, O. Synthesis, 2009, 40874109. Kharasch, M. S.; Fields, E. K. J. Am. Chem. Soc. 1941, 63, 2316-2320. Hebrard, F.; Kalck, P. Chem. Rev. 2009, 109, 42724282.


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